Erdafitinib formulations and systems for intravesical administration

Abstract

Provided herein are solid pharmaceutical compositions comprising 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 the benefit of and priority to U.S. Provisional Patent Application No. 63 / 254,974, filed October 12, 2021, U.S. Provisional Patent Application No. 63 / 255,387, filed October 13, 2021, and U.S. Provisional Patent Application No. 63 / 311,841, filed February 18, 2022, the contents of each of which are incorporated by reference in their entirety herein.

[0002] (Sequence Listing) The contents of the electronic sequence listing (761662001940seq.xml; size: 53,216 bytes, and creation date: October 6, 2022) are incorporated herein by reference in their 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. The synthetic preparation of erdafitinib is described in WO 2011 / 135376. 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 has a susceptible fibroblast growth factor receptor (FGFR)3 or FGFR2 genetic alteration and has progressed during or after at least one prior line of platinum-containing chemotherapy, where the at least one prior line of platinum-containing chemotherapy includes neoadjuvant or adjuvant platinum-containing chemotherapy within 12 months.

[0006] No. 10,898,482 to Broggini and International Patent Application Publication No. 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 solubilized drug is released from the drug reservoir lumen through a release opening due to osmotic pressure built up within the drug reservoir lumen.

[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. [Brief description of the drawings]

[0009] The detailed description is described with reference to the accompanying drawings. Use of the same reference numbers may indicate similar or identical items. Various embodiments may utilize elements and / or components other than those shown in the drawings, and some elements and / or components may not be present in various embodiments. The elements and / or components shown in the drawings are not necessarily drawn to scale. [Figure 1] FIG. 1 is a longitudinal cross-sectional view of one embodiment of a drug delivery system in a coiled retention configuration according to the present disclosure. [Diagram 2] 1 is a cross-sectional view of one embodiment of a drug delivery system according to the present disclosure. [Diagram 3] 1 is a cross-sectional view of one embodiment of a drug delivery system according to the present disclosure. [Figure 4] 1 is a photograph of one embodiment of a drug delivery system loaded with erdafitinib drug tablets according to the present disclosure. [Diagram 5] FIG. 1 is a longitudinal cross-sectional view of one embodiment of a drug delivery system in a coiled retained configuration prior to loading of a drug tablet with an elastic retaining frame according to the present disclosure. [Figure 6A] FIG. 13 is a longitudinal cross-sectional view of one embodiment of a resilient retention frame in a coiled retention configuration in accordance with the present disclosure. [Figure 6B] FIG. 6B is a partial enlarged view of one end of the holding frame of FIG. 6A. [Figure 7A]FIG. 1 is a perspective view of one embodiment of a drug delivery system in a relatively straightened configuration without a drug disposed therein or an elastic retaining frame in accordance with the present disclosure. [Figure 7B] FIG. 7B is a longitudinal cross-sectional view of the drug delivery system shown in FIG. 7A taken along line 7B-7B. [Figure 7C] FIG. 7C is a cross-sectional view of the drug delivery system shown in FIG. 7A taken along line 7C-7C. [Figure 8] 1 is a photograph showing a cross-section of a drug reservoir lumen of a drug delivery system without a drug disposed therein, according to the present disclosure. [Figure 9] 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 indicated. 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. [Figure 10] Figure 1 shows the effect of erdafitinib on ERK1 / 2 phosphorylation in orthotopic bladder UM-UC-1 tumors. Individual pERK and total ERK levels were measured from UM-UC-1 orthotopic bladder tumors from nude rats treated with vehicle, or a single IVES (1-hour infusion) or po dose of erdafitinib at the dose levels indicated. Doses of erdafitinib at the dose levels indicated. pERK and total ERK levels are reported as ratios to the vehicle group mean (pERK / ERK) for the corresponding time points, 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 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 11]The size of orthotopic bladder UC tumor cases versus control bladders at 14 days after implantation is shown. Formalin was used to fix tissue samples after autopsy. UC, urothelial carcinoma; NBTII, rat Nara bladder tumor No. 2 cells; T24, human bladder cancer cells. [Figure 12] FIG. 1 is a schematic diagram of a perfusion experiment in athymic rats with UM-UC-1 implanted within the bladder wall. [Figure 13] 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 legend 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. 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. SEM, standard error of the mean. [Figure 14] The mean percentage tumor weight reduction after considering 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 15]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 shown in the figure legend 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. No statistically significant differences, except for group 4 (*p<0.05) at day 11, 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. SEM, standard error of the mean. [Figure 16] Mean bladder weights of athymic nude rats bearing orthotopic RT-112 bladder tumors are shown. 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 17A] Plasma (FIG. 17A) and bladder (FIG. 17B) 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 17B] Plasma (FIG. 17A) and bladder (FIG. 17B) 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 18] Mean erdafitinib urinary concentrations in pigs after 7 days of erdafitinib bladder irrigation. Conc., concentration; SD (standard deviation), standard deviation. [Figure 19]Mean erdafitinib plasma concentrations in pigs after 7 days of erdafitinib bladder irrigation are shown. SD, standard deviation. [Figure 20] The results of screening of material permeability are shown. O, permeable; Δ, practically impermeable; ×, impermeable. a High variability between replicates. [Figure 21] Predicted (from short core) and actual (from full length) mean release rate profiles for permeation prototypes are shown. Erda, erdafitinib releasing intravesical system; HPbCD, hydroxypropyl β-cyclodextrin. [Figure 22] Average release rate profiles for erdafitinib free base + HP-β-CD permeation prototype (EG-80A striped material). Erda, erdafitinib; HP-β-CD, hydroxypropyl β-cyclodextrin; SU, simulated urine. [Figure 23] 1 shows the average release rate profiles for erdafitinib free base permeation prototypes with and without HP-β-CD (HP-60D-35 striped material). Erda, erdafitinib; HP-β-CD or HPbCD, hydroxypropyl β-cyclodextrin; SU, simulated urine. [Figure 24] FIG. 1 shows the in vitro release (IVR) profile for prototype 1 (permeation, erdafitinib free base, tablet, wireform). Erda, erdafitinib; IVR, in vitro release. [Diagram 25] FIG. 1 shows the IVR profile for prototype 2 (permeation, erdafitinib free base + HP-β-CD (10% w / w), tablet, wireform). Erda, erdafitinib; HP-β-CD, hydroxypropyl β-cyclodextrin; IVR, in vitro release. [Figure 26] 1 summarizes the in vivo release rate versus time profiles in minipigs for prototypes 1 and 2. [Figure 27]13 summarizes the mean urinary concentration versus time profiles in minipigs for prototypes 1 and 2. [Figure 28A] FIG. 1 is a diagram of an exemplary transmission system in which the base material is an impermeable TPU and the stripe material is a permeable TPU. [Figure 28B] 1 shows an overview of an exemplary permeation design: TPU or tPU, thermoplastic polyurethane; API, active pharmaceutical ingredient; HP-β-CD, hydroxypropyl β-cyclodextrin. [Figure 29] Provides a summary of erdafitinib free base drug solubility as a function of pH at 20 °C. a United States Pharmacopoeia / European Pharmacopoeia Terminology. [Figure 30A] Shows erdafitinib free base drug solubility as a function of pH at 37° C., adjusting the pH using HCl. Expon., exponential function. [Figure 31A] Figure 31A shows the solubility of erdafitinib free base drug and erdafitinib HCl salt Form 1 as a function of pH in simulated urine at 37°C (Figure 31B) in mg / mL, and the solubility of erdafitinib free base drug as a function of pH in simulated urine at 37°C (Figure 31B). HP-β-CD, hydroxypropyl β-cyclodextrin; Sim urinary, simulated urine. [Figure 31B] Figure 31A shows the solubility of erdafitinib free base drug and erdafitinib HCl salt Form 1 as a function of pH in simulated urine at 37°C (Figure 31B) in mg / mL, and the solubility of erdafitinib free base drug as a function of pH in simulated urine at 37°C (Figure 31B). HP-β-CD, hydroxypropyl β-cyclodextrin; Sim urinary, simulated urine. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] In some embodiments, an erdafitinib solid formulation containing high concentration of erdafitinib is provided, which is designed for intravesical drug delivery and controlled and extended drug release when deployed in the bladder.In some embodiments, the solid erdafitinib formulation is further adapted for large-scale manufacturing and further adapted to provide the structural and chemical integrity of solid formulations, particularly tablets, when used in an intravesical drug delivery system.Also provided is an improved intravesical drug delivery system, its manufacturing method, and drug delivery method.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 a therapeutically effective amount of drug, particularly erdafitinib.

[0011] Described herein is the development of erdafitinib formulations and release systems that are adapted to this administration route to take advantage of intravesical drug delivery.When formulated in solid form and administered in a suitable intravesical drug delivery system, such formulations can provide controlled drug release rate and extended drug release profile.Furthermore, a system is provided that can deliver erdafitinib at an effective release rate for the local treatment of bladder cancer.

[0012] Erdafitinib exhibits pH-dependent solubility over the normal urinary pH range of 5.5 to 7. In some embodiments, the formulation and release system are adapted to minimize the effect of urinary pH and composition on the system release rate.

[0013] 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.

[0014] Specific Terms Recurrence-free survival (RFS) is defined as the time from randomization to first detection of high-grade Ta or T1 bladder cancer or positive urinary cytology.

[0015] Complete response (CR) was defined as the absence of urothelial carcinoma by pathological confirmation by cystoscopy and negative urine cytology at the initial evaluation.

[0016] Duration of CR is defined as the time from first demonstration of CR to the date of documented recurrence or progression, or death, whichever occurs first.

[0017] Pathological Complete Response (pCR) rate is defined as the percentage of participants with no pathological evidence of intravesical disease (pT0) and no pathological evidence of lymph node metastasis (pN0).

[0018] The rate of no pathological evidence of intravesical disease (pT0) is defined as the percentage of participants with no pathological evidence of intravesical disease.

[0019] Downstaging rate to <(<)pT2 is defined as the percentage of participants with a pT stage <2.

[0020] As used herein, weight % with respect to a drug or excipient refers to weight % based on the total weight of the relevant formulation, unless otherwise specified.

[0021] Erdafitinib formulations and tablets 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 erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine).As another example, a drug tablet is provided that includes erdafitinib HCl salt.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 by diffusion, which causes a continuous release of drug into the bladder over a long period of time when the drug is released from the tablet in the system.

[0022] 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 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. Unless otherwise stated, weight percentages are for the entire solid pharmaceutical composition.

[0023] The erdafitinib drug tablet of the present disclosure includes an erdafitinib content and an excipient content. The drug content can include one or more forms of erdafitinib, such as free base or salt forms, and the excipient content can include one or more excipients. Certain embodiments include erdafitinib free base API, and the exemplary formulations presented herein include erdafitinib free base API. The term "excipient" is known in the art, and representative examples of excipients useful in the disclosed drug tablet can 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.

[0024] Another aspect of the present disclosure provides a process for making a solid pharmaceutical composition, which may include: (a) preparing an intragranular solid composition, the intragranular solid composition comprising or consisting essentially of (i) erdafitinib free base and (ii) 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 an embodiment, the erdafitinib free base may be present in a concentration of at least 45% by weight of the solid pharmaceutical composition. The at least one intragranular pharmaceutical excipient and the at least one extragranular pharmaceutical excipient may include or be selected from at least one common (present in both) pharmaceutical excipient, or there may be no common (present in both) pharmaceutical excipient between the intragranular excipient and the extragranular pharmaceutical excipient. The solid pharmaceutical composition may be made by a process comprising preparing an intragranular solid composition by a roller compaction process or by a fluidized bed granulation process. In some embodiments, the step of (a) preparing an intragranular solid composition comprises (1) preparing a preblend comprising erdafitinib free base and one or more excipients, (2) preparing a binder solution, and (3) preparing an intragranular solid composition by combining the preblend with the binder solution. In some embodiments, the step of (a) preparing an intragranular solid composition comprises (1) preparing a preblend comprising erdafitinib free base and one or more excipients, (2) preparing a binder solution, and (3) preparing an intragranular solid composition by combining the preblend with the binder solution by a fluidized bed granulation process. In some embodiments, the step of (a) preparing the intragranular solid composition comprises: (1) preparing a preblend comprising erdafitinib free base, a stabilizer, a solubilizer, and a filler; (2) preparing a binder solution comprising a binder and a solvent; and (3) preparing the intragranular solid composition by combining the preblend and the binder solution by a fluid bed granulation process.In some embodiments, the step of (a) preparing the intragranular solid composition comprises (1) preparing a preblend comprising erdafitinib free base, meglumine, hydroxypropyl-beta-cyclodextrin, and microcrystalline cellulose, (2) preparing a binder solution comprising hydroxypropyl methylcellulose and purified water, and (3) preparing the intragranular solid composition by combining the preblend and the binder solution by a fluid bed granulation process. In some embodiments, the step of (a) preparing the intragranular solid composition comprises (1) preparing a preblend comprising erdafitinib free base, a solubilizer, and a filler, (2) preparing a binder solution comprising a binder and a solvent, and (3) preparing the intragranular solid composition by combining the preblend and the binder solution by a fluid bed granulation process. In some embodiments, (a) the step of preparing the intragranular solid composition comprises: (1) preparing a preblend of erdafitinib free base, hydroxypropyl-beta-cyclodextrin, and microcrystalline cellulose; (2) preparing a binder solution comprising hydroxypropyl methylcellulose and purified water; and (3) preparing the intragranular solid composition by combining the preblend and the binder solution by a fluid bed granulation process.

[0025] Another aspect of the present disclosure provides a process for making a solid pharmaceutical composition, which may include: (a) preparing an intragranular solid composition, the intragranular solid composition comprising or consisting essentially of (i) an erdafitinib HCl salt form and (ii) 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 an embodiment, the erdafitinib HCl salt form may be present in a concentration of at least 45% by weight of the solid pharmaceutical composition. The at least one intragranular pharmaceutical excipient and the at least one extragranular pharmaceutical excipient may include or be selected from at least one common (present in both) pharmaceutical excipient, or there may be no common (present in both) pharmaceutical excipient between the intragranular excipient and the extragranular pharmaceutical excipient. The solid pharmaceutical composition may be made by a process including that an intragranular solid composition is prepared by a roller compaction process or by a fluid bed granulation process.

[0026] In an embodiment, the erdafitinib drug tablet contains erdafitinib in its free base form. Other embodiments of the erdafitinib drug tablet can contain erdafitinib in salt form. In one aspect, the erdafitinib drug tablet can contain 40% or more by weight of erdafitinib free base, with the remaining weight comprising excipients that facilitate the manufacture and use of the drug tablet, such as lubricants, binders, and stabilizers. Alternatively, the erdafitinib drug tablet can contain 45% or more by weight, 50% or more by weight, 55% or more by weight, or 60% or more by weight of erdafitinib free base. In each of these weight percentage embodiments, the practical upper limit of erdafitinib free base in the tablet formulation is about 65% by weight or 70% by weight. Thus, in one aspect, the pharmaceutical tablet may contain 40% to 60% by weight of erdafitinib in its free base form, or 45% to 55% by weight of erdafitinib in its free base form. In some of the above embodiments, the pharmaceutical tablet may contain about 5% to about 15% by weight of hydroxypropyl-β-cyclodextrin (HP-β-CD). In some of the above embodiments, the pharmaceutical tablet may contain about 10% by weight of hydroxypropyl-β-cyclodextrin (HP-β-CD). In an embodiment, the pharmaceutical tablet may contain 50% by weight of erdafitinib in its free base form, based on the total weight of the tablet. In an embodiment, the pharmaceutical tablet may contain 50% by weight of erdafitinib in its free base form, based on the total weight of the tablet, and may contain about 5% to about 15% by weight of hydroxypropyl-β-cyclodextrin (HP-β-CD). In an embodiment, the pharmaceutical tablet may contain 50% by weight of erdafitinib in its free base form and 10% by weight of hydroxypropyl-β-cyclodextrin (HP-β-CD), based on the total weight of the tablet.

[0027] In an embodiment, the erdafitinib drug tablet comprises erdafitinib in its HCl salt form. In one aspect, the erdafitinib drug tablet can comprise 40% or more by weight of erdafitinib HCl salt form, with the remainder of the weight comprising excipients, such as lubricants, binders, and stabilizers, that facilitate the manufacture and use of the drug tablet. Alternatively, the erdafitinib drug tablet can comprise 45% or more by weight, 50% or more by weight, 55% or more by weight, or 60% or more by weight of erdafitinib HCl salt form. In each of these weight percentage embodiments, the practical upper limit of the erdafitinib salt form in the tablet formulation is about 65% by weight or 70% by weight. Thus, in one aspect, the drug tablet can comprise 40% to 60% by weight of erdafitinib in its HCl salt form, or 45% to 55% by weight of erdafitinib in its HCl salt form. In an embodiment, the pharmaceutical tablet may contain 50% by weight of erdafitinib in its HCl salt form, based on the total weight of the tablet.

[0028] In one embodiment, the erdafitinib drug and excipients are selected to allow release of the drug from the tablet, and the tablet is so formulated. In some embodiments, the erdafitinib drug and excipients are selected to allow solubilization of the drug from the tablet, and the tablet is so formulated. 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.

[0029] In one aspect, erdafitinib drug tablet can be sized and shaped to be used with implantable drug delivery system, including intravesical drug delivery system disclosed herein.For example, erdafitinib drug tablet can be a "mini-tablet" that is generally smaller than a conventional tablet, and the mini-tablet can allow the drug tablet contained in the system to be inserted through a lumen, such as the urethra, into a cavity, such as the bladder.Erdafitinib tablet can be coated or uncoated.In particular, it has been found that the uncoated tablet formulated according to the present disclosure works well in combination with the system.

[0030] In embodiments, pharmaceutical tablets for intravesical insertion or other in vivo implantation may be in the form of a solid cylinder having a cylinder axis, a cylinder side, a circular end surface perpendicular to the cylinder axis, a diameter across 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 in value 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 embodiments, the mini can 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.

[0031] 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 tablet for use in the disclosed intravesical system can be formulated using erdafitinib free base or a salt thereof. In one aspect, the erdafitinib tablet for use in the disclosed intravesical system can include erdafitinib free base. In one aspect, the erdafitinib tablet for use in the disclosed intravesical system can include erdafitinib HCl salt, particularly erdafitinib HCl salt in crystalline form. In some embodiments of the above, the erdafitinib tablet for use in the disclosed intravesical system can include erdafitinib free base in crystalline form. As described herein, the inclusion of certain stabilizers, solubilizers, and excipients in the erdafitinib free base formulation can provide advantageous stabilization and dissolution properties for effective use of the free base formulation in the disclosed intravesical systems.

[0032] [ka]

[0033] 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, and at least one lubricant, etc., or any combination thereof. Any excipient or any combination of excipients may be present in the intragranular solid composition, the extragranular solid composition, or both the intragranular and extragranular solid compositions. In one aspect, 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 aspect, the intragranular pharmaceutical excipient and the extragranular pharmaceutical excipient do not include a common (present in both) pharmaceutical excipient, whereby the intragranular and extragranular excipients are mutually exclusive. In an embodiment, an erdafitinib drug tablet, particularly an erdafitinib drug tablet containing 40% to 70% by weight, or 40% to 60% by weight, or 45% to 55% by weight, e.g., 50% by weight of erdafitinib, comprises at least one solubilizer, at least one binder, at least one stabilizer, at least one diluent, at least one glidant, and at least one lubricant, etc., or any combination thereof. In an embodiment, an erdafitinib drug tablet, particularly an erdafitinib drug tablet containing 40% to 70% by weight, or 40% to 60% by weight, or 45% to 55% by weight, e.g., 50% by weight of erdafitinib, comprises at least one solubilizer, at least one binder, at least one diluent, at least one glidant, and at least one lubricant, etc., or any combination thereof.

[0034] It will be understood that these functional descriptions of the various excipients are generally used as follows: A solubilizer can improve or enhance the solubility of an API, e.g., erdafitinib free base, in the drug lumen of the disclosed system or in a body cavity, e.g., the bladder, when the API is released from the system. A binder can hold the solid particles of the composition together for physical stability. A wetting agent can reduce the surface tension between the drug and the medium in which the drug occurs, and can help maintain the solubility of the drug. A disintegrant can assist in mini-tablet disintegration upon contact with water to release the drug substance. A stabilizer can improve the chemical stability, e.g., thermal stability, of a formulation containing the API, or protect the API from degradation. A diluent can function as a bulking agent to increase the volume or weight of a composition, which can help provide a tablet of a desired size, or aid in the tabletability of an API-excipient blend. A lubricant can improve the flow properties of the (granulated) particles of tablet components or the powder blend to be tableted. The lubricant can prevent particles of the composition from adhering to components of the manufacturing equipment, such as the dies and punches of a tablet press. In one aspect, the excipient can be water soluble. In another aspect, the excipient can be colloidal in water. According to another aspect, the excipient can be soluble under the conditions of its deployment in the patient, for example, in the bladder. These and other excipients are described in more detail below.

[0035] Stabilizers such as formaldehyde scavengers In one aspect, erdafitinib API may be susceptible to degradation under certain conditions when incorporated into solid formulations.For example, erdafitinib can 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 can 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.

[0036] Thus, in one aspect, the erdafitinib pharmaceutical formulation can include a formaldehyde scavenger to improve the stability or shelf life of the formulation.Various formaldehyde scavengers can be used, and the formaldehyde scavenger can prevent, slow down, reduce, or postpone the formation of degradation products when erdafitinib comes into contact with formaldehyde.Thus, the stability of the erdafitinib pharmaceutical formulation, for example, its chemical stability, can be increased in the presence of the formaldehyde scavenger compared to the erdafitinib pharmaceutical formulation in the absence of the formaldehyde scavenger.In one aspect, the formaldehyde scavenger can 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.In one aspect, the formaldehyde scavenger, particularly meglumine, is present in the solid pharmaceutical composition as a component of the intragranular solid composition.

[0037] The formaldehyde scavenger 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, it is believed that these compounds react with formaldehyde to form Schiff base imines (R 1 R 2 C=NR 3 , where R 3is not hydrogen), and it is believed that the Schiff base imine itself can bind formaldehyde. Examples of such formaldehyde scavengers include, but are not limited to, amino acids, amino sugars, alpha-(α-)amine compounds, their conjugates and derivatives, and mixtures thereof. Such formaldehyde scavenger compounds can include two or more amine and / or amide moieties capable of scavenging formaldehyde.

[0038] In one embodiment, the formaldehyde scavenger may comprise 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, conjugates thereof, pharma- ceutically acceptable salts thereof, or any combination thereof. According to one embodiment, the formaldehyde scavenger may comprise or be selected from meglumine or a pharma- ceutically acceptable salt thereof, in particular meglumine base.

[0039] Therefore, one aspect of the present disclosure is the use of formaldehyde scavenger, particularly meglumine, in erdafitinib pharmaceutical formulations, such as drug tablet formulations, to increase the stability of erdafitinib in any of the forms of erdafitinib, including erdafitinib free base, its salt, or its solvate.The chemical stability of erdafitinib pharmaceutical formulations is increased compared to erdafitinib pharmaceutical formulations or compositions that do not contain formaldehyde scavenger.One aspect of the present disclosure is a method of preventing, slowing, reducing, or postponing the formation of degradation products that can be formed from erdafitinib in the presence of formaldehyde, such as the following compounds:

[0040] [ka] 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.

[0041] When present in an erdafitinib solid pharmaceutical composition, the formaldehyde scavenger can 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. In some embodiments, when present in an erdafitinib solid pharmaceutical composition, the formaldehyde scavenger can be present in a concentration of about 1% by weight. When present in an erdafitinib solid pharmaceutical composition, the formaldehyde scavenger can be present in the solid pharmaceutical composition at a concentration of, for example, 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. In some embodiments, the erdafitinib solid pharmaceutical composition contains erdafitinib free base and a formaldehyde scavenger is present. In some embodiments, the erdafitinib solid pharmaceutical composition contains erdafitinib free base and the formaldehyde scavenger is present in the solid pharmaceutical composition at a concentration of 0.01% to 5%, 0.05% to 3%, 0.1% to 2%, 0.5% to 1.5%, or about 1% by weight. In some embodiments, the erdafitinib solid pharmaceutical composition contains erdafitinib free base and the formaldehyde scavenger is present in the solid pharmaceutical composition at a concentration of about 1% by weight. In some embodiments of any of the above, the formaldehyde scavenger is meglumine.

[0042] In some embodiments, the pharmaceutical compositions described herein, particularly the erdafitinib drug tablets, do not contain stabilizers or formaldehyde scavengers.

[0043] Solubilizer In one aspect, the erdafitinib formulation can include a solubilizer. The solubilizer can be in the intragranular component, the extragranular component, or both the intragranular and extragranular components of the formulation. In an embodiment, the solubilizer can 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.

[0044] 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 hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose E5 (HPMC-E5), or combinations thereof.

[0045] The oligosaccharide solubilizer can be present in the erdafitinib tablet formulation, e.g., the erdafitinib free base formulation, 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 can be present in the erdafitinib tablet formulation, e.g., the erdafitinib free base 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.

[0046] In one aspect, the solubilizer for the erdafitinib tablet formulation disclosed herein may include or be hydroxypropyl-beta-cyclodextrin (HP-β-CD). One embodiment of the erdafitinib free base formulation includes an erdafitinib free base formulation that includes a hydroxypropyl-beta-cyclodextrin solubilizer, specifically including an erdafitinib free base formulation that includes hydroxypropyl-beta-cyclodextrin at a concentration of 8% to 12% by weight, or alternatively, 10% or about 10% by weight. In some embodiments, the formulation includes hydroxypropyl-beta-cyclodextrin at a concentration of about 10% by weight. In this formulation, the erdafitinib free base API can be present at a concentration of 40% to 70% by weight, or 40% to 60% by weight, or 45% to 55% by weight, for example, 50% by weight. In one embodiment, the hydroxypropyl-beta-cyclodextrin is present in the intragranular solid composition. In an embodiment, the pharmaceutical tablet may contain 50% by weight of erdafitinib in its free base form, 1% by weight of meglumine, and 8% to 12% by weight, or alternatively, 10% by weight or about 10% by weight of hydroxypropyl-beta-cyclodextrin. In an embodiment, the pharmaceutical tablet may contain 50% by weight of erdafitinib in its free base form, 10% by weight of hydroxypropyl-beta-cyclodextrin (HP-β-CD), and 1% by weight of meglumine, based on the total weight of the tablet. In an embodiment, the pharmaceutical tablet may contain at least about 45% by weight of erdafitinib in its free base form, 10% by weight of hydroxypropyl-beta-cyclodextrin (HP-β-CD), and 0% by weight of meglumine, based on the total weight of the tablet. In an embodiment, the pharmaceutical tablet may contain 50% by weight of erdafitinib in its free base form, 10% by weight of hydroxypropyl-β-cyclodextrin (HP-β-CD), and 0% by weight of meglumine, based on the total weight of the tablet.

[0047] 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 and extragranular solid compositions. Suitable binders may be water-soluble, water-insoluble, or slightly water-soluble, or a combination thereof. In one aspect, the binder may include a polymer binder, such as a water-soluble polymer binder, a slightly water-soluble polymer binder, a water-insoluble polymer binder, or any combination thereof. The polymer binder may include a non-ionic polymer.

[0048] Those skilled in the art will appreciate that binders can also function as diluents (also called fillers) in pharmaceutical compositions. Thus, the binders provided in this disclosure can also be used for their diluent function, if desired, unless otherwise indicated.

[0049] In one aspect, a suitable binder may include or be selected from polyvinylpyrrolidone (also referred to as PVP, polyvidone, povidone, or poly(1-vinyl-2-pyrrolidinone)), poly(vinyl acetate) (PVA), vinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide (also referred to as PEO, poly(ethylene glycol) or PEG), polypropylene oxide (also referred to as PPO, 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, 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, a suitable binder may include or be selected from hydroxypropyl methylcellulose (HPMC), vinylpyrrolidone-vinyl acetate copolymer (copovidone), or a combination thereof. In some embodiments, the binder may be hydroxypropyl methylcellulose (HPMC). In some embodiments, the binder may be hydroxypropyl methylcellulose (HPMC) at a concentration of about 1.5% by weight of the solid composition. In some embodiments, the binder may be hydroxypropyl methylcellulose (HPMC) at 1.5% by weight of the solid composition and is present in the intragranular solid composition.

[0050] In a further embodiment, suitable binders may include or be selected from polymers or copolymers of vinylpyrrolidone (VP, also 1-vinyl-2-pyrrolidinone) and vinyl acetate (VA). Such copolymers of VP and VA may also be referred to as "copovidone". Suitable binders may also include or be selected from polymers or copolymers of ethylene oxide (EO) and propylene oxide (PO). Similarly, these binders may be used in combination with other binders, for example in combination with microcrystalline cellulose, hydroxypropyl cellulose (HPC), or hydroxypropyl methylcellulose (HPMC).

[0051] In one aspect, the total concentration of the at least one binder in the solid pharmaceutical composition can be 1% to 30% by weight, 2% to 30% by weight, 5% to 30% by weight, 5% to 25% by weight, 10% to 25% by weight, 10% to 22% by weight, 12% to 22% by weight, 14% to 19% by weight, or 12% to 19% by weight.

[0052] According to another aspect, suitable polymeric binders may include or be selected from copolymers of vinylpyrrolidone and vinyl acetate, which may be referred to as poly(vinylpyrrolidone-co-vinyl acetate) or poly(VP-co-VA). Examples of suitable poly(vinylpyrrolidone-co-vinyl acetate) 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.

[0053] In embodiments, the polymeric binder, e.g., vinylpyrrolidone-vinyl acetate copolymer, can 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 can be present in the erdafitinib tablet formulation, e.g., the erdafitinib free base 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, e.g., 7.5% by weight. In one aspect, the vinylpyrrolidone-vinyl acetate copolymer is present at a concentration of 8% by weight of the solid composition. In one embodiment, the vinylpyrrolidone-vinyl acetate copolymer is present in the intragranular solid composition. In one embodiment, the vinylpyrrolidone-vinyl acetate copolymer is present in the intragranular solid composition, which is prepared by roller compaction. In one embodiment, the vinylpyrrolidone-vinyl acetate copolymer is present in the intragranular solid composition, which is prepared by fluidized bed granulation. In one embodiment, the vinylpyrrolidone-vinyl acetate copolymer is present in the extragranular solid composition. In one embodiment, the vinylpyrrolidone-vinyl acetate copolymer is present in a concentration of about 7.5% by weight of the solid composition. In one embodiment, the vinylpyrrolidone-vinyl acetate copolymer is present in a concentration of about 7.5% by weight of the solid composition, which is in the extragranular solid composition.

[0054] In one embodiment, the binder may include or be microcrystalline cellulose. For example, the microcrystalline cellulose may be present in the solid pharmaceutical composition at a concentration of 5% to 30%, 10% to 20%, 5% to 20%, 6% to 15%, or 7% to 12% by weight. For example, the microcrystalline cellulose may be present in the solid pharmaceutical composition as a filler and / or binder at a concentration of about 17.5% by weight. For example, the microcrystalline cellulose may be present in the solid pharmaceutical composition at a concentration of about 17.5% by weight of the solid composition and is present in the intragranular solid composition and the extragranular solid composition. For example, the microcrystalline cellulose may be present in the solid pharmaceutical composition as a filler in the intragranular composition at a concentration of about 10% by weight of the solid composition and is present in the solid pharmaceutical composition as a binder in the extragranular composition at a concentration of about 7.5% by weight of the solid composition.

[0055] In another embodiment, the binder may include or be silicified 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.

[0056] In further embodiments, the binder may include or be hydroxypropyl methylcellulose (HPMC). For example, hydroxypropyl methylcellulose (HPMC) may be present in the solid pharmaceutical composition at a concentration of 0.25% to 5%, 0.5% to 4%, or 0.75% to 3% by weight. In one embodiment, the HPMC binder may be present in the solid pharmaceutical composition in an intragranular solid composition.

[0057] Wetting Agent Pharmaceutical excipients for erdafitinib solid pharmaceutical compositions may include one or more wetting agents. 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, a polysorbate, e.g., 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 solid composition. In one embodiment, the wetting agent is sodium lauryl sulfate.

[0058] In one embodiment, the erdafitinib solid pharmaceutical composition does not include one or more humectants.

[0059] Disintegrants The pharmaceutical excipients for 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 and extragranular solid compositions. In one embodiment, the disintegrant is present in the intragranular solid composition. In one embodiment, the disintegrant is present in the intragranular solid composition, and the intragranular solid composition is prepared by roller compaction.

[0060] In an exemplary embodiment, the disintegrant may comprise or be independently selected from a functionalized polysaccharide or a cross-linked polymer. For example, in one aspect, the disintegrant may comprise or be independently selected from, for example, (a) a cellulose functionalized with a methoxy moiety, a 2-hydroxypropoxy moiety, or a carboxymethoxy moiety, a salt thereof, or a combination thereof, (b) a carboxymethylated starch, or (c) a cross-linked polymer.

[0061] 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.

[0062] When present, disintegrants can be present in a range of concentrations, hi embodiments, the total concentration of disintegrant in the solid pharmaceutical composition can be 0.1% to 3%, 0.5% to 2.5%, 1% to 2%, or about 1.5% by weight.

[0063] In one embodiment, the erdafitinib solid pharmaceutical composition does not include one or more disintegrants.

[0064] 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.

[0065] In exemplary embodiments, the diluent may include or be selected from sugars, starches, microcrystalline cellulose, sugar alcohols, hydrogen phosphates, dihydrogen phosphates, carbonates, or combinations thereof. In one aspect, the diluent may include or be selected from lactose, dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, silicified microcrystalline cellulose, calcium hydrogen phosphate, calcium hydrogen phosphate anhydrous, calcium carbonate, sucrose, or any combination thereof.

[0066] In embodiments, the total concentration of the diluent in the solid pharmaceutical composition can be 10% to 60% by weight, 10% to 50% by weight, 10% to 40% by weight, 12% to 30% by weight, 15% to 25% by weight, or 18% to 22% by weight, or 20% to 40% by weight, or 20% to 30% by weight, or 25% to 30% by weight. 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, or 15% to 20% by weight. In further aspects, the diluent may comprise or be selected from anhydrous calcium hydrogen phosphate at a concentration of 18% to 20% by weight. In further aspects, the diluent may comprise or be anhydrous calcium hydrogen phosphate at a concentration of about 19% by weight. In a further embodiment, the diluent may comprise or be anhydrous calcium hydrogen phosphate at a concentration of about 19% by weight present in the extragranular solid composition. In a further embodiment, the diluent may comprise or be selected from silicified microcrystalline cellulose at a concentration of 10% to 20% by weight, or 10% to 15% by weight, or 10% to 12% by weight. For example, the diluent may comprise silicified microcrystalline cellulose at a concentration of about 10.75% or 11.75% by weight of the solid composition. For example, the diluent may comprise silicified microcrystalline cellulose at a concentration of about 10.75% or 11.75% by weight of the solid composition and present in the extragranular composition. For example, the diluent may comprise silicified microcrystalline cellulose at a concentration of about 10.75% by weight of the solid composition and present in the extragranular composition. For example, the diluent may comprise silicified microcrystalline cellulose at a concentration of about 11.75% by weight of the solid composition and present in the extragranular composition. In further embodiments, the diluent does not include silicified microcrystalline cellulose. In further embodiments, the diluent may include microcrystalline cellulose and silicified microcrystalline cellulose. In further embodiments, the diluent may include microcrystalline cellulose or silicified microcrystalline cellulose. In further embodiments, the diluent may include microcrystalline cellulose at a concentration of about 10% by weight. In further embodiments, the diluent may include microcrystalline cellulose at a concentration of about 10% by weight present in the intragranular composition.For example, microcrystalline cellulose can be present in the solid pharmaceutical composition as a filler and / or binder at a concentration of about 17.5% by weight. For example, microcrystalline cellulose can be present in the solid pharmaceutical composition at a concentration of about 17.5% by weight of the solid composition, and is present in the intragranular solid composition and the extragranular solid composition. For example, microcrystalline cellulose can be present in the solid pharmaceutical composition as a filler in the intragranular composition at a concentration of about 10% by weight of the solid composition, and is present in the solid pharmaceutical composition as a binder in the extragranular composition at a concentration of about 7.5% by weight of the solid composition.

[0067] 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 both a binder function and a diluent / filler function.

[0068] Lubricants Pharmaceutical excipients for erdafitinib solid pharmaceutical composition 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 solid composition. In one embodiment, the lubricant is present in the extragranular solid composition. As used in this disclosure, lubricant refers to a pharmaceutical excipient that improves or optimizes the particle flow properties of granulated or powdered tablet components in particulate form by reducing the interaction, attraction, cohesion, or friction between particles. A pharma-ceutically acceptable lubricant is a non-toxic and pharmacologically inactive substance. Furthermore, the lubricant can be water-soluble or water-insoluble.

[0069] In one aspect, the lubricant 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 lubricant in the solid pharmaceutical composition can 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 one embodiment, the lubricant is colloidal silicon dioxide. In some embodiments, the lubricant is colloidal silicon dioxide at about 0.5% by weight of the solid composition. In some embodiments, the lubricant is colloidal silicon dioxide at about 0.5% by weight of the solid composition and is present in the extragranular composition. In some embodiments, the lubricant is colloidal silicon dioxide at about 0.25% by weight of the solid composition. In some embodiments, the lubricant is colloidal silicon dioxide at about 0.25% by weight of the solid composition and is present in the extragranular composition.

[0070] 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 solid compositions. In one aspect, the lubricant is present in the extragranular solid composition. In one aspect, the lubricant is present in the intragranular solid 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 an embodiment, the lubricant can 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 can 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 can be water-soluble or water-insoluble.

[0071] In one aspect, the lubricant may comprise 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 comprise 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 combinations thereof. Examples of 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 can be 0.05% to 5% by weight, 0.1% to 3% by weight, 1% to 2% by weight, or about 1.5% by weight. In one embodiment, the lubricant is magnesium stearate. In some embodiments, the lubricant is magnesium stearate and is present in the intragranular composition or the extragranular composition. In some embodiments, the lubricant is magnesium stearate and is present in the intragranular composition and the extragranular composition. In some embodiments, the lubricant is magnesium stearate at about 1.5% by weight of the solid composition. In some embodiments, the lubricant is magnesium stearate at about 1.5% by weight of the solid composition and is present in the intragranular composition. In some embodiments, the lubricant is magnesium stearate at about 1.5% by weight of the solid composition and is present in the extragranular composition. In some embodiments, the lubricant is magnesium stearate at about 1.5% by weight of the solid composition and is present in the intragranular composition and the extragranular composition.

[0072] Formulation Development 1. An erdafitinib formulation, particularly an erdafitinib tablet, that (a) comprises a high erdafitinib drug loading, for example, an erdafitinib drug loading in the range of 40% to 70% by weight, or 40% to 60% by weight, or 45% to 55% by weight, or about 50% by weight, or in the range of 45% to 55% by weight, or about 50% by weight, (b) provides acceptable chemical stability of erdafitinib, and (c) supports high production rates for tablet manufacture, for example, tablet manufacture on an industrial scale, particularly tablets having a length (L) that exceeds a diameter (D), and thus an aspect ratio (L:D) of greater than 1:1. Provided herein are erdafitinib formulations, particularly erdafitinib tablets, that (d) support high production rates for the manufacture of such tablets, particularly industrial scale manufacture of such tablets, particularly mini-tablets, having a cylindrical 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, (e) provide tablets that are sufficiently physically robust, particularly tablets that are suitable for inclusion within the drug delivery systems described herein, particularly permeation systems, and / or (f) exhibit desired disintegration and / or dissolution characteristics.

[0073] Erdafitinib formulations with a range of excipient combinations, both intragranular and extragranular, are provided in Table 1 in the Examples, which describes Formulation 4A, Formulation 4B, Formulation 4C, and Formulation 4D. Further erdafitinib formulations with a range of excipient combinations are provided in Table 3 and in the Examples, which describes Formulations 3.2, 3.3, 3.4, and 4.1.

[0074] Provided herein is an erdafitinib solid formulation, particularly an erdafitinib mini-tablet, having a high erdafitinib drug loading, for example, in the range of 40% to 70% by weight, or 40% to 60% by weight, or 45% to 55% by weight, or about 50% by weight, or in the range of 45% to 55% by weight, or about 50% by weight. In one embodiment, the tablet can be obtained by a process comprising fluidized bed granulation. In one embodiment, the tablet can be obtained by a process comprising roller compaction. In one embodiment, the intragranular solid composition comprises a cyclodextrin, particularly hydroxypropyl-beta-cyclodextrin. In one embodiment, the formulation does not comprise mannitol in the intragranular solid composition. In one embodiment, the intragranular solid composition does not comprise a water-soluble filler. In one embodiment, the formulation comprises a water-insoluble filler, for example, microcrystalline cellulose.

[0075] In one embodiment, a fluid bed granulation process for making a granule is provided, the granule comprising erdafitinib and hydroxypropyl-beta-cyclodextrin. In one aspect, the process does not include the use of a water soluble filler, such as mannitol.

[0076] Provided herein is an erdafitinib solid formulation, particularly an erdafitinib mini-tablet, having a high erdafitinib drug loading, for example, an erdafitinib drug loading in the range of 45% to 55% by weight or about 50% by weight, comprising vinylpyrrolidinone-vinyl acetate copolymer and microcrystalline cellulose, particularly in a weight ratio in the range of 1:99 to 99:1, or 5:95 to 95:5, or 10:90 to 90:10, or 20:80 to 80:20, or 30:70 to 70:30, or 40:60 to 60:40, or 50:50. Unexpectedly, it has been found that the ejection force during tableting, particularly the ejection force during tableting of mini-tablets, such as those described herein, is reduced in the presence of this mixture. Powder formulations containing such mixtures have been found to have good flow properties. In one embodiment, the formulation further comprises hydroxypropyl-beta-cyclodextrin. In one embodiment, the formulation does not comprise mannitol.

[0077] In one embodiment there is provided a process for making tablets, in particular mini-tablets as described herein, wherein the powder blend to be compressed comprises vinylpyrrolidinone-vinyl acetate copolymer and microcrystalline cellulose, in particular in a weight ratio in the range of 1:99 to 99:1, or 5:95 to 95:5, or 10:90 to 90:10, or 20:80 to 80:20, or 30:70 to 70:30, or 40:60 to 60:40, or 50:50. In one aspect, there is provided a process for making tablets, particularly mini-tablets as described herein, wherein the powder blend to be compressed comprises erdafitinib, vinylpyrrolidinone-vinyl acetate copolymer, and microcrystalline cellulose, particularly the weight ratio of vinylpyrrolidinone-vinyl acetate copolymer to microcrystalline cellulose ranges from 1:99 to 99:1, or 5:95 to 95:5, or 10:90 to 90:10, or 20:80 to 80:20, or 30:70 to 70:30, or 40:60 to 60:40, or 50:50. In one aspect, the powder blend to be compressed further comprises hydroxypropyl-beta-cyclodextrin. In one aspect, the powder blend to be compressed does not comprise mannitol.

[0078] Provided herein is an erdafitinib solid formulation, particularly an erdafitinib powder formulation or an erdafitinib mini-tablet, having a high erdafitinib drug loading, for example, 40% to 70% by weight, or 40% to 60% by weight, or 45% to 55% by weight, or about 50% by weight, or 45% to 55% by weight, or about 50% by weight, and a low content of fine particles, for example, less than 20%, or less than 10%, or less than 5%, or about 3% or less than 3%, or about 2% or less than 2%. The fine particles can increase the ejection force during tableting, particularly during tableting of the mini-tablets described herein, particularly when tableting at high speed, for example, 2500 tablets / min.

[0079] In one embodiment, provided herein is a formulation, particularly a tablet or mini-tablet, comprising erdafitinib, particularly a high erdafitinib drug loading, for example, 40% to 70% by weight, or 40% to 60% by weight, or 45% to 55% by weight, or about 50% by weight, or 45% to 55% by weight, or about 50% by weight, hydroxypropyl-beta-cyclodextrin, vinylpyrrolidinone-vinyl acetate copolymer, and microcrystalline cellulose. In one aspect, the formulation further comprises meglumine. In one aspect, the formulation does not comprise mannitol. In one aspect, the formulation further comprises at least one of, or all of, a lubricant, such as colloidal silica; a lubricant, such as magnesium stearate; a binder, such as a cellulose derivative, such as hydroxypropyl methylcellulose; a filler, such as silicified microcrystalline cellulose.

[0080] In one embodiment, provided herein is a formulation, particularly a tablet or mini-tablet, comprising erdafitinib, particularly a high erdafitinib drug loading, for example, 40% to 70% by weight, or 40% to 60% by weight, or 45% to 55% by weight, or about 50% by weight, or 45% to 55% by weight, or about 50% by weight, hydroxypropyl-beta-cyclodextrin, vinylpyrrolidinone-vinyl acetate copolymer, and microcrystalline cellulose. In one aspect, the formulation further comprises at least one of, or all of, a lubricant, such as colloidal silica; a lubricant, such as magnesium stearate; a binder, such as a cellulose derivative, such as hydroxypropyl methylcellulose; a filler, such as silicified microcrystalline cellulose. In one aspect, the formulation does not comprise a stabilizer, such as meglumine. In one embodiment, the formulation is mannitol-free.

[0081] In one embodiment, the formulation is Formulation 4A. In one embodiment, the formulation is Formulation 4B. In one embodiment, the formulation is Formulation 4C. In one embodiment, the formulation is Formulation 4D.

[0082] Thus, a compounded 4D formulation is encompassed by the present disclosure, in which the solid pharmaceutical composition comprises (a) 50% by weight of erdafitinib free base, (b) 10% by weight of hydroxypropyl-beta-cyclodextrin, (c) 1% by weight of meglumine, (d) 17.5% by weight of microcrystalline cellulose, (e) 10.75% by weight of silicified microcrystalline cellulose, (f) 7.5% by weight of vinylpyrrolidone-vinyl acetate copolymer, (g) 0.25% by weight of colloidal silicon dioxide, (h) 1.5% by weight of hydroxypropyl methylcellulose, and (i) 1.5% by weight of magnesium stearate, these weight percentages being based on the total solid pharmaceutical composition. In one aspect, the formulation comprises: (a) preparing an intragranular solid composition by a fluid bed granulation process, the intragranular solid composition consisting essentially of (i) erdafitinib free base at a concentration of 50% by weight of the solid pharmaceutical composition; (ii) hydroxypropyl-beta-cyclodextrin at a concentration of 10% by weight of the solid pharmaceutical composition; (iii) meglumine at a concentration of 1% by weight of the solid pharmaceutical composition; (iv) microcrystalline cellulose at a concentration of 10% by weight of the solid pharmaceutical composition; and (v) hydroxypropyl methylcellulose at a concentration of 1.5% by weight of the solid pharmaceutical composition; and (b) combining the intragranular solid composition with extragranular components to form a granular solid composition. The solid pharmaceutical composition may be prepared by a process comprising: forming a blend, the extragranular component consisting essentially of (i) microcrystalline cellulose at a concentration of 7.5% by weight of the solid pharmaceutical composition, (ii) vinylpyrrolidone-vinyl acetate copolymer at a concentration of 7.5% by weight of the solid pharmaceutical composition, (iii) silicified microcrystalline cellulose at a concentration of 10.75% by weight of the solid pharmaceutical composition, (iv) colloidal silicon dioxide at a concentration of 0.25% by weight of the solid pharmaceutical composition, and (iv) magnesium stearate at a concentration of 1.5% by weight of the solid pharmaceutical composition; and (c) compressing the blend to form a solid pharmaceutical composition in the form of mini-tablets. In one embodiment, the tablet contains 11.5 mg of erdafitinib.

[0083] Thus, the formulation 4C is encompassed by the present disclosure, in which the solid pharmaceutical composition comprises (a) 50% by weight of erdafitinib free base, (b) 10% by weight of hydroxypropyl-beta-cyclodextrin, (c) 1% by weight of meglumine, (d) 1.5% by weight of hydroxypropylmethylcellulose, (e) 21.0% by weight of mannitol, (f) 0.25% by weight of sodium lauryl sulfate, (g) 7.25% by weight of microcrystalline cellulose, (h) 7.25% by weight of vinylpyrrolidone-vinyl acetate copolymer, (i) 0.25% by weight of colloidal silicon dioxide, and (j) 1.50% by weight of magnesium stearate, these weight percentages being based on the total solid pharmaceutical composition. In one aspect, the formulation may be prepared by a process comprising: (a) preparing an intragranular solid composition by a fluid bed granulation process, (b) combining the intragranular solid composition with an extragranular component to form a blend, and (c) compressing the blend to form a solid pharmaceutical composition in the form of mini-tablets, wherein the intragranular and extragranular components are set forth in the examples in Table 1. In one embodiment, the tablet comprises 11.5 mg of erdafitinib.

[0084] Thus, formulation 4B is encompassed by the present disclosure, in which the solid pharmaceutical composition comprises (a) 50% by weight of erdafitinib free base, (b) 10% by weight of hydroxypropyl-beta-cyclodextrin, (c) 1% by weight of meglumine, (d) 24.5% by weight of microcrystalline cellulose, (e) 6.0% by weight of silicified microcrystalline cellulose, (f) 6.0% by weight of vinylpyrrolidone-vinyl acetate copolymer, (g) 0.5% by weight of colloidal silicon dioxide, and (h) 2.0% by weight of magnesium stearate, these weight percentages being based on the total solid pharmaceutical composition. In one aspect, the formulation may be prepared by a process comprising: (a) preparing an intragranular solid composition by a fluid bed granulation process; (b) combining the intragranular solid composition with an extragranular component to form a blend; and (c) compressing the blend to form a solid pharmaceutical composition in the form of mini-tablets, the intragranular and extragranular components being described in the examples in Table 1. In one aspect, the formulation may be prepared by a process comprising: (a) preparing an intragranular solid composition by a roller compaction process; (b) combining the intragranular solid composition with an extragranular component to form a blend; and (c) compressing the blend to form a solid pharmaceutical composition in the form of mini-tablets, the intragranular and extragranular components being described in the examples in Table 1. In one embodiment, the tablet comprises 11.5 mg of erdafitinib.

[0085] Thus, Formulation 4A is encompassed by the present disclosure, in which the solid pharmaceutical composition comprises (a) 50% by weight of erdafitinib free base, (b) 10% by weight of hydroxypropyl-beta-cyclodextrin, (c) 1% by weight of meglumine, (d) 10% by weight of microcrystalline cellulose, (e) 19% by weight of anhydrous calcium hydrogen phosphate, (f) 8% by weight of vinylpyrrolidone-vinyl acetate copolymer, (g) 0.5% by weight of colloidal silicon dioxide, and (h) 1.50% by weight of magnesium stearate, these weight percentages being based on the total solid pharmaceutical composition. In one aspect, the formulation may be prepared by a process comprising: (a) preparing an intragranular solid composition by a fluid bed granulation process; (b) combining the intragranular solid composition with an extragranular component to form a blend; and (c) compressing the blend to form a solid pharmaceutical composition in the form of mini-tablets, the intragranular and extragranular components being described in the examples in Table 1. In one aspect, the formulation may be prepared by a process comprising: (a) preparing an intragranular solid composition by a roller compaction process; (b) combining the intragranular solid composition with an extragranular component to form a blend; and (c) compressing the blend to form a solid pharmaceutical composition in the form of mini-tablets, the intragranular and extragranular components being described in the examples in Table 1. In one embodiment, the tablet comprises 11.5 mg of erdafitinib.

[0086] Thus, Formulation 4.1 is encompassed by the present disclosure, in which the solid pharmaceutical composition comprises (a) 50% by weight of erdafitinib free base, (b) 10% by weight of hydroxypropyl-beta-cyclodextrin, (c) 17.5% by weight of microcrystalline cellulose, (d) 11.75% by weight of silicified microcrystalline cellulose, (e) 7.5% by weight of vinylpyrrolidone-vinyl acetate copolymer, (f) 0.25% by weight of colloidal silicon dioxide, (g) 1.5% by weight of hydroxypropyl methylcellulose, and (h) 1.5% by weight of magnesium stearate, these weight percentages being based on the total solid pharmaceutical composition. In one aspect, the formulation comprises: (a) preparing an intragranular solid composition by a fluid bed granulation process, the intragranular solid composition consisting essentially of (i) erdafitinib free base at a concentration of 50% by weight of the solid pharmaceutical composition; (ii) hydroxypropyl-beta-cyclodextrin at a concentration of 10% by weight of the solid pharmaceutical composition; (iii) microcrystalline cellulose at a concentration of 10% by weight of the solid pharmaceutical composition; and (iv) hydroxypropyl methylcellulose at a concentration of 1.5% by weight of the solid pharmaceutical composition; and (b) combining the intragranular solid composition with an extragranular component to form a blend. The extragranular component may be prepared by a process comprising: forming a solid pharmaceutical composition in which the extragranular component consists essentially of (i) microcrystalline cellulose at a concentration of 7.5% by weight of the solid pharmaceutical composition, (ii) vinylpyrrolidone-vinyl acetate copolymer at a concentration of 7.5% by weight of the solid pharmaceutical composition, (iii) silicified microcrystalline cellulose at a concentration of 11.75% by weight of the solid pharmaceutical composition, (iv) colloidal silicon dioxide at a concentration of 0.25% by weight of the solid pharmaceutical composition, and (iv) magnesium stearate at a concentration of 1.5% by weight of the solid pharmaceutical composition, and (c) compressing the blend to form a solid pharmaceutical composition in the form of mini-tablets. In one embodiment, the tablet contains 11.5 mg of erdafitinib.

[0087] Diffusion-Based Drug Delivery Systems Described herein are drug delivery systems that are particularly suitable for the effective release of drug formulations containing Erdafitinib, such as those detailed above or below. These particular systems have been developed in which, instead of an osmotic drug release mechanism, drug release is controlled by drug diffusion through a drug-permeable polymeric component that defines a portion of the system housing.

[0088] In certain embodiments, the system includes a drug-permeable polymer component or portion, which forms a portion of the housing. For example, the drug-permeable component or portion of the system can be a portion of the housing, which portion of the housing is formed from a different material than the remainder of the housing (e.g., a strip or multiple strips of material extending along at least a portion of the length of the housing), such that the size, shape (e.g., arc angle), thickness, and material properties of the drug-permeable wall structure can be selected to achieve a desired drug release rate. In certain embodiments, the drug-permeable portion, the drug-impermeable portion, or both the drug-permeable and impermeable portions are formed from a thermoplastic polyurethane composition to provide (i) controlled diffusion of drug from the system, (ii) desired mechanical properties (e.g., the ability to be straightened for insertion / removal, being flexible enough to be well tolerated while in place, the tube remaining intact with small compression / extension, elastic deformation ability (compliance) in response to detrusor contracture), (iii) a system that can be heat-shaped to have a desired retention shape, and / or (iv) a system that can be manufactured in a coextrusion process.

[0089] In some embodiments, the drug permeable portion is permeable to erdafitinib free base. In some embodiments, the drug permeable portion is permeable to erdafitinib free base and erdafitinib free base formulated with HP-β-CD. In some embodiments, the drug permeable portion is permeable to erdafitinib free base, erdafitinib HCl salt, and erdafitinib free base formulated with HP-β-CD. In some embodiments of any of the above, the material of the drug permeable portion is an aliphatic polyether-based TPU. In some embodiments of the above, the material of the drug permeable portion is an aliphatic polyether-based TPU, the TPU being Lubrizol Tecophilic HP-60D-35 or HP-93A-100.

[0090] In some embodiments, the drug permeable portion is permeable to erdafitinib free base formulated with HP-β-CD. In some embodiments, the drug permeable portion is permeable to erdafitinib free base formulated with HP-β-CD and is impermeable or substantially impermeable to erdafitinib free base formulated without HP-β-CD. In some embodiments of any of the above, the material of the drug permeable portion is an aliphatic polyether-based TPU. In some embodiments of the above, the material of the drug permeable portion is Lubrizol Tecoflex EG-80A.

[0091] Exemplary materials for the drug-permeable portion (e.g., the "stripe" material of the permeable system) include, but are not limited to, aliphatic polyether-based thermoplastic polyurethanes (TPUs), such as Lubrizol Tecophilic HP-60D-35, Tecophilic HP-93A-100, and Tecoflex EG-80A. In some embodiments, the drug-permeable portion material is Lubrizol Tecophilic HP-60D-35, Tecophilic HP-93A-100, or Tecoflex EG-80A. In some embodiments, the drug-permeable portion material is Lubrizol Tecoflex EG-80A. In some embodiments, the drug is erdafitinib free base and the drug-permeable portion material is Lubrizol Tecophilic HP-60D-35 or Tecophilic HP-93A-100. In some embodiments, the drug is erdafitinib free base, the drug is formulated with HP-β-CD, and the material of the drug permeable portion is Lubrizol Tecophilic HP-60D-35, Tecophilic HP-93A-100, or Tecoflex EG-80A. In some embodiments, the drug is erdafitinib free base, the drug is formulated with HP-β-CD, and the material of the drug permeable portion is Lubrizol Tecoflex EG-80A. In some embodiments, the drug is erdafitinib HCl salt, and the material of the drug permeable portion is Lubrizol Tecophilic HP-60D-35 or Tecophilic HP-93A-100.

[0092] Exemplary materials for the drug impermeable portion (e.g., the "base" material of a permeable system) include, but are not limited to, silicone elastomer materials, such as NuSil MED-4750; TPUs, such as Lubrizol Carbothane Aliphatic PC-3575A, Tecothane Soft AR-62A, AR-75A-B20, AC-4075A-B20, Carbothane Aromatic AC-4075A, Tecothane TT-1074A, Tecoflex EG-80A; and ethylene vinyl acetate, such as 3M CoTran 9712. In some embodiments, the material of the drug impermeable portion is selected from MED-4750, PC-3575A, PC-3575A, AR-62A, AR-75A-B20, AC-4075A-B20, AC-4075A, TT-1074A, EG-80A, and CoTran 9712. In some embodiments, the material of the drug impermeable portion is selected from MED-4750, PC-3575A, PC-3575A, AR-62A, AR-75A-B20, AC-4075A-B20, AC-4075A, TT-1074A, and CoTran 9712. In some embodiments, the material of the drug impermeable portion is AR-75A-B20. In some embodiments, the material of the drug impermeable portion is AC-4075A-B20.

[0093] In some embodiments, the material of the drug-permeable portion is EG-80A and the material of the drug-impermeable portion is AR-75A-B20.In some embodiments, the material of the drug-permeable portion is EG-80A and the material of the drug-impermeable portion is AC-4075A-B20.

[0094] It should be understood that Lubrizol Tecophilic HP series materials are aliphatic polyether-based TPUs that are formulated to absorb an equilibrium water content of up to 100% of the dry resin weight, designed for extrusion, and processable by injection molding. HP-60D-35 has a Shore hardness (ASTM D2240) of about 42D; a specific gravity (ASTM D792) of about 1.12; a flexural modulus (psi) of 4000 (ASTM D790); a ultimate tensile (psi) of about 7,800 dry and 4900 wet (ASTM D412); a ultimate elongation (%) of about 450 dry and 390 wet (D412); and a water absorption (% by Lubrizol method) of about 35. HP-93A-100 has a Shore hardness (ASTM D2240) of about 83A; a specific gravity (ASTM D792) of about 1.13; a flexural modulus (psi) of 2900 (ASTM D790); a ultimate tensile (psi) of about 2200 dry and 1400 wet (ASTM D412); a ultimate elongation (%) of about 1040 dry and 620 wet (D412); and a water absorption (% by Lubrizol method) of about 100.

[0095] It is understood that the Lubrizol Tecoflex material is an aliphatic polyether-based TPU that is processable by extrusion and injection molding. EG-80A has a Shore hardness (ASTM D2240) of about 72A; a specific gravity (ASTM D792) of about 1.04; a flexural modulus (psi) of 1,000 (ASTM D790); a ultimate tensile (psi) of about 5,800 (ASTM D412); a ultimate elongation (%) of about 660 (D412); a tensile modulus (psi) of about 300 at 100% elongation, about 500 at 200% elongation, and about 800 at 300% elongation (ASTM D412); and a mold shrinkage (in / in) of about 0.008 to 0.012 (ASTM D955).

[0096] It should be understood that Lubrizol aromatic Carbothane AC series materials are radiopaque (20% BaSO4 filled) polycarbonate-based aromatic TPUs that are processable by extrusion or injection molding. AC-4075A-B20 has a Shore hardness (ASTM D2240) of about 78A; a specific gravity (ASTM D792) of about 1.38; an ultimate tensile (psi) of about 8300 (ASTM D412); an ultimate elongation (%) of about 400 (D412); a tensile modulus (psi) of about 560 at 100% elongation, about 1300 at 200% elongation, and about 3400 at 300% elongation (ASTM D412); a flexural modulus (psi) of about 1800; a Vicat temperature (°C) of about 55; and a mold shrinkage (in / in) (1 inch x 0.25 inch x 6 inch bar) (ASTM D955) of about 0.011.

[0097] It is to be understood that the Lubrizol Tecothane Soft material is an aromatic polyester hydrocarbon-based TPU that can be processed by extrusion or injection molding. AR-75A has a Shore hardness (ASTM D785) of about 79A; a specific gravity (ASTM D792) of about 1.03; an ultimate tensile (psi) (ASTM D412) of about 2000; an ultimate elongation (%) of about 530 (ASTM D412); a tensile modulus (psi) of about 730 at 100% elongation, about 1000 at 200% elongation, and about 1300 at 300% elongation (ASTM D412); a flexural modulus (psi) of about 2500 (ASTM 790); a Vicat softening point (°C) of about 75; and a mold shrinkage (in / in) (1 inch x 0.25 inch x 6 inch bar) (ASTM D955) of about 0.08. AR-75A-B20 is AR-75A filled with 20% BaSO4 and may be manufactured, for example, by Compounding Solutions.

[0098] It should be further understood that the above test results for the Lubrizol Tecophilic HP. Tecoflex, aromatic Carbothane AC, and Tecothane Soft materials are approximated based on small samples of TPU, and therefore the properties of these materials may show slight variations from the properties listed herein.

[0099] In one aspect, as shown in FIG. 1, a drug delivery system 100 is provided that includes a tubular housing having a drug reservoir lumen 106 bounded by a wall structure 104, where (i) at least a portion of the wall structure 104 is water permeable, and (ii) at least a portion of the wall structure is permeable to a drug (contained in a drug unit 108), such that the drug is releasable in vivo by diffusion through the drug-permeable portion of the wall structure 104. In certain embodiments, as discussed in more detail below, the wall structure includes a first wall structure and a second wall structure, the first wall structure and the second wall structure together forming a housing. As used herein, the phrase "diffusion through the drug-permeable portion" (e.g., diffusion through the "second wall structure") refers to the drug being released by passing through the material forming the wall by molecular diffusion, and not by passing through an opening or open structure extending through the wall.

[0100] In one aspect, as shown in Figure 2, a drug delivery system 200 is provided that includes a housing having a first wall structure 206 formed from a first material and a second wall structure 205 formed from a second material, the first wall structure 206 and the second wall structure 205 adjacent to one another and together forming a tube that defines a drug reservoir lumen 208, where (i) the second wall structure 205, or both the first wall structure 206 and the second wall structure 205, are permeable to water, and (ii) the first wall structure 206 is impermeable to the drug and the second wall structure 205 is permeable to the drug, such that the drug is releasable in vivo by diffusion through the second wall structure 205. As used herein, the term "impermeable to drug" refers to the wall being substantially impermeable to the solubilized drug, such that a substantial amount of the solubilized drug cannot diffuse through the wall over a therapeutic period that the system is located in vivo.

[0101] In certain embodiments, the tube is a cylinder or another suitable shape or design. As used herein, the term "cylinder" when used in reference to a tubular housing refers to the housing having a substantially cylindrical outer wall. In some embodiments, the system is "closed" and thus does not include an opening. Drug release is solely by diffusion through the second wall structure.

[0102] In some embodiments, the first wall structure 206 / 306 and the second wall structure 205 / 305 are adjacent to one another and together form a cylindrical tube, as shown in Figures 2 and 3. For example, such a system may be formed in a co-extrusion or 3D printing process such that the first wall structure and the second wall structure are integrally formed. In one embodiment, the co-extruded first and second wall structures are thermoplastic polymers having desired properties.

[0103] As shown in FIG. 3, the first wall structure 306 and the second wall structure 305 together form a cylindrical tube having a lumen 308 in which the drug formulation is contained. The second wall structure 305 is in the form of a longitudinal strip extending along at least a portion of the length of the first wall structure 306 and is permeable to the drug, while the first wall structure 306 is not permeable to the drug. In certain embodiments, multiple drug-permeable strips may be used in a single system. In certain embodiments, one permeable strip may be used in a single system. Thus, the size, shape, thickness, and material properties of the second wall structure may be selected to achieve a desired drug release rate.

[0104] In a preferred embodiment, as discussed in more detail below, the system is elastically deformable between a low-profile deployed shape (e.g., a relatively straightened shape) suitable for insertion through the patient's urethra and into the patient's bladder, and a relatively expanded retained shape (e.g., a pretzel shape, a bi-elliptical coil shape, an S-shape, etc.) suitable for retention within the bladder.

[0105] 7A-7C, the system further includes a retention frame lumen 734. In certain embodiments, the retention frame lumen includes an elastic wire, such as a Nitinol wire. In certain other embodiments, the retention frame lumen is filled with a shape-setting elastic polymer.

[0106] In other embodiments, as shown in Figures 1-3 and 8, the system does not include a retention frame lumen, or a retention frame or lead. Instead, the housing material is configured to be elastically deformable between a straightened shape and a retention shape in the absence of a retention frame or lead. In certain embodiments, the tubular system is heat-shaped to have a coiled or other retention shape. Thus, in such embodiments, the design and manufacture of the system is simplified, and the overall size of the system is minimized (or the drug payload may be increased if the size of the system remains constant). In embodiments without a retention frame, the tubular housing material serves the functions of (i) forming a drug reservoir lumen, (ii) controlling drug release, and (iii) retaining the system within the bladder during deployment.

[0107] In one embodiment, as shown in Figures 7A-7C, a drug delivery system 700 is provided that includes an elongated elastic housing 702 having a drug reservoir lumen 700 extending between a first end 706 and a second end 708. The elastic housing 702 is formed from a tubular wall structure 710 including a first wall structure 716 and a second wall structure 724 that are adjacent to one another and together form a tube that defines the drug reservoir lumen 704, and (i) the second wall structure 724, or both the first wall structure 716 and the second wall structure 724, are permeable to water, and (ii) the first wall structure 716 is impermeable to the drug and the second wall structure 724 is permeable to the drug, such that the drug is releasable in vivo by diffusion through the second wall structure 724.

[0108] In embodiments where the first and second wall structures together form a cylindrical tube, any suitable end plugs or closures, or thermoformed seals, may be used to seal the ends of the tube after the drug has been loaded. These end plugs / closures ensure that the drug-permeable polymer portion that forms part of the outer tube is the only pathway for drug release.

[0109] In some embodiments, as shown in Figures 2 and 3, the wall 206, 205 / 306, 305 has a substantially constant thickness around the circumference of the wall 206, 205 / 306, 305. For example, the inner diameter 210 / 310 and the outer diameter 212 / 312 of the first wall structure 206, 205 / 306, 305 (which together form a cylindrical tube) are the same. In other embodiments, the wall may have a thickness that varies around the circumference of the wall.

[0110] Thus, for the systems described herein, drug release is controlled by diffusion of the drug through a drug-permeable component that defines a portion of the system housing. The drug-permeable wall structure may be positioned, dimensioned, and have material properties to provide a desired rate of controlled drug diffusion out of the device.

[0111] The particular material and arc angle of the drug permeable portion or wall structure can be selected to achieve a particular drug release profile, i.e., water and drug permeation rates. As used herein, the phrase "arc angle" refers to the angular dimension of the arc of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube.

[0112] For example, in certain embodiments, as shown in Figures 2 and 3, the second wall structure 205 / 305 comprises less than 90 percent of the cross-sectional area of ​​the tube in a cross-section perpendicular to the longitudinal axis of the tube. In one embodiment, the second wall structure comprises less than 50 percent of the cross-sectional area of ​​the tube in a cross-section perpendicular to the longitudinal axis of the tube. In one embodiment, the second wall structure comprises less than 25 percent of the cross-sectional area of ​​the tube in a cross-section perpendicular to the longitudinal axis of the tube.

[0113] In certain embodiments, as shown in Figures 2, 3, 7A-7C, and 8, the first wall structure and the second wall structure forming the tube bounding the drug reservoir lumen are adjacent to each other at two interface edges, such that the wall structures collectively form the tube that defines the drug reservoir lumen. In these embodiments, the two interface edges are disposed at an arc angle of about 15 degrees to about 270 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. As used herein, the term "about" with respect to the arc angle of the second wall structure refers to an arc angle of plus or minus 3 degrees.

[0114] In one embodiment, as shown in FIG. 2, the second wall structure 205 has an arc angle 214 of about 60 degrees of the circumference of the cylindrical tube 200 in cross section. In one embodiment, as shown in FIG. 3, the second wall structure 305 has an arc angle 314 of about 30 degrees of the circumference of the cylindrical tube 300 in cross section. In one embodiment, the second wall structure has an arc angle of about 15 degrees to about 270 degrees. As described further below, in certain embodiments, the second wall structure has an arc angle of about 45 degrees to about 90 degrees, about 150 degrees to about 270 degrees, or about 210 degrees to about 270 degrees, such as about 45 degrees, about 90 degrees, about 180 degrees, and about 240 degrees. In certain embodiments, the second wall structure has an arc angle of about 45 degrees, about 90 degrees, about 180 degrees, about 240 degrees, or about 270 degrees.

[0115] When the system is formed to have the retaining shape shown in Figure 1, the second wall structure can be located at the inward curve (0 degrees), outward curve (180 degrees), at the top (90 degrees), or on the middle. The top (90 degrees) position may be preferred when the second wall structure is formed from a material that swells significantly when it absorbs water.

[0116] Therefore, tubular systems designed to reduce or control the drug release rate without negatively changing the mechanical properties and dimensions suitable for system deployment and tolerance have been developed. In some embodiments, the design reduces the drug release rate by reducing the length of the drug permeable region so that the length extends along only a portion of the overall length of the system. Thus, a larger arc angle of the drug permeable region can be used to tailor the drug release rate from the system. In addition, by reducing the length of the drug permeable region, a smaller amount of drug permeable material can be used to provide a reduced drug release rate compared to conventional systems.

[0117] When the drug is loaded into the drug reservoir lumen, any suitable end plugs or closures, or thermoformed seals, may be used to block / close the first and second ends of the drug reservoir lumen. These end plugs / closures ensure that the second material forming a portion of the elastomeric housing is the only path for drug release. In certain embodiments, the end plugs are formed from a first material (i.e., the material forming the first wall structure) that is impermeable to the drug.

[0118] In the above embodiment, the first material or first wall structure, the second material or first wall structure, or both are formed of water-permeable materials. In a preferred embodiment, as described above for the erdafitinib solid formulation, the drug is in a solid form (e.g., a tablet or multiple tablets), and at least a portion of the tubular body is water-permeable to allow in vivo solubilization of the drug while in the drug reservoir lumen. In an embodiment, the first material or first wall structure may be the only water-permeable portion. In other embodiments, both the first material / wall structure and the second material / wall structure may be water-permeable.

[0119] The material for the wall structure of the present system may be selected from a variety of suitable thermoplastic polyurethane (TPU)-based materials. In particular, the first material forming the first wall structure (i.e., the material that is impermeable to the drug contained in the drug reservoir) may be a polycarbonate-based aromatic thermoplastic polyurethane (e.g., CARBOTHANE™ TPU, e.g., AC-4075A, available from Lubrizol) or an aromatic polyester hydrocarbon-based thermoplastic polyurethane (e.g., TECOTHANE™ TPU, e.g., AR-75A, available from Lubrizol). For example, CARBOTHANE polyurethanes are alicyclic polymers and are of the type made from polycarbonate-based polyols. The general structure of the polyol segment is O--[(CH2)6--CO3] n The polyol segment is represented as --(CH2)--O--. AC-4075A has a durometer shore hardness of 77A, a specific gravity of 1.19, a flexural modulus of 1500 psi, and a maximum elongation of 400%. AR-75A has a durometer shore hardness of 79A, a specific gravity of 1.03, a flexural modulus of 2500 psi, and a maximum elongation of 530%. In particular, the second material forming the second wall structure (i.e., the material that is permeable to the drug contained within the drug reservoir) can be an aliphatic polyether-based thermoplastic polyurethane (e.g., TECOFLEX™ TPU, e.g., EG-80A, available from Lubrizol. For example, TECOFLEX polyurethanes are alicyclic polymers and are of the type made from polyether-based polyols. The general structure of the polyol segment is O--(CH2--CH2--CH2--CH2) x The EG-80A has a durometer Shore hardness of 72A, a specific gravity of 1.04, a flexural modulus of 1000 psi, and a maximum elongation of 660%. The TPU may further include a radiopaque agent, such as barium sulfate, e.g., AC-4075A-B20, which is a polycarbonate-based aromatic thermoplastic polyurethane with 20% barium sulfate loading.

[0120] In one embodiment, the inner diameter of the cylindrical tube can be from about 1.0 mm to about 2.5 mm. In one embodiment, the outer diameter of the cylindrical tube is from about 2.0 mm to about 4.1 mm. In one embodiment, the thickness of the first wall structure, the second wall structure, or both, is from about 0.2 mm to about 1.0 mm.

[0121] Thus, compared to drug delivery systems that use homogeneous materials (e.g., blends of permeable and impermeable thermoplastic materials) to form drug-permeable tubes, the mechanical properties of tubes that use dual-wall structures (e.g., drug-permeable stripe embodiments) can be decoupled from the drug release (e.g., diffusion) properties of the tube. For example, in a single-material tube, changing the material of the tube essentially affects both the mechanical and diffusion properties of the system. Being able to control the release rate with the stripe angle can have the added benefit of not changing the system outer diameter. In contrast, control by changing the wall thickness may be too large to pass through the urethra or too thin to provide the required mechanical strength of the system. Also, the drug release properties of blended polymers may not be easily predictable. In addition, it is often difficult to achieve a truly homogeneous blend when mixing two thermoplastics. Thus, such tubular drug delivery systems require experimentation to tailor the drug release rate. In contrast, the dual-wall structures described herein can provide enhanced flexibility in tailoring a particular drug release rate from the delivery system.

[0122] For use within the bladder, it is important that the device is compliant (i.e., easily flexes and feels soft) during detrusor contracture to avoid or reduce discomfort and irritation to the patient. Thus, it should be noted that the durometer of the first and second construction materials is important, and the proportion of high durometer materials may be limited in constructing a system housing of a given size while still providing suitable compliance within the bladder. For example, a suitable first wall material, such as TECOTHANE or CARBOTHANE, may have a Shore hardness of greater than 70A, e.g., 77A to 65D, and a suitable second wall material, such as TECOFLEX, may have a Shore hardness of less than 90A or less than 80A, e.g., 72A. In some embodiments, the first material has a Shore hardness value of 70A to 80A, and the second material has a Shore hardness value of 70A to 75A. Thus, in certain embodiments, the second wall material has a Shore hardness that is less than that of the first wall material, and both wall materials have a Shore hardness less than 80 A. Thus, rather than making the entire system housing from a water-swellable, hydrophilic, drug-permeable second material, it may be advantageous to use a combination of two different polymeric materials to achieve the desired mechanical properties of the tube.

[0123] 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 an 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. In certain embodiments, the lag time can be at least about 30 minutes, about 12 hours to about 24 hours, or up to about 2 days. These systems can be effective to release a therapeutically effective amount of the drug over a period of up to 6 months or up to 3 months (90 days).

[0124] As discussed in more detail below, a drug formulation, such as those described throughout this disclosure, is disposed within the drug reservoir lumen defined by the first wall structure and the second wall structure. In a particularly preferred embodiment, the drug is an erdafitinib-based pharmaceutical formulation as described herein. In certain 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 such embodiments, the two interface edges may be disposed at an arc angle of 45 degrees to 90 degrees. In some embodiments, the system is configured to release erdafitinib at an average rate of 4 mg / day to 6 mg / day. In such embodiments, the two interface edges may be disposed at an arc angle of 150 degrees to 270 degrees.

[0125] In one embodiment, the system is configured to release erdafitinib at an average rate of 1 mg / day, and the two interface edges are disposed at an arc of about 45 degrees. In another embodiment, the system is configured to release erdafitinib at an average rate of 2 mg / day, and the two interface edges are disposed at an arc of about 90 degrees. In another embodiment, the system is configured to release erdafitinib at an average rate of 4 mg / day, and the two interface edges are disposed at an arc of about 180 degrees. In one embodiment, the system is configured to release erdafitinib at an average rate of 6 mg / day, and the two interface edges are disposed at an arc of 240 degrees. In certain embodiments, the release profile of the drug is substantially independent of pH over a pH range of 5 to 7. In certain embodiments, the release profile of the drug is substantially independent of pH over a pH range of 5.5 to 7. In certain embodiments, the release profile of the drug is substantially independent of pH over a pH range of 5.5 to 8. In certain embodiments, the release rate is maintained over a period of up to 6 months, particularly up to 3 months or 90 days.

[0126] In one embodiment, a drug delivery system is provided having (i) a housing defining a drug reservoir lumen and a retaining frame lumen, (ii) a plurality of tablets comprising erdafitinib disposed within the drug reservoir lumen, and (iii) a nitinol lead configuration (retaining frame) disposed within the retaining frame lumen. The drug reservoir lumen is defined / bounded by a first wall structure (base) formed from a first material that is an aromatic polyester hydrocarbon-based thermoplastic polyurethane, particularly AC-4075A-B20, and a second wall structure (stripes) formed from a second material made from an aliphatic polyether-based thermoplastic polyurethane, particularly EG-80A, the first wall structure and the second wall structure being adjacent to each other at two interface edges and together forming a tube that defines a closed drug reservoir lumen. In one embodiment, the closed drug reservoir lumen contains a plurality of tablets, particularly a plurality of mini tablets, particularly erdafitinib mini tablets as described herein. In one embodiment, the amount of erdafitinib in the drug reservoir lumen is about 500 mg. In one embodiment, the drug reservoir lumen comprises about 44 erdafitinib mini-tablets, particularly erdafitinib tablets as described herein. In one embodiment, the plurality of tablets comprises 44 mini-tablets, totaling about 500 mg of erdafitinib. In one embodiment, the stripe angle is 90 degrees, and the average release rate of erdafitinib from the system is about 2 mg / day. In one embodiment, the stripe angle is 180 degrees, and the average release rate of erdafitinib from the system is about 4 mg / day. In one embodiment, the stripe angle is 210-270 degrees, and the average release rate of erdafitinib from the system is about 6 mg / day. In one embodiment, the stripe angle is 45 degrees, and the average release rate of erdafitinib from the system is about 1 mg / day. In one embodiment, the stripe angle is 90 degrees and the average release rate of erdafitinib from the system is approximately 2 mg / day. In one embodiment, the stripe angle is 90 degrees and the average release rate of erdafitinib from the system is approximately 2 mg / day at a pH of about 5 to about 6.8 and approximately 1 mg / day at a pH of about 8.In one embodiment, the stripe angle is 180 degrees and the average release rate of erdafitinib from the system is approximately 4 mg / day. In one embodiment, the stripe angle is 180 degrees and the average release rate of erdafitinib from the system is approximately 4 mg / day at a pH of about 5 to about 6.8 and approximately 2 mg / day at a pH of about 8. In one embodiment, the stripe angle is 210 to 270 degrees, particularly 270 degrees, and the average release rate of erdafitinib from the system is approximately 6 mg / day. In one embodiment, the stripe angle is 210 to 270 degrees, particularly 270 degrees, and the average release rate of erdafitinib from the system is approximately 6 mg / day at a pH of about 5 to about 6.8 and approximately 3 mg / day at a pH of about 8. In one embodiment, the stripe angle is 45 degrees and the average release rate of erdafitinib from the system is approximately 1 mg / day. In one embodiment, the stripe angle is 45 degrees and the average release rate of erdafitinib from the system is approximately 1 mg / day at a pH of about 5 to about 6.8 and approximately 0.5 mg / day at a pH of about 8. In one embodiment, the tablet has formulation 4D as described herein. In one embodiment, the tablet has formulation 4C as described herein. In one embodiment, the tablet has formulation 4B as described herein. In one embodiment, the tablet has formulation 4A as described herein.

[0127] Other aspects of the drug delivery system In certain embodiments, the system is configured for intravesical insertion and retention in a patient. For example, the system can be elastically deformable between a relatively low profile (e.g., straightened) shape suitable for insertion through a lumen into a body cavity of a patient, e.g., the shape shown in Figures 7A-7B, and a relatively expanded, retained shape suitable for retaining the system within a body cavity, e.g., the bladder, e.g., the shape shown in Figures 1, 4, 5, and 6A. The relatively expanded shape can include a pair of overlapping coils, often referred to as a "pretzel" shape. In certain embodiments, the ends of the extended system are generally within the bounds of a bi-ellipse-like shape.

[0128] After deployment in the bladder, when in the expanded, retained configuration, for example, the system may resist expulsion in response to urination or other forces. After drug release, the system may be removed, for example, by cystoscope and forceps, or may be at least partially bioerodible to avoid a retrieval procedure.

[0129] The system may be loaded with one or more drug units, e.g., at least one drug in the form of a tablet as described throughout this disclosure. A solid drug composition form, e.g., a tablet, may provide a relatively large drug payload volume relative to the total system volume, potentially enhancing the stability of the drug during transportation, storage, prior to use, or prior to drug release. However, the solid drug may need to be solubilizable in vivo to diffuse in therapeutically effective amounts through the drug-permeable component into the surrounding tissue or cavity of the patient. The drug reservoir lumen may hold some of the disclosed drug tablets in an end-to-end continuous arrangement in an elongated form. In some embodiments, the system holds about 10-100 cylindrical drug tablets (e.g., 44 tablets), e.g., mini tablets, which may be continuously loaded into the drug reservoir lumen. In one aspect, the tablet is as described herein. In one aspect, the tablet is of Formulation 4A. In one aspect, the tablet is of Formulation 4B. In one aspect, the tablet is of Formulation 4C. In one embodiment the tablet is of formulation 4D.

[0130] The system may be inserted into a patient using a cystoscope or catheter, or any other suitable or customized inserter device. Typically, a cystoscope for an adult has an outer diameter of about 5 mm and a working channel with an inner diameter of about 2.4 mm to about 2.6 mm. In embodiments, the cystoscope may have a working channel with a larger inner diameter, for example, an inner diameter of 4 mm or more. Thus, the system may be relatively small in size. For example, when the system is elastically deformed into a relatively straightened shape, a system for an adult patient may have a total outer diameter that is less than about 2.6 mm, for example, about 2.0 mm to about 2.4 mm. In addition to allowing insertion, the relatively small size of the system may also reduce patient discomfort and trauma to the bladder. In one embodiment, the overall configuration of the system promotes in vivo tolerability for most patients. In certain embodiments, the system is configured for tolerability based on the bladder characteristics and design considerations described in U.S. Pat. No. 11,065,426.

[0131] Within the three-dimensional space occupied by the system in the retained configuration, the maximum dimension of the system in any direction is preferably less than 10 cm, which is the approximate diameter of the bladder when filled. In some embodiments, the maximum dimension of the system in any direction may be less than about 9 cm, e.g., about 8 cm, 7 cm, 6 cm, 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 or less. In certain embodiments, the maximum dimension of the system in any direction is less than about 7 cm, e.g., about 6 cm, 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 cm or less. In preferred embodiments, the maximum dimension of the system in any direction is less than about 6 cm, e.g., about 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 cm or less. More specifically, the three-dimensional space occupied by the system is defined by three perpendicular directions. Along one of these directions, the system has its maximum dimension, and along the two other directions, the system may have a smaller dimension. For example, the smaller dimension in the two other directions can be less than about 4 cm, e.g., about 3.5 cm, 3 cm, 2.5 cm or less. In preferred embodiments, the system has a dimension in at least one of these directions that is less than 3 cm.

[0132] In some embodiments, the system may have different dimensions in at least two of the three directions, and in some cases in each of the three directions, such that the system is of a non-uniform shape. Due to the non-uniform shape, the system may be able to achieve a reduced compression orientation in an empty bladder, which is also of a non-uniform shape. In other words, a particular orientation of the system in an empty bladder may allow the system to exert less contact pressure against the bladder wall, making the system better tolerated by the patient.

[0133] The overall shape of the system may allow the system to reorient itself within the bladder to reduce engagement or contact of the system with the bladder wall. For example, the overall outer shape of the system may be curved and all or most of the outer or exposed surfaces of the system may be substantially rounded. The system may also be substantially devoid of sharp edges and the outer surfaces of the system may be formed from a material that experiences reduced frictional engagement with the bladder wall. Such a configuration allows the system to reposition itself within an empty bladder, such that the system applies a lower contact pressure to the bladder wall. In other words, the system may slide or roll against the bladder wall to a lower energy position, meaning a position where the system experiences less compression.

[0134] In one embodiment, the system occupies a three-dimensional space but is generally planar in shape. Such a system may define a short axis and may be substantially symmetrical about the short axis and a long axis that is substantially perpendicular to the short axis. The system may have a maximum dimension in the direction of the long axis that does not exceed about 6 cm, and in certain embodiments, the maximum dimension in the direction of the long axis is less than 5 cm, e.g., about 4.5 cm, about 4 cm, about 3.5 cm, about 3 cm, or less. The system may have a maximum dimension in the direction of the short axis that does not exceed about 4.5 cm, and in certain embodiments, the maximum dimension in the direction of the short axis is less than 4 cm, e.g., about 3.5 cm, about 3 cm, or less. The system is curved around substantially the entire perimeter of the system in both the long and short cross-sectional planes. In other words, the overall outer shape of the system is curved and the cross-sectional shape of the system is round. Thus, the system is substantially devoid of edges, except for edges on the two flat ends, which are fully protected within the interior of the system when it is in a plane. These features allow the system to reorient itself into a position of reduced compression when it is in an empty bladder.

[0135] The system may also be small enough in the retained configuration to allow intravesical mobility. In particular, the system may be small enough to move within the bladder when deployed, e.g., move freely or unhindered throughout the bladder under most conditions of bladder distension, facilitating patient tolerability of the system. Free movement of the system also promotes uniform drug delivery throughout the bladder.

[0136] The system may also be configured to promote buoyancy by using low density construction materials for the housing components and / or incorporating gas or gas generating materials within the housing, for example, as described in U.S. Patent No. 9,457,176. Generally, the drug loaded dry system may have a density ranging from about 0.5 g / mL to about 1.5 g / mL, e.g., from about 0.7 g / mL to about 1.3 g / mL. In some embodiments, the drug loaded dry system has a density that is less than 1 g / mL.

[0137] In one embodiment, the intravesical drug delivery system is non-bioerodible. In another embodiment, the intravesical drug delivery system can be made to be fully or partially bioerodible, such that explantation or retrieval of the system is not required after release of the drug formulation. In some embodiments, the system is partially bioerodible, such that upon partial disintegration, the system breaks down into non-disintegrating pieces small enough to be excreted from the bladder. For example, the systems described herein can be designed to match the characteristics of those described in U.S. Pat. No. 8,690,840.

[0138] The drug delivery system is sterilized before being inserted into a patient. In one embodiment, the system is sterilized using a suitable process, such as gamma irradiation or ethylene oxide sterilization, although other sterilization processes may be used.

[0139] The systems described herein may include radiopaque portions or structures to facilitate detection or viewing of the system by medical personnel (e.g., by x-ray imaging or fluoroscopy) as part of the implantation and / or retrieval procedure. In one embodiment, the housing is constructed from a material that includes a radiopaque material, such as barium sulfate, or another radiopaque material known in the art. Some housings may be made radiopaque by blending in a radiopaque filler, such as barium sulfate or another suitable material, during processing of the material from which the housing is formed. The radiopaque material may be associated with a retaining frame in embodiments that include a retaining frame. Ultrasound imaging or fluoroscopy may be used to image the system in vivo.

[0140] In some embodiments, the device component of the system comprises a drug-impermeable base material and a drug-permeable stripe material, where the base material is a TPU with 20% BaSO4 filler, such as Lubrizol's Carbothane™ AC-4075A-B20 or Tecothane™ AR-75A-B20. (Lubrizol Life Science, Bethlehem, PA)

[0141] The drug delivery system may further include a retrieval feature, such as a string, loop, or other structure to facilitate removal of the system from the patient. In some cases, the system may be removed from the bladder by engaging the string and pulling the system through the urethra. The system may be configured to assume a relatively narrow or linear shape when pulled by the retrieval feature into the lumen of a catheter or cystoscope, or into the urethra.

[0142] Retention of the system within the body cavity The systems described herein are elastically deformable between a relatively low profile (e.g., straightened or uncoiled) shape suitable for insertion through a patient's lumen into the patient's bladder (or other body cavity) and a relatively expanded retention shape suitable for retaining the system within the bladder (or other body cavity). In certain embodiments, the drug delivery system may naturally assume the retention shape and may be deformed manually or with the assistance of an external device to a relatively straightened shape for insertion into the body. Upon deployment, the device may spontaneously or naturally return to the initial retention shape for retention within the body.

[0143] For purposes of this disclosure, the terms "retained shape" and "relatively expanded shape" and the like generally refer to any shape suitable for retaining the system within an intended implantation location, including, but not limited to, a coiled or "pretzel" shape suitable for retaining the system within the bladder, such as the shapes shown in Figures 1 and 4. Similarly, the terms "deployed shape", "relatively low profile shape", and "relatively straightened shape" and the like generally refer to any shape suitable for deploying the drug delivery system within the body, including, but not limited to, a linear or elongated shape suitable for deploying the system through a working channel of a catheter, cystoscope, or other deployment instrument positioned within a body lumen, such as the urethra, such as the shapes shown in Figures 7A-7B. For example, a 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 shape and directed toward each other when the system is in the relatively expanded retained shape.

[0144] In some embodiments, as shown in Figures 7A-7C, the system further includes a retention frame lumen 734 and a retention frame (not shown) positioned within the retention frame lumen. For example, the retention frame lumen and retention frame can be as described in U.S. Patent Application Publication Nos. 2010 / 0331770, 2010 / 0060309, 2011 / 0202036, and 2011 / 0152839, which are incorporated herein by reference. For example, the retention frame lumen can be sealed with a suitable plug or adhesive material, such as a silicone adhesive material.

[0145] Figure 4 shows the system 300 with a drug tablet 108 loaded into the drug reservoir lumen of the system housing 304. As can be seen in Figure 5, prior to loading the tablet, the retaining frame 305 biases the system housing 304 into a different expanded shape compared to the retained shape achieved when the system is loaded with the drug tablet 108.

[0146] In certain embodiments where increased payload is desired, additional length of drug reservoir lumen / tube may be provided. In one embodiment, as shown in Figures 6A-6B, the retention frame has a periphery defined by two overlapping portions (coils) of a Nitinol lead. Each end of the lead is directed inward from the periphery and includes (i) a curved transition region having a smaller radius of curvature than the periphery of the lead, and (ii) a straight portion terminating in a rounded end cap. In contrast, in the system shown in Figure 5, the retention frame has a periphery defined by a single coil. A system with the retention frame of Figures 6A-6B allows for a relatively longer drug reservoir (e.g., to accommodate more tablets) in a system having the same "footprint" (periphery shape and dimensions) as the system shown in Figure 5.

[0147] In other embodiments, as shown in Figures 1-3, the system does not include a retention frame lumen, or a retention frame or lead. Instead, the housing material is configured to be elastically deformable between a straightened shape and a retained shape in the absence of a retention frame or lead. In such embodiments, the design and manufacture of the system is simplified, and the overall size of the system is minimized (or the drug payload may be increased if the size of the system remains constant). In embodiments without a retention frame, the tubular housing material serves the functions of (i) forming a drug reservoir lumen, (ii) controlling drug release, and (iii) retaining the system within the bladder during deployment.

[0148] For example, the tubular housing may be heat shaped to have the retained shape. Thus, the housing may comprise one or more thermoplastic materials suitable for being thermoformed into the retained shape. In certain embodiments, the drug delivery system includes a tubular housing having a closed drug reservoir lumen bounded by a wall structure comprising at least one thermoplastic material, (i) at least a portion of the wall structure is water permeable and at least a portion of the wall structure is drug permeable, (ii) the tubular housing is elastically deformable from a retained shape suitable for retaining the system in the bladder to a relatively straightened shape suitable for insertion through the lumen into the bladder, and (iii) the tubular wall is thermoformed to have the retained shape.

[0149] In one particular embodiment, the first and second wall structures are each thermoplastic polyurethane, and the tubular housing is thermoformed to have a retained shape. In one embodiment, the tubular wall has a spring constant effective to prevent the system from assuming a relatively straightened shape when implanted in the bladder. Thus, the properties of the tubular wall may cause the system to act as a spring, deforming in response to a compressive load, but spontaneously returning to the initial shape of the system when the load is removed.

[0150] In certain embodiments, the system may naturally assume a retained shape, may deform to a relatively straightened shape, and may spontaneously return to the retained shape upon insertion into the body. The tubular wall structure in the retained shape may be shaped to be retained within a body cavity, and the tubular wall structure in the relatively straightened shape may be shaped to be inserted into the body through a working channel of a deployment instrument, e.g., a catheter or cystoscope. To achieve such a result, the tubular wall structure may have an elastic limit, elastic modulus, and / or spring constant selected to prevent the system from assuming a relatively low profile shape when implanted. Such a configuration may limit or prevent accidental expulsion of the system from the body under anticipated forces. For example, the system may be retained within the bladder during micturition or detrusor contracture.

[0151] In preferred embodiments, the system is elastically deformable between a relatively straightened shape suitable for insertion through a catheter or cystoscope extending through the patient's urethra, and a curved or coiled shape suitable for retaining the system within the bladder after it is released from the end of the catheter or cystoscope (i.e., preventing the system from being expelled from the bladder during urination).

[0152] As shown in FIG. 1, the retention shape may include a coiled or "pretzel" shape. The pretzel shape essentially comprises at least two generally circles, each with its own smaller arch, and sharing a common larger arch. When the pretzel shape is first compressed, the larger arch absorbs most of the compression force and begins to deform, but with continued compression, the smaller arches overlap, after which all three arches resist the compression force. The resistance of the system as a whole to compression increases when the two generally circles overlap, preventing collapse and emptying of the system when the bladder contracts during urination.

[0153] The wall structure in the retaining shape may have a two-dimensional structure confined to a plane, a three-dimensional structure, for example, a structure occupying the interior of a spheroid, or some combination thereof. The retaining shape may comprise one or more loops, curls, or generally circles, connected either linearly or radially, curving in the same or alternating directions, overlapping or non-overlapping. The retaining shape may comprise one or more circles or ellipses arranged in a two-dimensional or three-dimensional configuration, where the circles or ellipses may be either closed or open, may have the same or different sizes, may overlap or not overlap, and may be joined together at one or more connection points. The retaining shape may also be a three-dimensional structure shaped to occupy or wrap around a spheroid-shaped space, for example, a spherical space, a space having a proportional spheroid shape, or a space having an oblate spheroid shape. The wall structure in the retained shape may be shaped to occupy or wrap around a spherical space. The wall structure in the retained shape may have the general shape of two intersecting circles in different planes, two intersecting circles in different planes with inwardly curled ends, three intersecting circles in different planes, or a spherical spiral. In each of these examples, the wall structure may stretch into a linear shape for deployment through a deployment instrument. The wall structure may wrap around or through a spherical or other spheroidal shaped space in a variety of other ways.

[0154] Drug delivery systems using thermoformed and co-extruded tubing with drug-permeable and drug-impermeable portions may integrate three functional components (drug reservoir / housing, drug permeable pathway, and retention feature) into a single thermoformed and co-extruded tubing component, which may simplify the system design and the ability to control drug release rate. As discussed herein, in such systems, drug release rate may be relatively easily modified by controlling the angle and thickness of the drug-permeable portion (e.g., strip) without changing the entire tubing housing material.

[0155] Thermoformed and coextruded tubular housings may be packed with pharmaceutical tablets and both ends may be thermally or adhesively sealed (e.g., with the first wall material). Tablet packing becomes difficult if local tube cross-sectional deformation or tube kinking occurs. Therefore, tube dimensions should be selected to prevent kinking when the tube is being thermoformed. The critical bending radius of curvature (R) of an elastic tube under pure bending conditions is * ) can be approximated using the following formula:

[0156]

number

[0157] Drug tablets As discussed herein with respect to the erdafitinib pharmaceutical formulation, the drug may be provided in a solid form (e.g., solid mini-tablets) suitable for loading into the drug reservoir lumen of the system. In a preferred embodiment, the drug formulation is formed into drug units 108 loaded into the drug reservoir lumen of the system 100, as shown in FIG. 1. Each of the drug units is a separate solid object that substantially retains a selectively imparted shape (at the temperature and pressure conditions to which the drug units (e.g., tablets) and delivery systems are typically exposed during assembly (e.g., loading into the system drug reservoir), storage, and handling prior to in vivo insertion).

[0158] The individual drug units may have essentially any selected shape and size that fits within the system described herein. In one embodiment, the drug units are sized and shaped such that the drug reservoir lumen in the housing is substantially filled by a selected number of the drug units. Each drug unit 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 drug units may be substantially cylindrical in shape for positioning within a substantially cylindrical drug reservoir lumen. When packed, the drug units substantially fill the drug reservoir lumen that, in some embodiments, forms the drug housing portion.

[0159] In one embodiment, the drug units are shaped to align 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 the individual drug units to retain the solid form of the drug unit. Thus, the drug delivery system may be relatively flexible or deformable even when packed with solid drug compositions, for example, tablets, since each drug unit may be allowed to move relative to adjacent drug units.

[0160] In embodiments where the drug unit is designed to be inserted or implanted via a drug delivery system into a lumen or cavity in the body, e.g., the bladder, the drug unit may be a "mini-tablet" suitably sized and shaped for insertion through a natural lumen of the body, e.g., the urethra. For purposes of this disclosure, the term "mini-tablet" generally refers to a solid drug unit that is substantially cylindrical in shape with end faces and sides that are substantially cylindrical. The mini-tablet has a diameter extending along the end face ranging from about 1.0 to about 3.2 mm, e.g., from about 1.5 to about 3.1 mm. The mini-tablet has a length extending along the side 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%. In one aspect, the tablet is as described herein. In one aspect, the tablet is of Formulation 4A. In one aspect, the tablet is of Formulation 4B. In one aspect, the tablet is of Formulation 4C. In one embodiment the tablet is of formulation 4D.

[0161] Methods of Drug Delivery The systems and methods or uses 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.

[0162] 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 the 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 the 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 bacillus calmette-guerin (BCG) naive bladder cancer. In one embodiment, the patient, particularly a human, is a BCG-experienced bladder or NMIBC or MIBC cancer patient. In one embodiment, the patient, particularly a human, is a BCG-naive bladder or NMIBC or MIBC cancer patient. In one embodiment, the patient, particularly a human, is a recurrent 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 aspect, 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 aspect, 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 an MIBC cancer patient scheduled for RCy who has refused or is ineligible for cisplatin-based neoadjuvant chemotherapy.

[0163] In certain embodiments, the urothelial cancers described herein are susceptible to FGFR2 and / or FGFR3 genetic alterations.

[0164] As used herein, "FGFR gene alteration" refers to an alteration in a wild-type FGFR gene, which includes, but is 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 certain embodiments, the FGFR2 or FGFR3 gene alteration is an FGFR gene fusion. "FGFR fusion" or "FGFR gene fusion" refers to a gene that encodes a part of an FGFR (e.g., FGRF2 or FGFR3) and one or a part of one of the fusion partners disclosed herein, which is created by 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 certain embodiments, 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 sequences represent the fusion partners.

[0165] [Table 1]

[0166]

Table 2-1

[0167]

Table 2-2

[0168]

Table 2-3

[0169]

Table 2-4

[0170]

Table 2-5

[0171]

Table 2-6

[0172]

Table 2-7

[0173] 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, can 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.

[0174] [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 often incorrectly referred to as Y375C in the literature.

[0175] In certain embodiments, the method or use for treating urothelial cancer described herein comprises, consists of, or consists essentially of administering the drug delivery system described herein to a patient who has been diagnosed with urothelial cancer described herein and has 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.

[0176] Also described herein is a method or use for treating urothelial cancer as described herein, comprising, consisting of, or consisting essentially of: (a) evaluating a biological sample from a patient having a urothelial cancer 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.

[0177] 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.

[0178] 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 US Patent Application No. 16 / 723,975, which are incorporated herein by reference 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 can 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 can include amplifying cDNA from a patient with 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 can be pre-amplified. In some aspects, the evaluating step can include isolating RNA from the sample, synthesizing cDNA from the isolated RNA, and pre-amplifying the cDNA.

[0179] 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.

[0180] [Table 4]

[0181] 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 thereof.

[0182] 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.

[0183] 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 certain embodiments, the biological sample is a blood sample or a urine sample.

[0184] Methods for identifying and analyzing genetic alterations and protein upregulation are 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 fluorescence in situ hybridization (FISH).

[0185] 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 can 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.In addition, diagnosis of tumors carrying such genetic alterations can be performed using methods such as RT-PCR and FISH, known to those skilled in the art and as described herein.

[0186] In addition, for example, genetic alterations of FGFR can be identified by, for example, direct sequencing of tumor biopsies using PCR and methods for direct sequencing of PCR products as described above. Those skilled in the art will recognize that any such well-known techniques for detecting overexpression, activation or mutation of the above proteins can be applied in the present invention.

[0187] In screening by RT-PCR, the level of mRNA in tumors 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 known to those skilled in the art. Nucleic acid manipulations and PCR are carried out 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., Enzymol., 152:649).

[0188] 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 a 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 to allow specific hybridization with the target nucleic acid under stringent conditions, for example, from about 50, 100, or 200 nucleotides to about 1000 nucleotides or more. Standard methods for performing FISH are described in Fluorescence In Situ Hybridization: Technical Overview by Ausubel, FM et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and John MS Bartlett, Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed. ISBN: 1-59259-760-2; March 2004, pps. 077-088; Series: Methods in Molecular Medicine.

[0189] 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 chemically fragmented according to the protocol described by Affymetrix (Santa Clara, CA, USA) and then hybridized overnight on the Human Genome Array.

[0190] 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, flow cytometry, and other methods 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.

[0191] Abnormal levels of proteins such as FGFR can be measured using standard enzyme assays, such as those described herein. Activation or overexpression can also be detected in tissue samples, such as tumor tissue, by measuring tyrosine kinase activity with an assay, such as an assay from Chemicon International. The tyrosine kinase of interest is immunoprecipitated from the sample lysate and its activity is measured.

[0192] 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.

[0193] Thus, all of these techniques can also be used to identify tumors that are particularly suitable for treatment with the drug delivery system of the present invention.

[0194] 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.

[0195] 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 one embodiment, the drug is released from the drug reservoir lumen via diffusion through the second material of the wall structure. In certain embodiments, the release profile of the drug is substantially independent of pH over a pH range of 5 to 7. In certain embodiments, the release profile of the drug is substantially independent of pH over a pH range of 5.5 to 7. In certain embodiments, the release profile of the drug is substantially independent of pH over a pH range of 5.5 to 8.

[0196] In certain embodiments, allowing the drug to be released from the system includes allowing water to be absorbed through the water-permeable wall portion (e.g., solubilizing the drug only through the second wall structure / material or through both the first and second wall structures / materials) and allowing the solubilized drug to be released from the system by diffusion through the second wall structure / material. That is, in certain embodiments, elution of the drug from the system occurs following dissolution of the drug within the system. Body fluids enter the system, contact the drug, solubilize the drug, and then the dissolved drug diffuses out of the system. For example, the drug may be solubilized upon contact with urine when the system is inserted into the bladder. In one embodiment, releasing the drug from the system includes solubilizing the drug with water or aqueous media, e.g., urine, absorbed through the second wall structure / material or both the first and second wall structures / materials.

[0197] In some embodiments, the device component of the system comprises a water-permeable and drug-impermeable base material and a water-permeable and drug-permeable stripe material. For example, the base material can be a TPU, such as Lubrizol's Carbothane™ AC-4075A or Tecothane™ AR-75A, and the stripe material can be a TPU, such as Lubrizol TECOFLEX™ TPU, such as EG-80A. (Lubrizol Life Science, Bethlehem, Pa.)

[0198] 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 implantation 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 instrument. For example, the system may be deployed into a natural lumen of the body, such as the urethra, or through a deployment instrument, such as a catheter or cystoscope, positioned in a body cavity, such as the bladder. The deployment instrument 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.

[0199] 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 patient's body, e.g., into a body cavity, e.g., 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 cavity. The deployment instrument can be a commercially available system or a system specially adapted for the present drug delivery system. In one embodiment, deploying the drug delivery system into the patient includes (i) elastically deforming the system into a relatively straightened shape, (ii) inserting the system into the patient's urethra, and (iii) releasing the system into the patient's bladder such that the system assumes a coiled retained shape.

[0200] The drug delivery system may pass through the deployment instrument, eg, a lubricant-assisted deployment instrument, until it exits the lumen of the instrument and enters the bladder, driven by a stylet.

[0201] In certain embodiments, the drug delivery system described herein is deployed transurethrally into a patient's bladder using a urinary placement catheter, which comprises two components: a catheter-like shaft and a stylet fitted inside the shaft. The shaft may comprise a single lumen extrusion, which comprises an atraumatic distal tip including a coude bend, an exit port near the distal tip, and an internal lumen extending from the exit port to an open proximal end. Depth markings on the shaft indicate the insertion depth and orientation of the coude tip to aid in the intravesical drug delivery system insertion procedure. The stylet is a single lumen extrusion, which is used to advance the drug delivery system through the transparent shaft lumen and into the bladder.

[0202] When deployed in vivo, the system then releases a drug (e.g., erdafitinib) for the treatment of one or more conditions or diseases locally to tissue at the deployment site. The release is controlled to release an effective amount of drug over an extended period of time. The system may then be removed, reabsorbed, excreted, or some combination thereof. In certain embodiments, the system resides in the bladder releasing drug for a predetermined period of time, for example, 2 weeks, 3 weeks, 4 weeks, 1 month, 2 months, 3 months, or more.

[0203] The deployed system releases a desired amount of drug for a desired, predetermined period of time. In embodiments, the system can deliver a desired dose of drug for an extended period of time, for example, 12 hours, 24 hours, 2 days, 3 days, 5 days, 7 days, 10 days, 14 days, or 20, 25, 30, 45, 60, or 90 days, 6 months, or more. The rate of delivery and dosage of the drug can 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.

[0204] The system may then be retrieved from the body, for example if the system is non-bioerodible or otherwise needs to be removed. Retrieval systems for this purpose may be known in the art or may be specially manufactured. The system may also be fully or partially bioerodible, resorbable, or biodegradable, whereby retrieval is not necessary, either because the entire system is resorbed, or because the system degrades sufficiently to be eliminated from the bladder, for example, during urination. The system may not be retrieved or resorbed until some, or preferably most or all, of the drug has been released. If required, a freshly loaded system may then be implanted during or after the same procedure as the retrieval.

[0205] Methods for Making Drug Delivery Systems The systems described herein are generally formed by using a co-extrusion or 3D printing process to form an elongated elastic housing of the system, loading the drug reservoir lumen with a suitable amount of drug (e.g., a suitable number of drug tablets), and closing the ends of the tubular housing.

[0206] In some embodiments, the tubular wall structure may include a retention lumen extending through or along the structure. The retention lumen may optionally be loaded with an elastic retention frame, such as a nitinol or other superelastic lead, which may then be sealed to keep the frame inside the lumen, and / or the retention lumen may optionally be filled with a gas (e.g., air), which may then be sealed at the end of the retention lumen before or after drug loading of the system. In another embodiment, the retention lumen may be filled with high durometer silicone prior to drug loading of the system, which then hardens into a solid elastic form effective to bias the tubular wall structure in a coiled bladder-retaining shape.

[0207] In other embodiments, the method includes heat shaping the tubular structure to have a coiled retaining shape that is elastically deformable to a non-coiled shape, in such embodiments, the retaining lumen and frame may not be required.

[0208] Some steps or sub-steps of the method of making the drug delivery system may be performed in other orders or simultaneously.

[0209] The present disclosure may be further understood with reference to the following non-limiting examples.

[0210] Embodiment 1. A solid pharmaceutical composition comprising: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of at least 45% by weight of the solid pharmaceutical composition; (b) at least one pharmaceutical excipient. 2. The solid pharmaceutical composition according to embodiment 1, 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, or any combination thereof. 3. The solid pharmaceutical composition according to embodiment 1, wherein the at least one pharmaceutical excipient comprises or is selected from a solubilizer, a binder, a diluent (filler), a glidant, a lubricant, a formaldehyde scavenger, or any combination thereof. 4. A process for making a solid pharmaceutical composition comprising: (a) preparing an intragranular solid composition, the intragranular solid composition comprising: (i) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine); (ii) preparing a pharmaceutical composition comprising, or consisting essentially of, at least one intragranular pharmaceutical excipient; (b) combining the intragranular solid composition with at least one extragranular pharmaceutical excipient to form a blend; (c) compressing the blend to form a solid pharmaceutical composition, wherein the erdafitinib free base is present in a concentration of at least 45% by weight of the solid pharmaceutical composition. 5. The process for making a solid pharmaceutical composition according to embodiment 4, wherein the at least one intragranular pharmaceutical excipient and the at least one extragranular pharmaceutical excipient comprise or are selected from at least one common (present in both) pharmaceutical excipient. 6. A process for making a solid pharmaceutical composition according to embodiment 4, wherein the at least one intragranular excipient and the at least one extragranular pharmaceutical excipient do not comprise a common (present in both) pharmaceutical excipient. 7. A process for making a solid pharmaceutical composition according to any one of embodiments 4 to 6, wherein the intragranular solid composition is prepared by a roller compaction process. 8. A process for making a solid pharmaceutical composition according to any one of embodiments 4 to 6, wherein the intragranular solid composition is prepared by a fluid bed granulation process. 9. A process for making a solid pharmaceutical composition according to any one of embodiments 4 to 8, wherein the at least one extragranular pharmaceutical excipient comprises microcrystalline cellulose and vinylpyrrolidone-vinyl acetate copolymer, particularly in a weight ratio of 50:50. 10. (a) the intragranular solid composition comprises a solubilizer, at least one binder, and a first amount of a lubricant; (b) the extragranular pharmaceutical excipients include a diluent, a lubricant, and a second amount of a lubricant; (c) A process for making a solid pharmaceutical composition according to any one of embodiments 4 to 6, wherein the intragranular solid composition is prepared by a roller compaction process. 11. the solubilizer is hydroxypropyl-beta-cyclodextrin; the binder is a combination of microcrystalline cellulose and vinylpyrrolidone-vinyl acetate copolymer; The lubricant is magnesium stearate, The diluent is anhydrous calcium hydrogen phosphate; 11. The process for making a solid pharmaceutical composition according to embodiment 10, wherein the lubricant is colloidal silicon dioxide. 12. (a) the intragranular solid composition comprises a solubilizer, a diluent, and a disintegrant; (b) the extragranular pharmaceutical excipients include a lubricant and at least one binder; (c) A process for making a solid pharmaceutical composition according to any one of embodiments 4-5, wherein the intragranular solid composition is prepared by a fluid bed granulation process. 13. the solubilizing agent comprises or is selected from hydroxypropyl-beta-cyclodextrin; the diluent comprises or is selected from microcrystalline cellulose; the disintegrant comprises or is selected from hydroxypropyl methylcellulose; at least one binder comprises or is selected from a combination of microcrystalline cellulose and vinylpyrrolidone-vinyl acetate copolymer; 13. The process for making a solid pharmaceutical composition according to embodiment 12, wherein the lubricant comprises or is selected from magnesium stearate. 14. The solid pharmaceutical composition or process for making a solid pharmaceutical composition according to any one of embodiments 1 to 13, wherein erdafitinib free base is present in the solid pharmaceutical composition in a concentration of 45% to 55% by weight, 47% to 53% by weight, or about 50% by weight. 15. The solid pharmaceutical composition or process for making a solid pharmaceutical composition according to any one of embodiments 1 to 13, wherein erdafitinib free base is present in the solid pharmaceutical composition in a concentration of 45% to 55% by weight, 47% to 53% by weight, or about 50% by weight, and the at least one extragranular excipient comprises microcrystalline cellulose and vinylpyrrolidone-vinyl acetate copolymer, particularly in a weight ratio of 50:50. 16. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to any one of embodiments 1 to 15, wherein the solid pharmaceutical composition further comprises a formaldehyde scavenger. 17. The solid pharmaceutical composition or process for making a solid pharmaceutical composition according to embodiment 16, wherein the formaldehyde scavenger comprises or is selected from amino acids, amino sugars, alpha-(α-)amine compounds, conjugates thereof, or any combination thereof. 18. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to embodiment 16, wherein the formaldehyde scavenger comprises or is selected from 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, conjugates thereof, pharma- ceutically acceptable salts thereof, or any combination thereof. 19. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to embodiment 16, wherein the formaldehyde scavenger is meglumine. 20. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to any one of embodiments 16 to 19, wherein the formaldehyde scavenger is 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. 21. A solid pharmaceutical composition comprising a compound of the formula

[0211] [ka] 21. The solid pharmaceutical composition or process for making a solid pharmaceutical composition according to any one of embodiments 1 to 20, further comprising a compound having the formula: 22. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to any one of embodiments 1 to 21, wherein at least one pharmaceutical excipient, at least one intragranular pharmaceutical excipient, or at least one extragranular pharmaceutical excipient comprises a solubilizer. 23. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to embodiment 22, wherein the solubilizer comprises or is selected from (a) cyclic oligosaccharides, (b) cellulose functionalized with methoxy, 2-hydroxypropoxy, acetyl, or succinoyl moieties, or a combination thereof, or (c) a salt thereof. 24. A solid pharmaceutical composition or process for making a solid pharmaceutical composition according to embodiment 22, wherein the solubilizer comprises or is selected from hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, sulfobutylether-beta-cyclodextrin sodium salt, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose E5 (HPMC-E5), or any combination thereof. 25. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to embodiment 22, wherein the at least one pharmaceutical excipient or the at least one intragranular pharmaceutical excipient comprises a solubilizer comprising hydroxypropyl-beta-cyclodextrin. 26. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to any one of embodiments 22 to 25, wherein the total concentration of solubilizer in the solid pharmaceutical composition is between 1% and 20% by weight, between 5% and 15% by weight, between 7% and 12% by weight, or about 10% by weight. 27. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to any one of embodiments 1 to 26, wherein at least one pharmaceutical excipient, at least one intragranular pharmaceutical excipient, or at least one extragranular pharmaceutical excipient comprises or further comprises at least one binder. 28. The solid pharmaceutical composition or process for making a solid pharmaceutical composition according to embodiment 27, wherein at least one binder comprises or is independently selected from a water soluble polymeric binder, a slightly water soluble polymeric binder, a water insoluble polymeric binder, or any combination thereof. 29. The solid pharmaceutical composition or process for making a solid pharmaceutical composition according to embodiment 27, wherein at least one binder comprises or is independently selected from polyvinylpyrrolidone (PVP), poly(vinyl acetate) (PVA), vinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide (PEO), polypropylene oxide (PPO), ethylene glycol-propylene glycol copolymer, poloxamer, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, silicified microcrystalline cellulose, or combinations thereof. 30. A solid pharmaceutical composition or process for making a solid pharmaceutical composition according to embodiment 27, wherein at least one binder comprises or is selected from vinylpyrrolidone-vinyl acetate copolymer, silicified microcrystalline cellulose, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), or any combination thereof. 31. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to embodiment 27, wherein at least one binder comprises or is microcrystalline cellulose. 32. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to embodiment 29 or 30, wherein the vinylpyrrolidone-vinyl acetate copolymer has a molecular weight (Mw) in the range of 45,000 g / mol to 70,000 g / mol. 33. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to any one of embodiments 27 to 32, wherein the total concentration of at least one binder in the solid pharmaceutical composition is from 5% to 30% by weight, from 10% to 25% by weight, from 12% to 22% by weight, or from 14% to 19% by weight. 34. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to any one of embodiments 27 to 33, wherein at least one binder comprises or further comprises vinylpyrrolidone-vinyl acetate copolymer present in the solid pharmaceutical composition in a concentration of 4% to 12% by weight, 6% to 10% by weight, or 7% to 8% by weight. 35. The solid pharmaceutical composition or process for making a solid pharmaceutical composition according to any one of embodiments 27-34, wherein the at least one binder comprises or further comprises: (a) microcrystalline cellulose present in the solid pharmaceutical composition at a concentration of 5% to 20%, 6% to 15%, or 7% to 12% by weight; (b) silicified microcrystalline cellulose present in the solid pharmaceutical composition at a concentration of 3% to 18%, 4% to 15%, or 5% to 12% by weight; or (c) a combination of both (a) and (b). 36. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to any one of embodiments 1 to 35, wherein at least one pharmaceutical excipient, at least one intragranular pharmaceutical excipient, or at least one extragranular pharmaceutical excipient comprises or further comprises a wetting agent. 37. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to embodiment 36, wherein the wetting agent comprises or is an anionic surfactant. 38. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to embodiment 36, wherein the wetting agent comprises or is independently selected from sodium lauryl sulfate, sodium stearyl fumarate, polysorbate 80, docusate sodium, or any combination thereof. 39. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to any one of embodiments 36 to 38, wherein the total concentration of the wetting agent in the solid pharmaceutical composition is 0.01% to 2.5% by weight, 0.05% to 1.0% by weight, or 0.1% to 0.5% by weight. 40. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to any one of embodiments 1 to 39, wherein at least one pharmaceutical excipient, at least one intragranular pharmaceutical excipient, or at least one extragranular pharmaceutical excipient comprises or further comprises a disintegrant. 41. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to embodiment 40, wherein the disintegrant comprises or is independently selected from a functionalized polysaccharide or a crosslinked polymer. 42. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to embodiment 40, wherein the disintegrant comprises or is selected from (a) cellulose functionalized with methoxy, 2-hydroxypropoxy, or carboxymethoxy moieties, their salts, or combinations thereof, (b) carboxymethylated starch, or (c) a crosslinked polymer. 43. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to embodiment 40, wherein the disintegrants comprise or are 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. 44. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to any one of embodiments 40 to 43, wherein the total concentration of the disintegrant in the solid pharmaceutical composition is 0.1% to 3% by weight, 0.5% to 2.5% by weight, 1% to 2% by weight, or about 1.5% by weight. 45. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to any one of embodiments 1 to 44, wherein at least one pharmaceutical excipient, at least one intragranular pharmaceutical excipient, or at least one extragranular pharmaceutical excipient comprises or further comprises a diluent. 46. ​​A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to embodiment 45, wherein the diluent comprises or is selected from sugars, starches, microcrystalline cellulose, sugar alcohols, hydrogen phosphates, dihydrogen phosphates, carbonates, or combinations thereof. 47. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to embodiment 45, wherein the diluent comprises or is selected from lactose (lactose monohydrate), dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, calcium hydrogen phosphate, calcium hydrogen phosphate anhydrous, calcium carbonate, sucrose, or any combination thereof. 48. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to any one of embodiments 45 to 47, wherein the total concentration of diluent in the solid pharmaceutical composition is from 12% to 30% by weight, from 15% to 25% by weight, or from 18% to 22% by weight. 49. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to embodiment 47, wherein the diluent comprises or is selected from anhydrous calcium hydrogen phosphate in a concentration of 18% to 20% by weight. 50. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to embodiment 47, wherein the diluent comprises or is selected from microcrystalline cellulose at a concentration of 20% to 22% by weight. 51. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to any one of embodiments 1 to 50, wherein at least one pharmaceutical excipient, at least one intragranular pharmaceutical excipient, or at least one extragranular pharmaceutical excipient comprises or further comprises a lubricant. 52. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to embodiment 51, wherein the lubricant comprises or is selected from colloidal silicon dioxide, colloidal anhydrous silicon dioxide, talc, or any combination thereof. 53. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to embodiment 51, wherein the lubricant comprises or is colloidal silicon dioxide. 54. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to any one of embodiments 51 to 53, wherein the total concentration of the lubricant in the solid pharmaceutical composition is 0.01% to 5% by weight, 0.05% to 3% by weight, 0.1% to 1% by weight, or about 0.5% by weight. 55. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to any one of embodiments 1 to 54, wherein at least one pharmaceutical excipient, at least one intragranular pharmaceutical excipient, or at least one extragranular pharmaceutical excipient comprises or further comprises a lubricant. 56. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to embodiment 55, wherein the lubricant comprises or is selected from fatty acids, fatty acid salts, fatty acid esters, talc, glyceride esters, metal silicates, or any combination thereof. 57. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to embodiment 55, wherein the lubricant comprises or is selected from magnesium stearate, stearic acid, magnesium silicate, aluminum silicate, isopropyl myristate, sodium oleate, sodium stearoyl lactylate, sodium stearoyl fumarate, titanium dioxide, or a combination thereof. 58. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to embodiment 55, wherein the lubricant comprises or is magnesium stearate. 59. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to any one of embodiments 55 to 58, wherein the total concentration of the lubricant in the solid pharmaceutical composition is 0.05% to 5% by weight, 0.1% to 3% by weight, 1% to 2% by weight, or about 1.5% by weight. 60. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to any one of embodiments 1 to 59, wherein the solid pharmaceutical composition is a mini-tablet. 61. A solid pharmaceutical composition or process for making a solid pharmaceutical composition according to embodiment 60, wherein the mini-tablets are in the form of a solid cylinder, the solid cylinder having a cylindrical axis, a cylindrical side surface, a circular end surface perpendicular to the cylindrical axis, a diameter across the circular end surface, and a length along the cylindrical side surface. 62. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to embodiment 61, wherein the length of the mini-tablets exceeds the diameter of the mini-tablets so as to provide mini-tablets with an aspect ratio (length:diameter) of more than 1:1. 63. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to embodiment 61 or 62, wherein the mini-tablets have a diameter of 1.0 mm to 3.2 mm or 1.5 mm to 3.1 mm. 64. A solid pharmaceutical composition or a process for making a solid pharmaceutical composition according to any one of embodiments 61 to 63, wherein the mini-tablets have a length of 1.7 mm to 4.8 mm or 2.0 mm to 4.5 mm. 65. A solid pharmaceutical composition comprising: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50% by weight of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin at a concentration of 10% by weight of the solid pharmaceutical composition; (c) meglumine at a concentration of 1% by weight of the solid pharmaceutical composition; and (d) microcrystalline cellulose at a concentration of 10% by weight of the solid pharmaceutical composition; (e) anhydrous calcium dibasic phosphate in a concentration of 19% by weight of the solid pharmaceutical composition; (f) vinylpyrrolidone-vinyl acetate copolymer at a concentration of 8% by weight of the solid pharmaceutical composition; (g) colloidal silicon dioxide at a concentration of 0.5% by weight of the solid pharmaceutical composition; (h) magnesium stearate in a concentration of 1.50% by weight of the solid pharmaceutical composition; or 1. A solid pharmaceutical composition comprising: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50% by weight of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin; and (c) meglumine, (d) microcrystalline cellulose; (e) anhydrous calcium hydrogen phosphate; (f) vinylpyrrolidone-vinyl acetate copolymer; and (g) colloidal silicon dioxide; (h) magnesium stearate. 66. A solid pharmaceutical composition comprising: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50% by weight of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin at a concentration of 10% by weight of the solid pharmaceutical composition; (c) meglumine at a concentration of 1% by weight of the solid pharmaceutical composition; and (d) microcrystalline cellulose at a concentration of 24.5% by weight of the solid pharmaceutical composition; (e) silicified microcrystalline cellulose at a concentration of 6.0% by weight of the solid pharmaceutical composition; (f) vinylpyrrolidone-vinyl acetate copolymer at a concentration of 6.0% by weight of the solid pharmaceutical composition; (g) colloidal silicon dioxide at a concentration of 0.5% by weight of the solid pharmaceutical composition; (h) magnesium stearate at a concentration of 2.0% by weight of the solid pharmaceutical composition; or 1. A solid pharmaceutical composition comprising: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50% by weight of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin; and (c) meglumine, (d) microcrystalline cellulose; (e) silicified microcrystalline cellulose; (f) vinylpyrrolidone-vinyl acetate copolymer; and (g) colloidal silicon dioxide; (h) magnesium stearate. 67. A solid pharmaceutical composition comprising: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50% by weight of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin at a concentration of 10% by weight of the solid pharmaceutical composition; (c) meglumine at a concentration of 1% by weight of the solid pharmaceutical composition; and (d) hydroxypropyl methylcellulose at a concentration of 1.5% by weight of the solid pharmaceutical composition; (e) mannitol in a concentration of 21.0% by weight of the solid pharmaceutical composition; (f) sodium lauryl sulfate at a concentration of 0.25% by weight of the solid pharmaceutical composition; (g) microcrystalline cellulose at a concentration of 7.25% by weight of the solid pharmaceutical composition; (h) vinylpyrrolidone-vinyl acetate copolymer at a concentration of 7.25% by weight of the solid pharmaceutical composition; (i) colloidal silicon dioxide at a concentration of 0.25% by weight of the solid pharmaceutical composition; (j) magnesium stearate in a concentration of 1.50% by weight of the solid pharmaceutical composition; or 1. A solid pharmaceutical composition comprising: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50% by weight of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin; and (c) meglumine, (d) hydroxypropyl methylcellulose; (e) mannitol, (f) sodium lauryl sulfate; (g) microcrystalline cellulose; (h) vinylpyrrolidone-vinyl acetate copolymer; and (i) colloidal silicon dioxide; (j) magnesium stearate. 68. A solid pharmaceutical composition comprising: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50% by weight of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin at a concentration of 10% by weight of the solid pharmaceutical composition; (c) meglumine at a concentration of 1% by weight of the solid pharmaceutical composition; and (d) microcrystalline cellulose at a concentration of 17.5% by weight of the solid pharmaceutical composition; (e) silicified microcrystalline cellulose at a concentration of 10.75% by weight of the solid pharmaceutical composition; (f) vinylpyrrolidone-vinyl acetate copolymer at a concentration of 7.5% by weight of the solid pharmaceutical composition; (g) colloidal silicon dioxide at a concentration of 0.25% by weight of the solid pharmaceutical composition; and (h) hydroxypropyl methylcellulose at a concentration of 1.5% by weight of the solid pharmaceutical composition; (i) magnesium stearate at a concentration of 1.5% by weight of the solid pharmaceutical composition; or 1. A solid pharmaceutical composition comprising: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50% by weight of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin; and (c) meglumine, (d) microcrystalline cellulose; (e) silicified microcrystalline cellulose; (f) vinylpyrrolidone-vinyl acetate copolymer; and (g) colloidal silicon dioxide; (h) hydroxypropyl methylcellulose; (i) magnesium stearate. 69. A process for making a solid pharmaceutical composition, comprising: (a) preparing an intragranular solid composition by a roller compaction process, the intragranular solid composition comprising: (i) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50% by weight of the solid pharmaceutical composition; (ii) hydroxypropyl-beta-cyclodextrin at a concentration of 10% by weight of the solid pharmaceutical composition; (iii) meglumine at a concentration of 1% by weight of the solid pharmaceutical composition; and (iv) microcrystalline cellulose at a concentration of 10% by weight of the solid pharmaceutical composition; (v) vinylpyrrolidone-vinyl acetate copolymer at a concentration of 8% by weight of the solid pharmaceutical composition; (vi) magnesium stearate at a concentration of 0.75% by weight of the solid pharmaceutical composition; (b) combining the intragranular solid composition with an extragranular component to form a blend, the extragranular component comprising: (i) anhydrous calcium dibasic phosphate in a concentration of 19% by weight of the solid pharmaceutical composition; (ii) colloidal silicon dioxide at a concentration of 0.5% by weight of the solid pharmaceutical composition; and (iii) forming a solid pharmaceutical composition consisting essentially of magnesium stearate at a concentration of 0.75% by weight of the solid pharmaceutical composition; (c) compressing the blend to form a solid pharmaceutical composition in the form of mini-tablets. 70. A process for making a solid pharmaceutical composition, comprising: (a) preparing an intragranular solid composition by a roller compaction process, the intragranular solid composition comprising: (i) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50% by weight of the solid pharmaceutical composition; (ii) hydroxypropyl-beta-cyclodextrin at a concentration of 10% by weight of the solid pharmaceutical composition; (iii) meglumine at a concentration of 1% by weight of the solid pharmaceutical composition; and (iv) microcrystalline cellulose at a concentration of 24.5% by weight of the solid pharmaceutical composition; (v) colloidal silicon dioxide at a concentration of 0.2% by weight of the solid pharmaceutical composition; and (vi) magnesium stearate at a concentration of 0.75% by weight of the solid pharmaceutical composition. (b) combining the intragranular solid composition with an extragranular component to form a blend, the extragranular component comprising: (i) silicified microcrystalline cellulose at a concentration of 6.0% by weight of the solid pharmaceutical composition; (ii) vinylpyrrolidone-vinyl acetate copolymer at a concentration of 6.0% by weight of the solid pharmaceutical composition; (iii) colloidal silicon dioxide at a concentration of 0.3% by weight of the solid pharmaceutical composition; and (iv) magnesium stearate at a concentration of 1.25% by weight of the solid pharmaceutical composition; (c) compressing the blend to form a solid pharmaceutical composition in the form of mini-tablets. 71. A process for making a solid pharmaceutical composition, comprising: (a) preparing an intragranular solid composition by a fluid bed granulation process, the intragranular solid composition comprising: (i) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50% by weight of the solid pharmaceutical composition; (ii) hydroxypropyl-beta-cyclodextrin at a concentration of 10% by weight of the solid pharmaceutical composition; (iii) meglumine at a concentration of 1% by weight of the solid pharmaceutical composition; and (iv) mannitol in a concentration of 21% by weight of the solid pharmaceutical composition; and (v) sodium lauryl sulfate at a concentration of 0.25% by weight of the solid pharmaceutical composition; and (vi) hydroxypropyl methylcellulose at a concentration of 1.5% by weight of the solid pharmaceutical composition; (b) combining the intragranular solid composition with an extragranular component to form a blend, the extragranular component comprising: (i) microcrystalline cellulose at a concentration of 7.25% by weight of the solid pharmaceutical composition; (ii) vinylpyrrolidone-vinyl acetate copolymer at a concentration of 7.25% by weight of the solid pharmaceutical composition; (iii) colloidal silicon dioxide at a concentration of 0.25% by weight of the solid pharmaceutical composition; and (iv) forming a solid pharmaceutical composition consisting essentially of magnesium stearate in a concentration of 1.50% by weight of the solid pharmaceutical composition; (c) compressing the blend to form a solid pharmaceutical composition in the form of mini-tablets. 72. A process for making a solid pharmaceutical composition, comprising: (a) preparing an intragranular solid composition by a fluid bed granulation process, the intragranular solid composition comprising: (i) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of 50% by weight of the solid pharmaceutical composition; (ii) hydroxypropyl-beta-cyclodextrin at a concentration of 10% by weight of the solid pharmaceutical composition; (iii) meglumine at a concentration of 1% by weight of the solid pharmaceutical composition; and (iv) microcrystalline cellulose at a concentration of 10% by weight of the solid pharmaceutical composition; (v) hydroxypropyl methylcellulose at a concentration of 1.5% by weight of the solid pharmaceutical composition; (b) combining the intragranular solid composition with an extragranular component to form a blend, the extragranular component comprising: (i) microcrystalline cellulose at a concentration of 7.5% by weight of the solid pharmaceutical composition; (ii) vinylpyrrolidone-vinyl acetate copolymer at a concentration of 7.5% by weight of the solid pharmaceutical composition; (iii) silicified microcrystalline cellulose at a concentration of 10.75% by weight of the solid pharmaceutical composition; (iv) colloidal silicon dioxide at a concentration of 0.25% by weight of the solid pharmaceutical composition; and (iv) magnesium stearate at a concentration of 1.5% by weight of the solid pharmaceutical composition; (c) compressing the blend to form a solid pharmaceutical composition in the form of mini-tablets. 73. a housing defining a closed drug reservoir lumen bounded by a first wall structure formed from a first material and a second wall structure formed from a second material, the first wall structure and the second wall structure abutting one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprising an aliphatic polyether-based thermoplastic polyurethane; A drug delivery system comprising: a drug formulation disposed within a closed drug reservoir lumen, the drug formulation comprising a drug, A drug delivery system, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the drug and the second wall structure is permeable to the drug, whereby the drug is releasable in vivo by diffusion through the second material forming the second wall structure. 74. a housing defining a closed drug reservoir lumen bounded by a first wall structure formed from a first material and a second wall structure formed from a second material, the first wall structure and the second wall structure adjacent one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the first material comprising an aromatic polyester hydrocarbon-based thermoplastic polyurethane and the second material comprising an aliphatic polyether-based thermoplastic polyurethane; A drug delivery system comprising: a drug formulation disposed within a closed drug reservoir lumen, the drug formulation comprising a drug, A drug delivery system, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the drug and the second wall structure is permeable to the drug, such that the drug is releasable in vivo by diffusion through the second wall structure. 75. A drug delivery system as described in embodiment 73 or 74, wherein the second wall structure forms a longitudinal strip extending along the length of the tube. 76. A system according to any one of embodiments 73 to 75, wherein the system is configured to release a therapeutically effective amount of the drug at a substantially zero order release rate over a period of at least 36 hours. 77. A system described in any one of embodiments 73 to 76, wherein the system is configured to release the drug over a period of 2 days to 6 months. 78. A system according to any one of embodiments 73 to 77, wherein the two interface edges are arranged at an arc angle of 15 degrees to 270 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. 79. The system of any one of embodiments 73 to 78, wherein the drug comprises erdafitinib, in particular erdafitinib. 80. The system of embodiment 79, wherein the system is configured to release erdafitinib at an average rate of 1 mg / day to 10 mg / day. 81. The system of embodiment 79, wherein the system is configured to release erdafitinib at an average rate of 1 mg / day to 2 mg / day. 82. The system of embodiment 81, wherein the two interface edges are disposed at an arc angle of 45 degrees to 90 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. 83. The system of embodiment 79, wherein the system is configured to release erdafitinib at an average rate of 4 mg / day to 6 mg / day. 84. The system of embodiment 83, wherein the two interface edges are disposed at an arc angle of 150 degrees to 270 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. 85. The system of embodiment 79, wherein the system is configured to release erdafitinib at an average rate of 1 mg / day. 86. The system of embodiment 85, wherein the two interface edges are disposed at an arc angle of about 45 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. 87. The system of embodiment 79, wherein the system is configured to release erdafitinib at an average rate of 2 mg / day. 88. The system of embodiment 87, wherein the two interface edges are disposed at an arc angle of about 90 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. 89. The system of embodiment 79, wherein the system is configured to release erdafitinib at an average rate of 4 mg / day. 90. The system of embodiment 89, wherein the two interface edges are disposed at an arc angle of about 180 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. 91. The system of embodiment 79, wherein the system is configured to release erdafitinib at an average rate of 6 mg / day. 92. The system of embodiment 91, wherein the two interface edges are disposed at an arc angle of 210 degrees to 270 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. 93. The system of any one of embodiments 79-92, wherein the system comprises 500 mg of erdafitinib. 94. A system according to any one of embodiments 73 to 93, wherein the release profile of the drug is substantially independent of pH over a pH range of 5 to 7. 95. The system of any one of embodiments 73-94, wherein the second wall structure constitutes less than 50 percent of the cross-sectional area of ​​the tube in a cross section perpendicular to the longitudinal axis of the tube. 96. A system according to any one of embodiments 73-94, wherein the second wall structure constitutes less than 25 percent of the cross-sectional area of ​​the tube in a cross section perpendicular to the longitudinal axis of the tube. 97. The system of any one of embodiments 73-96, wherein the tube has a substantially constant thickness around the circumference of the tube. 98. The system of any one of embodiments 73 to 97, further comprising a pair of end plugs and / or adhesive material for sealing the ends of the tube. 99. The system of any one of embodiments 73 to 98, wherein the first wall structure and the second wall structure are integrally formed. 100. The system of embodiment 99, wherein the tube is formed in an extrusion process. 101. A system described in any one of embodiments 73 to 100, 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. 102. A system described in any one of embodiments 73 to 101, wherein the system is elastically deformable and has overlapping curls formed by a tube, the 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. 103. A system described in any one of embodiments 73 to 102, wherein the system is elastically deformable, has a bi-elliptical retaining shape, and the tube has two opposing free ends located within the outer boundary of the bi-elliptical retaining shape. 104. The system of any one of embodiments 73 to 103, further comprising a retaining frame lumen. 105. The system of embodiment 104, further comprising a Nitinol lead disposed within the retaining frame lumen. 106. The system of any one of embodiments 73 to 105, wherein the first material has a Shore durometer value of 70A to 80A. 107. The system of any one of embodiments 73 to 106, wherein the second material has a Shore durometer value of 70A to 75A. 108. The system according to any one of embodiments 73 to 107, wherein the drug formulation comprises a solid pharmaceutical composition according to any one of embodiments 1, 2, 3, and 14 to 68. 109. The system of any one of embodiments 73 to 108, wherein the drug formulation is in the form of a plurality of mini-tablets arranged consecutively within the drug lumen. 110. The system of embodiment 109, wherein the plurality of mini-tablets comprises a mini-tablet according to any one of embodiments 60 to 64. 111. a housing defining a drug reservoir lumen bounded by a first wall structure formed from a first material and a second wall structure formed from a second material, the first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprising an aliphatic polyether-based thermoplastic polyurethane; a drug formulation disposed within a drug reservoir lumen, the drug formulation comprising erdafitinib; A drug delivery system, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, such that erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure. 112. The system of embodiment 111, wherein the first wall structure and the second wall structure are adjacent to each other at two interface edges and together form a tube, and (i) the system is configured to release erdafitinib at an average rate of 2 mg / day and the two interface edges are disposed at an arc of about 90 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, (ii) the system is configured to release erdafitinib at an average rate of 4 mg / day and the two interface edges are disposed at an arc of about 180 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, or (iii) the system is configured to release erdafitinib at an average rate of 6 mg / day and the two interface edges are disposed at an arc of 240 degrees. 113. a housing defining a drug reservoir lumen bounded by a first wall structure formed from a first material and a second wall structure formed from a second material, the first material comprising an aromatic polyester hydrocarbon-based thermoplastic polyurethane and the second material comprising an aliphatic polyether-based thermoplastic polyurethane; a drug formulation disposed within a closed drug reservoir lumen, the drug formulation comprising erdafitinib; A drug delivery system, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, such that erdafitinib is releasable in vivo by diffusion through the second wall structure. 114. The system of embodiment 113, wherein the first wall structure and the second wall structure are adjacent to each other at two interface edges and together form a tube, and (i) the system is configured to release erdafitinib at an average rate of 2 mg / day and the two interface edges are disposed at an arc of about 90 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, or (ii) the system is configured to release erdafitinib at an average rate of 4 mg / day and the two interface edges are disposed at an arc of about 180 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. 115. A system described in any one of embodiments 111 to 114, wherein the system is elastically deformable and has overlapping curls formed by a tube, the 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. 116. A system according to any one of embodiments 111 to 115, wherein the release profile of erdafitinib is substantially independent of pH over a pH range of 5 to 7. 117. a housing defining a closed drug reservoir lumen bounded by a first wall structure formed from a first material and a second wall structure formed from a second material, the first wall structure and the second wall structure abutting one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the second wall structure forming a longitudinal strip extending along the length of the tube, the first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprising an aliphatic polyether-based thermoplastic polyurethane; A drug delivery system comprising: a drug formulation disposed within a closed drug reservoir lumen, the drug formulation comprising a solid pharmaceutical composition according to any one of embodiments 1, 2, 3, and 14-68; (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water; (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, whereby erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure; the system is configured to release a therapeutically effective amount of erdafitinib at a substantially zero order release rate over at least three days; A drug delivery system, wherein: (i) the system is configured to release erdafitinib at an average rate of 2 mg / day and the two interface edges are disposed at an arc of about 90 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube; (ii) the system is configured to release erdafitinib at an average rate of 4 mg / day and the two interface edges are disposed at an arc of about 180 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube; or (iii) the system is configured to release erdafitinib at an average rate of 6 mg / day and the two interface edges are disposed at an arc of 240 degrees. 118. a housing defining a closed drug reservoir lumen bounded by a first wall structure formed from a first material and a second wall structure formed from a second material, the first wall structure and the second wall structure abutting one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the second wall structure forming a longitudinal strip extending along the length of the tube, the first material comprising an aromatic polyester hydrocarbon-based thermoplastic polyurethane and the second material comprising an aliphatic polyether-based thermoplastic polyurethane; A drug delivery system comprising: a drug formulation disposed within a closed drug reservoir lumen, the drug formulation comprising a solid pharmaceutical composition according to any one of embodiments 1, 2, 3, and 14-68; (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water; (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, such that erdafitinib can be released in vivo by diffusion through the second wall structure; the system is configured to release a therapeutically effective amount of erdafitinib at a substantially zero order release rate over at least three days; A drug delivery system, wherein (i) the system is configured to release erdafitinib at an average rate of 2 mg / day and the two interface edges are disposed at an arc of about 90 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, or (ii) the system is configured to release erdafitinib at an average rate of 4 mg / day and the two interface edges are disposed at an arc of about 180 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. 119. A method for treating bladder cancer, comprising locally delivering erdafitinib to the bladder of a patient in need of treatment in an amount effective to treat bladder cancer. 120. The method of embodiment 119, wherein the bladder cancer is muscle-invasive bladder cancer. 121. The method of embodiment 119, wherein the bladder cancer is non-muscle invasive bladder cancer. 122. The method of embodiment 119, wherein the bladder cancer is bacillus Calmette-Guerin (BCG) naive. 123. The method according to any one of embodiments 119-122, wherein erdafitinib is in the form of a solid pharmaceutical composition according to any one of embodiments 1, 2, 3, and 14-68. 124. A method for intravesical administration of erdafitinib, comprising: Deploying an intravesical system in the patient's bladder, the system comprising a solid pharmaceutical composition according to any one of embodiments 1, 2, 3, and 14-68; and releasing erdafitinib from the system. 125. The method of embodiment 124, wherein the intravesical system is a drug delivery system described in any one of embodiments 73 to 118, and releasing erdafitinib from the system comprises releasing erdafitinib from the drug reservoir lumen via diffusion through the second wall structure. 126. The method of embodiment 124 or 125, wherein the system is elastically deformed into a low-profile deployed shape, inserted through the urethra into the patient's bladder, and then assumes a relatively expanded retained shape within the bladder. 127. a device configured for intravesical deployment; A drug delivery system comprising: a drug formulation disposed within the device, the drug formulation comprising erdafitinib; A drug delivery system, wherein the system is configured to release erdafitinib from the device following intravesical deployment of the drug delivery system. 128. The drug delivery system of embodiment 127, wherein the drug formulation comprises a plurality of tablets containing erdafitinib. 129. The drug delivery system of embodiment 128, wherein the tablet comprises a solid pharmaceutical composition of any one of embodiments 1, 2, 3, and 14 to 68. 130. A drug delivery system according to any one of embodiments 127-129, wherein the system is configured to release erdafitinib by diffusion through a drug-permeable portion of the device. 131. A drug delivery system according to any one of embodiments 127 to 130, wherein the system is configured to release erdafitinib at a release rate of about 1 mg / day to about 6 mg / day, for example, 2 to 4 mg / day. 132. A method for treating non-muscle invasive bladder cancer (NMIBC) or muscle invasive bladder cancer (MIBC) in a cancer patient, comprising: A method comprising locally delivering a therapeutically effective amount of erdafitinib into the bladder of a patient. 133. The method of embodiment 132, wherein locally delivering erdafitinib comprises releasing erdafitinib from an intravesical system at a release rate of about 1 mg / day to about 6 mg / day, for example, 2 to 4 mg / day. 134. The method of embodiment 133, wherein the intravesical system is maintained in the patient's bladder for up to 90 days and then, optionally, replaced with another erdafitinib-releasing intravesical system. 135. A method for 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 to T3a muscle invasive urothelial carcinoma of the bladder in a cancer patient, comprising: A method comprising locally delivering a therapeutically effective amount of erdafitinib into the bladder of a patient. 136. The method of embodiment 131, wherein the patient undergoes transurethral resection of bladder tumor (TURBT) to reduce total tumor size to 3 cm or less, and then erdafitinib is delivered locally into the bladder. 137. The method of embodiment 135 or 136, wherein locally delivering erdafitinib comprises releasing erdafitinib from an intravesical system at a release rate of about 1 mg / day to about 6 mg / day, for example, 2 to 4 mg / day. 138. The method of embodiment 137, wherein the intravesical system is maintained in the patient's bladder for up to 90 days and then, optionally, replaced with another erdafitinib-releasing intravesical system. 139. A method of treating Bacillus Calmette-Guerin (BCG)-experienced patients 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 into the bladder of a patient. 140. The method of embodiment 139, wherein locally delivering erdafitinib comprises releasing erdafitinib from an intravesical system at a release rate of about 1 mg / day to about 6 mg / day, for example, 2 to 4 mg / day. 141. The method of embodiment 140, wherein the intravesical system is maintained in the patient's bladder for up to 90 days and then, optionally, replaced with another erdafitinib-releasing intravesical system. 142. The method of any one of embodiments 132-141, wherein erdafitinib is locally delivered into the bladder from a drug delivery system described in any one of embodiments 127-131. 143. The method of any one of embodiments 132-142, wherein the patient carries at least one FGFR2 genetic alteration and / or FGFR3 genetic alteration. EXAMPLES

[0212] The following examples are intended to be purely illustrative of the present invention and therefore should not be construed as limiting the present invention in any way. The following examples and detailed description are offered by way of illustration and not by way of limitation.

[0213] Organ-confined bladder cancer represents a global unmet need, as reflected by its high incidence and limited improvements in treatment over the past two decades. Globally, bladder cancer is the 6th and 17th most commonly occurring cancer in men and women, respectively. There were nearly 550,000 new cases of bladder cancer diagnosed worldwide in 2018. Most bladder cancer is diagnosed early in the disease stage, with 70%-75% presenting as non-muscle invasive bladder cancer (NMIBC) and 25%-30% presenting as muscle invasive bladder cancer (MIBC).

[0214] Disease progression is a devastating, life-changing event that often results in bladder removal for patients eligible for surgery. After surgery, for the majority of patients who are not suitable for surgery, the tumor often recurs and progresses to metastatic disease, where the 5-year survival rate is 5%. New therapies are particularly difficult to develop because only a small fraction of systemically administered drugs reach tumors located in the urothelium. Thus, there is a significant need for new targeted therapies to treat early disease and prevent progression to invasive forms of bladder cancer.

[0215] Example 1. Sample mini-tablet formulation Table 1 illustrates selected aspects and embodiments of mini-tablet formulations for use with the disclosed drug delivery system. The following tablets were prepared with a loading of 11.5 mg of API drug to provide a 23.0 mg tablet.

[0216] [Table 5]

[0217] Intragranular solid compositions of Formula 4A and Formula 4B were prepared by roller compaction process. Intragranular solid compositions of Formula 4C and Formula 4D were prepared by fluid bed granulation process.

[0218] In one embodiment, the exemplary formulations shown herein can be prepared by any method.For example, the intragranular solid composition can be prepared by roller compaction process, fluidized bed granulation process, or other process.In one embodiment, the intragranular solid composition of Formula 4A and Formula 4B can be prepared by roller compaction process.In a further embodiment, the intragranular solid composition of Formula 4C and Formula 4D can be prepared by fluidized bed granulation process.

[0219] Example 2. Tablet manufacturing evaluation of roller compaction versus fluid bed granulation. Several manufacturing modes were investigated and the concepts of roller compaction (RC) versus fluid bed granulation (FBG) were compared for tablet manufacturing. As shown in this example, certain performance characteristics or criteria are necessary for the adaptation of a formulation to high speed tableting.

[0220] Tablet ejection forces resulting from roller compaction (RC) and fluid bed granulation (FBG) processes were investigated. Lower ejection forces were observed for the FBG process. In RC tablets, the ejection force was higher, which poses a potential risk of process interruption, especially in the case of high speed tableting.

[0221] In-process controls were within specification for both RC and FBG methods, but showed greater variability (higher relative standard deviation, RSD) in the RC tablets.

[0222] It was found that higher production rates were more achievable in the FBG batch. For example, the FBG tablet batch could be run at a high speed of about 2500 tablets / min (tablets per minute) or 6 hours / 20 kg run. In contrast, the RC tablet batch could be run at a moderate speed of about 1800 tablets / min or 9 hours / 20 kg run, since higher production rates were not achievable due to the higher ejection force.

[0223] The FBG process was generally a more robust method compared to the RC process: no flashing or tablet defects were observed in the FBG tablet batches, whereas the RC tablets tended to break and "round up" more easily during system construction, and flashing was observed towards the end of the run with the RC tablets.

[0224] Tablets of formulations 4A and 4B described in Table 1 were prepared by roller compaction (RC) process. Tablets of formulations 4C and 4D described in Table 1 were prepared by fluidized bed granulation (FBG) process. In contrast to tablets of formulations 4A and 4B, tablets of formulations 4C and 4D fluidized bed granulation (FBG) could be produced at higher production speeds due to lower ejection force, and the resulting tablets were more robust and less susceptible to breakage.

[0225] The compounded 4A formulation tablets were prepared by the RC process as follows. 1. The following components of the intragranular phase were pre-blended: microcrystalline cellulose, erdafitinib, hydroxypropyl beta cyclodextrin, meglumine, and anhydrous colloidal silica. 2. The preblend from step 1 was screened. 3. The sieved pre-blend is blended using a suitable blender to obtain a homogenous blend. 4. Sieved magnesium stearate is blended into the blend and mixed using a suitable blender to obtain a homogenous blend. 5. Roller compaction was carried out to obtain granules. 6. The following components of the granular outer phase were pre-blended: silicified microcrystalline cellulose, copovidone, anhydrous colloidal silica. 7. The preblend from step 6 was screened. 8. The sieved mixture is added to the granules and mixed using a suitable blender to obtain a homogenous blend. 9. Sieved magnesium stearate is added to the blend and mixed using a suitable blender to obtain a homogenous blend. 10. The blend is compressed into mini tablets using a suitable tablet press and the tablets are passed through a dust remover and a metal detector. 11. The mini tablets were packaged in a suitable packaging configuration.

[0226] Formulation 4B formulation tablets were prepared following a process similar to that of Formulation 4A.

[0227] The compounded 4D formulation tablets were prepared by a fluid bed granulation process as follows. 1. The sieved components of the intragranular phase, Erdafitinib, Meglumine, Hydroxypropyl beta cyclodextrin, Microcrystalline cellulose were pre-blended using a suitable blender to obtain a homogenous blend. 2. Binder solution was made by dissolving Hypromellose 2910 15 mPa.s in Water for Injection until a clear solution with no lumps was obtained. 3. Fluid bed granulation was carried out. 4. The granules were sieved using a suitable sieve. 5. The following sieved ingredients Copovidone, Microcrystalline Cellulose, Silicified Microcrystalline Cellulose, Anhydrous Colloidal Silica are added to the granules and mixed using a suitable blender to obtain a homogenous blend. 6. Sieved magnesium stearate is added to the blend and further mixed using a suitable blender. 7. The blend is compressed into mini tablets using a suitable tablet press and de-dusted. 8. The mini tablets were packaged in a suitable packaging configuration.

[0228] Formulation 4C tablets were prepared following a process similar to that of formulation 4D.

[0229] Example 3. Further exemplary Erdafitinib formulations The following erdafitinib formulations shown in Tables 2 and 3 were prepared and investigated for suitability for tablet formation. Tablets based on these formulations were prepared with a loading of 11.5 mg of API drug to provide 23.0 mg tablets.

[0230] [Table 6]

[0231] [Table 7]

[0232] Compression studies of the above formulations were carried out for each of the formulations using a fluid bed granulation process.

[0233] Component 4.1 Formulation Tablets were prepared by a fluid bed granulation process as follows. 1. The sieved components of the intragranular phase, Erdafitinib, Hydroxypropyl beta cyclodextrin, Microcrystalline cellulose were pre-blended using a suitable blender to obtain a homogenous blend. 2. Binder solution was made by dissolving Hypromellose 2910 15 mPa.s in Water for Injection until a clear solution with no lumps was obtained. 3. Fluid bed granulation was carried out. 4. The granules were sieved using a suitable sieve. 5. The following sieved ingredients Copovidone, Microcrystalline Cellulose, Silicified Microcrystalline Cellulose, Anhydrous Colloidal Silica are added to the granules and mixed using a suitable blender to obtain a homogenous blend. 6. Sieved magnesium stearate is added to the blend and further mixed using a suitable blender. 7. The blend is compressed into mini tablets using a suitable tablet press and de-dusted. 8. The mini tablets were packaged in a suitable packaging configuration.

[0234] Data was also obtained on the tablet hardness resulting from intermittent air compression for each of formulations 1.1-4.1. Tablet thickness resulting from intermittent air compression for each of formulations 1.1-4.1 was also studied. These data suggest that tablet hardness and thickness remained relatively consistent for these formulations.

[0235] Example 4. Process monitoring control of compression force and ejection force for Erdafitinib formulations Compressive force and ejection force process monitoring control considerations for erdafitinib test formulations were investigated and compared with formulations 4B and 4C with formulations 1.1, 2.2, 3.4 and 4.1. (See Tables 2 and 3 above.)

[0236] Example 5. Screening of permeable materials and API forms for erdafitinib release Several polymeric materials were tested to determine their suitability as construction materials for the elastic system body for the release of various erdafitinib formulations in a permeation controlled release system. The materials included silicone, several thermoplastic polyurethanes (TPUs) manufactured by Lubrizol Life Science (Bethlehem, PA). The results are listed in Table 4.

[0237] [Table 8]

[0238] In Table 4, "O" is permeable (suitable for striped materials), "Δ" is substantially impermeable, and "X" is impermeable (suitable for base materials, i.e., non-striped portions of the system body).

[0239] Based in part on the results above, prototype system compositions were tested with erdafitinib free base and erdafitinib free base + 10% HP-β-CD.The system compositions were extruded tubes of two materials (strip + base) and then assembled with certain of the erdafitinib formulations and the release rates were tested in vitro in simulated urine at various pH levels.The results are listed in Table 5.

[0240] [Table 9]

[0241] Based on these results, the preferred permeation system appears to be a combination of AC-4075A-B20 (or AR-62A)-based and EG-80A stripe device constructs with a drug formulation containing erdafitinib-based + 10% HP-β-CD.

[0242] Example 6. 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.

[0243] In vitro protein binding showed that erdafitinib exists primarily in the free form in urine. The percent erdafitinib free 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.

[0244] Erdafitinib in vitro binding to normal / tumor bladder tissues showed significant free fractions. The free fraction of erdafitinib in minipig bladder tissues was 79%, two-fold higher than that in rats (33%) and humans (39%). In tumor tissues, the free fraction was 40%.

[0245] Bladder irrigation studies in pigs and rats showed good distribution from the urine into the bladder, especially into the urothelium. Low systemic bioavailability (approximately 5% in rats and 12% in minipigs) was observed after localized bladder dosing.

[0246] 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.

[0247] Example 7. Erdafitinib + Cyclodextrin In Vitro Release Study Erdafitinib co-formulated with cyclodextrin (HPβCD) was tested in systems with a base material of AC-4075A-B20 and stripes of EG-80A, with a 90° stripe angle or a 180° stripe angle in simulated urine at pH 5, pH 6.8, and pH 8. They showed minimal pH dependence at physiological pH (pH 5-7) and were capable of achieving delivery at target rates of 2-4 mg / day for 90 days.

[0248] Example 8. Minipig study with Erdafitinib + Cyclodextrin A prototype system with the design described in Example 7 was tested in minipigs. Urinary drug concentrations were maintained over 90 days. Mean urinary concentration: approximately 1313 ng / mL (above target of 1190 ng / mL). Acceptable bladder local tolerance was observed and no systemic toxicity was observed. Results were confirmed in a one-month minipigs tolerability and GLP toxicology study.

[0249] Example 9. Human studies with Erdafitinib Clinical studies are conducted in human participants (patients) to evaluate the safety, pharmacokinetics (PK), and preliminary efficacy of the erdafitinib-releasing intravesical system in participants with intermediate- or high-risk papillary non-muscle-invasive bladder cancer (NMIBC) or muscle-invasive bladder cancer (MIBC) with select FGFR mutations or fusions.

[0250] the study The study uses an erdafitinib intravesical delivery system according to the present invention (hereinafter "TAR-210"), which is retained in the bladder after insertion using a urinary placement catheter and provides sustained release of erdafitinib in the bladder for up to 90 days. TAR-210 is removed transurethrally from the bladder via cystoscopy and non-cutting endoscopic grasping forceps.

[0251] This open-label, multicenter, Phase 1 study of TAR-210 in adult participants with either NMIBC or MIBC will enroll four cohorts of participants. Cohort 1: recurrent bacillus Calmette-Guerin (BCG)-experienced high-risk papillary-only NMIBC (high-grade Ta / T1) who refused or were ineligible for radical cystectomy (RCy); Cohort 2: recurrent BCG-experienced high-risk papillary-only NMIBC (high-grade Ta / T1) scheduled for RCy; Cohort 3: recurrent intermediate-risk NMIBC (Ta and T1) with a history of only low-grade disease, and Cohort 4: MIBC scheduled for RCy who refused or were ineligible for cisplatin-based neoadjuvant chemotherapy.

[0252] For cohorts 1 and 2, all visible tumors must be completely resected prior to the start of study treatment and documented at screening cystoscopy. For cohort 4, participants must have a total tumor size of 3 cm or less to be eligible.

[0253] The study includes two parts: Part 1 (dose escalation) and Part 2 (dose expansion). Part 1 dose escalation includes participants from cohorts 1 and 3 and is supported by a Bayesian Optimization Interval (BOIN) design. Two dose levels can be evaluated in this study, an intravesical delivery system with an estimated maximum erdafitinib release of approximately 2 mg / day and an intravesical delivery system with an estimated maximum erdafitinib release of approximately 4 mg / day. Dose escalation is guided by a BOIN design with a target dose limiting toxicity (DLT) rate of 28% or less.

[0254] All participants will be screened for qualifying FGFR mutations or fusions in tumor tissue. Qualifying FGFR alterations must be identified prior to the start of study treatment. Approximately 12 participants are planned for enrollment in part 1, and 50-80 participants are planned for enrollment in part 2 (15-25 per cohort for cohorts 1, 3, and 4 across all dose levels tested; there is no specific enrollment target for cohort 2), with a maximum of approximately 92 participants planned.

[0255] Upon the preliminary RP2D being found safe by the Study Evaluation Team (SET), participants from all four cohorts may then be enrolled in a separate expansion cohort at this dose level in part 2 to further characterize safety, PK, and preliminary antitumor activity. One or both dose levels may be expanded as the RP2D in part 2. Participants scheduled for RCy (cohorts 2 and 4) will be enrolled in part 2 only when initial safety and PK data are available in NMIBC participants from cohorts 1 and 3. Safety will be monitored by SET at each dose escalation step and at regular intervals during dose expansion during the study.

[0256] Clinical activity will be assessed after bladder tumor biopsy / transurethral resection (TURBT) or RCy using the following evaluations: cystoscopy, computed tomography (CT) or magnetic resonance (MR) urography, urinary cytology, and pathological evaluation.

[0257] Blood and urine samples will be collected from participants at multiple time points to characterize the plasma and urinary PK of erdafitinib. Bladder tissue will be collected and tissue PK of erdafitinib will be analyzed, where feasible.

[0258] Safety assessments will be based on medical review of AE reports and results of vital sign measurements, physical examinations, ophthalmologic evaluations, laboratory tests, and other safety assessments at specific time points. Concomitant medication use will be recorded. Adverse events will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE, version 5.0).

[0259] Participants will have TAR-210 inserted transurethrally into the bladder using a urinary placement catheter on day 1 of the treatment phase. TAR-210 will be removed after 3 months (day 90) for cohorts 1 and 3 or 8 months (day 57) for cohorts 2 and 4, or sooner in case of disease recurrence or progression, or unacceptable toxicity. To reduce the risk of urinary tract infection, participants may receive a dose of prophylactic pre-treatment antibiotics for the intravesical study procedure. Cystoscopy for removal of TAR-210 may be used to facilitate removal with a non-cutting grasping forceps, where TAR-210 is fully grasped and removed from the bladder under direct vision, not through the working channel of the cystoscope.

[0260] After completion of the first 3-month dosing cycle, participants in cohorts 1 and 3 will undergo disease response assessment with cystoscopy with biopsy and urine cytology. Those participants with a complete response (CR) may continue to receive up to three additional 3-month dosing cycles with TAR-210 for a maximum treatment duration of 1 year in the absence of disease recurrence or progression, or unacceptable toxicity. Participants in cohorts 2 and 4 will receive RCy after 8 weeks of dosing and will not receive further study treatment.

[0261] For all participants, an End of Treatment (EOT) visit will occur 30 (+7) days after removal of the last TAR-210 system. Participants in cohorts 1 and 3 who do not recur or progress will enter a follow-up phase and undergo cystoscopy, urinary cytology, and upper tract imaging for up to 3 years after day 1 or until disease recurrence or progression, new anticancer therapy is initiated, or the participant leaves the study. Participants in cohorts 2 and 4 will have a follow-up visit 3 months after RCy. For cohorts 1 and 3, disease assessment will be performed 90 days after study treatment (1 cycle), including cystoscopy with biopsy of visible disease (or biopsy of previous disease site if no visible disease) and urinary cytology. Participants with a complete response (CR) may continue to receive TAR-210 in 90-day cycles for a total duration of up to 1 year.

[0262] The study includes molecular eligibility, screening, treatment, and follow-up phases.

[0263] Molecular eligibility will be established for each potential participant prior to screening for other eligibility criteria, unless a fresh tumor biopsy is required to obtain tissue for FGFR testing. Testing to demonstrate FGFR alterations may be performed on fresh biopsies from recurrent disease or on archived tumor tissue from before recurrence. Eligible FGFR alterations must be identified prior to the initiation of study treatment.

[0264] High-risk NMIBC participants (Cohorts 1 and 2) must have had a TURBT for their recurrent disease within 12 weeks prior to screening. For participants with lamina propria invasion (T1) at screening biopsy / TURBT, muscularis propria must be present to exclude MIBC. All visible tumor must be completely resected as demonstrated by screening cystoscopy. According to the inclusion criteria and schedule of activities, MIBC participants (Cohort 4) must have had a diagnostic TURBT within 12 weeks prior to the planned start of study treatment (Day 1) and a repeat TURBT within 8 weeks prior to Day 1 if required to reduce total tumor size to 3 cm or less. The last TURBT must have been completed >14 days prior to Day 1. Intermediate-risk participants in Cohort 3 do not have a complete TURBT during screening or prior to the start of study treatment.

[0265] The treatment phase begins on day 1 for participants who meet all eligibility criteria, at which point participants have TAR-210 placed in the bladder with a urinary placement catheter. After completion of the first dosing cycle, participants in cohorts 1 and 3 undergo biopsy to assess response. Those participants with a CR may continue to receive up to three additional 3-month dosing cycles with TAR-210 for a 1-year treatment duration unless there is disease recurrence or progression, or unmanageable toxicity. Participants with MIBC (cohort 4) and those with high-risk NMIBC in cohort 2 receive RCy after 8 weeks of treatment and do not receive further study treatment.

[0266] Upon discontinuation of treatment with TAR-210, participants will have an end of treatment (EOT) visit (30 [± 7] days after last system removal). Participants in cohorts 2 and 4 will have a follow-up visit 3 months (± 2 weeks) after RCy. Participants in cohorts 1 and 3 who do not recur or progress will enter a follow-up phase and undergo disease surveillance with cystoscopy, urine cytology, and upper tract imaging for up to 3 years after Day 1 or until disease recurrence or progression, new anticancer therapy is initiated, or the participant withdraws from the study.

[0267] Efficacy analyses will be performed separately for each cohort. Secondary endpoints for the four cohorts to evaluate preliminary clinical activity include RFS for cohorts 1 and 2, CR rate and duration of CR for cohort 3, and CR rate, pT0 rate, and rate of downstaging to less than pT2 for cohort 4. Cohort 1 * and complete response for 3 is defined as follows: Negative cystoscopy and negative (including atypical) urine cytology Positive cystoscopy and negative (including atypia) cytology in biopsy-proven benign or low-grade NMIBC ● * Note that for cohort 1, CR has the same operational definition as freedom from recurrence following.

[0268] Recurrence is defined as the first appearance of histologically proven high-grade Ta or T1 disease bladder cancer after initiation of study treatment (Cohorts 1 and 2) or after achievement of CR (Cohort 3). Freedom from recurrence for participants with NMIBC is defined as: • Negative cystoscopy and negative (including atypical) urinary cytology. Positive cystoscopy and negative (including atypia) cytology in biopsy-proven benign or low-grade NMIBC Cohort 2 must be pT0 (no pathological evidence of intravesical disease) at radical cystectomy pathology evaluation

[0269] A pathologic complete response for cohort 4 is defined as no pathologic evidence of intravesical disease (pT0) and no pathologic evidence of lymph node metastasis (pN0).

[0270] Participants inclusion / exclusion criteria Each potential participant must meet all of the following criteria to be enrolled in the study:

[0271] age 1. 18 years of age or older (or the legal age of consent in the jurisdiction where the study is conducted) at the time of informed consent.

[0272] Participant types and disease characteristics 2. Recurrent non-muscle invasive or muscle invasive urothelial carcinoma of the bladder. Mixed histology tumors are permitted when urothelial differentiation predominates (i.e., <20% variant histology), however, the presence of micropapillary, signet ring cell, plasmacytoid, neuroendocrine, or sarcomatoid features is excluded. b. High-risk papillary disease defined as histologically confirmed high-grade Ta / T1 lesions (Cohorts 1 [Parts 1 and 2] and 2 [Part 2 only]). Concurrent CIS is not allowed. All visible tumor must be completely resected prior to initiation of study treatment and must be demonstrated at screening cystoscopy. c. Intermediate-risk papillary disease (Cohort 3, Parts 1 and 2) defined as all prior tumors being low-grade Ta or T1 and no prior CIS. Cystoscopic demonstration of recurrence is sufficient. Negative urine cytology for high-grade urothelial carcinoma is required. d. Muscle-invasive disease (Cohort 4, Part 2 only) cT2 to T3a, N0. To be eligible, participants must have a post-TURBT gross tumor size of 3 cm or less at an evaluation within 8 weeks prior to the start of study treatment or have had a second debulking TURBT to reduce the tumor to 3 cm or less. 3. Activating tumor FGFR mutations or fusions as determined by sponsor-approved local or central testing prior to initiation of study treatment: * Local tissue-based results from next-generation sequencing (NGS) or polymerase chain reaction (PCR) testing performed in a CLIA-certified or equivalent laboratory (if already present), or results from a commercially available PCR or NGS test. 4. Cohorts 1 and 2: BCG-experienced participants or BCG-naive participants due to BCG not being available as a treatment option in the participant's location within the past 2 years and not currently available. BCG-experienced is defined as: Recurrent high-grade Ta / T1 disease within 18 months of completion of previous BCG therapy ● Previous BCG (minimum treatment requirement): 1) At least 5 of the 6 total doses of the initial induction course. The total dose of BCG must be at least 1 × 10 8 Defined as one total vial containing colony forming units. or 2) At least 5 of 6 total doses of the initial induction course plus at least 1 maintenance (2 of 3 weekly doses) for a 6 month period. Half or third doses are allowed during maintenance. Note: Cohort 3 has no predefined prior BCG or intravesical chemotherapy requirements. 5. Cohort 1 only: Refuses or is not eligible for RCy 6. Cohorts 2 and 4: Willingness and eligibility for RCy 7. Cohort 4: Refusing cisplatin-based combination chemotherapy (and understanding the risks and benefits of cisplatin-based combination chemotherapy) or considered ineligible for cisplatin-based chemotherapy by meeting at least one of the following criteria: Creatinine clearance (CrCl) less than 60mL / min Audiometry hearing loss of NCI-CTCAE version 5.0 grade 2 or higher Peripheral neuropathy of grade 2 or higher according to NCI-CTCAE version 5.0 Eastern Cooperative Oncology Group (ECOG) performance status score ≤8.2 (Cohorts 1 and 3) or ECOG performance status score ≤1 (Cohorts 2 and 4) 9. Adequate bone marrow, liver, and renal function: Bone marrow function (no growth factor or transfusion support in the past 2 weeks): ○1,000 / mm 3 Absolute neutrophil count (ANC) above ○75,000 / mm 3 Platelet count above Hemoglobin level of 8.0 g / dL or higher b. Liver function: Total bilirubin below 1.5 x the upper limit of normal (ULN) or direct bilirubin below 1.5 x ULN for participants with Gilbert syndrome and total bilirubin levels above 1.5 x ULN Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) below 2.5 x ULN c. Renal function: - Estimated glomerular filtration rate of >30 mL / min calculated using the Modified Diet in Renal Disease (MDRD) formula

[0273] Potential subjects who meet any of the following criteria will be excluded from participating in the study. Medical conditions 1. Concurrent extravesical (i.e., urethra, ureter, renal pelvis) transitional cell carcinoma of the urothelium. 2. Previous treatment with an FGFR inhibitor. 3. Known hypersensitivity to any study components, including: Erdafitinib (or other drug excipients) or chemically related drugs, TAR-210 device construction materials (e.g., thermoplastic polyurethane, silicone, nitinol); Urinary placement catheter material (e.g., thermoplastic polyurethane). 4. Received pelvic radiotherapy 6 months or less prior to planned initiation of study treatment. If pelvic radiotherapy was received more than 6 months prior to initiation of study treatment, there must be no cystoscopic evidence of radiation cystitis. 5. The presence of any bladder or urethral anatomical features that, in the opinion of the investigator, may prevent the safe placement, indwelling use, or removal of TAR-210. 6. Placement of a urethral catheter. Intermittent catheterization is possible. 7. Cystoscopic evidence of bladder perforation, unless such perforation has resolved prior to dosing. 8. Bladder post-void residual (PVR) of more than 350 mL after the second void. 9. History of clinically significant polyuria with documented 24-hour urinary volume greater than 4,000 mL. 10. Subjects with active bladder stones or a history of bladder stones less than 6 months prior to the start of study treatment. 11. Active malignancy (i.e., progressing or requiring a change in therapy within the past 24 months) other than the disease being treated under the study. Potential exceptions include the following (others may be allowed with sponsor approval): A skin cancer (non-melanoma or melanoma) that is considered to be completely cured. Non-invasive cervical cancer that is considered to be completely cured. Adequately treated lobular carcinoma in situ (LCIS) and ductal CIS History of localized breast cancer and receiving antihormonal drugs History of localized prostate cancer (N0M0) and receiving androgen deprivation therapy Localized Prostate Cancer (N0M0): had a Gleason score of 6 and had been treated within the past 24 months or had not been treated and was under surveillance; have a Gleason score of 3+4, have been treated >6 months prior to full study screening, and are considered to have a very low risk of recurrence; or have a history of localized prostate cancer, have received androgen deprivation therapy, and are considered to have a very low risk of recurrence. 12. Current central serous retinopathy or retinal pigment epithelial detachment of any grade. 13. History of uncontrolled cardiovascular disease, including: Any of the following within 3 months prior to the start of study treatment: unstable angina, myocardial infarction, ventricular arrhythmia or clinically significant atrial arrhythmia (e.g., atrial fibrillation with an uncontrolled rate), cardiac arrest or known congestive New York Heart Association Class III-IV heart failure (see https: / / www.heart.org / en / health-topics / heart-failure / what-is-heart-failure / classes-of-heart-failure, accessed July 16, 2021), cerebrovascular accident, or transient ischemic attack. Pulmonary embolism or other venous thromboembolism within 1 month prior to the planned start of study treatment. 14. Active or chronic hepatitis B or C infection according to the following criteria: Seropositivity for Hepatitis B: defined by a positive test for hepatitis B surface antigen (HBsAg). Participants with resolved infection (i.e., participants who are HBsAg negative with antibodies to total hepatitis B core antigen (anti-HBc) with or without hepatitis B surface antibody (anti-HBs) present) must be screened using real-time polymerase chain reaction (RT-PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are RT-PCR positive will be excluded. Participants with anti-HBs positivity as the only serological marker and a known history of previous HBV vaccination do not need to be tested for HBV DNA by RT-PCR. Hepatitis C infection as defined by a positive hepatitis C antibody (anti-HCV) test. Participants who test positive for anti-HCV are eligible if they have an undetectable RNA viral load (spontaneous recovery or after completing treatment for hepatitis C virus infection). 15. Major surgery within 4 weeks prior to Day 1 (TURBT is not considered major surgery) 16. Urinary tract infection requiring oral or systemic therapy within 7 days prior to Day 1 * Active bacterial, viral and fungal infections, including * Urinary tract infections occur in 10% of urine voided by a woman. 5 Bacterial counts of ≥ 10 colony forming units (CFU) / mL or ≥ 10 in voided urine from men or in straight catheterized urine from women 4 Symptomatic infection is defined as a positive urine culture with bacterial counts > CFU / mL. Symptoms may include dysuria, urgency, frequency, and / or systemic symptoms, such as fever, chills, elevated white blood cells, and / or abdominal / flank pain. 5Participants without culture evidence of > CFU may be eligible. 17. Toxicity from prior anticancer therapy has not recovered to baseline levels or to a grade of ≤1 (stable on hormone replacement and excluding alopecia, vitiligo, peripheral neuropathy, or endocrine disorders which may be grade 2). 18. Known human immunodeficiency virus (HIV) positive participant with one or more of the following: Not receiving highly active antiretroviral therapy (ART) Had a change in ART within 6 months of starting screening Receiving ART that may interfere with the study treatment CD4+ count <350 at screening Acquired immunodeficiency syndrome (AIDS)-related opportunistic infections within 6 months of the start of screening Do not agree to initiate ART and do not agree to receive ART more than 4 weeks prior to the start of study treatment. Only participants who have an HIV viral load of less than 400 copies / mL at the end of the 4-week period and agree to continue ART (to ensure that ART is tolerated and HIV is controlled) are eligible. Previous / Concurrent Clinical Research Experience 19. Has received an investigational intervention (including an investigational vaccine) or used an invasive investigational medical device within 28 days prior to the planned start of study treatment, or is currently enrolled in an investigational study. 20. Previous anticancer therapy within 4 weeks prior to the planned start of study treatment. Exception: A single intravesical chemotherapy treatment immediately following TURBT is permitted. 21. Any condition where, in the investigator's opinion, participation would not be in the participant's best interest (e.g., compromising health) or which might interfere with, limit, or confound the protocol-specified evaluations.

[0274] Example 10: Pharmacokinetics (PK) and pharmacodynamics (PD) of single-dose intravesical erdafitinib administration in orthotopic bladder tumor-bearing rats. The objective of Example 10 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 were given a single oral dose of erdafitinib into the bladder (20 mg / kg erdafitinib in 10% weight per volume (w / v) HP-β-CD solution) or a 1-hour intravesical instillation of erdafitinib into the bladder (6 mg / kg erdafitinib in 10% w / v HP-β-CD solution). 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. In addition, a group of nude rats bearing subcutaneous (sc) tumors (UM-UC-1) were given erdafitinib orally and concentrations were measured in plasma and tumors at 2, 7, 48, and 120 hours after dosing.

[0275] Intravesical administration resulted in mean erdafitinib exposure levels that were equivalent to those of the 20 mg / kg oral dose (Table 6). 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 exposure observed in the same groups of rats (Figure 9).

[0276] [Table 10] HP-β-CD, hydroxypropyl β-cyclodextrin; IVES, intravesical (bladder instillation); LLOQ, lower limit of quantitation PO or po, oral. Values ​​are means with standard deviations in brackets. Mean exposures for the 48 and 120 hour time points were low (<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)

[0277] 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 samples. With one exception, there were no vehicle-treated samples at the 120 hour time point, so the pERK / ERK ratio for the erdafitinib-treated samples at the 120 hour time point was divided by the mean of the 48 hour vehicle-treated group.

[0278] 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 10, Table 7). 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.

[0279] [Table 11] 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 were dosed with vehicle. a Ratio of pERK / ERK mean group values ​​divided by the mean of the vehicle-treated group. Standard deviation in brackets. b One-way ANOVA, Dunnett's test for multiple comparisons. c Divided by the mean of the 48-hour vehicle-treated group.

[0280] Overall, these data indicate that intravesical administration of erdafitinib provides adequate tumor PK / PD while dramatically reducing plasma exposure, thereby decreasing the potential for on-target off-tumor toxicity compared to oral therapy.

[0281] Example 11: 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 6Cells) 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. 12. 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.

[0282] 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 11). Thus, the total bladder weight is an accurate measure of drug response.

[0283] Five days of continuous erdafitinib infusion 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. 13. 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.

[0284] 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 average bladder weights in animals receiving different erdafitinib concentrations are shown in Figure 14. 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)

[0285] Example 12: 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 11 (Figure 12), 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 15. 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.

[0286] The effect of intravesical erdafitinib exposure on tumor growth as determined by changes in total bladder weight is shown in Figure 16. Mean bladder weights tended to be lower with increasing erdafitinib concentrations, but the reductions were 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.

[0287] 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 when compared to the vehicle control group, indicating that bladder perfusion with erdafitinib reduced tumor growth.

[0288] Example 13: Intravesical pharmacokinetic and distribution studies in rats and minipigs. Systemic and bladder PK studies were performed after a single intravesical (bolus) administration of erdafitinib formulation in solution (HP-β-CD) to rats and minipigs.In addition, bladder tissue was evaluated for gross and microscopic examination to determine whether there was any local effect of the drug or formulation in the study.The goal of Example 13 was to determine the feasibility of intravesical erdafitinib therapy with bladder placement of erdafitinib.

[0289] 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 this catheter. Solution formulations were prepared in various strengths and administered in a volume of 0.5 mL to each rat bladder 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 moved 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 contact period following dosing. At each blood sampling time point, bladder samples were collected from each rat for drug analysis. In addition, bladders collected at 96 hours in the 18 mg / kg dose (high dose) group were evaluated microscopically. Urine collection from all rats was restricted to the initial 0-6 hours after dosing.

[0290] 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.

[0291] 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 moved to individual metabolic cages and allowed free access to food and water during a 1-week post-operative recovery period. On the study day, erdafitinib solution (0.1 mg / mL, 0.1 mL / hr, pH 5.5 citrate buffer containing 5% w / v HP-β-CD) was perfused into the rat bladder via the catheter for more than 72 hours. The first group (n=3) was sacrificed 24 hours after perfusion, and two of the four remaining groups were sacrificed 48 and 72 hours after 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 (Table 8). 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. 17A. No levels (below the limit of quantification; 0.2 ng / mL) were detected in plasma samples 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 FIG. 17B. 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.

[0292] [Table 12] AUC 0~xh, area under the plasma concentration-time curve from time of administration to x hours; C xh , plasma concentration at time x; NC, not calculated. a The average daily urinary concentration at this time point was approximately 10,000 ng / mL.

[0293] 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.

[0294] Systemic and bladder PK of continuous intravesical erdafitinib in pigs: Systemic and bladder PK of erdafitinib was evaluated in five female pigs (domestic Yorkshire cross pigs) 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 mouse 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 formulation analysis of all days, 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.

[0295] Mean (±SD) erdafitinib urinary concentrations ranged from 1,255±554 to 873±179 ng / mL on days 2-8 (Figure 18). 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 in 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 dose of erdafitinib administered.

[0296] Erdafitinib plasma concentrations ranged from a mean (±SD) of 0.622±0.250 to 0.828±0.487 ng / mL on days 2 to 8 (Figure 19).

[0297] 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 underlying tissue layers (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 layers, suggesting that the drug was primarily retained in the urothelium. Mean bladder versus urinary concentrations were calculated for animals in the 6-day and 8-day perfusion groups with values ​​of 0.60 and 2.33, respectively. Mean data are presented in Table 9.

[0298] [Table 13] conc, concentration; O'all, overall; Rem layer, bladder subtissue layer; Urothel layer, bladder urothelium.

[0299] Example 14: 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.

[0300] Example 15: 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.

[0301] A chemical gradient delivery approach was investigated to determine the optimal device release mechanism. 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.

[0302] A factorial analysis-based 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 with known precise alignment to the full 15 cm design. Drug formats evaluated included erdafitinib free base, erdafitinib free base plus HP-β-CD, and erdafitinib salts, e.g., HCl salt.

[0303] Materials Screening Generally, materials that are impermeable to the API erdafitinib are suitable for use as the base material in the permeable system. Materials that are permeable to the API are suitable for use as the stripe material in the permeable system. Platinum-cured silicone, thermoplastic polyurethane (TPU), and ethylene vinyl acetate (EVA) materials were screened (Table 10). 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.

[0304] [Table 14] EVA, ethylene vinyl acetate; NA, not available; TPU, thermoplastic polyurethane

[0305] The permeability screening results are shown in Figure 20. Materials that were suitable for use as base materials in the permeable system were impermeable or substantially impermeable to the API, which resulted in release rates that were too slow to achieve the target dose (e.g., TPUs AR-62A, AR-75A, AC-4075A, and EG-80A). Materials that were suitable for use as stripe materials in the permeable system were permeable to the API. TPU materials HP-60D-35, HP-93A-100, or EG-80A were selected as possible stripe materials for further development of permeable prototypes.

[0306] Transparent System The release rates from the material screening study were used to determine the specifications for the stripe material, stripe angle (30°-180°), and wall thickness (0.2-0.41 mm) for the custom permeation tube extrudates. The inner diameter (ID) of the custom extrudates was set at 2.64 mm.

[0307] The short-core system allowed for rapid screening of both drugs and device constructs. Figure 21 shows the release rates from the full-length system versus the permeation system.

[0308] The emission rate increases as the stripe angle increases. Short-core systems were constructed with a stripe angle of 30° versus 90°, the difference between the two device configurations.

[0309] Simulates urine pH effect The pH range for normal human urine ranges from 5.5 to 7, but some disease states can result in higher urinary pH values ​​(pH 8). Several permeation system prototypes showed similar release profiles in simulated urine at pH 5 and 6.8, with slightly lower release rates at pH 8. Figure 22 shows that permeation prototypes with erdafitinib free base + HP-β-CD tablets (JNJ-42756493-1) and EG-80A as the stripe material had similar release profiles in simulated urine at pH 5 and 6.8. Figure 22 also shows that the release is zero order for at least 160 days. Based on these results, it was determined that permeation prototypes with erdafitinib free base + HP-β-CD tablets, EG-80A stripes (45° to 180°), 0.2 mm wall thickness, and 15 cm drug core would result in a release profile of 1 to 4 mg FBE / day based on the stripe angle. The base material for this tube can be either AR-75A-B20 or AC-4075A-B20.

[0310] Additional short core prototype systems were tested to better understand the reduced pH effect. Short cores were fabricated with the same device composition, AR-62A base and 90° HP-60D-35 stripes, 2.64 mm ID, 0.41 mm wall thickness. The drug composition in these systems was erdafitinib free base with HP-β-CD and erdafitinib free base without HP-β-CD. The drug composition with HP-β-CD contained 50% erdafitinib free base, 10% HP-β-CD, 25% Avicel PH101, 12.5% ​​DCP, 1% meglumine, 0.5% Aerosil, and 1% magnesium stearate (w / w). The drug formulation without HP-β-CD contained 50% erdafitinib free base, 20% MCC, 18.5% dibasic calcium phosphate, 8% Kollidon, 1% meglumine, 0.5% Aerosil, and 2% magnesium stearate. Figure 23 shows that the addition of HP-β-CD to the erdafitinib free base formulation did not change the release profile with the HP-60D-35 stripe material, and the release profiles in simulated urine at pH 5 and 6.8 were not well matched for erdafitinib free base tablets (with or without HP-β-CD) when used with the HP-60D-35 stripe material. This is in contrast to the release profile for erdafitinib free base + HP-β-CD tablets when used with the EG-80A stripe material (Figure 22).

[0311] Transmission systems with erdafitinib free base Two permeation system prototypes with erdafitinib free base were tested in minipigs (Prototype 1: permeation (wireform), erdafitinib free base, tablet; Prototype 2: permeation (wireform), erdafitinib free base + HP-β-CD (10% w / w), tablet). Drug and device compositions are listed in Tables 11 and 12, respectively. In vitro release (IVR) studies were performed on both prototypes 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). The IVR profile for prototype 1 showed some simulated urine pH dependence, with the fastest release at pH 5 and the slowest release at pH 8 (Figure 24). The IVR profile for prototype 2 showed zero order release over 90 days with good agreement in simulated urine at pH 5 and pH 6.8, with a slightly slower release in simulated urine at pH 8 (Figure 25).

[0312] [Table 15] API, active pharmaceutical ingredient; HP-β-CD, hydroxypropyl β-cyclodextrin; NA, not applicable; w / w, weight / weight.

[0313] [Table 16] API Active Pharmaceutical Ingredient; FBE, Free Base Equivalent; ID, Inner Diameter

[0314] Pharmacokinetic evaluation in minipigs The permeation design released erdafitinib at a rate designed to provide at or above the target urinary concentration. Both first-order and zero-order release profiles were observed depending on the release rate. The first-order design showed a peak in vitro release rate of up to 8 mg / day compared to the zero-order system (defined as release at a constant rate for at least 30 days) of up to 2 mg / day (for a duration of more than 90 days). pH dependence was observed and found to be dependent on the drug format. Both erdafitinib free base and erdafitinib HCl salt showed significant pH dependence, with the highest release rate observed at pH 5 compared to a significantly reduced rate at pH 8. Inter- and intra-device release rate variability was lowest for the zero-order system.

[0315] Based on the short core data, a series of full length systems 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 permeation designs. The in vivo results largely confirmed the in vitro findings. Figure 26 summarizes the in vitro release characteristics of representative permeation systems selected for minipigs testing. Figure 27 summarizes the urinary concentration versus time profiles of the same systems. Prototype 1 was a representative first order design based on the permeation tube design. Prototype 2 was a representative zero order design based on the permeation design.

[0316] Prototype 2 was selected for further development. Selection was based on achieving an average urinary concentration of at least 1 μg / mL, achieving zero order release over at least 90 days, and demonstrating the ability to tailor the drug delivery rate up to 4 mg / day. Prototype 2 was further refined to increase the release rate to 2 and 4 mg / day (pH 7), which was achieved by increasing the surface area (defined by the stripe angle) of the permeable polymer coextruded with the non-permeable base polymer.

[0317] Example 16: Device Development. Formulation-Device Development Formulation development focused on erdafitinib free base + 10% w / w HP-β-CD minitablets (Table 13).

[0318] [Table 17] API, active pharmaceutical ingredient; HP-β-CD, hydroxypropyl β-cyclodextrin; w / w, weight / weight.

[0319] A permeable TPU system (diffusion-driven, no orifice) was evaluated. The permeable design is shown in Figures 28A and 28B. The solubility of JNJ-42756493-AAA (free base) as a function of pH at 20°C and 37°C is shown in Figures 29 and 30A. The solubility of JNJ-42756493-AAA (free base) and JNJ-42756493-AAC (HCl salt form 1) as a function of pH at 20°C and in simulated urine at 37°C is shown in Figures 31A-B. Varying the stripe angle of the permeable tube controlled the release rate of the drug.

[0320] Many modifications and other implementations of the disclosure described herein will become apparent having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. It is therefore to be understood 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.

[0321] In the description provided herein, the terms "includes," "is," "containing," "having," and "comprises" are used in an open-ended manner and should therefore be construed to mean "including, but not limited to." When a method, composition, or apparatus is claimed or described in terms of "comprising" various steps or components, the method, composition, or apparatus can also "consist essentially of" or "consist of" the various steps or components, unless otherwise noted. In the case of a chemical compound or composition, the use of "consist essentially of" means that only additional components that do not materially affect the essential characteristics of the particular compound or composition may be present.

Claims

1. 1. A solid pharmaceutical composition comprising: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of at least 45% by weight of said solid pharmaceutical composition; (b) at least one pharmaceutical excipient; or (a) 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) in a concentration of at least 45% by weight of said solid pharmaceutical composition; (b) at least one pharmaceutical excipient. (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) in a concentration of at least 45% by weight of the solid pharmaceutical composition; (b) at least one pharmaceutical excipient.

3. 10. The solid pharmaceutical composition of claim 1, wherein the at least one pharmaceutical excipient comprises a solubilizer, a binder, a diluent, a wetting agent, a disintegrant, a glidant, a lubricant, a formaldehyde scavenger, or any combination thereof.

4. 1. A process for making a solid pharmaceutical composition comprising: (a) preparing an intragranular solid composition, said intragranular solid composition comprising: (i) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine), (ii) at least one intragranular pharmaceutical excipient; (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, wherein the erdafitinib free base is present in a concentration of at least 45% by weight of the solid pharmaceutical composition; or (a) preparing an intragranular solid composition, said intragranular solid composition comprising: (i) 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); (ii) at least one intragranular pharmaceutical excipient; (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, wherein the salt form of erdafitinib is present in a concentration of at least 45% by weight of the solid pharmaceutical composition. (a) preparing an intragranular solid composition, the intragranular solid composition comprising: (i) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine), (ii) at least one intragranular pharmaceutical excipient; (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, wherein the erdafitinib free base is present in a concentration of at least 45% by weight of the solid pharmaceutical composition.

6. 6. The solid pharmaceutical composition of any one of claims 1 to 3 or the process for making the solid pharmaceutical composition of claim 4 or 5, wherein the erdafitinib free base or a salt form of erdafitinib is present in the solid pharmaceutical composition at a concentration of 45% to 55% by weight, 47% to 53% by weight, or about 50% by weight, and / or the at least one extragranular excipient comprises microcrystalline cellulose and vinylpyrrolidone-vinyl acetate copolymer, particularly in a weight ratio of 50:

50.

7. 6. The solid pharmaceutical composition of any one of claims 1 to 3 or the process for making the solid pharmaceutical composition of claim 4 or 5, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient, or the at least one extragranular pharmaceutical excipient comprises a solubilizer selected from the group consisting of hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, sulfobutylether-beta-cyclodextrin sodium salt, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose E5 (HPMC-E5), or any combination thereof.

8. 8. The solid pharmaceutical composition or process for making a solid pharmaceutical composition according to claim 7, wherein the solubilizing agent is hydroxypropyl-beta-cyclodextrin.

9. 9. The solid pharmaceutical composition or the process for making a solid pharmaceutical composition of claim 8, wherein the total concentration of the solubilizing agent in the solid pharmaceutical composition is between 1% and 20% by weight, between 5% and 15% by weight, between 7% and 12% by weight, or about 10% by weight.

10. 6. A solid pharmaceutical composition according to any one of claims 1 to 3 or a process for making a solid pharmaceutical composition according to claim 4 or 5, wherein said solid pharmaceutical composition is a mini-tablet.

11. A solid pharmaceutical composition or process for making a solid pharmaceutical composition as described in claim 10, wherein the mini-tablet is in the form of a solid cylinder, the solid cylinder having a cylindrical axis, cylindrical sides, a circular end face perpendicular to the cylindrical axis, a diameter across the circular end face, and a length along the cylindrical sides, the length of the mini-tablet exceeding the diameter of the mini-tablet so as to provide the mini-tablet with an aspect ratio of greater than 1:1, the aspect ratio being the ratio of the length to the diameter, and optionally the mini-tablet having a diameter of 1.0 mm to 3.2 mm or 1.5 mm to 3.1 mm.

12. A solid pharmaceutical composition according to claim 6, comprising erdafitinib free base, or a process for preparing the solid pharmaceutical composition according to claim 6, wherein the solid pharmaceutical composition comprises erdafitinib free base.

13. 1. A solid pharmaceutical composition comprising: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin at a concentration of 10% by weight of said solid pharmaceutical composition; (c) meglumine at a concentration of 1% by weight of said solid pharmaceutical composition; and (d) microcrystalline cellulose at a concentration of 17.5% by weight of said solid pharmaceutical composition; (e) silicified microcrystalline cellulose at a concentration of 10.75% by weight of said solid pharmaceutical composition; (f) vinylpyrrolidone-vinyl acetate copolymer at a concentration of 7.5% by weight of said solid pharmaceutical composition; (g) colloidal silicon dioxide at a concentration of 0.25% by weight of said solid pharmaceutical composition; (h) hydroxypropyl methylcellulose at a concentration of 1.5% by weight of said solid pharmaceutical composition; (i) magnesium stearate at a concentration of 1.5% by weight of said solid pharmaceutical composition; or 1. A solid pharmaceutical composition comprising: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin; and (c) meglumine, (d) microcrystalline cellulose; (e) silicified microcrystalline cellulose; (f) vinylpyrrolidone-vinyl acetate copolymer; and (g) colloidal silicon dioxide; (h) hydroxypropyl methylcellulose; (i) magnesium stearate.

14. 1. A solid pharmaceutical composition comprising: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin at a concentration of 10% by weight of said solid pharmaceutical composition; (c) microcrystalline cellulose at a concentration of 17.5% by weight of said solid pharmaceutical composition; (d) silicified microcrystalline cellulose at a concentration of 11.75% by weight of said solid pharmaceutical composition; (e) vinylpyrrolidone-vinyl acetate copolymer at a concentration of 7.5% by weight of said solid pharmaceutical composition; (f) colloidal silicon dioxide at a concentration of 0.25% by weight of said solid pharmaceutical composition; (g) hydroxypropyl methylcellulose at a concentration of 1.5% by weight of said solid pharmaceutical composition; (h) magnesium stearate at a concentration of 1.5% by weight of said solid pharmaceutical composition; or 1. A solid pharmaceutical composition comprising: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition; (b) hydroxypropyl-beta-cyclodextrin; and (c) microcrystalline cellulose; (d) silicified microcrystalline cellulose; (e) vinylpyrrolidone-vinyl acetate copolymer; and (f) colloidal silicon dioxide; (g) hydroxypropyl methylcellulose; (h) magnesium stearate.

15. 1. A process for making a solid pharmaceutical composition comprising: (a) preparing an intragranular solid composition by a fluid bed granulation process, said intragranular solid composition comprising: (i) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition; (ii) hydroxypropyl-beta-cyclodextrin at a concentration of 10% by weight of said solid pharmaceutical composition; (iii) meglumine at a concentration of 1% by weight of said solid pharmaceutical composition; (iv) microcrystalline cellulose at a concentration of 10% by weight of said solid pharmaceutical composition; (v) hydroxypropyl methylcellulose at a concentration of 1.5% by weight of said solid pharmaceutical composition; (b) combining the intragranular solid composition with an extragranular component to form a blend, wherein the extragranular component comprises: (i) microcrystalline cellulose at a concentration of 7.5% by weight of said solid pharmaceutical composition; (ii) vinylpyrrolidone-vinyl acetate copolymer at a concentration of 7.5% by weight of said solid pharmaceutical composition; (iii) silicified microcrystalline cellulose at a concentration of 10.75% by weight of said solid pharmaceutical composition; (iv) colloidal silicon dioxide at a concentration of 0.25% by weight of said solid pharmaceutical composition; and (iv) magnesium stearate at a concentration of 1.5% by weight of said solid pharmaceutical composition; (c) compressing the blend to form a solid pharmaceutical composition in the form of mini-tablets.

16. 1. A process for making a solid pharmaceutical composition comprising: (a) preparing an intragranular solid composition by a fluid bed granulation process, said intragranular solid composition comprising: (i) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition; (ii) hydroxypropyl-beta-cyclodextrin at a concentration of 10% by weight of said solid pharmaceutical composition; (iii) microcrystalline cellulose at a concentration of 10% by weight of said solid pharmaceutical composition; (iv) hydroxypropyl methylcellulose at a concentration of 1.5% by weight of said solid pharmaceutical composition; (b) combining the intragranular solid composition with an extragranular component to form a blend, wherein the extragranular component comprises: (i) microcrystalline cellulose at a concentration of 7.5% by weight of said solid pharmaceutical composition; (ii) vinylpyrrolidone-vinyl acetate copolymer at a concentration of 7.5% by weight of said solid pharmaceutical composition; (iii) silicified microcrystalline cellulose at a concentration of 11.75% by weight of said solid pharmaceutical composition; (iv) colloidal silicon dioxide at a concentration of 0.25% by weight of said solid pharmaceutical composition; and (iv) magnesium stearate at a concentration of 1.5% by weight of said solid pharmaceutical composition; (c) compressing the blend to form a solid pharmaceutical composition in the form of mini-tablets.

17. a housing defining a closed drug reservoir lumen bounded by a first wall structure formed from a first material and a second wall structure formed from a second material, the first wall structure and the second wall structure adjoining each other at two interface edges and together forming a tube defining the closed drug reservoir lumen, the first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprising an aliphatic polyether-based thermoplastic polyurethane; a drug formulation disposed within the closed drug reservoir lumen, the drug formulation comprising a drug, the drug comprising erdafitinib free base or a salt form of erdafitinib; A drug delivery system wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the drug and the second wall structure is permeable to the drug, whereby the drug is releasable in vivo by diffusion through the second material forming the second wall structure.

18. a housing defining a closed drug reservoir lumen bounded by a first wall structure formed from a first material and a second wall structure formed from a second material, the first wall structure and the second wall structure adjoining each other at two interface edges and together forming a tube defining the closed drug reservoir lumen, the first material comprising an aromatic polyester hydrocarbon-based thermoplastic polyurethane and the second material comprising an aliphatic polyether-based thermoplastic polyurethane; a drug formulation disposed within the closed drug reservoir lumen, the drug formulation comprising a drug, the drug comprising erdafitinib free base or a salt form of erdafitinib; 1. A drug delivery system, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water; and (ii) the first wall structure is impermeable to the drug and the second wall structure is permeable to the drug, whereby the drug is releasable in vivo by diffusion through the second wall structure, and optionally the first material comprises AR-75A.

19. 19. A drug delivery system according to claim 17 or 18, wherein the second wall structure forms a longitudinal strip extending along the length of the tube.

20. 19. The drug delivery system of claim 17 or 18, wherein the drug delivery system is configured to release the drug over a period of 2 days to 6 months, optionally over a period of 90 days or 3 months.

21. 19. The drug delivery system of claim 17 or 18, wherein the two interface edges are disposed at an arc angle of 15 degrees to 270 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube.

22. 19. The drug delivery system of claim 17 or 18, wherein the drug is erdafitinib free base.

23. 23. The drug delivery system of claim 22, wherein the drug delivery system is configured to release the erdafitinib at an average rate of 1 mg / day to 10 mg / day.

24. The drug delivery system described in claim 23, wherein the drug delivery system is configured to release the erdafitinib at an average rate of 2 mg / day to 4 mg / day.

25. 24. The drug delivery system of claim 23, wherein the two interface edges are disposed at an arc angle of 150 to 270 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube.

26. 24. The drug delivery system of claim 23, wherein the system is configured to release the erdafitinib at an average rate of 2 mg / day.

27. 27. The drug delivery system of claim 26, wherein the two interface edges are disposed at an arc angle of about 90 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube.

28. 24. The drug delivery system of claim 23, wherein the system is configured to release the erdafitinib at an average rate of 4 mg / day.

29. 29. The drug delivery system of claim 28, wherein the two interface edges are disposed at an arc angle of about 180 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube.

30. 19. The drug delivery system of claim 17 or 18, wherein the system comprises 500 mg of the erdafitinib.

31. 19. The drug delivery system of claim 17 or 18, wherein the second wall structure comprises less than 50 percent of the cross-sectional area of ​​the tube in a cross section perpendicular to the longitudinal axis of the tube.

32. 19. The drug delivery system of claim 17 or 18, 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.

33. 19. A drug delivery system as described in claim 17 or 18, wherein the system is elastically deformable and has a bi-elliptical retention shape, and the tube has two opposing free ends located within the outer boundary of the bi-elliptical retention shape.

34. 19. The drug delivery system of claim 17 or 18, further comprising a retaining frame lumen.

35. 19. The drug delivery system of claim 17 or 18, wherein the first material has a Shore durometer value of 70A to 80A.

36. 19. The drug delivery system of claim 17 or 18, wherein the drug formulation comprises a solid pharmaceutical composition according to any one of claims 1 to 3 and 13 to 14.

37. 19. The drug delivery system of claim 17 or 18, wherein the drug formulation is in the form of a plurality of mini-tablets sequentially disposed within the drug lumen.

38. 38. The drug delivery system of claim 37, wherein the plurality of mini-tablets comprises the mini-tablets of claim 11.

39. a housing defining a drug reservoir lumen bounded by a first wall structure formed from a first material and a second wall structure formed from a second material, the first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprising an aliphatic polyether-based thermoplastic polyurethane; a drug formulation disposed within the drug reservoir lumen, the drug formulation comprising erdafitinib free base; A drug delivery system wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib is releasable in vivo by diffusion through the second material forming the second wall structure.

40. The drug delivery system described in claim 39, wherein the drug delivery system is configured to release the erdafitinib at an average rate of 2 mg / day to 4 mg / day.

41. 41. The drug delivery system of claim 39 or 40, wherein the first wall structure and the second wall structure are adjacent to each other at two interface edges and together form a tube, and (i) the drug delivery system is configured to release the erdafitinib at an average rate of 2 mg / day and the two interface edges are disposed at an arc of about 90 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, (ii) the drug delivery system is configured to release the erdafitinib at an average rate of 4 mg / day and the two interface edges are disposed at an arc of about 180 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, or (iii) the drug delivery system is configured to release the erdafitinib at an average rate of 6 mg / day and the two interface edges are disposed at an arc of 240 degrees.

42. a housing defining a closed drug reservoir lumen bounded by a first wall structure formed from a first material and a second wall structure formed from a second material, the first wall structure and the second wall structure abutting one another at two interface edges and together forming a tube defining the closed drug reservoir lumen, the second wall structure forming a longitudinal strip extending along the length of the tube, the first material comprising an aromatic polyester hydrocarbon-based thermoplastic polyurethane and the second material comprising an aliphatic polyether-based thermoplastic polyurethane; a drug formulation disposed within the closed drug reservoir lumen, the drug formulation comprising the solid pharmaceutical composition of any one of claims 1 to 3 and 13 to 14, (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water; (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, whereby the erdafitinib can be released in vivo by diffusion through the second wall structure; the drug delivery system is configured to release a therapeutically effective amount of the erdafitinib at a substantially zero order release rate over a period of at least 3 days; (i) the drug delivery system is configured to release the erdafitinib at an average rate of 2 mg / day, and the two interface edges are disposed at an arc of about 90 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube; or (ii) the drug delivery system is configured to release the erdafitinib at an average rate of 4 mg / day, and the two interface edges are disposed at an arc of about 180 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube; or (iii) the drug delivery system is configured to release the erdafitinib at an average rate of 2 mg / day to 4 mg / day.

43. A drug delivery system described in claim 39 or 42, wherein the drug formulation comprises a solid pharmaceutical composition described in any one of claims 2 and 13-14.

44. 43. The drug delivery system of any one of claims 17, 18, 39 and 42, wherein the drug delivery device comprises 44 to 46 erdafitinib mini-tablets.

45. 45. The drug delivery system of claim 44, wherein the erdafitinib mini-tablet comprises the solid pharmaceutical formulation of claim 13.

46. 45. The drug delivery system of claim 44, wherein the erdafitinib mini-tablet comprises the solid pharmaceutical formulation of claim 14.

47. 43. The drug delivery system of any one of claims 17, 18, 39 and 42, wherein the first material comprises AC-4075A-B20 or AR-75A and the second material comprises EG-80A.

48. Use of erdafitinib in the manufacture of a medicament for the treatment of bladder cancer, said treatment comprising locally delivering erdafitinib to the bladder of a patient in need thereof in an amount effective to treat bladder cancer, said erdafitinib being in the form of a solid pharmaceutical composition described in any one of claims 1 to 3 and 13 to 14, and optionally, said bladder cancer being non-muscle invasive bladder cancer or said bladder cancer being intermediate or high risk papillary non-muscle invasive bladder cancer.

49. Use of an intravesical system in the manufacture of a medicament for the treatment of bladder cancer, said treatment comprising deploying said intravesical system in the bladder of a patient in need of treatment, said intravesical system comprising a solid pharmaceutical composition described in any one of claims 1 to 3 and 13 to 14, and optionally said bladder cancer being non-muscle invasive bladder cancer or said bladder cancer being moderate or high risk papillary non-muscle invasive bladder cancer.

50. Use of erdafitinib in the manufacture of a medicament for the treatment of bladder cancer, said treatment comprising delivering erdafitinib to the patient's bladder by deploying a drug delivery system described in any one of claims 17, 18, 39 and 42 within the patient's bladder, optionally wherein the bladder cancer is non-muscle invasive bladder cancer or the bladder cancer is moderate or high risk papillary non-muscle invasive bladder cancer.

51. The use of claim 50, wherein erdafitinib is released over a period of 90 days or 3 months.

52. A solid pharmaceutical composition according to any one of claims 1 to 3 and 13 to 14 for the treatment of bladder cancer, wherein the treatment comprises locally delivering erdafitinib to the bladder of a patient in need of treatment in an amount effective to treat bladder cancer, and optionally the bladder cancer is non-muscle invasive bladder cancer or the bladder cancer is intermediate or high-risk papillary non-muscle invasive bladder cancer.

53. An intravesical system for the treatment of bladder cancer, wherein the treatment comprises deploying the intravesical system in the bladder of a patient in need of treatment, the intravesical system comprising a solid pharmaceutical composition described in any one of claims 1 to 3 and 13 to 14, and optionally, the bladder cancer is non-muscle invasive bladder cancer or the bladder cancer is moderate or high risk papillary non-muscle invasive bladder cancer.

54. A drug delivery system as described in any one of claims 17, 18, 39 and 42 for treating bladder cancer in a patient, wherein the treatment comprises delivering erdafitinib to the patient's bladder by deploying the drug delivery system within the patient's bladder, and optionally the bladder cancer is non-muscle invasive bladder cancer or the bladder cancer is moderate or high-risk papillary non-muscle invasive bladder cancer.

55. The drug delivery system of claim 54, wherein erdafitinib is released over a period of 90 days or 3 months.

56. An intravesical system as described in claim 53 or a drug delivery system as described in claim 54, wherein the bladder cancer is non-muscle invasive bladder cancer.

57. The intravesical system described in claim 53 or the drug delivery system described in claim 54, wherein the bladder cancer is moderate or high-risk non-muscle-invasive papillary bladder cancer.

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