Erdafitinib for intravesical administration for use in the treatment of bladder cancer

Abstract

A method for treating bladder cancer having one or more FGFR changes, comprising locally delivering erdafitinib to the bladder of a patient, erdafitinib for use, and the use of erdafitinib for treatment are provided herein.

Description

[Technical Field]

[0001] (Field of invention) This disclosure generally falls under the field of methods for treating bladder cancer, including methods for treating bladder cancer having one or more FGFR changes.

[0002] (Cross-reference of related applications) This application claims priority to U.S. Provisional Patent Application No. 63 / 484,591, filed on 13 February 2023, and U.S. Provisional Patent Application No. 63 / 623,193, filed on 19 January 2024, the contents of which are incorporated herein by reference in their entirety.

[0003] (Refer to the electronic sequence list) The contents of the electronic sequence listing (761662003040seq.xml, size: 53,214 bytes, and creation date: February 8, 2024) are incorporated herein by reference in their entirety. [Background technology]

[0004] Erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-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 International Publication No. 2011 / 135376. Erdafitinib has been found to inhibit FGFR phosphorylation and signaling, reducing cell viability in cell lines expressing FGFR gene 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] Currently, erdafitinib (BALVERSA®) is available as a film-coated tablet for oral administration and is intended for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma, the locally advanced or metastatic urothelial carcinoma having a fibroblast growth factor receptor (FGFR)3 or FGFR2 gene alteration and progressing during or after at least one prior platinum-containing chemotherapy line, the at least one prior platinum-containing chemotherapy line including neoadjuvant or adjuvant platinum-containing chemotherapy for 12 months or less.

[0006] Broggini's U.S. Patent No. 10,898,482 and De Porre's International Patent Application Publication No. 2020 / 201138 describe certain erdafitinib formulations and treatment methods.

[0007] Examples of intravesical drug delivery systems are described in U.S. Patent No. 8,679,094 by Cima et al., U.S. Patent No. 9,017,312 by Lee et al., U.S. Patent No. 9,107,816 by Lee et al., and U.S. Patent No. 9,457,176 by 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 in vivo drug release occurs when water from the bladder diffuses into the drug reservoir lumen, solubilizing the drug, and then, due to the osmotic pressure accumulated in the drug reservoir lumen, the solubilized drug is released from the drug reservoir lumen through a release opening.

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

[0009] This disclosure generally relates to methods of treating bladder cancer with one or more FGFR changes using erdafitinib, erdafitinib for use, and the use of erdafitinib for treatment, including local delivery of erdafitinib to the patient's bladder, and more specifically, methods and uses using erdafitinib-based pharmaceutical formulations and drug-device combination products, and more specifically, erdafitinib-based formulations and systems for intravesical administration of such formulations.

[0010] In certain embodiments, a method is provided for treating bladder cancer having one or more FGFR gene mutations, comprising delivering a dose effective for the treatment of bladder cancer to the bladder of a patient in need thereof, wherein one or more FGFR gene mutations are detected in a urine sample from the patient, in particular, by a urine-based PCR assay or NGS assay. In certain embodiments, a method is provided for treating bladder cancer having one or more FGFR gene mutations, comprising, or essentially comprising: (a) evaluating a urine sample from a patient having bladder cancer for the presence of one or more FGFR gene mutations, in particular by a urine-based PCR assay or NGS assay; and (b) delivering erdafitinib locally if one or more FGFR gene mutations are present in the sample. In a particular embodiment, a method is provided for treating bladder cancer having one or more FGFR gene mutations, comprising delivering a therapeutically effective amount of erdafitinib locally to the bladder of a patient in need thereof, wherein the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a urine sample from the patient, and in particular, the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a urine sample from the patient using a urine-based PCR assay or NGS assay.

[0011] In a particular embodiment, a method is provided for treating bladder cancer having one or more FGFR gene mutations, comprising delivering a therapeutically effective amount of erdafitinib locally to the bladder of a patient in need thereof, wherein the patient's eligibility for treatment is determined by detecting one or more FGFR gene mutations in a urine sample from the patient, and in particular, the patient's eligibility for treatment is determined by detecting one or more FGFR gene mutations in a urine sample from the patient using a urine-based PCR assay or NGS assay.

[0012] In a particular embodiment, erdafitinib for use in the treatment of bladder cancer in a patient having one or more FGFR gene mutations is provided, wherein the erdafitinib is delivered locally to the patient's bladder, and one or more FGFR gene mutations are detected in a urine sample from the patient, in particular, one or more FGFR gene mutations are detected in a urine sample from the patient using a urine-based PCR assay or NGS assay.

[0013] In a particular embodiment, erdafitinib for use in the treatment of bladder cancer in a patient having one or more FGFR gene mutations is provided, comprising, consisting of, or essentially consisting of: (a) evaluating a urine sample from a patient having bladder cancer for the presence of one or more FGFR gene mutations, particularly using a urine-based PCR assay or NGS assay; and (b) if one or more FGFR gene mutations are present in the sample, delivering erdafitinib topically to the patient.

[0014] Erdafitinib for use in the treatment of bladder cancer having one or more FGFR gene alterations in a patient, wherein the erdafitinib is for local delivery to the patient's bladder, and the patient is selected for treatment based on detection of one or more FGFR gene alterations in a urine sample from the patient, particularly, the patient is selected for treatment based on detection of one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or NGS assay, is provided. In certain embodiments, erdafitinib for use in the treatment of bladder cancer having one or more FGFR gene alterations in a patient, wherein the erdafitinib is for local delivery to the patient's bladder, and the eligibility of the patient for treatment is determined by detecting one or more FGFR gene alterations in a urine sample from the patient, particularly, the eligibility of the patient for treatment is determined by detecting one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or NGS assay, is provided. In certain embodiments, use of erdafitinib for the manufacture of a medicament for the treatment of bladder cancer having one or more FGFR gene alterations in a patient, wherein the erdafitinib is for local delivery to the patient's bladder, and the one or more FGFR gene alterations are detected in a urine sample from the patient, particularly, the one or more FGFR gene alterations are detected in a urine sample from the patient using a urine-based PCR assay or NGS assay, is provided.

[0015] In a particular embodiment, there is a use of erdafitinib for the manufacture of a drug for the treatment of bladder cancer having one or more FGFR gene mutations in a patient, comprising, consisting of, or essentially consisting of: (a) evaluating a urine sample from a patient having bladder cancer for the presence of one or more FGFR gene mutations, particularly using a urine-based PCR assay or NGS assay; and (b) locally delivering erdafitinib if one or more FGFR gene mutations are present in the sample.

[0016] In a particular embodiment, there is a use of erdafitinib for the manufacture of a drug for the treatment of bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is delivered locally to the patient's bladder, and the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a urine sample from the patient, and in particular, the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or NGS assay.

[0017] In certain embodiments, a use of erdafitinib is provided for the manufacture of a drug for the treatment of bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is to be delivered topically to the patient's bladder, and the patient's eligibility for treatment is determined by detecting one or more FGFR gene alterations in a urine sample from the patient, in particular by detecting one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or NGS assay. The method or use may include topically delivering or administering erdafitinib (e.g., as in any of the formulations described herein) to the bladder of a patient in need of treatment, in particular a cancer patient, in an effective dose for the treatment of bladder cancer (e.g., about 1 to 10 mg / day, as described herein). 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, in particular, is a BCG-experiencing bladder or NMIBC or MIBC cancer patient. In another embodiment, the patient, in particular, is a BCG-naive bladder or NMIBC or MIBC cancer patient. In yet another embodiment, the patient, in particular, is a recurrent Bacillus calmette-guerin (BCG)-experiencing high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient who refuses or is ineligible for radical cystectomy (RCy). In one embodiment, the patient, in particular, is a patient with recurrent BCG-treated, high-risk papillary NMIBC (high-grade Ta / T1) cancer who is scheduled for RCy. In another embodiment, the patient, in particular, is a patient with recurrent, moderate-risk NMIBC (Ta and T1) cancer who has a history of only low-grade disease.In one aspect, the patient, particularly a human, is a MIBC cancer patient scheduled for RCy who has refused cisplatin-based neoadjuvant chemotherapy or is ineligible for cisplatin-based neoadjuvant chemotherapy.

[0018] In certain embodiments, a method of treating bladder cancer having one or more FGFR gene alterations, comprising locally delivering an effective amount of erdafitinib for treating bladder cancer to the bladder of a patient who needs it, wherein the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient, particularly, the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient using a tissue-based PCR assay or NGS assay, or the one or more FGFR gene alterations are detected in a histopathological image of the tumor tissue via digital tissue pathology analysis, is provided.

[0019] In a particular embodiment, a method is provided for treating bladder cancer having one or more FGFR gene mutations, comprising, or essentially comprising: (a) evaluating a tumor tissue sample from a patient having bladder cancer for the presence of one or more FGFR gene mutations, in particular by using a tissue-based PCR assay or NGS assay to evaluate a tumor tissue sample from a patient having bladder cancer for the presence of one or more FGFR gene mutations, or by evaluating a histopathological image of tumor tissue from a patient having bladder cancer for the presence of one or more FGFR gene mutations via digital histopathological analysis; and (b) if one or more FGFR gene mutations are present in the sample, locally delivering erdafitinib. In a particular embodiment, a method is provided for treating bladder cancer having one or more FGFR gene mutations, comprising locally delivering a therapeutically effective amount of erdafitinib to the bladder of a patient in need thereof, wherein the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a tumor tissue sample from the patient, in particular, the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a tumor tissue sample from the patient using a tissue-based PCR assay or NGS assay, or the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a histopathological image of the tumor tissue via digital histopathological analysis.

[0020] In a particular embodiment, a method is provided for treating bladder cancer having one or more FGFR gene mutations, comprising locally delivering a therapeutically effective amount of erdafitinib to the bladder of a patient in need thereof, wherein the patient's eligibility for treatment is determined by detecting one or more FGFR gene mutations in a tumor tissue sample from the patient, in particular by detecting one or more FGFR gene mutations in a tumor tissue sample from the patient using a tissue-based PCR assay or NGS assay, or by detecting one or more FGFR gene mutations in a histopathological image of the tumor tissue via digital histopathological analysis.

[0021] In a particular embodiment, erdafitinib for use in the treatment of bladder cancer having one or more FGFR gene mutations in a patient is provided, wherein erdafitinib is delivered locally to the patient's bladder, and one or more FGFR gene mutations are detected in a tumor tissue sample from the patient, in particular, one or more FGFR gene mutations are detected in a tumor tissue sample from the patient using a tissue-based PCR assay or NGS assay, or one or more FGFR mutations are detected in a histopathological image of the tumor tissue via digital histopathological analysis.

[0022] In a particular embodiment, there is provided erdafitinib for use in the treatment of bladder cancer in a patient having one or more FGFR gene mutations, comprising, consisting of, or essentially consisting of: (a) evaluating a tumor tissue sample from a patient having bladder cancer for the presence of one or more FGFR gene mutations, in particular by using a tissue-based PCR assay or NGS assay to evaluate a tumor tissue sample from a patient having bladder cancer for the presence of one or more FGFR gene mutations, or by evaluating a histopathological image of tumor tissue from a patient having bladder cancer for the presence of one or more FGFR gene mutations via digital histopathological analysis; and (b) if one or more FGFR gene mutations are present in the sample, delivering erdafitinib topically to the patient.

[0023] In a particular embodiment, erdafitinib for use in the treatment of bladder cancer having one or more FGFR gene alterations in a patient is provided, wherein the erdafitinib is delivered locally to the patient's bladder, and the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a tumor tissue sample from the patient, in particular, the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR assay or NGS assay, or the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a histopathological image of the tumor tissue via digital histopathological analysis.

[0024] In a particular embodiment, erdafitinib for use in the treatment of bladder cancer having one or more FGFR gene mutations in a patient is provided, wherein the erdafitinib is delivered locally to the patient's bladder, and the patient's eligibility for treatment is determined by detecting one or more FGFR gene mutations in a tumor tissue sample from the patient, in particular by detecting one or more FGFR gene mutations in a tumor tissue sample from the patient using a tissue-based PCR assay or NGS assay, or by detecting one or more FGFR gene mutations in a histopathological image of the tumor tissue via digital histopathological analysis.

[0025] In a particular embodiment, there is a use of erdafitinib for the manufacture of a drug for the treatment of bladder cancer having one or more FGFR gene mutations in a patient, wherein the erdafitinib is delivered locally to the patient's bladder, and one or more FGFR gene mutations are detected in a tumor tissue sample from the patient, in particular, one or more FGFR gene mutations are detected in a tumor tissue sample from the patient using a tissue-based PCR assay or NGS assay, or one or more FGFR mutations are detected in a histopathological image of the tumor tissue via digital histopathological analysis.

[0026] In certain embodiments, there is a use of erdafitinib for the manufacture of a drug for the treatment of bladder cancer having one or more FGFR gene mutations in a patient, comprising, consisting of, or essentially consisting of: (a) evaluating a tumor tissue sample from a patient having bladder cancer for the presence of one or more FGFR gene mutations, in particular by using a tissue-based PCR assay or NGS assay to evaluate a tumor tissue sample from a patient having bladder cancer for the presence of one or more FGFR gene mutations, or by evaluating a histopathological image of tumor tissue from a patient having bladder cancer for the presence of one or more FGFR gene mutations via digital histopathological analysis; and (b) locally delivering erdafitinib if one or more FGFR gene mutations are present in the sample.

[0027] In a particular embodiment, there is a use of erdafitinib for the manufacture of a drug for the treatment of bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is delivered locally to the patient's bladder, and the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a tumor tissue sample from the patient, in particular, the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR assay or NGS assay, or the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a histopathological image of the tumor tissue via digital histopathological analysis.

[0028] In certain embodiments, a use of erdafitinib is provided for the manufacture of a drug for the treatment of bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is to be delivered topically to the patient's bladder, and the patient's eligibility for treatment is determined by detecting one or more FGFR gene alterations in a tumor tissue sample from the patient, in particular by detecting one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR assay or NGS assay, or by detecting one or more FGFR gene alterations in a histopathological image of the tumor tissue via digital histopathological analysis. The method or use may include topically delivering or administering erdafitinib (e.g., as in any of the formulations described herein) to the bladder of a patient in need of treatment, in particular a cancer patient, in an effective dose for the treatment of bladder cancer (e.g., about 1 to 10 mg / day, as described herein). For example, the treatment may be effective in the treatment of muscle-invasive bladder cancer (MIBC), non-muscle-invasive bladder cancer (NMIBC), and / or Bacillus calmette-Guérin (BCG) naive bladder cancer. In one embodiment, the patient, in particular, is a BCG-experienced bladder or NMIBC or MIBC cancer patient. In one embodiment, the patient, in particular, is a BCG-naive bladder or NMIBC or MIBC cancer patient. In one embodiment, the patient, in particular, is a recurrent BCG-experienced high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient who refuses or is ineligible for radical cystectomy (RCy). In one embodiment, the patient, in particular, is a recurrent BCG-experienced high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient for whom RCy is planned. In one embodiment, the patient, in particular, is a patient with recurrent moderate-risk NMIBC (Ta and T1) cancer who has a history of only low-grade diseases.In one embodiment, the patient, in particular, is a MIBC cancer patient scheduled for RCy who has refused or is unsuitable for cisplatin-based neoadjuvant chemotherapy. [Brief explanation of the drawing]

[0029] Detailed descriptions are provided with reference to the attached drawings. The use of the same reference numeral may indicate similar or identical items. Various embodiments may utilize elements and / or components other than those illustrated in the drawings, and some elements and / or components may not be present in various embodiments. The elements and / or components shown in the drawings are not necessarily drawn to scale. [Figure 1] This is a longitudinal cross-sectional view of one embodiment of a drug delivery system in a coiled holding shape according to the present disclosure. [Figure 2] This is a cross-sectional view of one embodiment of the drug delivery system according to the present disclosure. [Figure 3] This is a cross-sectional view of one embodiment of the drug delivery system according to the present disclosure. [Figure 4] This is a photograph of one embodiment of a drug delivery system packed with erdafitinib drug tablets as disclosed herein. [Figure 5] This is a longitudinal cross-sectional view of one embodiment of a drug delivery system according to the present disclosure, in which drug tablets having an elastic retaining frame are held in a coiled shape before being packed. [Figure 6A] This is a longitudinal cross-sectional view of one embodiment of an elastic retaining frame in a coiled retaining shape according to the present disclosure. [Figure 6B] This is a magnified view of one end of the retaining frame in Figure 6A. [Figure 7A] This is a perspective view of one embodiment of a drug delivery system having a relatively straight shape in which the drug is not disposed inside or does not have an elastic retaining frame, as disclosed herein. [Figure 7B] This is a longitudinal cross-sectional view along line 7B-7B of the drug delivery system shown in Figure 7A. [Figure 7C]This is a cross-sectional view of the drug delivery system shown in Figure 7A, along line 7C-7C. [Figure 8] This is a photograph showing a cross-section of the lumen of a drug reservoir in a drug delivery system without a drug inside, as disclosed herein. [Figure 9] This shows single-dose erdafitinib exposure in plasma from nude rats with subcutaneous or orthotopic UM-UC-1 tumors. Exposure levels were measured in plasma from nude rats with naive orthotopic bladder or scUM-UC-1 tumors. Rats were administered a single IVES (1-hour intravenous infusion) or PO dose of erdafitinib at the indicated dose levels. 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] This study demonstrates the effect of erdafitinib on ERK1 / 2 phosphorylation in orthotopic bladder UM-UC-1 tumors. Nude rat UM-UC-1 orthotopic bladder tumors were administered a single dose of erdafitinib via vehicle or at the indicated dose level, either by IVES (1-hour intravenous infusion) or PO, and individual pERK and total ERK levels were measured. pERK and total ERK levels are reported as ratios (pERK / ERK) to the mean of the vehicle group at the corresponding time point, 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 a 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 tumors relative to a control bladder 14 days after implantation is shown. Formalin was used to fix the tissue samples after autopsy. UC, urothelial carcinoma; NBTII, rat Nara bladder tumor No. 2 cells; T24, human bladder cancer cells. [Figure 12] This is a schematic diagram of a perfusion experiment in athymic rats with UM-UC-1 implanted in the bladder wall. [Figure 13] This graph shows the percentage change in body weight of athymic rats with orthotopic UM-UC-1 bladder tumors and bladder cannula insertion. Graph values ​​are expressed as the mean ± SEM of 10-13 animals in each group. The concentrations indicated in the graph are nominal target urinary concentrations. Statistical analysis was performed using GraphPad Prism (version 8.3.0) with two-way ANOVA followed by Bonferroni multiple comparison tests. There was no statistically significant difference in the percentage change in body weight between the erdafitinib (0.5, 1.0, and 5.0 μg / mL) treatment groups and the vehicle control group. SEM, standard error of the mean. [Figure 14] This shows the mean percentage reduction in tumor weight after considering the bladder weight without tumors. Values ​​(groups 1-4) are expressed as the mean ± SEM of 10-13 animals in each group. Statistical analysis was performed using GraphPad Prism (version 8.3.0) with one-way ANOVA followed by Dunnett's multiple comparison test. Conc: concentration; SEM: standard error of mean. [Figure 15]This figure shows the percentage change in body weight of cannula-inserted, athymic nude rats with orthotopic RT-112 bladder tumors. Values ​​are expressed as the mean ± SEM of 2–14 animals in each group. The concentrations indicated in the index of the figure are nominal target urinary concentrations. Statistical analysis was performed using GraphPad Prism (version 8.3.0) with two-way ANOVA followed by Bonferroni multiple comparison tests. When the percentage change in body weight in the erdafitinib (0.5, 1.0, and 5.0 μg / mL) treatment groups was compared to the percentage change in body weight in the vehicle control group, there was no statistically significant difference except for group 4 (*p<0.05) on day 11. SEM, standard error of mean. [Figure 16] This shows the mean bladder weight of athymic nude rats with orthotopic RT-112 bladder tumors. Values ​​(groups 1-5) are expressed as the mean ± SEM of 2-14 animals in each group. Statistical analysis was performed using GraphPad Prism (version 8.3.0) with one-way ANOVA followed by Dunnett's multiple comparison test. *p<0.05. Conc, concentration; SEM, standard error of mean; ns, not significant. [Figure 17A] This shows the plasma concentrations of erdafitinib in rats after bladder perfusion. Bladder perfusion with erdafitinib solution (0.1 mg / mL, 0.1 mL / hour, cumulative dose of 0.72 mg) was performed over 72 hours. Concentrations are expressed as mean 24-hour urinary concentrations in ng / mL. [Figure 17B] This shows the intrabladder concentrations of erdafitinib in rats after bladder perfusion. Bladder perfusion with erdafitinib solution (0.1 mg / mL, 0.1 mL / hour, cumulative dose of 0.72 mg) was performed over 72 hours. Concentrations are expressed as mean 24-hour urinary concentrations in ng / mL. [Figure 18] This table shows the mean urinary erdafitinib concentrations in pigs after 7 days of erdafitinib bladder perfusion. Conc.: concentration; SD: standard deviation. [Figure 19]The mean erdafitinib plasma concentrations in pigs after 7 days of erdafitinib bladder perfusion are shown. SD, standard deviation. [Figure 20] The results of material permeability screening are shown. O indicates permeability, Δ indicates substantially impermeable; × indicates impermeable. a indicates high variability between replicates. [Figure 21] Predicted (from short core) and actual (from full length) mean release rate profiles for the permeation prototype are shown. Erda, erdafitinib-releasing intrabladder system; HPbCD, hydroxypropyl β-cyclodextrin. [Figure 22] The mean release rate profile for the erdafitinib free base + HP-β-CD permeable prototype (EG-80A stripe material) is shown. Erda: erdafitinib; HP-β-CD: hydroxypropyl β-cyclodextrin; SU: simulated urine. [Figure 23] The mean release rate profiles for erdafitinib free base permeability prototypes with and without HP-β-CD (HP-60D-35 stripe material) are shown. Erda, erdafitinib, HP-β-CD or HPbCD, hydroxypropyl β-cyclodextrin;SU, simulated urine. [Figure 24] This shows the in vitro release (IVR) profile for Prototype 1 (permeabilization, erdafitinib free base, tablet, wireform). Erda, erdafitinib; IVR, in vitro release. [Figure 25] The IVR profile for Prototype 2 (permeabilization, erdafitinib free base + HP-β-CD (10% w / w), tablet, wireform) is shown. Erda, erdafitinib; HP-β-CD, hydroxypropyl β-cyclodextrin; IVR, in vitro release. [Figure 26]This section summarizes the in vivo release rate versus time profiles in miniature pigs for prototypes 1 and 2. [Figure 27] We summarize the mean urinary concentration versus time profiles in miniature pigs for prototypes 1 and 2. [Figure 28A] This is a diagram illustrating an exemplary permeability system in which the base material is impermeable TPU and the stripe material is permeable TPU. [Figure 28B] An example of a permeable design is outlined. TPU or tPU, thermoplastic polyurethane; API, active pharmaceutical ingredient; HP-β-CD, hydroxypropyl β-cyclodextrin. [Figure 29] This provides an overview of the solubility of the free base drug erdafitinib as a function of pH at 20°C. (US Pharmacopoeia / European Pharmacopoeia Terminology). [Figure 30] The solubility of erdafitinib free base drug as a function of pH at 37°C, adjusted using HCl. (Exponential function). [Figure 31A] The solubility of erdafitinib free base drug and erdafitinib HCl salt form 1 as a function of pH in simulated urine at 37°C is shown in mg / mL. HP-β-CD, hydroxypropyl β-cyclodextrin; Sim urine, simulated urine. [Figure 31B] The solubility of erdafitinib free base drug as a function of pH in simulated urine at 37°C is shown in mg / mL. HP-β-CD, hydroxypropyl β-cyclodextrin; Sim urine, simulated urine. [Figure 32] This is a schematic diagram of a concordance study of tissue and urine assays using paired samples from bladder cancer patients from the German Bladder BRIDGister clinical trial. [Figure 33-1]This is a heatmap of genetic alterations identified from matched urinary NGS and FFPE tissue RT-PCR samples (from bladder cancer patients in the German Bladder BRIDGister clinical trial). [Figure 33-2] This is a heatmap of genetic alterations identified from matched urinary NGS and FFPE tissue RT-PCR samples (from bladder cancer patients in the German Bladder BRIDGister clinical trial). [Figure 34A] This is a scatter plot of variant allele frequencies (VAF) between matched urinary NGS (X-axis) variants and tissue (FFPE) RT-PCR (Y-axis) variants for all identified genetic alterations, including somatic and germline variants. [Figure 34B] This is a scatter plot of variant allele frequencies (VAF) between matched urinary NGS (X-axis) variants and tissue "FFPE" RT-PCR (Y-axis) variants for somatic cell FGFR3 changes. [Figure 35] A flowchart comparing the performance of urine and tissue tests from all screened NMIBC patients (N=178) at the cutoff date is shown. The patients are from the first human study, as described in Example 9. [Figure 36A] This is a swimlane plot showing clinical efficacy data (treatment duration and response) for disease-evaluable HR-NMIBC patients in Cohort 1 who were screened by urine sample assay and / or tumor tissue sample assay and treated with the intravesical drug delivery system TAR-210-B (approximately 2 mg / day of erdafitinib) or TAR-210-D (approximately 4 mg / day of erdafitinib). The patients are from the first human study, as described in Example 9. A key indicating patient enrollment by tumor tissue sample assay (left of key) or urine sample assay (right of key) ("Enrolled by"; left of figure) is included, along with the corresponding checkmark. Another key describing the patient's treatment status and milestones is included (right of figure). [Figure 36B]This is a swimlane plot showing clinical efficacy data (treatment duration and response) for disease-evaluable IR-NMIBC patients in Cohort 3 who were screened by urine sample assay and / or tumor tissue sample assay and treated with the intravesical drug delivery system TAR-210-B (approximately 2 mg / day of erdafitinib) or TAR-210-D (approximately 4 mg / day of erdafitinib). Patients are from the first human study, as described in the examples. A key indicating patient enrollment by tumor tissue sample assay (left of key) or urine sample assay (right of key) ("Enrolled by"; left of figure) is included, along with the corresponding checkmark. Another key is included (right of figure) describing the patient's treatment status and milestones. [Figure 37] This shows the landscape of pathogenic somatic variants for the 15 most common genes detected in urine from all evaluable samples. Del = deletion; UTR = untranslated region; Ins = insertion; CNV = copy number variation. [Modes for carrying out the invention]

[0030] In some embodiments, erdafitinib solid formulations containing a high concentration of erdafitinib are provided, which are designed for intravesical drug delivery and for controlled and prolonged drug release once deployed in the bladder. In some embodiments, the solid erdafitinib formulations are further adapted for large-scale production and are further adapted to provide structural and chemical integrity of the solid formulation, particularly tablets, when used in an intravesical drug delivery system. Also provided are improved intravesical drug delivery systems, methods for manufacturing the same, and methods for drug delivery. In certain embodiments, the system is configured for intravesical insertion and sustained drug delivery, preferably to provide a therapeutically effective amount of the drug, particularly erdafitinib, at a zero-order release rate.

[0031] The development of erdafitinib formulations and release systems adapted to this administration route to utilize intravesical drug delivery is described herein. When formulated in solid form and administered in a suitable intravesical drug delivery system, such formulations may provide a controlled drug release rate and an extended drug release profile. A system capable of delivering erdafitinib at a release rate effective for local treatment of bladder cancer is further provided.

[0032] Erdafitinib exhibits pH-dependent solubility across the normal urinary pH range of 5.5–7. In some embodiments, the formulation and release system are adapted to minimize the effect of urinary pH and composition on the system release rate.

[0033] In certain embodiments, the drug delivery system described herein is a drug device combination comprising a device component, in particular an intravesical device, and a drug component, in particular an erdafitinib formulation, such as an erdafitinib tablet.

[0034] Specific terms Recurrence-free survival (RFS) is defined as the time from randomization to the first detection of high-grade Ta or T1 bladder cancer or a positive urine cytology test.

[0035] Complete response (CR) is defined as the absence of urothelial carcinoma on pathologically confirmed cystoscopy and a negative urine cytology test in the initial evaluation.

[0036] The duration of complete response (CR) is defined as the time from the first demonstration of CR to the earlier of the date of demonstrated relapse or progression, or death.

[0037] The pathological complete response (pCR) rate is defined as the percentage of participants who have no pathological evidence of bladder disease (pT0) and no pathological evidence of lymph node metastasis (pN0).

[0038] The rate of participants with no pathological evidence of bladder disease (pT0) is defined as the percentage of participants who did not have pathological evidence of bladder disease.

[0039] The downstaging rate to less than pT2 is defined as the percentage of participants who have a pT stage of less than 2.

[0040] When used herein, weight percent for a drug or excipient refers to weight percent based on the total weight of the relevant preparation, unless otherwise specified.

[0041] Erdafitinib preparations and tablets In one embodiment, the disclosure provides erdafitinib formulations, particularly erdafitinib tablets, suitable for use in the disclosed intravesical drug delivery system. Specifically, drug tablets containing erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-6-yl]ethane-1,2-diamine) are provided. Another example is a drug tablet containing 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 embodiment, for example, the drug delivery system may operate by diffusion, which results in a prolonged, continuous release of the drug into the bladder as the drug is released from the tablets in the system.

[0042] To increase or maximize the amount of drug that can be stored in and released from the disclosed drug delivery system, drug tablets may have a relatively high erdafitinib content by weight. This relatively high weight fraction of erdafitinib in a 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, any terms such as “weight fraction,” “weight percentage,” and “percentage by weight” relating to a drug or API (active pharmaceutical ingredient) refer to the drug or API in the form used, whether in free base form, free acid form, salt form, or hydrate form. For example, a drug tablet having 90 wt% of the drug or excipient in salt form may contain less than 90 wt% of the drug in free base form. Unless otherwise stated, weight percentages are relative to the entire solid pharmaceutical composition.

[0043] The erdafitinib drug tablets of this disclosure include an erdafitinib content and an excipient content. The drug content may include erdafitinib in one or more forms, e.g., a free base or a salt form, while the excipient content may include one or more excipients. Certain embodiments include an erdafitinib free base API, and exemplary formulations presented herein include an erdafitinib free base API. The term “excipient” is known in the art and representative examples of excipients useful in the disclosed drug tablets include, but are not limited to, components such as binders, lubricants, flow enhancers, disintegrants, solubilizers, colorants, fillers or diluents, wetting agents, stabilizers, formaldehyde scavengers, coatings, and preservatives, or any combination thereof, as well as other components for facilitating the manufacture, storage, or administration of the drug tablets.

[0044] Another aspect of the present disclosure provides a process for producing a solid pharmaceutical composition, comprising: (a) preparing an intragranular solid composition such that the intragranular solid composition comprises, or is essentially composed 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 into tablets to form a solid pharmaceutical composition. In embodiments, 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 (both present) pharmaceutical excipient, or there may be no common (both present) pharmaceutical excipient between the intragranular and extragranular pharmaceutical excipients. Solid pharmaceutical compositions may be produced by a process that includes preparing a solid composition within granules by a roller compression process or a fluidized bed granulation process. In some embodiments, (a) the step of preparing a solid composition within granules includes (1) preparing a preblend containing erdafitinib free base and one or more excipients, (2) preparing a binder solution, and (3) preparing a solid composition within granules by combining the preblend and the binder solution. In some embodiments, (a) the step of preparing a solid composition within granules includes (1) preparing a preblend containing erdafitinib free base and one or more excipients, (2) preparing a binder solution, and (3) preparing a solid composition within granules by combining the preblend and the binder solution by a fluidized bed granulation process. In some embodiments, the step of preparing the solid composition within the granules (a) includes (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 solid composition within the granules by combining the preblend and the binder solution by a fluidized bed granulation process.In some embodiments, (a) the step of preparing the solid composition within the granules includes (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 solid composition within the granules by combining the preblend and the binder solution by a fluidized bed granulation process. In some embodiments, (a) the step of preparing the solid composition within the granules includes (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 solid composition within the granules by combining the preblend and the binder solution by a fluidized bed granulation process. In some embodiments, (a) the step of preparing the solid composition within the granules includes (1) preparing a preblend of erdafitinib free base, hydroxypropyl-beta-cyclodextrin, and microcrystalline cellulose; (2) preparing a binder solution containing hydroxypropyl methylcellulose and purified water; and (3) preparing the solid composition within the granules by combining the preblend and the binder solution by a fluidized bed granulation process.

[0045] Another aspect of the present disclosure provides a process for producing a solid pharmaceutical composition, comprising: (a) preparing an intragranular solid composition such that the intragranular solid composition comprises, or is essentially composed of, (i) 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 into tablets to form a solid pharmaceutical composition. In embodiments, 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 (both present) pharmaceutical excipient, or there may be no common (both present) pharmaceutical excipient between the intragranular and extragranular pharmaceutical excipients. Solid pharmaceutical compositions may be prepared by a process that includes preparing the solid composition within the granules by a roller compression process or a fluid bed granulation process.

[0046] In one embodiment, the erdafitinib drug tablet contains erdafitinib in its free base form. Other embodiments of the erdafitinib drug tablet may contain erdafitinib in salt form. In one embodiment, the erdafitinib drug tablet may contain 40% by weight or more of erdafitinib free base, and the remainder by weight shall consist of excipients, such as lubricants, binders, and stabilizers, to facilitate the preparation and use of the drug tablet. Alternatively, the erdafitinib drug tablet may contain 45% by weight or more, 50% by weight or more, 55% by weight or more, or 60% by weight or more of erdafitinib free base. In each of these weight percentage embodiments, the substantial upper limit of erdafitinib free base in the tablet formulation is about 65% by weight or 70% by weight. Therefore, in one embodiment, the drug 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 drug tablet may contain about 5% to about 15% by weight of hydroxypropyl-β-cyclodextrin (HP-β-CD). In some of the above embodiments, the drug tablet may contain about 10% by weight of hydroxypropyl-β-cyclodextrin (HP-β-CD). In an embodiment, the drug 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 drug 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 embodiments, the drug 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.

[0047] In one embodiment, the erdafitinib drug tablet contains erdafitinib in its HCl salt form. In one embodiment, the erdafitinib drug tablet may contain 40% by weight or more of erdafitinib HCl salt form, with the remainder by weight comprising excipients that facilitate the preparation and use of the drug tablet, such as lubricants, binders, and stabilizers. Alternatively, the erdafitinib drug tablet may contain 45% by weight or more, 50% by weight or more, 55% by weight or more, or 60% by weight or more of erdafitinib HCl salt form. In each of these weight percentage embodiments, the substantial upper limit of the erdafitinib salt form in the tablet formulation is about 65% by weight or 70% by weight. Thus, in one embodiment, the drug tablet may contain 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 the embodiment, the drug tablet may contain 50% by weight of erdafitinib in its HCl salt form, based on the total weight of the tablet.

[0048] In one embodiment, the erdafitinib drug and excipients are selected to enable the release of the drug from the tablet, and the tablet is formulated in that manner. In some embodiments, the erdafitinib drug and excipients are selected to enable the solubilization of the drug from the tablet, and the tablet is formulated in that manner. In embodiments, erdafitinib is formulated in the pharmaceutical composition so that it can be sterilized either within or outside the drug delivery system without causing substantial or harmful 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 embodiment, the erdafitinib drug and excipients are selected for their suitability to the sterilization process. 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.

[0049] In one embodiment, erdafitinib drug tablets may be sized and molded for use with implantable drug delivery systems, including intravesical drug delivery systems disclosed herein. For example, erdafitinib drug tablets may be “mini-tablets,” which are generally smaller in size than conventional tablets, and mini-tablets may allow drug tablets housed in the system to be inserted through a lumen, such as the urethra, into a cavity, such as the bladder. Erdafitinib tablets may or may not be coated. In particular, uncoated tablets formulated according to this disclosure have been found to function well in combination with systems.

[0050] In embodiments, drug tablets for intravesical insertion or other in vivo implantation may be in the form of a 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. In the cylindrical form, each minitablet may have a length (L) greater than its diameter (D), and thus the minitablet has an aspect ratio (L:D) greater than 1:1. For example, the aspect ratio (L:D) of each minitablet may be in the range of 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, or values ​​between these aspect ratios. Embodiments of minitablets may have cylindrical diameters 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.

[0051] The API used in the solid tablet formulation may be erdafitinib, which is N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-6-yl]ethane-1,2-diamine, the chemical structure of which is shown below. The disclosed erdafitinib tablets for use in the intravesical system may be formulated using erdafitinib free base or a salt thereof. In one embodiment, the disclosed erdafitinib tablets for use in the intravesical system may contain erdafitinib free base. In one embodiment, the disclosed erdafitinib tablets for use in the intravesical system may contain erdafitinib HCl salt, in particular erdafitinib HCl salt in crystalline form. In some of the above embodiments, the disclosed erdafitinib tablets for use in the intravesical system may contain 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 solubility properties for effective use of the free base formulation in the disclosed intravesical system.

[0052] [ka]

[0053] In embodiments, erdafitinib drug tablets can incorporate a variety of excipients, which include, but are 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 flow enhancer, and at least one lubricant, 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 embodiment, at least one intragranular pharmaceutical excipient and at least one extragranular pharmaceutical excipient may be the same, that is, they may be selected from at least one common (present in both) pharmaceutical excipient. In further embodiments, the intragranular and extragranular pharmaceutical excipients do not include a common (present in both) pharmaceutical excipient, thereby making the intragranular and extragranular excipients mutually exclusive. In embodiments, erdafitinib drug tablets, particularly erdafitinib drug tablets containing 40% to 70% by weight, or 40% to 60% by weight, or 45% to 55% by weight, for example 50% by weight of erdafitinib, include at least one solubilizer, at least one binder, at least one stabilizer, at least one diluent, at least one flow enhancer, and at least one lubricant, or any combination thereof. In embodiments, erdafitinib drug tablets, particularly erdafitinib drug tablets containing 40% to 70% by weight, or 40% to 60% by weight, or 45% to 55% by weight, for example 50% by weight of erdafitinib, include at least one solubilizer, at least one binder, at least one diluent, at least one flow enhancer, and at least one lubricant, or any combination thereof.

[0054] These functional descriptions of various excipients will generally be understood to be used as follows: Solubilizers can improve or enhance the solubility of APIs, such as erdafitinib free base, in the drug lumen of a system or in a body cavity, such as the bladder, when released from the system in which the API is disclosed. Binders can hold together the solid particles of a composition for physical stability. Wetting agents can reduce the surface tension between the drug and the medium from which the drug is released, thereby helping to maintain the solubility of the drug. Disintegrants can assist in the disintegration of minitablets when they come into contact with water and release the drug substance. Stabilizers can improve chemical stability, such as the thermal stability of a formulation containing an API, or protect the API from degradation. Diluents can act as volume extenders to increase the volume or weight of a composition, which can help provide tablets of a desired size or improve the tabletability of an API-excipient blend. Flow enhancers can improve the flow properties of the (granulated) particles of the tablet components or the powder blend being tableted. Lubricants can prevent particles of the composition from adhering to components of the manufacturing apparatus, such as the dies and punches of a tablet press. In one embodiment, the excipient may be water-soluble. In another embodiment, the excipient may be colloidal in water. According to yet another embodiment, the excipient may be soluble in a patient, for example, under the conditions of its deployment in the bladder. These and other excipients are described in more detail below.

[0055] Stabilizers such as formaldehyde scavengers In one embodiment, the erdafitinib API may be susceptible to degradation under certain conditions when incorporated into a solid formulation. For example, erdafitinib may decompose or be converted in the presence of formaldehyde to form the cyclization product 6,8-dimethoxy-4-(1-methylethyl)-1-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-6-yl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine. Formaldehyde may come into contact with erdafitinib from various sources in the environment, such as from packaging materials or as an inclusion in excipients or other components of the formulation.

[0056] Therefore, in one embodiment, the erdafitinib pharmaceutical formulation may contain a formaldehyde scavenger to improve the stability or shelf life of the formulation. Various formaldehyde scavengers may be used, and the formaldehyde scavenger may prevent, slow down, reduce, or postpone the formation of decomposition products when erdafitinib comes into contact with formaldehyde. Therefore, the stability of the erdafitinib pharmaceutical formulation, for example, its chemical stability, can be increased in the presence of a formaldehyde scavenger compared to the erdafitinib pharmaceutical formulation in the absence of a formaldehyde scavenger. In one embodiment, the formaldehyde scavenger may be present in the solid pharmaceutical composition as a component of the solid composition within granules, the solid composition outside granules, or both the solid and solid compositions within granules. In one embodiment, the formaldehyde scavenger, in particular meglumine, may be present in the solid pharmaceutical composition as a component of the solid composition within granules.

[0057] The formaldehyde scavenger may include, or be selected from, compounds containing a reactive nitrogen center, such as compounds containing an amine or amide group. While not theoretically bound, these compounds react with formaldehyde to form Schiff base imines (R 1 R 2 C=NR 3 , here, R 3It is thought that the Schiff base imine itself can form a non-hydrogen (i) compound and can bind to 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 may contain two or more amine and / or amide moieties capable of scavenging formaldehyde.

[0058] In one embodiment, the formaldehyde scavenger may include, 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, their conjugates, their pharmaceutically acceptable salts, or any combination thereof, or selected from thereto. According to one embodiment, the formaldehyde scavenger may include meglumine or a pharmaceutically acceptable salt thereof, in particular meglumine base, or selected from thereto.

[0059] Accordingly, one aspect of the present disclosure is the use of a formaldehyde scavenger, particularly meglumine, in an erdafitinib pharmaceutical formulation, such as a drug tablet formulation, to increase the stability of erdafitinib in any of the forms of erdafitinib, including erdafitinib free base, its salts, or its solvates. The chemical stability of the erdafitinib pharmaceutical formulation is increased compared to an erdafitinib pharmaceutical formulation or composition that does not contain a formaldehyde scavenger. One aspect of the present disclosure is a method for preventing, slowing, reducing, or delaying the formation of degradation products that may be formed from erdafitinib in the presence of formaldehyde, such as the following compounds:

[0060] [ka]

[0061] In one embodiment, decomposition products, such as those described above, may occur in solid tablet compositions, such as mini-tablet formulations, particularly in mini-tablets disclosed herein.

[0062] When present in an erdafitinib solid pharmaceutical composition, the formaldehyde scavenger can be present in the solid pharmaceutical composition at concentrations 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 at 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 concentrations 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 the 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 concentrations 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, 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 of the embodiments described above, the formaldehyde scavenger is meglumine.

[0063] In some embodiments, the pharmaceutical compositions described herein, in particular the erdafitinib drug tablets, do not contain stabilizers or formaldehyde scavengers.

[0064] Solubilizer In one embodiment, the erdafitinib formulation may contain a solubilizer. The solubilizer may be present in the intragranular components, extragranular components, or both intragranular and extragranular components of the formulation. In embodiments, the solubilizer may include, for example, (a) a cyclic oligosaccharide, (b) cellulose functionalized with a methoxy moiety, a 2-hydroxypropoxy moiety, an acetyl moiety, or a succinoyl moiety, or a combination thereof, or (c) salts thereof, or can be selected from thereto. In one embodiment, the solubilizer is present in the intragranular components.

[0065] In embodiments, the solubilizer for erdafitinib tablet formulations may contain or be selected from oligosaccharides. In embodiments, the solubilizer may contain or be selected from cyclic oligosaccharides, such as cyclodextrins. Suitable cyclodextrin solubilizers for erdafitinib tablet formulations include, but are not limited to, hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, sulfobutyl ether-beta-cyclodextrin sodium salt, or any combination thereof. In other embodiments, the solubilizer may contain or be hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose E5 (HMC-E5), or a combination thereof.

[0066] Oligosaccharide solubilizers may be present in erdafitinib tablet formulations, such as erdafitinib free base formulations, at concentrations 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. Cyclodextrin solubilizers may be present in erdafitinib tablet formulations, such as erdafitinib free base formulations, at concentrations of 1% by weight, 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, 16% by weight, 17% by weight, 18% by weight, 19% by weight, or 20% by weight, or any range within any of these weight percentages.

[0067] In one embodiment, the solubilizer for the erdafitinib tablet formulation disclosed herein may contain hydroxypropyl-beta-cyclodextrin (HP-β-CD). One embodiment of the erdafitinib free base formulation includes a hydroxypropyl-beta-cyclodextrin solubilizer, and in particular includes an erdafitinib free base formulation containing hydroxypropyl-beta-cyclodextrin at a concentration of 8% to 12% by weight, or alternatively, 10% by weight or about 10% by weight. In some embodiments, the formulation contains hydroxypropyl-beta-cyclodextrin at a concentration of about 10% by weight. In this formulation, the erdafitinib free base API may 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 solid composition within the granules. In embodiments, the drug tablet may contain 50% by weight of erdafitinib in its free base form, 1% by weight of meglumine, and 8% to 12% by weight of hydroxypropyl-beta-cyclodextrin, or alternatively, 10% by weight or about 10% by weight. In embodiments, the drug tablet may contain 50% by weight of erdafitinib in its free base form, based on the total weight of the tablet, and may contain 10% by weight of hydroxypropyl-beta-cyclodextrin (HP-β-CD) and 1% by weight of meglumine. In embodiments, the drug tablet may contain at least about 45% by weight of erdafitinib in its free base form, based on the total weight of the tablet, and may contain 10% by weight of hydroxypropyl-beta-cyclodextrin (HP-β-CD) and 0% by weight of meglumine. In the embodiment, the drug 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.

[0068] Binder The pharmaceutical excipients for erdafitinib solid pharmaceutical compositions may comprise one or more binders. These binders may be present in the solid pharmaceutical composition as components of the intragranular solid composition, the extragranular solid composition, or both intragranular and extragranular solid compositions. Suitable binders may be water-soluble, water-insoluble, slightly water-soluble, or a combination thereof. In one embodiment, the binder may include polymer binders, such as water-soluble polymer binders, slightly water-soluble polymer binders, water-insoluble polymer binders, or any combination thereof. The polymer binder may include nonionic polymers.

[0069] Those skilled in the art will understand that binders can also function as diluents (also referred to as fillers) in pharmaceutical compositions. Therefore, the binders provided herein may also be used for these diluent functions, as needed, unless otherwise specified.

[0070] In one embodiment, a suitable binder may include, or be selected from, polyvinylpyrrolidone (PVP, also known as polyvidone, povidone, or poly(1-vinyl-2-pyrrolidon)), poly(vinyl acetate, PVA), vinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide (PEO, also known as poly(ethylene glycol) or PEG), polypropylene oxide (PPO, also known as poly(propylene glycol) or PPG), ethylene glycol-propylene glycol copolymer, poloxamer, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, silicified microcrystalline cellulose, or a combination thereof. In one embodiment, a suitable binder may include, or may be selected from, polyvinylpyrrolidone (also known as PVP, polyvidone, povidone, or poly(1-vinyl-2-pyrrolidinone)), poly(vinyl acetate) (PVA), vinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide (also known as PEO, poly(ethylene glycol), or PEG), polypropylene oxide (also known as PPO, poly(propylene glycol), or PPG), ethylene glycol-propylene glycol copolymer, poloxamer, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, or a combination thereof.In one embodiment, 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 solid composition within the granules.

[0071] In further embodiments, preferred binders may include, or be selected from, polymers or copolymers of vinylpyrrolidone (VP, or 1-vinyl-2-pyrrolidinone) and vinyl acetate (VA). Such copolymers of VP and VA may also be referred to as "copovidone." Preferred 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, with microcrystalline cellulose, hydroxypropyl cellulose (HPC), or hydroxypropyl methylcellulose (HPMC).

[0072] In one embodiment, the total concentration of at least one binder in the solid pharmaceutical composition may 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.

[0073] In another embodiment, a suitable polymer binder may include, or be selected from, a copolymer 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 light scattering measurements in solution. Another suitable binder is Kollidon® K30.

[0074] In embodiments, polymer binders, such as vinylpyrrolidone-vinyl acetate copolymer, may be present in the disclosed erdafitinib tablet formulations at concentrations of 2% to 15% by weight, alternatively 4% to 12% by weight, alternatively 6% to 10% by weight, or alternatively 8% by weight or about 8% by weight. For example, the vinylpyrrolidone-vinyl acetate copolymer binder may be present in the erdafitinib tablet formulation, such as the erdafitinib free base formulation, at concentrations 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 of these weight percentages, for example, 7.5% by weight. In one embodiment, 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 solid composition within the granules. In one embodiment, the vinylpyrrolidone-vinyl acetate copolymer is present in the solid composition within the granules, and the solid composition within the granules is prepared by roller compression. In one embodiment, the vinylpyrrolidone-vinyl acetate copolymer is present in the solid composition within the granules, and the solid composition within the granules is prepared by fluid bed granulation. In one embodiment, the vinylpyrrolidone-vinyl acetate copolymer is present in the solid composition outside the granules. In one embodiment, the vinylpyrrolidone-vinyl acetate copolymer is present at a concentration of about 7.5% by weight of the solid composition and is located in the solid composition outside the granules.

[0075] In one embodiment, the binder may contain or be microcrystalline cellulose. For example, microcrystalline cellulose may be present in the solid pharmaceutical composition at concentrations of 5% to 30% by weight, 10% to 20% by weight, 5% to 20% by weight, 6% to 15% by weight, or 7% to 12% by weight. For example, 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, microcrystalline cellulose may be present in the solid pharmaceutical composition at a concentration of about 17.5% by weight of the solid composition, and may be present in the solid composition inside and outside the granules. For example, microcrystalline cellulose may be present in the solid pharmaceutical composition as a filler in the solid composition inside the granules at a concentration of about 10% by weight of the solid composition, and may be present in the solid pharmaceutical composition as a binder in the composition outside the granules at a concentration of about 7.5% by weight of the solid composition.

[0076] In another embodiment, the binder may contain or be composed of silicified microcrystalline cellulose. For example, silicified microcrystalline cellulose may be present in the solid pharmaceutical composition at concentrations of 3% to 18% by weight, 4% to 15% by weight, or 5% to 12% by weight.

[0077] In a further embodiment, the binder may contain or be composed of hydroxypropyl methylcellulose (HPMC). For example, hydroxypropyl methylcellulose (HPMC) may be present in the solid pharmaceutical composition at concentrations of 0.25% to 5% by weight, 0.5% to 4% by weight, or 0.75% to 3% by weight. In one embodiment, the HPMC binder may be present in the solid pharmaceutical composition, or in the solid composition within the granules.

[0078] Humectant The pharmaceutical excipients for the erdafitinib solid pharmaceutical composition may include one or more wetting agents. The one or more wetting agents may be present in the solid pharmaceutical composition as an intragranular solid composition, an extragranular solid composition, or both intragranular and extragranular solid compositions. In exemplary embodiments, the wetting agent may include anionic surfactants or nonionic surfactants, particularly anionic surfactants, or may be independently selected from them. For example, the wetting agent may include sodium lauryl sulfate, sodium stearyl fumarate, polysorbates, such as polysorbate 80, sodium docusate, or any combination thereof, or may be independently selected from them. In embodiments, 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.

[0079] In one embodiment, the erdafitinib solid pharmaceutical composition does not contain one or more wetting agents.

[0080] Disintegrant The pharmaceutical excipients for the erdafitinib solid pharmaceutical composition may include one or more disintegrants. The one or more disintegrants may be present in the solid pharmaceutical composition as an intragranular solid composition, an extragranular solid composition, or both. In one embodiment, the disintegrant is present in the intragranular solid composition. In one embodiment, the disintegrant is present in the intragranular solid composition, which is prepared by roller compression.

[0081] In exemplary embodiments, the disintegrant may include or be independently selected from functionalized polysaccharides or crosslinked polymers. For example, in one embodiment, the disintegrant may include, for example, (a) cellulose functionalized with a methoxy moiety, a 2-hydroxypropoxy moiety, or a carboxymethoxy moiety, salts thereof, or combinations thereof, (b) carboxymethylated starch, or (c) a crosslinked polymer, or can be selected from there.

[0082] In the embodiment, the disintegrant may include hydroxypropyl methylcellulose, low-substituted hydroxypropylcellulose, crospovidone (cross-linked polyvinylpyrrolidone), croscarmellose sodium (cross-linked carboxymethylcellulose sodium), sodium starch glycolate, or any combination thereof, or may be independently selected from there.

[0083] When present, the disintegrant can be present in a range of concentrations. In embodiments, the total concentration of the disintegrant in the solid pharmaceutical composition can be 0.1% to 3% by weight, 0.5% to 2.5% by weight, 1% to 2% by weight, or about 1.5% by weight.

[0084] In one embodiment, the erdafitinib solid pharmaceutical composition does not contain one or more disintegrants.

[0085] Diluent or filler The pharmaceutical excipients for the erdafitinib solid pharmaceutical composition may include one or more diluents. The one or more diluents may be present in the solid pharmaceutical composition as components of the solid composition within granules, the solid composition outside of granules, or both the solid composition within and outside of granules.

[0086] 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 embodiment, the diluent may include, or be selected from, lactose, dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, silicified microcrystalline cellulose, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium carbonate, sucrose, or any combination thereof.

[0087] 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 embodiments, the diluent may contain 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 embodiments, the diluent may contain or be selected from anhydrous calcium hydrogen phosphate at a concentration of 18% to 20% by weight. In further embodiments, the diluent may contain or be selected from anhydrous calcium hydrogen phosphate at a concentration of about 19% by weight. In a further embodiment, the diluent may contain, or may not contain, anhydrous calcium hydrogen phosphate at a concentration of about 19% by weight present in the non-granular solid composition. In a further embodiment, the diluent may contain, or may 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 contain silicified microcrystalline cellulose at a concentration of about 10.75% by weight or 11.75% by weight of the solid composition. For example, the diluent may contain silicified microcrystalline cellulose at a concentration of about 10.75% by weight or 11.75% by weight of the solid composition and is present in the non-granular composition. For example, the diluent may contain silicified microcrystalline cellulose at a concentration of about 10.75% by weight of the solid composition and is present in the non-granular composition. For example, the diluent may contain silicified microcrystalline cellulose at a concentration of about 11.75% by weight of the solid composition and is present in the non-granular composition. In a further embodiment, the diluent does not contain silicified microcrystalline cellulose. In a further embodiment, the diluent may contain microcrystalline cellulose and silicified microcrystalline cellulose. In a further embodiment, the diluent may contain microcrystalline cellulose or silicified microcrystalline cellulose. In a further embodiment, the diluent may contain microcrystalline cellulose at a concentration of about 10% by weight. In a further embodiment, the diluent may contain microcrystalline cellulose present in the granular composition at a concentration of about 10% by weight.For example, microcrystalline cellulose can be present in a 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 a solid pharmaceutical composition at a concentration of about 17.5% by weight of the solid composition, and can be present in both the solid and non-granular solid compositions. For example, microcrystalline cellulose can be present in a solid pharmaceutical composition as a filler in the solid granular composition at a concentration of about 10% by weight of the solid composition, and can be present in a solid pharmaceutical composition as a binder in the non-granular composition at a concentration of about 7.5% by weight of the solid composition.

[0088] Those skilled in the art will understand that some of the diluents / fillers disclosed herein may also function as binders in pharmaceutical compositions. Accordingly, some compounds or materials may be described herein as providing both binder and diluent / filler functions.

[0089] Flow accelerator A pharmaceutical excipient for an erdafitinib solid pharmaceutical composition may comprise one or more flow promoters. These one or more flow promoters may be present in the solid pharmaceutical composition as components of the intragranular solid composition, the extragranular solid composition, or both the intragranular and extragranular solid compositions. In one embodiment, the flow promoter is present in the extragranular solid composition. As used in this disclosure, a flow promoter means a pharmaceutical excipient that improves or optimizes the particle flow properties of a granulated or powdered tablet component in particulate form by reducing inter-particle interactions, attractive forces, aggregation, or friction. A pharmaceutically acceptable flow promoter is a non-toxic and pharmacologically inert substance. Furthermore, the flow promoter may be water-soluble or water-insoluble.

[0090] In one embodiment, the flow accelerator may include colloidal silicon dioxide, colloidal anhydrous silicon dioxide, talc, or any combination thereof, or may be selected from thereto. In embodiments, the total concentration of the flow accelerator in the solid pharmaceutical composition may be 0.01% to 5% by weight, 0.05% to 3% by weight, 0.1% to 1% by weight, or about 0.2% by weight, or about 0.25% by weight, or about 0.3% by weight, about 0.35% by weight, or about 0.4% by weight, or about 0.45% by weight, or about 0.5% by weight. In one embodiment, the flow accelerator is colloidal silicon dioxide. In some embodiments, the flow accelerator is colloidal silicon dioxide in an amount of about 0.5% by weight of the solid composition. In some embodiments, the flow accelerator is colloidal silicon dioxide in an amount of about 0.5% by weight of the solid composition and is present in the non-granular composition. In some embodiments, the flow enhancer is colloidal silicon dioxide in an amount of about 0.25% by weight of the solid composition. In some embodiments, the flow enhancer is colloidal silicon dioxide in an amount of about 0.25% by weight of the solid composition and is present in the extragranular composition.

[0091] lubricant Pharmaceutical excipients for erdafitinib solid pharmaceutical compositions may comprise one or more lubricants. One or more lubricants may exist in the solid pharmaceutical composition as components of the intragranular solid composition, the extragranular solid composition, or both intragranular and extragranular solid compositions. In one embodiment, the lubricant is present in the extragranular solid composition. In one embodiment, the lubricant is present in the intragranular solid composition, which is prepared by roller compression. As used in this disclosure, a lubricant refers to a pharmaceutical excipient added to a tablet formulation to reduce friction on the surface of the tablet. In embodiments, a lubricant may reduce friction between the tablet surface and processing equipment, for example, friction between the tablet surface and the wall of the die cavity in which the tablet is formed. Thus, a lubricant may reduce friction between the die wall and the granules of the formulation when the tablet is formed and ejected. A pharmaceutically acceptable lubricant is a non-toxic and pharmacologically inert substance. Furthermore, a lubricant may be water-soluble or water-insoluble.

[0092] In one embodiment, the lubricant may include, for example, fatty acids, fatty acid salts, fatty acid esters, talc, glyceride esters, metal silicates, or any combination thereof, or may be selected from there. In embodiments, the lubricant may include, or may be selected from there, magnesium stearate, stearic acid, magnesium silicate, aluminum silicate, isopropyl myristate, sodium oleate, sodium stearoyl lactylate, sodium stearoyl fumarate, titanium dioxide, or a combination thereof. Examples of lubricants, but not limited to, include leucine, sodium lauryl sulfate, sucrose stearate, boric acid, sodium acetate, sodium oleate, sodium stearyl fumarate, and PEG. In another embodiment, the total concentration of the lubricant in the solid pharmaceutical composition may be 0.05% to 5% by weight, 0.1% to 3% by weight, 1% to 2% by weight, or about 1.5% by weight. In one embodiment, the lubricant is magnesium stearate. In some embodiments, the lubricant is magnesium stearate and is present in the granular composition or the extragranular composition. In some embodiments, the lubricant is magnesium stearate and is present in the granular and extragranular compositions. In some embodiments, the lubricant is magnesium stearate in an amount of about 1.5% by weight of the solid composition. In some embodiments, the lubricant is magnesium stearate in an amount of about 1.5% by weight of the solid composition and is present in the granular composition. In some embodiments, the lubricant is magnesium stearate in an amount of about 1.5% by weight of the solid composition and is present in the extragranular composition. In some embodiments, the lubricant is magnesium stearate in an amount of about 1.5% by weight of the solid composition and is present in the granular and extragranular compositions.

[0093] Formulation development Erdafitinib formulations, particularly erdafitinib tablets, comprising (a) a high erdafitinib drug packing, 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 in the range of 45% to 55% by weight, or in the range of about 50% by weight; (b) providing acceptable chemical stability of erdafitinib; and (c) supporting tablet manufacturing, for example, high manufacturing speed for tablet manufacturing on an industrial scale, in particular having a length (L) greater than the diameter (D), and thus having an aspect ratio (L:D) greater than 1:1. , in particular, erdafitinib formulations, in particular erdafitinib tablets, are provided herein, which support the manufacture of such 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, in particular, the manufacture of such tablets on an industrial scale, in particular, support high manufacturing speeds for the manufacture of such tablets on an industrial scale, in particular, minitablets, (d) provide tablets that are sufficiently physically robust, in particular provide tablets that are suitable for inclusion in drug delivery systems, in particular, permeation systems, as described herein, and / or (e) exhibit desired disintegration and / or dissolution properties.

[0094] Erdafitinib formulations having a series of excipient combinations, both intragranular and extragranular, are provided in Table 1 of the Examples, which describes formulations 4A, 4B, 4C, and 4D. Further erdafitinib formulations having a series of excipient combinations are provided in Table 3 and the Examples, which describe formulations 3.2, 3.3, 3.4, and 4.1.

[0095] Solid formulations of erdafitinib, particularly erdafitinib minitablets, are provided herein, having a particularly high erdafitinib drug engulfation, 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 tablets may be obtained by a process comprising fluid bed granulation. In one embodiment, the tablets may be obtained by a process comprising roller compression. In one embodiment, the solid composition within the granules comprises cyclodextrin, particularly hydroxypropyl-beta-cyclodextrin. In one embodiment, the formulation does not contain mannitol in the solid composition within the granules. In one embodiment, the solid composition within the granules does not contain a water-soluble filler. In one embodiment, the formulation comprises a water-insoluble filler, for example, microcrystalline cellulose.

[0096] In one embodiment, a fluid bed granulation process for producing granules is provided, wherein the granules comprise erdafitinib and hydroxypropyl-beta-cyclodextrin. In one embodiment, the process does not involve the use of a water-soluble filler, such as mannitol.

[0097] Solid formulations of erdafitinib, particularly erdafitinib minitablets, are provided herein, having a particularly high erdafitinib drug engulfation, for example, in the range of 45% to 55% by weight or about 50% by weight, and containing vinylpyrrolidinone-vinyl acetate copolymer and microcrystalline cellulose, particularly in weight ratios 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 minitablets, for example, 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 contain mannitol.

[0098] In one embodiment, a process is provided for producing tablets, in particular minitablets as described herein, wherein the powder blend to be compressed comprises vinylpyrrolidinone-vinyl acetate copolymer and microcrystalline cellulose in weight ratios 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 embodiment, a process is provided for producing tablets, in particular minitablets as described herein, wherein the powder blend to be compressed comprises erdafitinib, vinylpyrrolidinone-vinyl acetate copolymer, and microcrystalline cellulose, in particular, the weight ratio of vinylpyrrolidinone-vinyl acetate copolymer to microcrystalline cellulose is 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 embodiment, the powder blend to be compressed further comprises hydroxypropyl-beta-cyclodextrin. In one embodiment, the powder blend to be compressed does not contain mannitol.

[0099] Solid formulations of erdafitinib, particularly erdafitinib powder formulations or erdafitinib minitablets, are provided herein, having in particular a high erdafitinib drug engulfing, e.g., 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 in the range of about 50% by weight, and having a low content of fine particles, e.g., 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 minitablets described herein, especially when tableting at high speed, e.g., 2500 tablets / min.

[0100] In one embodiment, a formulation, particularly a tablet or minitablet, comprising erdafitinib, particularly a high erdafitinib drug engulfation, e.g., 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, hydroxypropyl-beta-cyclodextrin, vinylpyrrolidinone-vinyl acetate copolymer, and microcrystalline cellulose, is provided herein. In one embodiment, the formulation further comprises meglumine. In one embodiment, the formulation does not contain mannitol. In one embodiment, the formulation further comprises at least one or all of the following: a flow enhancer, e.g., colloidal silica; a lubricant, e.g., magnesium stearate; a binder, e.g., a cellulose derivative, e.g., hydroxypropyl methylcellulose; a filler, e.g., silicified microcrystalline cellulose.

[0101] In one embodiment, a formulation, particularly a tablet or minitablet, comprising erdafitinib, particularly a high erdafitinib drug engulfation, e.g., 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, and hydroxypropyl-beta-cyclodextrin, vinylpyrrolidinone-vinyl acetate copolymer, and microcrystalline cellulose, is provided herein. In one embodiment, the formulation further comprises at least one or all of the following: a flow enhancer, e.g., colloidal silica; a lubricant, e.g., magnesium stearate; a binder, e.g., a cellulose derivative, e.g., hydroxypropyl methylcellulose; and a filler, e.g., silicified microcrystalline cellulose. In one embodiment, the formulation does not contain a stabilizer, e.g., meglumine. In one embodiment, the preparation does not contain mannitol.

[0102] 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.

[0103] Accordingly, formulation 4D formulations are encompassed by this 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, the weight percentages of which are relative to the whole solid pharmaceutical composition. In one embodiment, the formulation is prepared by (a) preparing an intragranular solid composition by a fluid bed granulation process, wherein the intragranular solid composition essentially consists 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. The blend may be prepared by a process comprising: forming a blend in which the extragranular components essentially consist 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 into tablets to form a solid pharmaceutical composition in the form of minitablets. In one embodiment, the tablets contain 11.5 mg of erdafitinib.

[0104] Accordingly, formulation 4C is encompassed by this 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 hydroxypropyl methylcellulose, (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, the weight percentages of which are relative to the whole solid pharmaceutical composition. In one embodiment, 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 extragranular components to form a blend, and (c) compressing the blend into tablets to form a solid pharmaceutical composition in the form of minitablets, the intragranular and extragranular components being described in the examples in Table 1. In one embodiment, the tablet contains 11.5 mg of erdafitinib.

[0105] Accordingly, formulation 4B is encompassed by this disclosure, in which formulation 4B 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, the weight percentages of which are relative to the whole solid pharmaceutical composition. In one embodiment, 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 into tablets to form a solid pharmaceutical composition in the form of minitablets, the intragranular and extragranular components being described in the examples in Table 1. In one embodiment, the formulation may be prepared by a process comprising (a) preparing an intragranular solid composition by a roller compression process, (b) combining the intragranular solid composition with an extragranular component to form a blend, and (c) compressing the blend into tablets to form a solid pharmaceutical composition in the form of minitablets, the intragranular and extragranular components being described in the examples in Table 1.

[0106] Accordingly, Formulation 4A is encompassed by this disclosure, in which Formulation 4A 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, the weight percentages of which are relative to the whole solid pharmaceutical composition. In one embodiment, 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 into tablets to form a solid pharmaceutical composition in the form of minitablets, the intragranular and extragranular components being described in the examples in Table 1. In one embodiment, the formulation may be prepared by a process comprising (a) preparing an intragranular solid composition by a roller compression process, (b) combining the intragranular solid composition with an extragranular component to form a blend, and (c) compressing the blend into tablets to form a solid pharmaceutical composition in the form of minitablets, the intragranular and extragranular components being described in the examples in Table 1.

[0107] Accordingly, Formulation 4.1 is encompassed by this 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, the weight percentages of which are relative to the whole solid pharmaceutical composition. In one embodiment, the formulation is prepared by (a) a fluid bed granulation process in which the solid pharmaceutical composition comprises (i) erdafitinib free base at a concentration of 50% by weight of the solid pharmaceutical composition, (ii) preparing a solid pharmaceutical composition consisting of hydroxypropyl-beta-cyclodextrin at a concentration of 10% by weight, (iii) microcrystalline cellulose at a concentration of 10% by weight, and (iv) hydroxypropyl methylcellulose at a concentration of 1.5% by weight, and (b) forming a blend by combining an intragranular solid composition with an extragranular component, wherein the extragranular component consists of (i) microcrystalline cellulose at a concentration of 7.5% by weight of the solid pharmaceutical composition, The solid pharmaceutical composition may be prepared by a process comprising: (ii) forming a solid pharmaceutical composition consisting of 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 into tablets to form a solid pharmaceutical composition in the form of minitablets. In one embodiment, the tablets contain 11.5 mg of erdafitinib.

[0108] Diffusion-based drug delivery systems Drug delivery systems particularly suitable for the effective release of drug formulations containing erdafitinib, such as those described in detail above or below, are described herein. These specific systems have been developed in which, instead of an osmotic drug release mechanism, drug release is controlled by drug diffusion through drug-permeable polymer components defining a portion of the system housing.

[0109] In certain embodiments, the system includes drug-permeable polymer components or portions that form part of a housing. For example, the drug-permeable components or portions of the system may be part of a housing, and the portion of the housing is formed from a different material from the rest of the housing (e.g., strips or a number of strip materials extending along at least one portion of the length of the housing), so 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 drug-impermeable portions are formed from a thermoplastic polyurethane composition to provide (i) controlled diffusion of drugs from the system, (ii) desired mechanical properties (e.g., being able to be straightened for insertion / removal, being flexible enough to exhibit good tolerance while implanted, the tube remaining intact under small compression / stretching, elastic deformability (compliance) in response to detrusor contracture), (iii) a system that can be thermally shaped to have a desired retaining shape, and / or (iv) a system that can be manufactured in a co-extrusion process.

[0110] 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 of the above embodiments, the material of the drug-permeable portion is an aliphatic polyether-based TPU. In some of the above embodiments, the material of the drug-permeable portion is an aliphatic polyether-based TPU, which is Lubrizol Tecophilic HP-60D-35 or HP-93A-100.

[0111] 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 impermeable to or substantially impermeable to erdafitinib free base formulated without HP-β-CD. In some of the above embodiments, the material of the drug-permeable portion is an aliphatic polyether-based TPU. In some of the above embodiments, the material of the drug-permeable portion is Lubrizol Tecoflex EG-80A.

[0112] Exemplary materials for the drug-permeable portion (e.g., the “stripe” material of the permeability 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 material for the drug-permeable portion is Lubrizol Tecophilic HP-60D-35, Tecophilic HP-93A-100, or Tecoflex EG-80A. In some embodiments, the material for the drug-permeable portion is Lubrizol Tecoflex EG-80A. In some embodiments, the drug is erdafitinib free base, and the material for the drug-permeable portion 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.

[0113] Exemplary materials for the drug-impermeable portion (e.g., the “base” material of the permeability system) include, but are not limited to, silicone elastomer materials, e.g., NuSil MED-4750; TPUs, e.g., 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, e.g., 3M CoTran 9712. In some embodiments, the material for 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 for 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 for the drug-impermeable portion is AR-75A-B20. In some embodiments, the material for the drug-impermeable portion is AC-4075A-B20.

[0114] 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.

[0115] Lubrizol Tecophilic HP series materials are aliphatic polyether-based TPUs formulated to absorb up to 100% of the dry resin's weight in equilibrium water content, designed for extrusion, and also processable by injection molding. HP-60D-35 has a Shore hardness of approximately 42D (ASTM D2240); a specific gravity of approximately 1.12 (ASTM D792); a flexural modulus of 4000 (psi) (ASTM D790); a maximum tensile strength of approximately 7,800 dry and 4,900 wet (psi) (ASTM D412); a maximum elongation of approximately 450 dry and 390 wet (%) (D412); and a water absorption of approximately 35 (%) by Lubrizol method. HP-93A-100 has a Shore hardness of approximately 83A (ASTM D2240); a specific gravity of approximately 1.13 (ASTM D792); a flexural modulus of 2900 (psi) (ASTM D790); a maximum tensile strength of approximately 2200 dry and 1400 wet (psi) (ASTM D412); a maximum elongation of approximately 1040 dry and 620 wet (%) (D412); and a water absorption rate of approximately 100 (%) by the Lubrizol method.

[0116] It should be understood that Lubrizol Tecoflex material is an aliphatic polyether-based TPU that can be processed by extrusion and injection molding. EG-80A has a Shore hardness of approximately 72A (ASTM D2240); a specific gravity of approximately 1.04 (ASTM D792); a flexural modulus (psi) of 1,000 (ASTM D790); a maximum tensile strength (psi) of approximately 5,800 (ASTM D412); a maximum elongation (%) of approximately 660 (D412); a tensile modulus (psi) of approximately 300 at 100% elongation, approximately 500 at 200% elongation, and approximately 800 at 300% elongation (ASTM D412); and a molding shrinkage of approximately 0.008-0.012 (inches / inch) (ASTM D955).

[0117] Please understand that Lubrizol Aromatic Carbonate AC series materials are radiopaque (20% BaSO4 filled) polycarbonate-based aromatic TPUs that can be processed by extrusion or injection molding. AC-4075A-B20 has a Shore hardness of approximately 78A (ASTM D2240); a specific gravity of approximately 1.38 (ASTM D792); a maximum tensile strength of approximately 8300 (psi) (ASTM D412); a maximum elongation of approximately 400 (%) (D412); tensile modulus of elasticity of approximately 560 at 100% elongation, approximately 1300 at 200% elongation, and approximately 3400 at 300% elongation (psi) (ASTM D412); a flexural modulus of elasticity of approximately 1800 (psi); a Vicat temperature of approximately 55 (°C); and a forming shrinkage of approximately 0.011 (inches / inch) (1 inch × 0.25 inch × 6 inch bar) (ASTM D955).

[0118] It should be understood that 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 of approximately 79A (ASTM D785); a specific gravity of approximately 1.03 (ASTM D792); a maximum tensile strength (psi) of approximately 2000 (ASTM D412); a maximum elongation (%) of approximately 530 (ASTM D412); a tensile modulus (psi) of approximately 730 at 100% elongation, approximately 1000 at 200% elongation, and approximately 1300 at 300% elongation (ASTM D412); a flexural modulus (psi) of approximately 2500 (ASTM 790); a Vicat softening point of approximately 75 (°C); and a molding shrinkage of approximately 0.08 (inches / inch) (1 inch × 0.25 inch × 6 inch bar) (ASTM D955). AR-75A-B20 is AR-75A filled with 20% BaSO4 and can be manufactured, for example, by Compounding Solutions.

[0119] It should be further understood that the above test results for Lubrizol Tecophilic HP.Tecoflex, Aromatic Carbonate AC, and Tecothane Soft materials are approximate based on small samples of TPU. Therefore, the properties of these materials may show slight variations from the properties listed herein.

[0120] In one embodiment, as shown in Figure 1, a drug delivery system 100 is provided, comprising a tubular housing having a drug reservoir lumen 106 bounded by a wall structure 104, wherein (i) at least a portion of the wall structure 104 is permeable to water, and (ii) at least a portion of the wall structure is permeable to a drug (contained in a drug unit 108), thereby enabling the drug to be released in vivo by diffusion through the drug-permeable portion of the wall structure 104. In a particular embodiment, as will be discussed in more detail below, the wall structure comprises 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”) means that the drug is released by molecular diffusion through the material forming the wall, and not by release through openings or open structures extending through this wall.

[0121] In one embodiment, as shown in Figure 2, a drug delivery system 200 is provided, comprising a housing having a first wall structure 206 formed from a first material and a second wall structure 205 formed from a second material, wherein the first wall structure 206 and the second wall structure 205 are adjacent to each other and together form a tube defining a drug reservoir lumen 208, wherein (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 drugs and the second wall structure 205 is permeable to drugs, thereby enabling the drug to be released in vivo by diffusion through the second wall structure 205. As used herein, the term “impermeable to drugs” means that the wall is substantially impermeable to the solubilizing drug, thereby preventing a substantial amount of the solubilizing drug from diffusing through the wall over the therapeutic period in which the system is located in vivo.

[0122] In certain embodiments, the tube is cylindrical or of another preferred shape or design. As used herein, the term “cylindrical” means that the housing has a substantially cylindrical outer wall when used in reference to a tubular housing. In some embodiments, the system is “closed” and therefore does not include any openings, and drug release is solely by diffusion through a second wall structure.

[0123] In some embodiments, as shown in Figures 2 and 3, the first wall structure 206 / 306 and the second wall structure 205 / 305 are adjacent to each other and together form a cylindrical tube. For example, such a system may be formed by co-extrusion or 3D printing processes such that the first and second wall structures are formed integrally. In one embodiment, the co-extruded first and second wall structures are thermoplastic polymers having desired properties.

[0124] As shown in Figure 3, the first wall structure 306 and the second wall structure 305 together form a cylindrical tube having a lumen 308, in which a 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.

[0125] In a preferred embodiment, as will be discussed in more detail below, the system is elastically deformable between a low-profile unfolded shape (e.g., a relatively straight shape) suitable for insertion into the patient's bladder through the patient's urethra and a relatively expanded retaining shape (e.g., a pretzel shape, a double-elliptical coil shape, an S-shape, etc.) suitable for retention within the bladder.

[0126] In some embodiments, the system further includes a retaining frame lumen 734, as shown in Figures 7A–7C. In certain embodiments, the retaining frame lumen includes an elastic wire, such as a nitinol wire. In certain other embodiments, the retaining frame lumen is filled with a shape-setting elastic polymer.

[0127] In other embodiments, as shown in Figures 1-3 and 8, the system does not include a retaining frame lumen, or a retaining frame or wire. Instead, the housing material is configured to be elastically deformable between a straightened shape and a retaining shape in the absence of a retaining frame or wire. In certain embodiments, the tubular system is thermally shaped to have a coiled or other retaining shape. Thus, in such embodiments, the design and manufacture of the system are simplified, and the overall size of the system is minimized (or, if the size of the system remains constant, the drug payload may increase). In embodiments without a retaining frame, the tubular housing material serves to (i) form a drug reservoir lumen, (ii) control drug release, and (iii) hold the system in the bladder during deployment.

[0128] In one embodiment, as shown in Figures 7A to 7C, a drug delivery system 700 is provided which includes an elongated elastic housing 702, wherein the elongated elastic housing 702 has a drug reservoir lumen 704 extending between a first end 706 and a second end 708. The elastic housing 702 is formed from a tubular wall structure 710, which includes a first wall structure 716 and a second wall structure 724, the first wall structure 716 and the second wall structure 724 being adjacent to each other and together forming a tube defining the lumen of the drug reservoir 704, (i) the second wall structure 724, or both the first wall structure 716 and the second wall structure 724 being permeable to water, and (ii) the first wall structure 716 being impermeable to drugs and the second wall structure 724 being permeable to drugs, thereby allowing the drug to be released in vivo by diffusion through the second wall structure 724.

[0129] In embodiments where the first and second wall structures together form a cylindrical tube, any preferred end plug or closure, or a heat-formed seal, may be used to seal the end of the tube after the drug has been packed. These end plugs / closures ensure that the drug-permeable polymer portion forming part of the outer tube is the sole pathway for drug release.

[0130] In some embodiments, as shown in Figures 2 and 3, the walls 206, 205 / 306, 305 have a substantially constant thickness around their circumference. For example, the inner diameter 210 / 310 and outer diameter 212 / 312 of the first wall structure and the second wall structure 206, 205 / 306, 305 (which together form a cylindrical tube) are the same. In other embodiments, the walls may have a thickness that varies around their circumference.

[0131] Therefore, in the systems described herein, drug release is controlled by the diffusion of the drug through a drug-permeable component defining a portion of the system housing. The drug-permeable wall structure may be positioned, dimensionally set, and have material properties to provide a desired rate of controlled drug diffusion from the device.

[0132] The specific materials and arc angles of the drug-permeable portion or wall structure may be selected to achieve a specific drug release profile, i.e., water and drug permeation rates. As used herein, the term “arc angle” refers to the angular dimension of the arc around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube.

[0133] For example, in a particular embodiment, as shown in Figures 2 and 3, the second wall structure 205 / 305 constitutes less than 90 percent of the cross-sectional area of ​​the pipe in a section perpendicular to the longitudinal axis of the pipe. In one embodiment, the second wall structure constitutes less than 50 percent of the cross-sectional area of ​​the pipe in a section perpendicular to the longitudinal axis of the pipe. In one embodiment, the second wall structure constitutes less than 25 percent of the cross-sectional area of ​​the pipe in a section perpendicular to the longitudinal axis of the pipe.

[0134] In certain embodiments, as shown in Figures 2, 3, 7A–7C, and 8, the first and second wall structures forming a tube that borders the lumen of the drug reservoir are adjacent to each other at two boundary edges, so that the wall structures collectively form a tube that defines the lumen of the drug reservoir. In these embodiments, the two boundary edges are arranged at an arc angle of about 15 to about 270 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. As used herein, the phrase “about” with respect to the arc angle of the second wall structure refers to an arc angle of plus or minus 3 degrees.

[0135] In one embodiment, as shown in Figure 2, the second wall structure 205 has an arc angle 214 of about 60 degrees around the circumference of the cylindrical tube 200 in cross-section. In one embodiment, as shown in Figure 3, the second wall structure 305 has an arc angle 314 of about 30 degrees around 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 will be further described 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, for example, 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.

[0136] When the system is formed to have the retaining shape shown in Figure 1, the second wall structure can be located inwardly curved (0 degrees), outwardly curved (180 degrees), at the top (90 degrees), or in 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.

[0137] Therefore, tubular systems have been developed that are designed to reduce or control drug release rates without negatively altering mechanical properties or dimensions suitable for system deployment and tolerance. In some embodiments, the design reduces drug release rates by reducing the length of the drug-permeable region so that its length extends along only a portion of the overall length of the system. Thus, a larger arc angle of the drug-permeable region may be used to adapt 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 may be used compared to conventional systems to result in a reduced drug release rate.

[0138] When the drug is packed into the lumen of the drug reservoir, any suitable end plug or closure, or a thermoformed seal, may be used to seal / close the first and second ends of the lumen of the drug reservoir. These end plugs / closures ensure that the second material forming part of the elastic housing is the sole pathway for drug release. In certain embodiments, the end plugs are formed from a first material that is impermeable to the drug (i.e., the material forming the first wall structure).

[0139] In the embodiments described above, the first material or first wall structure, the second material or first wall structure, or both are formed from a water-permeable material. In preferred embodiments, as described above with respect to the erdafitinib solid formulation, the drug is in solid form (e.g., a tablet or a group of tablets), and at least a portion of the tubular body is water-permeable to allow in vivo solubilization of the drug while it is in the lumen of the drug reservoir. In embodiments, the first material or first wall structure may be the sole water-permeable portion. In other embodiments, both the first material / wall structure and the second material / wall structure may be water-permeable.

[0140] The material for the wall structure of this system can be selected from a variety of suitable thermoplastic polyurethane (TPU)-based materials. In particular, the first material forming the first wall structure (i.e., a material 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, commercially available from Lubrizol) or an aromatic polyester hydrocarbon-based thermoplastic polyurethane (e.g., TECOTHANE® TPU, e.g., AR-75A, commercially available from Lubrizol). For example, CARBOTHANE polyurethane is an alicyclic polymer of the type produced from a polycarbonate-based polyol. The general structure of the polyol segment is O--[(CH2)6--CO3] n It 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 in the drug reservoir) may be an aliphatic polyether-based thermoplastic polyurethane (e.g., TECOFLEX® TPU, commercially available from Lubrizol, e.g., EG-80A. For example, TECOFLEX polyurethane is an alicyclic polymer of the type produced from a polyether-based polyol. The general structure of the polyol segment is O--(CH2--CH2--CH2--CH2) x It is expressed as --O--. 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 contain a radiopaque agent, such as barium sulfate, for example, AC-4075A-B20, which is a polycarbonate-based aromatic thermoplastic polyurethane with a 20% barium sulfate filler.

[0141] In one embodiment, the inner diameter of the cylindrical tube may be approximately 1.0 mm to approximately 2.5 mm. In one embodiment, the outer diameter of the cylindrical tube is approximately 2.0 mm to approximately 4.1 mm. In one embodiment, the thickness of the first wall structure, the second wall structure, or both is approximately 0.2 mm to approximately 1.0 mm.

[0142] Therefore, 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 using double-walled structures (e.g., drug-permeable strip embodiments) can be separated from the drug release (e.g., diffusion) properties of the tube. For example, in a single-material tube, changing the material of the tube inherently affects both the mechanical and diffusion properties of the system. The ability to control the release rate with the stripe angle may have the additional advantage of not changing the outer diameter of the system. 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 can not be easily predicted. In addition, achieving a truly homogeneous blend when mixing two thermoplastic materials is often difficult. Therefore, such tubular drug delivery systems require experimentation to adjust the drug release rate. In contrast, the double-walled structures described herein may provide enhanced flexibility in adapting a specific drug release rate from the delivery system.

[0143] For use in the bladder, it is important that the device has compliance during detrusor contracture (i.e., is easily bendable and has a flexible feel) to avoid or reduce discomfort and irritation to the patient. Therefore, the durometer of the first and second building materials is important, and it should be noted that the proportion of high-durometer material may be limited when constructing a system housing of a given size while the system housing has suitable compliance in the bladder. For example, a suitable first wall material, e.g., TECOTHANE or CARBOTHANE, may have a Shore hardness greater than 70A, e.g., 77A to 65D, and a suitable second wall material, e.g., TECOFLEX, may have a Shore hardness 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. Therefore, in certain embodiments, the second wall material has a Shore hardness less than that of the first wall material, and both wall materials have a Shore hardness of less than 80A. Thus, it may be advantageous to achieve the desired mechanical properties of the pipe by using a combination of two different polymer materials rather than fabricating the entire system housing from a water-swellable, hydrophilic, drug-permeable second material.

[0144] In embodiments, the systems described herein are configured to release a therapeutically effective amount of drug, and the rate of drug release from the drug delivery system is zero-order for at least 36 hours. In one embodiment, the rate of drug release from the drug delivery system is essentially zero-order for at least 7 days. In embodiments, the system is configured to release a therapeutically effective amount of 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. Preferably, the rate of drug release from the drug delivery system is zero-order for at least 7 days, e.g., 7 to 14 days or longer, e.g., up to 3 months or 90 days. In certain embodiments, the system is configured to begin drug release after a lag time. In certain embodiments, the lag time may be at least about 30 minutes, about 12 hours to about 24 hours, or up to about 2 days. These systems may be effective in releasing a therapeutically effective amount of drug over a period of up to 6 months or up to 3 months (90 days).

[0145] As will be discussed in more detail below, a drug formulation, for example, one described throughout this disclosure, is disposed within a drug reservoir lumen defined by a first wall structure and a 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 therapeutic 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 arranged at an arc angle of 45 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 arranged at an arc angle of 150 to 270 degrees.

[0146] In one embodiment, the system is configured to release erdafitinib at an average rate of 1 mg / day, with the two interface edges arranged at an arc angle of approximately 45 degrees. In another embodiment, the system is configured to release erdafitinib at an average rate of 2 mg / day, with the two interface edges arranged at an arc angle of approximately 90 degrees. In yet another embodiment, the system is configured to release erdafitinib at an average rate of 4 mg / day, with the two interface edges arranged at an arc angle of approximately 180 degrees. In one embodiment, the system is configured to release erdafitinib at an average rate of 6 mg / day, with the two interface edges arranged at an arc angle of 240 degrees. In certain embodiments, the drug release profile is substantially pH-independent over a pH range of 5–7. In certain embodiments, the drug release profile is substantially pH-independent over a pH range of 5.5–7. In certain embodiments, the drug release profile is substantially pH-independent over a pH range of 5.5–8. In certain embodiments, the release rate is maintained for up to 6 months, and in particular, for a period of up to 3 months or 90 days.

[0147] In some embodiments, the system is configured to release erdafitinib at a rate of approximately 2 mg / day to approximately 4 mg / day. In some embodiments, the system comprises two interface edges arranged at an angle of approximately 90 to approximately 180 degrees. In some embodiments, the system is configured to release erdafitinib at an average rate of 2 mg / day to approximately 4 mg / day, and the two interface edges are arranged at an arc angle of approximately 90 to approximately 180 degrees.

[0148] In one embodiment, a drug delivery system is provided comprising (i) a housing defining a drug reservoir lumen and a retaining frame lumen, (ii) a plurality of tablets containing erdafitinib disposed within the drug reservoir lumen, and (iii) a nitinol wire form (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 which is an aromatic polyester hydrocarbon-based thermoplastic polyurethane, in particular AC-4075A-B20, and a second wall structure (stripe) formed from a second material which is an aliphatic polyether-based thermoplastic polyurethane, in particular EG-80A, wherein the first and second wall structures are adjacent to each other at the two interface edges and together form a tube which defines a closed drug reservoir lumen. In one embodiment, the closed drug reservoir lumen accommodates a plurality of tablets, in particular a plurality of minitablets, in particular erdafitinib minitablets as described herein. In one embodiment, the amount of erdafitinib in the lumen of the drug reservoir is approximately 500 mg. In one embodiment, the lumen of the drug reservoir comprises approximately 44 erdafitinib minitablets, in particular, the erdafitinib tablets described herein. In one embodiment, the group of tablets consists of 44 minitablets and has a total of approximately 500 mg of erdafitinib. 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 180 degrees and the average release rate of erdafitinib from the system is approximately 4 mg / day. In one embodiment, the stripe angle is 210-270 degrees and the average release rate of erdafitinib from the system is approximately 6 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. 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 pH approximately 5 to approximately 6.8, and approximately 1 mg / day at pH approximately 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 pH approximately 5 to approximately 6.8, and approximately 2 mg / day at pH approximately 8. In one embodiment, the stripe angle is 210 to 270 degrees, in particular 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, in particular 270 degrees, and the average release rate of erdafitinib from the system is approximately 6 mg / day at pH approximately 5 to approximately 6.8, and approximately 3 mg / day at pH approximately 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 pH approximately 5 to approximately 6.8 and approximately 0.5 mg / day at pH approximately 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.

[0149] Other aspects of drug delivery systems In certain embodiments, the system is configured for intravesical insertion and retention in a patient. For example, the system may be elastically deformable between a relatively low-profile (e.g., straightened) shape suitable for insertion into a patient's body cavity through a lumen, e.g., the shape shown in Figures 7A–7B, and a relatively expanded retaining shape suitable for retaining the system in a body cavity, e.g., the bladder, e.g., the shapes shown in Figures 1, 4, 5, and 6A. The relatively expanded shape may include a pair of overlapping coils, often referred to as a “pretzel” shape. In certain embodiments, the ends of the expanded system are generally within the boundaries of a bielliptical shape.

[0150] After deployment within the bladder, while in an expanded retaining shape, the system may, for example, resist excretion in response to urination or other forces. After drug release, the system may be removed, for example, by cystoscopy and forceps, or may be at least partially biodisintegrating to avoid retrieval procedures.

[0151] The system may be packed with one or more drug units, for example, at least one drug in the form of a tablet as described throughout this disclosure. Solid drug composition forms, such as tablets, can provide a relatively large drug payload volume relative to the total system volume and can potentially enhance the stability of the drug during transport, storage, before use, or before drug release. However, solid drugs may need to be solubilizable in vivo to diffuse in therapeutically effective amounts into the patient's surrounding tissues or lumens through drug-permeable components. The drug reservoir lumen may hold some of the drug tablets disclosed in an elongated form in a continuous end-to-end arrangement. In some embodiments, the system holds about 10 to 100 cylindrical drug tablets (e.g., 44 tablets), for example, minitablets, which may be continuously loaded into the drug reservoir lumen. In one embodiment, the tablets are those described herein. In one embodiment, the tablets are of formulation 4A. In one embodiment, the tablets are of formulation 4B. In one embodiment, the tablets are of formulation 4C. In one embodiment, the tablet is of formulation 4D.

[0152] The system can be inserted into the patient using a cystoscope, catheter, or any other suitable or customized inserter device. Typically, a cystoscope for adults 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, e.g., 4 mm or more. Thus, the system can be relatively small in size. For example, when the system is elastically deformed into a relatively straight shape, the system for adult patients may have a total outer diameter of less than about 2.6 mm, e.g., about 2.0 mm to about 2.4 mm. In addition to enabling insertion, the relatively small size of the system can also reduce patient discomfort and trauma to the bladder. In one embodiment, the overall configuration of the system facilitates in vivo tolerance for most patients. In certain embodiments, the system is configured for tolerance based on the bladder features and design considerations described in U.S. Patent No. 11,065,426.

[0153] In the three-dimensional space occupied by the system in its retaining shape, 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 cm 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 vertical directions. Along one of these directions, the system has its maximum dimension, and along the other two directions, the system may have smaller dimensions. For example, the smaller dimensions in the other two directions may be less than about 4 cm, e.g., about 3.5 cm, 3 cm, 2.5 cm or less. In a preferred embodiment, the system has dimensions in at least one of these directions that are less than 3 cm.

[0154] 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, resulting in a non-uniform shape. Due to this non-uniform shape, the system may be able to achieve a reduced compression orientation within an empty bladder, which also has a non-uniform shape. In other words, a specific orientation of the system within an empty bladder may allow the system to exert less contact pressure on the bladder wall, making the system more patient-tolerant.

[0155] The overall shape of the system may allow it to reorient itself within the bladder, reducing engagement or contact with the bladder wall. For example, the overall external shape of the system may be curved, and all or most of the system's external or exposed surfaces may be substantially rounded. The system may also substantially lack sharp edges, and the system's external surfaces 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, thereby applying 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, where the system experiences less compression.

[0156] In one embodiment, the system occupies three-dimensional space but has a generally planar shape. Such a system may have a minor axis, be substantially symmetrical about the minor axis, and may have a major axis substantially perpendicular to the minor axis. The system may have a maximum dimension in the direction of the major axis not exceeding about 6 cm, and in certain embodiments, the maximum dimension in the direction of the major 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 minor axis not exceeding about 4.5 cm, and in certain embodiments, the maximum dimension in the direction of the minor axis is less than 4 cm, e.g., about 3.5 cm, about 3 cm or less. The system is curved substantially around its entire outer circumference in both the long and short cross-sectional planes. In other words, the overall external shape of the system is curved, and the cross-sectional shape of the system is rounded. Therefore, the system is substantially edgeless except for the edges on the two flat ends, and the edges on the two flat ends are completely protected within the system when the system is in a plane. These features allow the system to reorient itself to a reduced compression position when it is in an empty bladder.

[0157] The system can also be small enough in its retained shape to allow for intravesical mobility. In particular, when deployed, the system can be small enough to move within the bladder, for example, small enough to move freely or unimpeded throughout the bladder under most conditions of bladder distension, thus promoting patient tolerance of the system. The free movement of the system also promotes uniform drug delivery throughout the bladder.

[0158] The system may also be configured to enhance buoyancy by using low-density building materials for housing components and / or by incorporating gases or gas-generating materials into the housing, for example, as described in U.S. Patent No. 9,457,176. Generally, a system in a dry state packed with the drug may have a density in the range of about 0.5 g / mL to about 1.5 g / mL, for example, about 0.7 g / mL to about 1.3 g / mL. In some embodiments, a system in a dry state packed with the drug has a density of less than 1 g / mL.

[0159] In one embodiment, the intravesical drug delivery system is non-biodegradable. In another embodiment, the intravesical drug delivery system may be constructed to be fully or partially biodegradable, so that explantation or recovery of the system is not required after release of the drug formulation. In some embodiments, the system is partially biodegradable, so that during partial disintegration, the system breaks down into non-disintegrable pieces small enough to be excreted from the bladder. For example, the system described herein may be designed to conform to the features of the one described in U.S. Patent No. 8,690,840.

[0160] The drug delivery system is sterilized before being inserted into the patient. In one embodiment, the system is sterilized using a preferred process, such as gamma irradiation or ethylene oxide sterilization, but other sterilization processes may be used.

[0161] The systems described herein may include radiopaque portions or structures to facilitate detection or visualization of the system (e.g., by X-ray imaging or fluoroscopy) by a medical professional as part of an implantation and / or retrieval procedure. In one embodiment, the housing is constructed from a material containing a radiopaque material, e.g., barium sulfate, or another radiopaque material known in the art. Some housings may be made radiopaque by blending a radiopaque filler, e.g., barium sulfate or another suitable material, during the processing of the material from which the housing is formed. The radiopaque material may be associated with the retaining frame in embodiments that include a retaining frame. Ultrasound imaging or fluoroscopy may be used to image the system in vivo.

[0162] In some embodiments, the device components of the system comprise a drug-impermeable base material and a drug-permeable stripe material, the base material being a TPU having 20% ​​BaSO4 filler, for example, Lubrizol's Carbothane® AC-4075A-B20 or Tecothane® AR-75A-B20 (Lubrizol Life Science (Bethlehem, PA)).

[0163] The drug delivery system may further include a retrieval feature, such as a string, loop, or other structure that facilitates the removal of the system from the patient. In some cases, the system may be removed from the bladder by engaging with a string and pulling the system through the urethra. The system may be configured to exhibit a relatively narrow or linear shape when pulled by the retrieval feature into the lumen of a catheter or cystoscope, or into the urethra.

[0164] Maintaining the system within the body cavity The systems described herein are elastically deformable between a relatively low profile (e.g., straight or non-coiled) shape suitable for insertion into the patient's bladder (or other body cavity) through the patient's lumen and a relatively expanded retaining shape suitable for retaining the system within the bladder (or other body cavity). In certain embodiments, the drug delivery system may naturally assume the retaining shape and may be deformed manually or with the assistance of an external device to become the relatively straightened shape for insertion into the body. When unfolded, the device may spontaneously or naturally return to the initial retaining shape for retention within the body.

[0165] For the purposes of this disclosure, terms such as “retaining shape” and “relatively extended shape” generally refer to any shape suitable for retaining the system within an intended implantation site, and this shape includes, but is not limited to, coiled or “pretzel” shapes suitable for retaining the system in the bladder, e.g., the shapes shown in Figures 1 and 4. Similarly, terms such as “deployed shape,” “relatively low profile shape,” and “relatively straightened shape” generally refer to any shape suitable for deploying the drug delivery system within the body, and this shape includes, but is not limited to, linear or extended shapes suitable for deploying the system through a lumen in the body, e.g., a catheter positioned in the urethra, a cystoscope, or the working channel of another deployment device, e.g., the shapes shown in Figures 7A to 7B. For example, the housing or tube of the system may have two opposing free ends, which are oriented away from each other when the system is a low profile deployed shape and toward each other when the system is a relatively extended retaining shape.

[0166] In some embodiments, as shown in Figures 7A–7C, the system further includes a retaining frame lumen 734 and a retaining frame (not shown) positioned within the retaining frame lumen. For example, the retaining frame lumen and retaining frame may be those described in U.S. Patent Publication Nos. 2010 / 0331770, 2010 / 0060309, 2011 / 0202036, and 2011 / 0152839, which are incorporated herein by reference. For example, the retaining frame lumen may be sealed with a suitable plug or adhesive material, such as a silicone adhesive.

[0167] Figure 4 shows the system 300 with a drug tablet 108 packed into the lumen of the drug reservoir in the system housing 304. As can be seen in Figure 5, before packing the tablet, the retaining frame 305 biases the system housing 304 into a different, expanded shape compared to the retaining shape achieved when the drug tablet 108 is packed into the system.

[0168] In certain embodiments where an increased payload is desired, an additional length of the drug reservoir lumen / tube may be provided. In one embodiment, as shown in Figures 6A–6B, the retaining frame has an outer circumference defined by two overlapping portions (coils) of a nitinol wire. Each end of the wire is oriented inward from the periphery and includes (i) a curved transition region having a smaller radius of curvature than the peripheral portion of the wire, and (ii) a straight portion terminating with a rounded end cap. In contrast, in the system shown in Figure 5, the retaining frame has a periphery defined by a single coil. The system with the retaining frame of Figures 6A–6B allows for a relatively longer drug reservoir (for example, to accommodate more tablets) in a system having the same “setup area” (peripheral shape and dimensions) as the system shown in Figure 5.

[0169] In other embodiments, as shown in Figures 1 to 3, the system does not include a retaining frame lumen, or a retaining frame or wire. Instead, the housing material is configured to be elastically deformable between a straightened shape and a retaining shape in the absence of a retaining frame or wire. Such embodiments simplify the design and manufacture of the system and minimize the overall size of the system (or, if the size of the system remains constant, the drug payload may increase). In embodiments without a retaining frame, the tubular housing material serves to (i) form a drug reservoir lumen, (ii) control drug release, and (iii) hold the system in the bladder during deployment.

[0170] For example, a tubular housing can be thermoformed to have a retaining shape. Thus, the housing may comprise one or more thermoplastic materials that are suitable for thermoforming into a retaining shape. In a particular embodiment, the drug delivery system comprises a tubular housing having a closed drug reservoir lumen bounded by a wall structure comprising at least one thermoplastic material, wherein (i) at least a portion of the wall structure is permeable to water and at least a portion of the wall structure is drug permeable, (ii) the tubular housing is elastically deformable from a retaining shape suitable for holding the system in the bladder to a relatively straightened shape suitable for insertion into the bladder through the lumen, and (iii) the tubular wall is thermoformed to have a retaining shape.

[0171] In certain embodiments, the first and second wall structures are each made of thermoplastic polyurethane, and the tubular housing is thermoformed to have a retaining shape. In one embodiment, the tubular wall has a spring constant that is effective in preventing the system from taking on a relatively straight shape when implanted in the bladder. Thus, the properties of the tubular wall can cause the system to function as a spring, deforming in response to a compression load, but spontaneously returning to the system's initial shape when the load is removed.

[0172] In certain embodiments, the system may naturally assume a retaining shape, deform into a relatively straightened shape, and spontaneously return to the retaining shape upon insertion into the body. The tubular wall structure in the retaining shape may be molded to be retained within a body cavity, while the tubular wall structure in the relatively straightened shape may be molded to be inserted into the body through a deployment instrument, such as a catheter or cystoscope working channel. To achieve such results, the tubular wall structure may have elastic limits, modulus, and / or spring constants selected to prevent the system from assuming a relatively low profile shape when implanted. Such a configuration may limit or prevent accidental ejection of the system from the body under expected forces. For example, the system may be retained in the bladder during urination or detrusor contracture.

[0173] In a preferred embodiment, the system is elastically deformable between a relatively straight 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 in the bladder after it has been released from the end of the catheter or cystoscope (i.e., preventing the system from being expelled from the bladder during urination).

[0174] As shown in Figure 1, the retaining shape may include a coiled or “pretzel” shape. The pretzel shape essentially comprises at least two approximate circles, each having a smaller bow of the approximate circle itself, and sharing a common larger bow. When the pretzel shape is first compressed, the larger bow absorbs most of the compression force and begins to deform, but with continued compression, the smaller bows overlap, and thereafter all three bows resist the compression force. The overall resistance of the system to compression increases when the two approximate circles overlap, preventing the collapse of the system and defecation when the bladder contracts during urination.

[0175] The wall structure in the retaining shape may have a two-dimensional structure limited 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 approximate circles, which are connected in either a linear or radial direction, curved in the same or alternating direction, overlapping or not overlapping. The retaining shape may comprise one or more circles or ellipses arranged in a two-dimensional or three-dimensional configuration, which may be closed or open, the same or different sizes, may overlap or not overlapping, and may be joined together at one or more connection points. The retaining shape may also be a three-dimensional structure formed to occupy a spheroidal space, for example, a spherical space, a space having a proportional spheroidal shape, or a space having an oblate circular spheroidal shape, or to wrap around a spheroidal space. The wall structure in the retaining shape may be formed to occupy a spherical space or to wrap around a spherical space. The wall structure in the retaining shape can generally have the 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 helix. In each of these examples, the wall structure can be extended into a linear shape for deployment through a deployment device. The wall structure can wrap around or through a spherical space or other ellipsoidal space in various other ways.

[0176] Drug delivery systems using thermoformed and co-extruded tubes having drug-permeable and drug-impermeable portions can integrate three functional components (drug reservoir / housing, drug delivery pathway, and retention feature) into a single thermoformed and co-extruded tube component, which can simplify system design and the ability to control drug release rates. As discussed herein, in such systems, drug release rates can be modified relatively easily by controlling the angle and thickness of the drug-permeable portion (e.g., strip) without altering the entire tube housing material.

[0177] Drug tablets can be packed into thermoformed and co-extruded tubular housings, and both ends can be sealed thermally or with adhesive (e.g., with the first wall material). If local tubular cross-sectional deformation or tube twisting occurs, tablet packing becomes difficult. Therefore, the tube dimensions should be selected to prevent twisting when the tube is thermoformed. The critical bending radius (R) of an elastic tube under pure bending conditions. * ) can be approximated using the following formula:

[0178]

number

[0179] Drug tablets As discussed herein with respect to erdafitinib formulations, the drug may be provided in a solid form (e.g., a solid minitablet) suitable for packing into the lumen of the system's drug reservoir. In a preferred embodiment, as shown in Figure 1, the drug formulation is formed in drug units 108 packed into the lumen of the system 100. Each drug unit is a separate solid object that substantially retains a selectively conferred shape (under the temperature and pressure conditions to which the drug unit (e.g., tablet) and the delivery system are typically exposed during assembly (e.g., packing into the system drug reservoir), storage, and handling before in vivo insertion).

[0180] Individual drug units may essentially have any selected shape and dimensions that fit within the system described herein. In one embodiment, drug units are sized and molded so that a drug reservoir lumen in a housing is substantially filled by a selected number of 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, a drug unit may be substantially cylindrical for positioning within a substantially cylindrical drug reservoir lumen. When packed, drug units substantially fill the drug reservoir lumen that forms a portion of the drug housing in some embodiments.

[0181] In one embodiment, drug units are molded to align in a row when the system is in its deployed configuration. For example, each drug unit may have a cross-sectional shape corresponding to the cross-sectional shape of the lumen of the drug reservoir within the housing, and each drug unit may have an end face shape corresponding to the end face of an adjacent drug unit. Gaps or interruptions between drug units can adapt to deformation or movement of the drug delivery system, for example, deformation or movement of the drug delivery system during deployment, while allowing individual drug units to maintain the solid form of the drug unit. Thus, the drug delivery system may be relatively flexible or deformable even when filled with a solid drug composition, such as a tablet, because each drug unit may be able to move relative to an adjacent drug unit.

[0182] In embodiments where the drug unit is designed to be inserted or implanted into a lumen or cavity within the body, such as the bladder, via a drug delivery system, the drug unit may be a “mini-tablet” that is suitably sized and molded for insertion through a natural lumen of the body, such as the urethra. For the purposes of this disclosure, the term “mini-tablet” generally refers to a solid drug unit that is substantially cylindrical in shape, having an end face and substantially cylindrical sides. A mini-tablet has a diameter extending along the end face in the range of about 1.0 to about 3.2 mm, for example, about 1.5 to about 3.1 mm. A mini-tablet has a length extending along the sides in the range of about 1.7 mm to about 4.8 mm, for example, about 2.0 mm to about 4.5 mm. The crushability of the tablet may be less than about 2%. In one embodiment, the tablet is as described herein. In one embodiment, the tablet is of formulation 4A. In one embodiment, the tablet is of formulation 4B. In one embodiment, the tablet is of formulation 4C. In one embodiment, the tablet is of formulation 4D.

[0183] Methods of drug delivery The systems and methods or uses disclosed herein may be adapted for use in humans or for veterinary or livestock applications. Accordingly, the term “patient” may refer to a human or other mammalian subject. In one embodiment, the patient is a human subject.

[0184] In certain embodiments, a method for treating urothelial carcinoma, for example, bladder cancer, is provided herein. In certain embodiments, the use of a drug delivery system described herein for the manufacture of a drug for the treatment of urothelial carcinoma, for example, bladder cancer, is provided herein. In certain embodiments, a drug delivery system described herein for use in the treatment of urothelial carcinoma, for example, bladder cancer, is provided herein. In certain embodiments, erdafitinib for use in a drug delivery system described herein for the treatment of urothelial carcinoma, for example, bladder cancer, is provided herein. The method or use may include topically delivering or administering erdafitinib (for example, erdafitinib in any of the formulations described herein) into the bladder of a patient in need of treatment, in particular a cancer patient, in an effective dose for the treatment of bladder cancer (for example, about 1 to 10 mg / day as described herein). For example, the treatment may be effective in the treatment of muscle-invasive bladder cancer (MIBC), non-muscle-invasive bladder cancer (NMIBC), and / or Bacillus calmette-Guérin (BCG) naive bladder cancer. In one embodiment, the patient, in particular, is a BCG-experienced bladder or NMIBC or MIBC cancer patient. In one embodiment, the patient, in particular, is a BCG-naive bladder or NMIBC or MIBC cancer patient. In one embodiment, the patient, in particular, is a recurrent BCG-experienced high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient who refuses or is ineligible for radical cystectomy (RCy). In one embodiment, the patient, in particular, is a recurrent BCG-experienced high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient for whom RCy is planned. In one embodiment, the patient, in particular, is a patient with recurrent moderate-risk NMIBC (Ta and T1) cancer who has a history of only low-grade disease. In another embodiment, the patient, in particular, is a patient with MIBC cancer scheduled for RCy who has refused or is ineligible for cisplatin-based neoadjuvant chemotherapy.

[0185] In certain embodiments, a method is provided for treating bladder cancer having one or more FGFR gene mutations, comprising delivering a dose effective for the treatment of bladder cancer to the bladder of a patient in need thereof, wherein one or more FGFR gene mutations are detected in a urine sample from the patient, in particular, by a urine-based PCR assay or NGS assay. In certain embodiments, a method is provided for treating bladder cancer having one or more FGFR gene mutations, comprising, or essentially comprising: (a) evaluating a urine sample from a patient having bladder cancer for the presence of one or more FGFR gene mutations, in particular by a urine-based PCR assay or NGS assay; and (b) delivering erdafitinib locally if one or more FGFR gene mutations are present in the sample. In certain embodiments, a method is provided for treating bladder cancer having one or more FGFR gene mutations, comprising delivering a therapeutically effective amount of erdafitinib locally to the bladder of a patient in need, wherein the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a urine sample from the patient, in particular, based on the detection of one or more FGFR gene mutations in a urine sample from the patient using a urine-based PCR assay or NGS assay. In certain embodiments, a method is provided for treating bladder cancer having one or more FGFR gene mutations, comprising delivering a therapeutically effective amount of erdafitinib locally to the bladder of a patient in need, wherein the patient's eligibility for treatment is determined by detecting one or more FGFR gene mutations in a urine sample from the patient, in particular, by detecting one or more FGFR gene mutations in a urine sample from the patient using a urine-based PCR assay or NGS assay.In a particular embodiment, erdafitinib for use in the treatment of bladder cancer in a patient having one or more FGFR gene mutations is provided, wherein the erdafitinib is delivered locally to the patient's bladder, and one or more FGFR gene mutations are detected in a urine sample from the patient, in particular, one or more FGFR gene mutations are detected in a urine sample from the patient using a urine-based PCR assay or NGS assay. In a particular embodiment, erdafitinib for use in the treatment of bladder cancer in a patient having one or more FGFR gene mutations is provided, comprising, consisting of, or essentially consisting of: (a) evaluating a urine sample from a patient having bladder cancer for the presence of one or more FGFR gene mutations, particularly using a urine-based PCR assay or NGS assay; and (b) if one or more FGFR gene mutations are present in the sample, delivering erdafitinib topically to the patient. In a particular embodiment, erdafitinib for use in the treatment of bladder cancer having one or more FGFR gene alterations in a patient is provided, wherein the erdafitinib is delivered locally to the patient's bladder, and the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a urine sample from the patient, and in particular, the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or NGS assay.In certain embodiments, erdafitinib is provided for use in the treatment of bladder cancer having one or more FGFR gene mutations in a patient, wherein erdafitinib is delivered locally to the patient's bladder, and the patient's eligibility for treatment is determined by detecting one or more FGFR gene mutations in a urine sample from the patient, in particular by detecting one or more FGFR gene mutations in a urine sample from the patient using a urine-based PCR assay or NGS assay. In certain embodiments, erdafitinib is provided for use in the manufacture of a drug for the treatment of bladder cancer having one or more FGFR gene mutations in a patient, wherein erdafitinib is delivered locally to the patient's bladder, and one or more FGFR gene mutations are detected in a urine sample from the patient, in particular by detecting one or more FGFR gene mutations in a urine sample from the patient using a urine-based PCR assay or NGS assay. In a particular embodiment, there is a use of erdafitinib for the manufacture of a drug for the treatment of bladder cancer having one or more FGFR gene mutations in a patient, comprising, consisting of, or essentially consisting of: (a) evaluating a urine sample from a patient having bladder cancer for the presence of one or more FGFR gene mutations, particularly using a urine-based PCR assay or NGS assay; and (b) locally delivering erdafitinib if one or more FGFR gene mutations are present in the sample.In certain embodiments, there is a use of erdafitinib for the manufacture of a drug for the treatment of bladder cancer having one or more FGFR gene mutations in a patient, wherein erdafitinib is delivered locally to the patient's bladder, and the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a urine sample from the patient, in particular, the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a urine sample from the patient using a urine-based PCR assay or NGS assay. The method or use may involve topically delivering or administering erdafitinib (e.g., as in any of the formulations described herein) to the bladder of a patient in need of treatment, particularly a cancer patient, in an effective dose for the treatment of bladder cancer (e.g., about 1 to 10 mg / day, as described herein). For example, the treatment may be effective in the treatment of muscle-invasive bladder cancer (MIBC), non-muscle-invasive bladder cancer (NMIBC), and / or Bacillus calmette-Guérin (BCG) naive bladder cancer. In one embodiment, the patient, particularly the human, is a BCG-naive bladder or NMIBC or MIBC cancer patient. In one embodiment, the patient, in particular, is a patient with recurrent BCG-experienced, high-risk, papillary-only, non-invasively minor intracellular cancer (NMIBC) (high-grade Ta / T1), who refuses or is unsuitable for radical cystectomy (RCy).In one embodiment, the patient, in particular, is a patient with recurrent BCG-experienced, high-risk papillary NMIBC (high-grade Ta / T1) cancer scheduled for RCy. In another embodiment, the patient, in particular, is a patient with recurrent, moderate-risk NMIBC (Ta and T1) cancer with a history of only low-grade disease. In yet another embodiment, the patient, in particular, is a patient with MIBC cancer scheduled for RCy who has refused or is ineligible for cisplatin-based neoadjuvant chemotherapy.

[0186] In a particular embodiment, a method is provided for treating bladder cancer having one or more FGFR gene mutations, comprising locally delivering an effective amount of erdafitinib to the bladder of a patient in need thereof, wherein one or more FGFR gene mutations are detected in a tumor tissue sample from the patient, in particular by detecting one or more FGFR gene mutations in a tumor tissue sample from the patient using a tissue-based PCR assay or NGS assay, or by detecting one or more FGFR gene mutations in a histopathological image of the tumor tissue via digital histopathological analysis. In a particular embodiment, a method is provided for treating bladder cancer having one or more FGFR gene mutations, comprising, or essentially comprising: (a) evaluating a tumor tissue sample from a patient having bladder cancer for the presence of one or more FGFR gene mutations, in particular by using a tissue-based PCR assay or NGS assay to evaluate a tumor tissue sample from a patient having bladder cancer for the presence of one or more FGFR gene mutations, or by evaluating a histopathological image of tumor tissue from a patient having bladder cancer for the presence of one or more FGFR gene mutations via digital histopathological analysis; and (b) if one or more FGFR gene mutations are present in the sample, locally delivering erdafitinib. In a particular embodiment, a method is provided for treating bladder cancer having one or more FGFR gene mutations, comprising locally delivering a therapeutically effective amount of erdafitinib to the bladder of a patient in need thereof, wherein the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a tumor tissue sample from the patient, in particular, the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a tumor tissue sample from the patient using a tissue-based PCR assay or NGS assay, or the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a histopathological image of the tumor tissue via digital histopathological analysis.In a particular embodiment, a method is provided for treating bladder cancer having one or more FGFR gene mutations, comprising locally delivering a therapeutically effective amount of erdafitinib to the bladder of a patient in need thereof, wherein the patient's eligibility for treatment is determined by detecting one or more FGFR gene mutations in a tumor tissue sample from the patient, in particular by detecting one or more FGFR gene mutations in a tumor tissue sample from the patient using a tissue-based PCR assay or NGS assay, or by detecting one or more FGFR gene mutations in a histopathological image of the tumor tissue via digital histopathological analysis. In a particular embodiment, erdafitinib for use in the treatment of bladder cancer having one or more FGFR gene mutations in a patient is provided, wherein erdafitinib is delivered locally to the patient's bladder, and one or more FGFR gene mutations are detected in a tumor tissue sample from the patient, in particular, one or more FGFR gene mutations are detected in a tumor tissue sample from the patient using a tissue-based PCR assay or NGS assay, or one or more FGFR mutations are detected in a histopathological image of the tumor tissue via digital histopathological analysis. In a particular embodiment, there is provided erdafitinib for use in the treatment of bladder cancer in a patient having one or more FGFR gene mutations, comprising, consisting of, or essentially consisting of: (a) evaluating a tumor tissue sample from a patient having bladder cancer for the presence of one or more FGFR gene mutations, in particular by using a tissue-based PCR assay or NGS assay to evaluate a tumor tissue sample from a patient having bladder cancer for the presence of one or more FGFR gene mutations, or by evaluating a histopathological image of tumor tissue from a patient having bladder cancer for the presence of one or more FGFR gene mutations via digital histopathological analysis; and (b) if one or more FGFR gene mutations are present in the sample, delivering erdafitinib topically to the patient.In a particular embodiment, erdafitinib for use in the treatment of bladder cancer having one or more FGFR gene alterations in a patient is provided, wherein the erdafitinib is delivered locally to the patient's bladder, and the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a tumor tissue sample from the patient, in particular, the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR assay or NGS assay, or the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a histopathological image of the tumor tissue via digital histopathological analysis. In a particular embodiment, erdafitinib for use in the treatment of bladder cancer having one or more FGFR gene mutations in a patient is provided, wherein the erdafitinib is delivered locally to the patient's bladder, and the patient's eligibility for treatment is determined by detecting one or more FGFR gene mutations in a tumor tissue sample from the patient, in particular by detecting one or more FGFR gene mutations in a tumor tissue sample from the patient using a tissue-based PCR assay or NGS assay, or by detecting one or more FGFR gene mutations in a histopathological image of the tumor tissue via digital histopathological analysis. In a particular embodiment, there is a use of erdafitinib for the manufacture of a drug for the treatment of bladder cancer having one or more FGFR gene mutations in a patient, wherein the erdafitinib is delivered locally to the patient's bladder, and one or more FGFR gene mutations are detected in a tumor tissue sample from the patient, in particular, one or more FGFR gene mutations are detected in a tumor tissue sample from the patient using a tissue-based PCR assay or NGS assay, or one or more FGFR mutations are detected in a histopathological image of the tumor tissue via digital histopathological analysis.In certain embodiments, there is a use of erdafitinib for the manufacture of a drug for the treatment of bladder cancer having one or more FGFR gene mutations in a patient, comprising, consisting of, or essentially consisting of: (a) evaluating a tumor tissue sample from a patient having bladder cancer for the presence of one or more FGFR gene mutations, in particular by using a tissue-based PCR assay or NGS assay to evaluate a tumor tissue sample from a patient having bladder cancer for the presence of one or more FGFR gene mutations, or by evaluating a histopathological image of tumor tissue from a patient having bladder cancer for the presence of one or more FGFR gene mutations via digital histopathological analysis; and (b) locally delivering erdafitinib if one or more FGFR gene mutations are present in the sample. In a particular embodiment, there is a use of erdafitinib for the manufacture of a drug for the treatment of bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is delivered locally to the patient's bladder, and the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a tumor tissue sample from the patient, in particular, the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR assay or NGS assay, or the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a histopathological image of the tumor tissue via digital histopathological analysis.In certain embodiments, a use of erdafitinib is provided for the manufacture of a drug for the treatment of bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is to be delivered topically to the patient's bladder, and the patient's eligibility for treatment is determined by detecting one or more FGFR gene alterations in a tumor tissue sample from the patient, in particular by detecting one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR assay or NGS assay, or by detecting one or more FGFR gene alterations in a histopathological image of the tumor tissue via digital histopathological analysis. The method or use may include topically delivering or administering erdafitinib (e.g., as in any of the formulations described herein) to the bladder of a patient in need of treatment, in particular a cancer patient, in an effective dose for the treatment of bladder cancer (e.g., about 1 to 10 mg / day, as described herein). For example, the treatment may be effective in the treatment of muscle-invasive bladder cancer (MIBC), non-muscle-invasive bladder cancer (NMIBC), and / or Bacillus calmette-Guérin (BCG) naive bladder cancer. In one embodiment, the patient, in particular, is a BCG-experienced bladder or NMIBC or MIBC cancer patient. In one embodiment, the patient, in particular, is a BCG-naive bladder or NMIBC or MIBC cancer patient. In one embodiment, the patient, in particular, is a recurrent BCG-experienced high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient who refuses or is ineligible for radical cystectomy (RCy). In one embodiment, the patient, in particular, is a recurrent BCG-experienced high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient for whom RCy is planned. In one embodiment, the patient, in particular, is a patient with recurrent moderate-risk NMIBC (Ta and T1) cancer who has a history of only low-grade diseases.In one embodiment, the patient, in particular, is a MIBC cancer patient scheduled for RCy who has refused or is unsuitable for cisplatin-based neoadjuvant chemotherapy.

[0187] In certain embodiments, the urothelial carcinoma described herein is sensitive to FGFR2 gene alterations and / or FGFR3 gene alterations.

[0188] As used herein, “FGFR gene alteration” refers to an alteration in the wild-type FGFR gene, which includes, but is not limited to, FGFR fusion genes, FGFR mutations, FGFR amplifications, or any combination thereof, in particular FGFR fusion genes, FGFR mutations, or any combination thereof. In certain embodiments, an FGFR2 or FGFR3 gene alteration is an FGFR gene fusion. “FGFR fusion” or “FGFR gene fusion” refers to a gene that encodes a portion of FGFR (e.g., FGFR2 or FGFR3) and one or a portion of one of the fusion partners disclosed herein, and is produced by a translocation between the 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 patient's biological sample—FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof—can be determined using the disclosed methods or uses, or by methods well 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 individual FGFR fusion genes are disclosed in Table A2. Underlined sequences correspond to either FGFR3 or FGFR2, and the sequences represent the fusion partner.

[0189] [Table 1]

[0190] Table 2-1

[0191] Table 2-2

[0192] Table 2-3

[0193] Table 2-4

[0194] Table 2-5

[0195] Table 2-6

[0196] Table 2-7

[0197] Table 2-8

[0198] Table 2-9

[0199] Table 2-10

[0200] FGFR gene variations include single nucleotide polymorphisms (SNPs) of FGFR. A “FGFR single nucleotide polymorphism” (SNP) refers to a single nucleotide that differs between individuals in the FGFR2 or FGFR3 gene. In certain embodiments, an FGFR2 or FGFR3 gene variation is an FGFR3 gene mutation. Specifically, a “FGFR single nucleotide polymorphism” (SNP) refers to a single nucleotide that differs between individuals in the FGFR3 gene. The presence of one or more of the following FGFR SNPs in a patient's biological sample, namely FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, FGFR3 Y373C, or any combination thereof, can be determined by methods well known to those skilled in the art or by methods disclosed in International Publication No. 2016 / 048833. The sequences of FGFR SNPs are provided in Table B.

[0201] [Table 3] The sequence corresponds to nucleotides 920-1510 of FGFR3 (Genebank identification number NM_000142.4). The nucleotides in bold and underlined represent SNPs. * In some literature, it is mistakenly referred to as Y375C.

[0202] In certain embodiments, the method or use for treating urothelial carcinoma described herein comprises, consists of, or essentially comprises administering the drug delivery system described herein to a patient diagnosed with urothelial carcinoma as described herein and having at least one FGFR2 gene mutation and / or FGFR3 gene mutation (i.e., one or more FGFR2 gene mutations, one or more FGFR3 gene mutations, or a combination thereof). In certain embodiments, the FGFR2 gene mutation and / or FGFR3 gene mutation is an FGFR3 gene mutation, or an FGFR2 gene fusion, or an FGFR3 gene fusion. In some embodiments, the FGFR3 gene mutation is R248C, S249C, G370C, Y373C, or any combination thereof. In further embodiments, the FGFR2 or FGFR3 gene fusion is FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof.

[0203] Furthermore, methods or uses for treating urothelial carcinoma as described herein are described herein, comprising, consisting of, or essentially consisting of: (a) evaluating a biological sample from a patient having urothelial carcinoma as described herein for the presence of one or more FGFR gene alterations, particularly one or more FGFR2 or FGFR3 gene alterations; and (b) if one or more FGFR gene alterations, particularly one or more FGFR2 or FGFR3 gene alterations, are present in the sample, administering to the patient the drug delivery system described herein.

[0204] The following methods for evaluating a biological sample for the presence of one or more FGFR gene mutations are equally applicable to any of the therapeutic methods and uses disclosed above.

[0205] Preferred methods for evaluating a biological sample for the presence of one or more FGFR gene alterations are described herein, in International Publication No. 2016 / 048833 and U.S. 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 gene alterations may include any combination of the steps of: isolating RNA from the biological sample; synthesizing cDNA from the RNA; and amplifying the cDNA (pre-amplified or unpre-amplified). In some embodiments, evaluating a biological sample for the presence of one or more FGFR gene alterations may include amplifying cDNA from a patient using a primer pair that binds to and amplifies one or more FGFR gene alterations, and determining whether one or more FGFR gene alterations are present in the sample. In some embodiments, the cDNA may be pre-amplified. In some embodiments, the evaluation step may include: isolating RNA from the sample; synthesizing cDNA from the isolated RNA; and pre-amplified the cDNA.

[0206] Suitable primer pairs for performing the amplification step include, but are not limited to, those disclosed in International Publication No. 2016 / 048833, as illustrated in Table C below.

[0207] [Table 4]

[0208] The presence of one or more FGFR gene mutations can be evaluated at any suitable time, including at the time of diagnosis, following tumor resection, following the first line of treatment, during clinical treatment, or any combination thereof.

[0209] The method and use may further include evaluating the presence of one or more FGFR gene alterations in the biological sample prior to the administration step.

[0210] Diagnostic tests and screenings are typically performed on biological samples selected from blood, lymph, bone marrow, solid tumor samples, 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.

[0211] Methods for identifying and analyzing gene alterations and protein upregulations are known in the art. Screening methods may include, but are not limited to, standard methods such as reverse transcriptase polymerase chain reaction (RT-PCR) or in situ hybridization such as fluorescence in situ hybridization (FISH).

[0212] Identifying individuals with genetic alterations in FGFR, particularly those possessing the FGFR genetic alterations described herein, may indicate that a patient is particularly suitable for treatment with erdafitinib. Tumors may be selectively screened for the presence of FGFR variants prior to treatment. Screening processes typically include direct sequencing, oligonucleotide microarray analysis, or variant-specific antibodies. Furthermore, diagnosis of tumors possessing such genetic alterations may be performed using methods known to those skilled in the art and described herein, such as RT-PCR, FISH, or next-generation sequencing (NGS).

[0213] In addition, for example, FGFR gene changes can be identified by direct sequencing of tumor biopsies using PCR, and by methods for directly sequencing PCR products as described above. Those skilled in the art will recognize that any of these well-known techniques for detecting overexpression, activation, or mutation of the above-mentioned proteins may be applied in the case of the present invention.

[0214] In RT-PCR screening, the level of mRNA in tumors is evaluated by generating a cDNA copy of the mRNA and then amplifying the cDNA by PCR. The PCR amplification method, primer selection, and amplification conditions are well known to those skilled in the art. Nucleic acid manipulation and PCR are performed according to 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, a commercially available kit for RT-PCR (e.g., Roche Molecular Biochemicals) may be used, or the methodologies described in U.S. Patents 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, these publications being incorporated herein by reference. An example of an in-situ hybridization technique for evaluating mRNA expression is fluorescence in-situ hybridization (FISH) (see Angerer (1987) Meth. Enzymol., 152:649).

[0215] In general, in-situ hybridization involves the following main steps: (1) fixation of the tissue to be analyzed, (2) pre-hybridization treatment of the sample to increase the accessibility of the target nucleic acid and reduce nonspecific binding, (3) hybridization of the nucleic acid mixture with the nucleic acid in the biological structure or tissue, (4) post-hybridization washing to remove nucleic acid fragments that did not bind during hybridization, and (5) detection of the hybridized nucleic acid fragments. Probes used in such applications are typically labeled with, for example, radioisotopes or fluorescent reporters. Preferred probes are of sufficient length, e.g., about 50, 100, or 200 nucleotides to about 1000 nucleotides or more, to enable specific hybridization with the target nucleic acid under stringent conditions. The standard method for performing FISH is described in Ausubel, FM et al., eds. (2004) Current Protocols in Molecular Biology, and Fluorescence In Situ Hybridization: Technical Overview by 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.

[0216] Methods for gene expression profiling are described by DePrimo et al. (2003), BMC Cancer, 3:3. Briefly, the protocol is as follows: Double-stranded cDNA is synthesized from total RNA using the (dT)24 oligomer (SEQ ID NO: 38: tttttttttt tttttttttt tttt) to prime the synthesis of the first-stranded cDNA, and then the second-stranded cDNA is synthesized with random hexamer primers. This double-stranded cDNA is used as a template for in vitro transcription of cRNA using biotinylated ribonucleotides. The cRNA is chemically fragmented according to the protocol described by Affymetrix (Santa Clara, CA, USA) and then hybridized overnight on a Human Genome Array.

[0217] Alternatively, the protein product expressed from mRNA may be assayed by immunohistochemistry of tumor samples, solid-phase immunoassays using microtiter plates, Western blotting, two-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry, and other methods known in the art for the detection of 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 FGFR upregulation or FGFR variants or mutants may be applicable in the present invention.

[0218] 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 using assays, such as those from Chemicon International. The tyrosine kinase of interest is immunoprecipitated from the sample lysate, and its activity is measured.

[0219] Another method for measuring the overexpression or activation of FGFR, including the isoform, is the measurement of microvessel density. This can be measured, for example, using the method described by Orre and Rogers (Int J Cancer (1999), 84(2) 101-8). The assay method also includes the use of markers.

[0220] Therefore, 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.

[0221] According to certain embodiments, FGFR2 and / or FGFR3 gene changes can be identified using commercially available kits, including but not limited to the QIAGEN therascreen® FGFR RGQ RT-PCR kit.

[0222] According to certain embodiments, FGFR2 and / or FGFR3 gene changes can be identified in a liquid biological sample, such as a urine sample, of a cancer patient. Detached urothelial bladder cancer cells can enter the urine. <000089​​​​​​​​ According to certain embodiments, urine-based molecular profiling can be performed using available kits including, but not limited to, PCR and NGS assays. Non-limiting examples of available kits include the Urodiag® PCR Kit (which includes the Mutated Allele Specific Oligonucleotide (MASO) (Mutated Allele Specific Oligonucleotide)-PCR assay), AssureMDX (which is a urine-based test for studying mutations, for example, in FGFR3), and PredicineCARE™, a urine cfDNA-based targeted NGS assay.

[0226] In some embodiments, FGFR gene alterations are detected using NGS assays or PCR assays of urine samples and tumor tissue samples obtained from patients. In some embodiments, there is a high concordance between FGFR alterations detected in urine sample assays and tumor tissue sample assays. In some embodiments, urine sample assays identify bladder cancer patients not identified by tumor tissue sample assays. In some embodiments, patients are identified by urine sample assays only. In some embodiments, patients are identified by urine sample assays only because there are no available samples or the tumor tissue is insufficient. In some embodiments, urine sample assays identify at least about 5%, 10%, 15%, 20%, 25%, or 27% more bladder cancer patients than tumor tissue sample assays. In some embodiments, urine sample assays identify about 5% to 50%, 10% to 45%, 15% to 40%, 20% to 35%, or 25% to 30% more bladder cancer patients than tumor tissue sample assays. In one embodiment, the urine sample assay is an NGS (next-generation sequencing) assay, particularly the PredicineCare™ NGS assay. In one embodiment, the tumor tissue sample assay is a PCR (polymerase chain reaction) assay, particularly the QIAGEN therascreen® FGFR RGQ RT-PCR Kit.

[0227] In certain embodiments, a method of administering a drug to a patient includes inserting a drug delivery system described herein into the patient and enabling the drug to be released from the system. For example, the system may include any feature or combination of feature components described herein. In one embodiment, the drug is released from the lumen of the drug reservoir via diffusion through a second material of the wall structure. In certain embodiments, the drug release profile is substantially pH-independent over a pH range of 5 to 7. In certain embodiments, the drug release profile is substantially pH-independent over a pH range of 5.5 to 7. In certain embodiments, the drug release profile is substantially pH-independent over a pH range of 5.5 to 8.

[0228] In certain embodiments, enabling the release of a drug from the system includes allowing water to be absorbed through the permeable wall portion (e.g., through the second wall structure / second material only, or through both the first wall structure / material and the second wall structure / material) and enabling the solubilized drug to be released from the system by diffusion through the second wall structure / material. In other words, in certain embodiments, drug elution from the system occurs following the dissolution of the drug within the system. Body fluids enter the system, come into contact with the drug, solubilize the drug, and then the dissolved drug diffuses out of the system. For example, if the system is inserted into a bladder, the drug may be solubilized upon contact with urine. In one embodiment, releasing a drug from the system includes solubilizing the drug in water or an aqueous medium, such as urine, absorbed through the second wall structure / material, or through both the first wall structure / material and the second wall structure / material.

[0229] In some embodiments, the device components of the system include a water-permeable and drug-impermeable base material and a water-permeable and drug-permeable stripe material. For example, the base material may be TPU, e.g., Lubrizol's Carbothane® AC-4075A or Tecothane® AR-75A, and the stripe material may be TPU, e.g., Lubrizol TECOFLEX® TPU, e.g., EG-80A (Lubrizol Life Science (Bethlehem, PA)).

[0230] In certain embodiments, insertion involves inserting the system through the patient's urethra and deploying it into the patient's bladder. The system may release the drug for several days, weeks, months, or longer after the implantation procedure is complete. In one embodiment, deploying the drug delivery system in a patient involves inserting the system into the patient's body cavity or lumen via a deployment device. For example, the system may be deployed through a deployment device positioned in a natural body cavity, e.g., the urethra, or in a body cavity, e.g., the bladder, e.g., a catheter or cystoscope. The deployment device is typically removed from the body cavity, and the drug delivery system remains in the bladder or other body cavity for a specified treatment period.

[0231] In one example, the system is deployed by passing the drug delivery system through a deployment device and releasing the system from the deployment device into the patient's body, for example, into a body cavity, for example, into the bladder. In an embodiment, the system exhibits a retaining shape, for example, an expanded or higher profile shape, when the system emerges into the cavity from the deployment device. The deployment device may be a commercially available system or a system specifically adapted for the 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 so that the system exhibits a coiled retaining shape.

[0232] The drug delivery system can typically pass through a dispensing device, such as a stylet, with the assistance of a lubricant, until it exits the lumen of the dispensing device and enters the bladder.

[0233] In certain embodiments, the drug delivery system described herein is deployed transurethrally into the patient's bladder using a urinary tract placement catheter, the urinary tract placement catheter comprising two components: a catheter-like shaft and a stylet fitted inside the shaft. The shaft may include a single lumen extruder, which comprises a non-traumatic distal end including a coudet bend, an exit port near the distal end, 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 coudet tip to assist in the insertion procedure of the intravesical drug delivery system. The stylet is a single lumen extruder and is used to advance the drug delivery system into the bladder through the lumen of the transparent shaft.

[0234] When deployed in vivo, the system subsequently releases a drug (e.g., erdafitinib) for the treatment of one or more conditions or diseases locally into the tissue at the deployment site. The release is controlled to release an effective amount of the drug over an extended period. The system may then be removed, reabsorbed, excreted, or undergo a combination of these processes. In certain embodiments, the system remains in the bladder for a predetermined period, e.g., two weeks, three weeks, four weeks, one month, two months, three months, or longer, while releasing the drug.

[0235] The deployed system releases a desired amount of drug over a desired predetermined period of time. In embodiments, the system can deliver a desired dose of drug over a long period, 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 longer. The drug delivery rate and dosage can be selected depending on the drug being delivered and the disease or condition being treated. In one embodiment, the rate of drug release from the drug delivery system is zero-order for at least 36 hours. In one embodiment, the rate of drug release 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 longer.

[0236] The system may then be recovered from the body, for example, if the system is non-biodegradable or otherwise needs to be removed. Recovery systems for this purpose are known in the art or can be specially manufactured. The system may also be fully or partially biodegradable, reabsorbable, or biodegradable, so that the entire system is reabsorbed or the system degrades sufficiently to be eliminated from the bladder, for example, during urination, thus eliminating the need for recovery. The system may not be recovered or reabsorbed until some, or preferably most or all, of the drug has been released. If necessary, a newly filled system of the drug may then be implanted during or after the same recovery procedure.

[0237] Method for creating a drug delivery system 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, filling the lumen of the drug reservoir with a suitable amount of drug (e.g., a suitable number of drug tablets), and closing the ends of the tubular housing.

[0238] In some embodiments, the tubular wall structure may include a retaining lumen extending through or along the structure. The retaining lumen may optionally be packed with an elastic retaining frame, e.g., nitinol wire or other superelastic wire, and the retaining lumen may then be sealed to keep the frame inside the lumen, and / or optionally, the retaining lumen may be filled with gas (e.g., air), and the retaining lumen may then be sealed at the ends of the retaining lumen before or after drug packing of the system. In another embodiment, the retaining lumen may be filled with high-durometer silicone before drug packing of the system, and the high-durometer silicone may then cure into a solid elastic form effective for biasing the tubular wall structure in a coiled bladder retaining shape.

[0239] In other embodiments, the method includes thermal shaping a tubular structure to have a coiled retaining shape that is elastically deformable into a non-coiled shape. In such embodiments, a retaining lumen and frame may not be necessary.

[0240] Some steps or substeps of the method for constructing a drug delivery system may be performed in other order or simultaneously.

[0241] This disclosure may be further understood by referring to the following non-limiting examples.

[0242] Embodiment 1. A solid pharmaceutical composition, (a) Eldafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-6-yl]ethane-1,2-diamine) at a concentration of at least 45% by weight of the solid pharmaceutical composition, (b) A solid pharmaceutical composition comprising at least one pharmaceutical excipient. 2. The solid pharmaceutical composition according to Embodiment 1, wherein at least one pharmaceutical excipient comprises a solubilizer, a binder, a diluent (filler), a wetting agent, a disintegrant, a flow promoter, a lubricant, a formaldehyde scavenger, or any combination thereof, or selected from thereto. 3. The solid pharmaceutical composition according to Embodiment 1, wherein at least one pharmaceutical excipient comprises a solubilizer, a binder, a diluent (filler), a flow promoter, a lubricant, a formaldehyde scavenger, or any combination thereof, or selected from thereto. 4. A process for preparing a solid pharmaceutical composition, (a) Preparing a solid composition within granules, wherein the solid composition within granules is (i) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-6-yl]ethane-1,2-diamine), (ii) preparing an intragranular solid composition comprising or essentially comprising at least one intragranular pharmaceutical excipient, (b) Combining the solid composition within the granules with at least one extragranule pharmaceutical excipient to form a blend, (c) A process comprising compressing the blend into tablets to form a solid pharmaceutical composition, wherein erdafitinib free base is present in a concentration of at least 45% by weight of the solid pharmaceutical composition. 5. A process for producing the solid pharmaceutical composition according to Embodiment 4, wherein at least one intragranular pharmaceutical excipient and at least one extragranular pharmaceutical excipient include or are selected from at least one common (present in both) pharmaceutical excipient. 6. A process for producing the solid pharmaceutical composition according to Embodiment 4, wherein at least one intragranular excipient and at least one extragranular pharmaceutical excipient do not contain a common (present in both) pharmaceutical excipient. 7. A process for producing a solid pharmaceutical composition according to any one of embodiments 4 to 6, wherein the solid composition within the granules is prepared by a roller compression process. 8. A process for producing a solid pharmaceutical composition according to any one of Embodiments 4 to 6, wherein the solid composition within the granules is prepared by a fluid bed granulation process. 9. A process for preparing the solid pharmaceutical composition according to any one of Embodiments 4 to 8, wherein at least one excipient for external use of granules contains microcrystalline cellulose and vinylpyrrolidone-vinyl acetate copolymer, particularly in a weight ratio of 50:50. 10. (a) The solid composition within the granules contains a solubilizing agent, at least one binder, and a first amount of lubricant. (b) The excipient for external use of granules contains a diluent, a fluidizing agent, and a second amount of lubricant. (c) A process for preparing the solid pharmaceutical composition according to any one of Embodiments 4 to 6, wherein the solid composition within the granules is prepared by a roller compression process. 11. The solubilizing agent is hydroxypropyl-beta-cyclodextrin. The binder is a combination of microcrystalline cellulose and vinylpyrrolidone-vinyl acetate copolymer. The lubricant is magnesium stearate. A method for preparing the solid pharmaceutical composition according to Embodiment 10, wherein the diluent is anhydrous calcium hydrogen phosphate and the fluidizing agent is colloidal silicon dioxide. 12. (a) The solid composition within the granules contains a solubilizing agent, a diluent, and a disintegrant. (b) The excipient for external use of granules contains a lubricant and at least one binder. (c) A process for preparing the solid pharmaceutical composition according to Embodiment 4 or 5, wherein the solid composition within the granules is prepared by a fluid bed granulation process. 13. The solubilizing agent contains or is selected from hydroxypropyl-beta-cyclodextrin. The diluent contains or is selected from microcrystalline cellulose. The disintegrant contains or is selected from hydroxypropylmethylcellulose. At least one binder contains or is selected from a combination of microcrystalline cellulose and vinylpyrrolidone-vinyl acetate copolymer. A process for producing the solid pharmaceutical composition according to Embodiment 12, wherein the lubricant comprises or is selected from magnesium stearate. 14. A solid pharmaceutical composition according to any one of Embodiments 1 to 13, or a process for preparing a solid pharmaceutical composition, wherein erdafitinib free base 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. 15. A solid pharmaceutical composition according to any one of Embodiments 1 to 13, or a process for producing a solid pharmaceutical composition, wherein erdafitinib free base 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 at least one extragranular excipient comprises microcrystalline cellulose and vinylpyrrolidone-vinyl acetate copolymer, particularly in a 50:50 weight ratio. 16. A solid pharmaceutical composition according to any one of Embodiments 1 to 15, or a process for producing a solid pharmaceutical composition, wherein the solid pharmaceutical composition further comprises a formaldehyde scavenger. 17. A solid pharmaceutical composition according to Embodiment 16 or a process for producing a solid pharmaceutical composition, wherein the formaldehyde scavenger comprises an amino acid, an amino sugar, an alpha-(α-)amine compound, a conjugate thereof, or any combination thereof, or selected therefrom. 18. A solid pharmaceutical composition or a process for producing a solid pharmaceutical composition according to Embodiment 16, wherein the formaldehyde scavenger comprises 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, pharmaceutically acceptable salts thereof, or any combination thereof, or selected from thereto. 19. The solid pharmaceutical composition according to Embodiment 16, or a process for producing a solid pharmaceutical composition, wherein the formaldehyde scavenger is meglumine. 20. A solid pharmaceutical composition according to any one of Embodiments 16 to 19, or a process for producing a solid pharmaceutical composition, wherein a 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, formula

[0243] [ka] A solid pharmaceutical composition or a process for producing a solid pharmaceutical composition according to any one of Embodiments 1 to 20, further comprising a compound having, a salt thereof, a solvate thereof, or a combination thereof. 22. A solid pharmaceutical composition according to any one of Embodiments 1 to 21, or a process for producing a solid pharmaceutical composition, 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 according to Embodiment 22 or a process for producing a solid pharmaceutical composition, wherein the solubilizer comprises (a) a cyclic oligosaccharide, (b) cellulose functionalized with a methoxy moiety, a 2-hydroxypropoxy moiety, an acetyl moiety, or a succinoyl moiety, or a combination thereof, or (c) a salt thereof, or a selection thereof. 24. The solid pharmaceutical composition according to Embodiment 22 or a process for producing a solid pharmaceutical composition, wherein the solubilizer comprises hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, sulfobutyl ether-beta-cyclodextrin sodium salt, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose E5 (HPMC-E5), or any combination thereof, or selected from thereto. 25. A solid pharmaceutical composition according to Embodiment 22 or a process for producing a solid pharmaceutical composition, wherein at least one pharmaceutical excipient or at least one granular pharmaceutical excipient comprises a solubilizer containing hydroxypropyl-beta-cyclodextrin. 26. A solid pharmaceutical composition or a process for producing a solid pharmaceutical composition according to any one of Embodiments 22 to 25, wherein the total concentration of the solubilizer in the solid pharmaceutical composition is 1% to 20% by weight, 5% to 15% by weight, 7% to 12% by weight, or about 10% by weight. 27. A solid pharmaceutical composition or a process for producing 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 according to Embodiment 27 or a process for producing a solid pharmaceutical composition, wherein at least one binder comprises a water-soluble polymer binder, a slightly water-soluble polymer binder, a water-insoluble polymer binder, or any combination thereof, or is independently selected therefrom. 29. A solid pharmaceutical composition according to Embodiment 27 or a process for producing a solid pharmaceutical composition, wherein at least one binder comprises 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 a combination thereof, or independently selected therefrom. 30. A solid pharmaceutical composition according to Embodiment 27 or a process for producing a solid pharmaceutical composition, wherein at least one binder comprises vinylpyrrolidone-vinyl acetate copolymer, silicified microcrystalline cellulose, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), or any combination thereof, or selected from thereto. 31. The solid pharmaceutical composition according to Embodiment 27 or a process for producing a solid pharmaceutical composition, wherein at least one binder comprises or is microcrystalline cellulose. 32. A solid pharmaceutical composition according to Embodiment 29 or 30, or a process for producing a solid pharmaceutical composition, 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 producing 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 5% to 30% by weight, 10% to 25% by weight, 12% to 22% by weight, or 14% to 19% by weight. 34. A solid pharmaceutical composition according to any one of Embodiments 27 to 33, or a process for producing a solid pharmaceutical composition, wherein at least one binder comprises or further comprises a vinylpyrrolidone-vinyl acetate copolymer present in the solid pharmaceutical composition at a concentration of 4% to 12% by weight, 6% to 10% by weight, or 7% to 8% by weight. 35. A solid pharmaceutical composition or a process for producing a solid pharmaceutical composition according to any one of Embodiments 27 to 34, wherein at least one binder comprises (a) microcrystalline cellulose present in the solid pharmaceutical composition at a concentration of 5% to 20% by weight, 6% to 15% by weight, or 7% to 12% by weight, (b) silicified microcrystalline cellulose present in the solid pharmaceutical composition at a concentration of 3% to 18% by weight, 4% to 15% by weight, or 5% to 12% by weight, or (c) a combination of both (a) and (b). 36. A solid pharmaceutical composition or a process for producing 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. The solid pharmaceutical composition according to Embodiment 36, or a process for producing a solid pharmaceutical composition, wherein the wetting agent comprises or contains an anionic surfactant. 38. The solid pharmaceutical composition according to Embodiment 36 or a process for producing a solid pharmaceutical composition, wherein the wetting agent comprises sodium lauryl sulfate, sodium stearyl fumarate, polysorbate 80, sodium docusate, or any combination thereof, or is independently selected therefrom. 39. A solid pharmaceutical composition or a process for producing 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 producing 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 contains or further contains a disintegrant. 41. The solid pharmaceutical composition according to Embodiment 40 or a process for producing a solid pharmaceutical composition, wherein the disintegrant comprises a functionalized polysaccharide or a crosslinked polymer, or is independently selected therefrom. 42. A solid pharmaceutical composition or a process for producing a solid pharmaceutical composition according to Embodiment 40, wherein the disintegrant comprises (a) cellulose functionalized with a methoxy moiety, a 2-hydroxypropoxy moiety, or a carboxymethoxy moiety, a salt thereof, or a combination thereof, (b) carboxymethylated starch, or (c) a crosslinked polymer, or a selection thereof. 43. The solid pharmaceutical composition according to Embodiment 40 or a process for producing a solid pharmaceutical composition, wherein the disintegrant comprises hydroxypropyl methylcellulose, low-substituted hydroxypropylcellulose, crospovidone (crosslinked polyvinylpyrrolidone), croscarmellose sodium (crosslinked carboxymethylcellulose sodium), sodium starch glycolate, or any combination thereof, or independently selected therefrom. 44. A solid pharmaceutical composition or a process for producing 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 producing 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. ​​The solid pharmaceutical composition according to Embodiment 45 or a process for producing a solid pharmaceutical composition, wherein the diluent comprises or is selected from sugars, starches, microcrystalline cellulose, sugar alcohols, hydrogen phosphates, dihydrogen phosphates, carbonates, or combinations thereof. 47. The solid pharmaceutical composition according to Embodiment 45 or a process for producing a solid pharmaceutical composition, wherein the diluent comprises lactose (lactose monohydrate), dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium carbonate, sucrose, or any combination thereof, or selected from thereto. 48. A solid pharmaceutical composition or a process for producing a solid pharmaceutical composition according to any one of embodiments 45 to 47, wherein the total concentration of the diluent in the solid pharmaceutical composition is 12% to 30% by weight, 15% to 25% by weight, or 18% to 22% by weight. 49. The solid pharmaceutical composition according to Embodiment 47 or a process for producing a solid pharmaceutical composition, wherein the diluent contains anhydrous calcium hydrogen phosphate at a concentration of 18% to 20% by weight, or selected from thereto. 50. A solid pharmaceutical composition according to Embodiment 47 or a process for producing a solid pharmaceutical composition, wherein the diluent contains or is selected from microcrystalline cellulose at a concentration of 20% to 22% by weight. 51. A solid pharmaceutical composition or a process for producing 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 flow promoter. 52. The solid pharmaceutical composition according to Embodiment 51 or a process for producing a solid pharmaceutical composition, wherein the flow promoter comprises colloidal silicon dioxide, colloidal anhydrous silicon dioxide, talc, or any combination thereof, or selected from thereto. 53. The solid pharmaceutical composition according to Embodiment 51, or a process for producing a solid pharmaceutical composition, wherein the flow promoter contains or is colloidal silicon dioxide. 54. A solid pharmaceutical composition or a process for producing a solid pharmaceutical composition according to any one of embodiments 51 to 53, wherein the total concentration of the flow promoter 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 producing 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. The solid pharmaceutical composition according to Embodiment 55 or a process for producing a solid pharmaceutical composition, wherein the lubricant comprises a fatty acid, a fatty acid salt, a fatty acid ester, talc, a glyceride ester, a metal silicate, or any combination thereof, or selected from thereto. 57. A solid pharmaceutical composition according to Embodiment 55 or a process for producing a solid pharmaceutical composition, wherein the lubricant comprises or is selected from magnesium stearate, stearic acid, magnesium silicate, aluminum silicate, isopropyl myristate, sodium oleate, sodium stearoyl lactate, sodium stearoyl fumarate, titanium dioxide, or a combination thereof. 58. The solid pharmaceutical composition according to Embodiment 55, or a process for producing a solid pharmaceutical composition, wherein the lubricant comprises or contains magnesium stearate. 59. A solid pharmaceutical composition or a process for producing 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 according to any one of Embodiments 1 to 59, or a process for producing a solid pharmaceutical composition, wherein the solid pharmaceutical composition is a minitablet. 61. The solid pharmaceutical composition or process for producing the solid pharmaceutical composition according to Embodiment 60, wherein the mini-tablet is in the form of a solid cylinder, and the solid cylinder has 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 producing a solid pharmaceutical composition according to Embodiment 61, wherein the length of the minitablet exceeds the diameter of the minitablet, so as to provide a minitablet having an aspect ratio (length:diameter) greater than 1:1. 63. A solid pharmaceutical composition or a process for producing 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 producing 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, (a) Eldafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-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 the solid pharmaceutical composition, (c) Meglumine at a concentration of 1% by weight of the solid pharmaceutical composition, (d) Microcrystalline cellulose at a concentration of 10% by weight of the solid pharmaceutical composition, (e) Anhydrous calcium hydrogen phosphate at a concentration of 19% by weight of the solid pharmaceutical composition, (f) A solid pharmaceutical composition containing vinylpyrrolidone-vinyl acetate copolymer at a concentration of 8% by weight, (g) Colloidal silicon dioxide at a concentration of 0.5% by weight of the solid pharmaceutical composition, (h) A solid pharmaceutical composition comprising, or A solid pharmaceutical composition, (a) Eldafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition, (b) Hydroxypropyl beta-cyclodextrin, (c) Megurumin and, (d) Microcrystalline cellulose and (e) Anhydrous calcium hydrogen phosphate and (f) vinylpyrrolidone-vinyl acetate copolymer, (g) Colloidal silicon dioxide and (h) A solid pharmaceutical composition comprising magnesium stearate. 66. A solid pharmaceutical composition, (a) Eldafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-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 the solid pharmaceutical composition, (c) Meglumine at a concentration of 1% by weight of the solid pharmaceutical composition, (d) Microcrystalline cellulose at a concentration of 24.5% by weight of the solid pharmaceutical composition, (e) A solid pharmaceutical composition containing silicified microcrystalline cellulose at a concentration of 6.0% by weight, (f) A solid pharmaceutical composition containing vinylpyrrolidone-vinyl acetate copolymer at a concentration of 6.0% by weight, (g) Colloidal silicon dioxide at a concentration of 0.5% by weight of the solid pharmaceutical composition, (h) A solid pharmaceutical composition comprising, or A solid pharmaceutical composition, (a) Eldafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition, (b) Hydroxypropyl beta-cyclodextrin, (c) Megurumin and, (d) Microcrystalline cellulose and (e) Silicified microcrystalline cellulose and (f) vinylpyrrolidone-vinyl acetate copolymer, (g) Colloidal silicon dioxide and (h) A solid pharmaceutical composition comprising magnesium stearate. 67. A solid pharmaceutical composition, (a) Eldafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-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 the solid pharmaceutical composition, (c) Meglumine at a concentration of 1% by weight of the solid pharmaceutical composition, (d) Hydroxypropyl methylcellulose at a concentration of 1.5% by weight of the solid pharmaceutical composition, (e) Mannitol at 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) A solid pharmaceutical composition containing vinylpyrrolidone-vinyl acetate copolymer at a concentration of 7.25% by weight, (i) Colloidal silicon dioxide at a concentration of 0.25% by weight of the solid pharmaceutical composition, (j) A solid pharmaceutical composition comprising, or A solid pharmaceutical composition, (a) Eldafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition, (b) Hydroxypropyl beta-cyclodextrin, (c) Megurumin and, (d) Hydroxypropyl methylcellulose and (e) Mannitol and, (f) Sodium lauryl sulfate and (g) Microcrystalline cellulose and (h) vinylpyrrolidone-vinyl acetate copolymer, (i) Colloidal silicon dioxide and (j) A solid pharmaceutical composition comprising magnesium stearate. 68. A solid pharmaceutical composition, (a) Eldafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-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 the solid pharmaceutical composition, (c) Meglumine at a concentration of 1% by weight of the solid pharmaceutical composition, (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) A 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, (h) Hydroxypropyl methylcellulose at a concentration of 1.5% by weight of the solid pharmaceutical composition, (i) A solid pharmaceutical composition comprising, or A solid pharmaceutical composition, (a) Eldafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition, (b) Hydroxypropyl beta-cyclodextrin, (c) Megurumin and, (d) Microcrystalline cellulose and (e) Silicified microcrystalline cellulose and (f) vinylpyrrolidone-vinyl acetate copolymer, (g) Colloidal silicon dioxide and (h) Hydroxypropyl methylcellulose and (i) A solid pharmaceutical composition comprising magnesium stearate. 69. A process for preparing a solid pharmaceutical composition, (a) Preparing a solid composition within granules by a roller compression process, wherein the solid composition within granules is (i) Eldafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-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 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, (v) A solid pharmaceutical composition containing vinylpyrrolidone-vinyl acetate copolymer at a concentration of 8% by weight, (vi) Preparation of a solid pharmaceutical composition consisting of magnesium stearate at a concentration of 0.75% by weight, (b) Combining the solid composition inside the granules with the extragranule components to form a blend, wherein the extragranule components are (i) Anhydrous calcium hydrogen phosphate at 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, (iii) Forming a solid pharmaceutical composition essentially consisting of magnesium stearate at a concentration of 0.75% by weight, (c) A process comprising compressing the blend into tablets to form a solid pharmaceutical composition in the form of mini-tablets. 70. A process for preparing a solid pharmaceutical composition, (a) Preparing a solid composition within granules by a roller compression process, wherein the solid composition within granules is (i) Eldafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-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 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 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, (vi) Preparation of a solid pharmaceutical composition consisting of magnesium stearate at a concentration of 0.75% by weight, (b) Combining the solid composition inside the granules with the extragranule components to form a blend, wherein the extragranule components are (i) A solid pharmaceutical composition containing silicified microcrystalline cellulose at a concentration of 6.0% by weight, (ii) A 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, (iv) Forming a solid pharmaceutical composition essentially consisting of magnesium stearate at a concentration of 1.25% by weight, (c) A process comprising compressing the blend into tablets to form a solid pharmaceutical composition in the form of mini-tablets. 71. A process for preparing a solid pharmaceutical composition, (a) Preparing a solid composition within granules by a fluid bed granulation process, wherein the solid composition within granules is (i) Eldafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-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 the solid pharmaceutical composition, (iii) Meglumine at a concentration of 1% by weight of the solid pharmaceutical composition, (iv) Mannitol at a concentration of 21% by weight of the solid pharmaceutical composition, (v) Sodium lauryl sulfate at a concentration of 0.25% by weight of the solid pharmaceutical composition, (vi) Preparation of a solid pharmaceutical composition essentially consisting of hydroxypropyl methylcellulose at a concentration of 1.5% by weight, (b) Combining the solid composition inside the granules with the extragranule components to form a blend, wherein the extragranule components are (i) Microcrystalline cellulose at a concentration of 7.25% by weight of the solid pharmaceutical composition, (ii) A 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, (iv) Forming a solid pharmaceutical composition essentially consisting of magnesium stearate at a concentration of 1.50% by weight, (c) A process comprising compressing the blend into tablets to form a solid pharmaceutical composition in the form of mini-tablets. 72. A process for preparing a solid pharmaceutical composition, (a) Preparing a solid composition within granules by a fluid bed granulation process, wherein the solid composition within granules is (i) Eldafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-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 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, (v) Preparation of a solid pharmaceutical composition consisting of hydroxypropyl methylcellulose at a concentration of 1.5% by weight, (b) Combining the solid composition inside the granules with the extragranule components to form a blend, wherein the extragranule components are (i) Microcrystalline cellulose at a concentration of 7.5% by weight of the solid pharmaceutical composition, (ii) A 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, (iv) Forming a solid pharmaceutical composition essentially consisting of magnesium stearate at a concentration of 1.5% by weight, (c) A process comprising compressing the blend into tablets 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, wherein the first and second wall structures are adjacent to each other at two interface edges and together form a tube defining the closed drug reservoir lumen, and the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane, and the second material comprises an aliphatic polyether-based thermoplastic polyurethane. A drug delivery system comprising a drug preparation containing a drug, disposed within the lumen of a closed drug reservoir, (i) The second wall structure, or both the first and second wall structures, is permeable to water, and (ii) the first wall structure is impermeable to drugs and the second wall structure is permeable to drugs, thereby enabling the drug to be released 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, wherein the first and second wall structures are adjacent to each other at two interface edges and together form a tube defining the closed drug reservoir lumen, and the first material comprises an aromatic polyester hydrocarbon-based thermoplastic polyurethane, and the second material comprises an aliphatic polyether-based thermoplastic polyurethane. A drug delivery system comprising a drug preparation containing a drug, disposed within the lumen of a closed drug reservoir, (i) The second wall structure, or both the first and second wall structures, is permeable to water, and (ii) the first wall structure is impermeable to drugs and the second wall structure is permeable to drugs, thereby enabling the drug to be released in vivo by diffusion through the second wall structure. 75. The drug delivery system according to embodiment 73 or 74, wherein the second wall structure forms a longitudinal strip extending along the length of the tube. 76. The system according to any one of embodiments 73 to 75, wherein the system is configured to release a therapeutically effective amount of drug at a substantially zero-order release rate over a period of at least 36 hours. 77. The system according to any one of embodiments 73 to 76, wherein the system is configured to release a drug over a period of 2 days to 6 months. 78. The system according to any one of embodiments 73 to 77, wherein two interface edges are arranged at an arc angle of 15 to 270 degrees around the circumference of the pipe in a cross section perpendicular to the longitudinal axis of the pipe. 79. The system according to any one of embodiments 73 to 78, wherein the drug comprises, and in particular is, erdafitinib. 80. The system according to 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 according to 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 according to embodiment 81, wherein the two boundary edges are arranged at an arc angle of 45 to 90 degrees around the circumference of the pipe in a cross section perpendicular to the longitudinal axis of the pipe. 83. The system according to 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 according to embodiment 83, wherein the two boundary edges are arranged at an arc angle of 150 to 270 degrees around the circumference of the pipe in a cross section perpendicular to the longitudinal axis of the pipe. 85. The system according to Embodiment 79, wherein the system is configured to release erdafitinib at an average rate of 1 mg / day. 86. The system according to embodiment 85, wherein the two boundary edges are arranged at an arc angle of approximately 45 degrees around the circumference of the pipe in a cross section perpendicular to the longitudinal axis of the pipe. 87. The system according to Embodiment 79, wherein the system is configured to release erdafitinib at an average rate of 2 mg / day. 88. The system according to embodiment 87, wherein the two boundary edges are arranged at an arc angle of approximately 90 degrees around the circumference of the pipe in a cross section perpendicular to the longitudinal axis of the pipe. 89. The system according to Embodiment 79, wherein the system is configured to release erdafitinib at an average rate of 4 mg / day. 90. The system according to embodiment 89, wherein the two boundary edges are arranged at an arc angle of approximately 180 degrees around the circumference of the pipe in a cross section perpendicular to the longitudinal axis of the pipe. 91. The system according to Embodiment 79, wherein the system is configured to release erdafitinib at an average rate of 6 mg / day. 92. The system according to embodiment 91, wherein the two boundary edges are arranged at an arc angle of 210 to 270 degrees around the circumference of the pipe in a cross section perpendicular to the longitudinal axis of the pipe. 93. The system according to any one of embodiments 79 to 92, wherein the system comprises 500 mg of erdafitinib. 94. The system according to any one of embodiments 73 to 93, wherein the drug release profile is substantially pH-independent over a pH range of 5 to 7. 95. The system according to any one of embodiments 73 to 94, wherein the second wall structure constitutes less than 50 percent of the cross-sectional area of ​​the pipe in a section perpendicular to the longitudinal axis of the pipe. 96. The system according to any one of embodiments 73 to 94, wherein the second wall structure constitutes less than 25 percent of the cross-sectional area of ​​the pipe in a section perpendicular to the longitudinal axis of the pipe. 97. The system according to any one of embodiments 73 to 96, wherein the pipe has a substantially constant thickness over the circumference of the pipe. 98. The system according to any one of embodiments 73 to 97, further comprising a pair of end plugs and / or adhesive material for sealing the ends of the pipe. 99. The system according to any one of embodiments 73 to 98, wherein the first wall structure and the second wall structure are integrally formed. 100. The system according to embodiment 99, wherein the tube is formed in an extrusion process. 101. The system according to any one of embodiments 73 to 100, wherein the system is elastically deformable between a relatively straightened unfolded shape suitable for insertion into the patient's bladder through the patient's urethra and a retaining shape suitable for holding the system within the bladder. 102. The system according to any one of embodiments 73 to 101, wherein the system is elastically deformable and comprises overlapping curls formed by a tube, the tube having two opposing free ends, the two opposing free ends being oriented away from each other when the system is in a low-profile unfolded shape and toward each other when the system is in a relatively expanded retained shape. 103. The system according to any one of embodiments 73 to 102, wherein the system is elastically deformable and has a double elliptical retaining shape, and the tube has two opposing free ends located within the outer boundary of the double elliptical retaining shape. 104. The system according to any one of embodiments 73 to 103, further comprising a retaining frame lumen. 105. The system according to embodiment 104, further comprising a nitinol wire disposed within the lumen of the retaining frame. 106. A system according to any one of embodiments 73 to 105, wherein the first material has a Shore durometer value of 70A to 80A. 107. The system according to any one of embodiments 73 to 106, wherein the second material has a Shore durometer value of 70A to 75A. 108. A 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 according to any one of embodiments 73 to 108, wherein the drug formulation is in the form of a plurality of mini-tablets arranged in a drug lumen. 110. The system according to embodiment 109, wherein the multiple mini-tablets include a mini-tablet described in 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, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane, A drug delivery system comprising a drug formulation disposed within the lumen of a drug reservoir, the drug formulation comprising erdafitinib, A drug delivery system in which (i) the second wall structure, or both the first and second wall structures, are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling in vivo release of erdafitinib by diffusion through the second material forming the second wall structure. 112. The system according to 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, with the two interface edges arranged at an arc angle of approximately 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, with the two interface edges arranged at an arc angle of approximately 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, with the two interface edges arranged at an arc angle 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, wherein the first material comprises an aromatic polyester hydrocarbon-based thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane, A drug delivery system comprising a drug formulation disposed within the lumen of a closed drug reservoir, the drug formulation comprising erdafitinib, (i) The second wall structure, or both the first and second wall structures, is permeable to water, and (ii) the first wall structure is impermeable to erdafitinib, and the second wall structure is permeable to erdafitinib, thereby enabling in vivo release of erdafitinib by diffusion through the second wall structure. 114. The system according to 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, with the two interface edges arranged at an arc angle of approximately 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, with the two interface edges arranged at an arc angle of approximately 180 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. 115. The system according to any one of embodiments 111 to 114, wherein the system is elastically deformable and comprises overlapping curls formed by a tube, the tube having two opposing free ends, the two opposing free ends being oriented away from each other when the system is in a low-profile unfolded 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 pH-independent 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, wherein the first and second wall structures are adjacent to each other at two interface edges and together form a tube defining the closed drug reservoir lumen, the second wall structure forms a longitudinal strip extending along the length of the tube, the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane, and the second material comprises an aliphatic polyether-based thermoplastic polyurethane, A drug delivery system comprising a drug formulation disposed within the lumen of a closed drug reservoir, the drug formulation comprising a solid pharmaceutical composition according to any one of embodiments 1, 2, 3, and 14-68, A drug delivery system in which (i) the second wall structure, or both the first and second wall structures, are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling in vivo release of erdafitinib by diffusion through the second material forming the second wall structure. The system is configured to deliver a therapeutically effective dose of erdafitinib at a substantially zero-order release rate over at least three days. A drug delivery system comprising: (i) a system configured to release erdafitinib at an average rate of 2 mg / day, with two interface edges positioned at an arc angle of approximately 90 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube; (ii) a system configured to release erdafitinib at an average rate of 4 mg / day, with two interface edges positioned at an arc angle of approximately 180 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube; or (iii) a system configured to release erdafitinib at an average rate of 6 mg / day, with two interface edges positioned at an arc angle 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, wherein the first and second wall structures are adjacent to each other at two interface edges and together form a tube defining the closed drug reservoir lumen, the second wall structure forms a longitudinal strip extending along the length of the tube, the first material comprises an aromatic polyester hydrocarbon-based thermoplastic polyurethane, and the second material comprises an aliphatic polyether-based thermoplastic polyurethane, A drug delivery system comprising a drug formulation disposed within the lumen of a closed drug reservoir, 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 and second wall structures, is permeable to water, and (ii) the first wall structure is impermeable to erdafitinib, and the second wall structure is permeable to erdafitinib, thereby allowing erdafitinib to be released in vivo by diffusion through the second wall structure. The system is configured to deliver a therapeutically effective dose of erdafitinib at a substantially zero-order release rate over at least three days. (i) A drug delivery system configured to release erdafitinib at an average rate of 2 mg / day, with two interface edges positioned at an arc angle of approximately 90 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, or (ii) A system configured to release erdafitinib at an average rate of 4 mg / day, with two interface edges positioned at an arc angle of approximately 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 in an effective dose for treating bladder cancer into the bladder of a patient in need of treatment. 120. The method according to Embodiment 119, wherein the bladder cancer is muscle-invasive bladder cancer. 121. The method according to Embodiment 119, wherein the bladder cancer is nonmuscle-invasive bladder cancer. 122. The method according to Embodiment 119, wherein the bladder cancer is Bacillus calmette-Guérin naive. 123. The method according to any one of Embodiments 119 to 122, wherein erdafitinib is in the form of a solid pharmaceutical composition according to any one of Embodiments 1, 2, 3, and 14 to 68. 124. A method of intravesical administration of erdafitinib, Deployment of an intravesical system into a patient's bladder, wherein the system comprises a solid pharmaceutical composition as described in any one of embodiments 1, 2, 3, and 14-68. A method for intravesical administration of erdafitinib, comprising releasing the erdafitinib from the system. 125. The method according to Embodiment 124, wherein the intravesical system is a drug delivery system according to any one of Embodiments 73 to 118, and the release of erdafitinib from the system comprises releasing erdafitinib from the lumen of the drug reservoir via diffusion through a second wall structure. 126. The method according to Embodiment 124 or 125, wherein the system elastically deforms into a low-profile unfolded shape, is inserted through the urethra into the patient's bladder, and then exhibits 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 a device, the drug formulation comprising erdafitinib, A drug delivery system configured to release erdafitinib from the device after intravesical deployment of the drug delivery system. 128. A drug delivery system according to Embodiment 127, wherein the drug formulation comprises a plurality of tablets containing erdafitinib. 129. The drug delivery system according to Embodiment 128, wherein the tablet comprises a solid pharmaceutical composition according to any one of Embodiments 1, 2, 3, and 14-68. 130. A drug delivery system according to any one of embodiments 127 to 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 deliver erdafitinib at a release rate of approximately 1 mg / day to approximately 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 cancer patients, A method comprising locally delivering a therapeutically effective dose of erdafitinib into the bladder of a patient. 133. The method according to Embodiment 132, wherein local delivery of erdafitinib is performed, and erdafitinib is released from the intrabladder system at a release rate of approximately 1 mg / day to approximately 6 mg / day, for example, 2 to 4 mg / day. 134. The method according to 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 nonmuscle-invasive urothelial carcinoma or muscle-invasive urothelial carcinoma of the bladder in a cancer patient, (ii) high- or moderate-risk papillary urothelial carcinoma of the bladder, or (iii) muscle-invasive urothelial carcinoma of the bladder at stage cT2 to T3a, A method comprising locally delivering a therapeutically effective dose of erdafitinib into the bladder of a patient. 136. The method according to Embodiment 131, wherein the patient undergoes transurethral resection of a bladder tumor (TURBT) to reduce the total tumor size to 3 cm or less, and subsequently erdafitinib is locally delivered into the bladder. 137. The method according to Embodiment 135 or 136, comprising delivering erdafitinib locally to release erdafitinib from the intrabladder system at a release rate of approximately 1 mg / day to approximately 6 mg / day, for example, 2 to 4 mg / day. 138. The method according to 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 for treating a BCG-experienced patient who has recurrent high-grade Ta / T1 urothelial carcinoma of the bladder within 18 months of completing previous BCG therapy, A method comprising locally delivering a therapeutically effective dose of erdafitinib into the bladder of a patient. 140. The method according to Embodiment 139, comprising delivering erdafitinib locally to release erdafitinib from the intrabladder system at a release rate of approximately 1 mg / day to approximately 6 mg / day, for example, 2 to 4 mg / day. 141. The method according to 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 according to any one of Embodiments 132 to 141, wherein erdafitinib is delivered locally into the bladder from a drug delivery system described in any one of Embodiments 127 to 131. 143. The method according to any one of Embodiments 132 to 142, wherein the patient has at least one FGFR2 gene alteration and / or FGFR3 gene alteration.

[0244] Further Embodiments 1. A method for treating bladder cancer having one or more FGFR gene mutations, comprising locally delivering an effective dose of erdafitinib to the bladder of a patient in need thereof, wherein one or more FGFR gene mutations are detectable in a urine sample from the patient, in particular, one or more FGFR gene mutations are detectable in a urine sample from the patient using a urine-based PCR assay or NGS assay. 2. A method for treating bladder cancer having one or more FGFR gene mutations, comprising, or essentially comprising: (a) evaluating a urine sample from a patient having bladder cancer for the presence of one or more FGFR gene mutations, particularly using a urine-based PCR assay or NGS assay to evaluate a urine sample from a patient having bladder cancer for the presence of one or more FGFR gene mutations; and (b) locally delivering erdafitinib if one or more FGFR gene mutations are present in the sample. 3. A method for treating bladder cancer having one or more FGFR gene mutations, comprising locally delivering a therapeutically effective amount of erdafitinib to the bladder of a patient in need thereof, wherein the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a urine sample from the patient, and in particular, the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a urine sample from the patient using a urine-based PCR assay or NGS assay. 4. A method for treating bladder cancer having one or more FGFR gene alterations, comprising locally delivering a therapeutically effective amount of erdafitinib to the bladder of a patient in need thereof, wherein the patient's eligibility for treatment is determined by detecting one or more FGFR gene alterations in a urine sample from the patient, in particular, by detecting one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or NGS assay. 5. Erdafitinib for use in the treatment of bladder cancer in patients having one or more FGFR gene alterations, wherein erdafitinib is delivered locally to the patient's bladder, one or more FGFR gene alterations are detected in a urine sample from the patient, in particular, one or more FGFR gene alterations are detected in a urine sample from the patient using a urine-based PCR assay or NGS assay. 6. Erdafitinib for use in the treatment of bladder cancer in patients with one or more FGFR gene alterations, comprising, consisting of, or essentially consisting of: (a) evaluating a urine sample from a patient with bladder cancer for the presence of one or more FGFR gene alterations, particularly using a urine-based PCR assay or NGS assay; and (b) delivering erdafitinib topically to the patient if one or more FGFR gene alterations are present in the sample. 7. Erdafitinib for use in the treatment of bladder cancer in patients having one or more FGFR gene alterations, wherein erdafitinib is delivered locally to the patient's bladder, and the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a urine sample from the patient, and in particular, the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or NGS assay. 8. Erdafitinib for use in the treatment of bladder cancer in patients having one or more FGFR gene alterations, wherein erdafitinib is delivered locally to the patient's bladder, and the patient's eligibility for treatment is determined by detecting one or more FGFR gene alterations in a urine sample from the patient, in particular, by detecting one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or NGS assay. 9. Use of erdafitinib for the manufacture of a drug for the treatment of bladder cancer in patients having one or more FGFR gene mutations, wherein erdafitinib is delivered locally to the patient's bladder, and one or more FGFR gene mutations are detected in a urine sample from the patient, in particular, one or more FGFR gene mutations are detected in a urine sample from the patient using a urine-based PCR assay or NGS assay. 10. Use of erdafitinib for the manufacture of a drug for the treatment of bladder cancer having one or more FGFR gene alterations in a patient, comprising, consisting of, or essentially consisting of: (a) evaluating a urine sample from a patient having bladder cancer for the presence of one or more FGFR gene alterations, in particular by using a urine-based PCR assay or NGS assay; and (b) locally delivering erdafitinib if one or more FGFR gene alterations are present in the sample. 11. Use of erdafitinib for the manufacture of a drug for the treatment of bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is delivered locally to the patient's bladder, and the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a urine sample from the patient, in particular, the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or NGS assay. 12. Use of erdafitinib for the manufacture of a drug for the treatment of bladder cancer in patients having one or more FGFR gene alterations, wherein erdafitinib is delivered locally to the patient's bladder, and the patient's eligibility for treatment is determined by detecting one or more FGFR gene alterations in a urine sample from the patient, in particular, the patient's eligibility for treatment is determined by detecting one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or NGS assay. 13. Erdafitinib for use, or use according to any one of Embodiments 1 to 12, wherein one or more FGFR gene alterations include one or more FGFR2 gene alterations or FGFR3 gene alterations. 14. Erdafitinib for use, or use according to any one of Embodiments 1 to 13, wherein one or more FGFR gene mutations include one or more FGFR 2-point mutations or fusions or FGFR 3-point mutations or fusions. 15. One or more FGFR gene alterations are detected in a patient's urine sample prior to topical delivery of erdafitinib, according to any one of Embodiments 1 to 14, erdafitinib for use, or use. 16. Erdafitinib is a solid pharmaceutical composition, (a) Eldafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-6-yl]ethane-1,2-diamine) at a concentration of at least 45% by weight of the solid pharmaceutical composition, (b) Erdafitinib for use, or use according to any one of Embodiments 1 to 15, which is delivered topically in the form of a solid pharmaceutical composition comprising at least one pharmaceutical excipient. 17. The method according to Embodiment 16, erdafitinib for use, or use, wherein at least one pharmaceutical excipient comprises a solubilizer, binder, diluent (filler), wetting agent, disintegrant, flow promoter, lubricant, formaldehyde scavenger, or any combination thereof. 18. Erdafitinib for use, or use according to Embodiment 16 or 17, wherein free erdafitinib base 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 solid pharmaceutical composition comprises an intragranular solid composition containing at least one intragranular pharmaceutical excipient and an extragranular solid composition containing at least one extragranular pharmaceutical excipient, wherein the at least one extragranular pharmaceutical excipient contains microcrystalline cellulose and vinylpyrrolidone-vinyl acetate copolymer, particularly in a 50:50 weight ratio. 19. The method according to any one of Embodiments 16 to 18, erdafitinib for use, or use, wherein the solid pharmaceutical composition further comprises a formaldehyde scavenger selected from the group consisting of 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, their conjugates, their pharmaceutically acceptable salts, or any combination thereof. 20. The method according to Embodiment 19, erdafitinib for use, or use, wherein the formaldehyde scavenger is meglumine. 21. Erdafitinib for use, or use according to Embodiment 19 or 20, 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. 22. The method according to any one of Embodiments 16 to 21, erdafitinib for use, or use, wherein at least one pharmaceutical excipient, at least one intragranular pharmaceutical excipient, or at least one extragranular pharmaceutical excipient comprises a solubilizer selected from the group consisting of hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, sulfobutyl ether-beta-cyclodextrin sodium salt, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose E5 (HPMC-E5), or any combination thereof. 23. The method according to Embodiment 22, erdafitinib for use, or use, wherein the solubilizer is hydroxypropyl-beta-cyclodextrin. 24. Erdafitinib for use, or use according to Embodiment 22 or 23, wherein the total concentration of the solubilizer in the solid pharmaceutical composition is 1% to 20% by weight, 5% to 15% by weight, 7% to 12% by weight, or about 10% by weight. 25. The method according to any one of Embodiments 16 to 24, erdafitinib for use, or use, 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 selected from the group consisting of 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, and combinations thereof. 26. Erdafitinib for use, or use according to Embodiment 25, wherein the total concentration of at least one binder in the solid pharmaceutical composition is 5% to 30% by weight, 10% to 25% by weight, 12% to 22% by weight, or 14% to 19% by weight. 27. The method according to any one of Embodiments 16 to 26, erdafitinib for use, or use, 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. 28. Erdafitinib for use, as described in Embodiment 27, or for use, wherein the wetting agent comprises sodium lauryl sulfate, sodium stearyl fumarate, polysorbate 80, sodium docusate, or any combination thereof. 29. Erdafitinib for use, or use according to Embodiment 27 or 28, 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. 30. The method according to any one of Embodiments 1 to 29, erdafitinib for use, or use, 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. 31. The method according to Embodiment 30, erdafitinib for use, or use, wherein the disintegrant comprises hydroxypropyl methylcellulose, low-substituted hydroxypropylcellulose, crospovidone (cross-linked polyvinylpyrrolidone), croscarmellose sodium (cross-linked carboxymethylcellulose sodium), sodium starch glycolate, or any combination thereof. 32. Erdafitinib for use, or use according to Embodiment 30 or 31, 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. 33. The method according to any one of Embodiments 1 to 32, erdafitinib for use, or use, wherein at least 16 pharmaceutical excipients, at least 1 intragranular pharmaceutical excipient, or at least 1 extragranular pharmaceutical excipient comprises or further comprises a diluent. 34. The method according to Embodiment 33, erdafitinib for use, or use, wherein the diluent comprises lactose (lactose monohydrate), dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium carbonate, sucrose, or any combination thereof. 35. Erdafitinib for use, or use according to Embodiment 33 or 34, wherein the total concentration of the diluent in the solid pharmaceutical composition is 12% to 30% by weight, 15% to 25% by weight, or 18% to 22% by weight. 36. The method according to any one of Embodiments 1 to 35, erdafitinib for use, or use, wherein at least 16 pharmaceutical excipients, at least 1 intragranular pharmaceutical excipient, or at least 1 extragranular pharmaceutical excipient comprises or further comprises a flow enhancer. 37. The method according to Embodiment 36, erdafitinib for use, or use, wherein the flow promoter comprises colloidal silicon dioxide, colloidal anhydrous silicon dioxide, talc, or any combination thereof. 38. Erdafitinib for use, or use according to Embodiment 36 or 37, wherein the total concentration of the flow promoter 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. 39. The method according to any one of Embodiments 1 to 38, erdafitinib for use, or use, wherein at least 16 pharmaceutical excipients, at least 1 intragranular pharmaceutical excipient, or at least 1 extragranular pharmaceutical excipient comprises or further comprises a lubricant. 40. Eldafitinib for use, as described in Embodiment 39, or for use, wherein the lubricant comprises magnesium stearate, stearic acid, magnesium silicate, aluminum silicate, isopropyl myristate, sodium oleate, sodium stearoyl lactate, sodium stearoyl fumarate, titanium dioxide, or a combination thereof. 41. Erdafitinib for use, or use according to Embodiment 39 or 40, 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. 42. The method according to any one of Embodiments 16 to 41, erdafitinib for use, or use, wherein the solid pharmaceutical composition is a minitablet. 43. Erdafitinib for use, or use according to Embodiment 42, wherein the minitablet is in the form of a 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. 44. Erdafitinib for use, as described in Embodiment 43, or for use, to provide a minitablet whose length exceeds the diameter of the minitablet, so as to provide a minitablet whose length has an aspect ratio (length:diameter) greater than 1:1. 45. Erdafitinib for use, as described in Embodiment 43 or 44, or for use, wherein the mini-tablets have a diameter of 1.0 mm to 3.2 mm, or 1.5 mm to 3.1 mm. 46. ​​A solid pharmaceutical composition (a) Eldafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-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 the solid pharmaceutical composition, (c) Meglumine at a concentration of 1% by weight of the solid pharmaceutical composition, (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) A 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, (h) Hydroxypropyl methylcellulose at a concentration of 1.5% by weight of the solid pharmaceutical composition, (i) A solid pharmaceutical composition comprising, or A solid pharmaceutical composition (a) Eldafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition, (b) Hydroxypropyl beta-cyclodextrin, (c) Megurumin and, (d) Microcrystalline cellulose and (e) Silicified microcrystalline cellulose and (f) vinylpyrrolidone-vinyl acetate copolymer, (g) Colloidal silicon dioxide and (h) Hydroxypropyl methylcellulose and (i) Magnesium stearate, and the method according to any one of Embodiments 16 or 42-45, erdafitinib for use, or use. 47. A solid pharmaceutical composition (a) Eldafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-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 the solid pharmaceutical composition, (c) Microcrystalline cellulose at a concentration of 17.5% by weight of the solid pharmaceutical composition, (d) Silicified microcrystalline cellulose at a concentration of 11.75% by weight of the solid pharmaceutical composition, (e) A vinylpyrrolidone-vinyl acetate copolymer at a concentration of 7.5% by weight of the solid pharmaceutical composition, (f) A solid pharmaceutical composition containing colloidal silicon dioxide at a concentration of 0.25% by weight, (g) Hydroxypropyl methylcellulose at a concentration of 1.5% by weight of the solid pharmaceutical composition, (h) A solid pharmaceutical composition comprising, or A solid pharmaceutical composition (a) Eldafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-4-yl)quinoxaline-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition, (b) Hydroxypropyl beta-cyclodextrin, (c) Microcrystalline cellulose and, (d) Silicified microcrystalline cellulose and (e) vinylpyrrolidone-vinyl acetate copolymer, (f) Colloidal silicon dioxide and (g) Hydroxypropyl methylcellulose and, (h) Magnesium stearate, the method according to any one of Embodiments 16 or 42-45, erdafitinib for use, or use. 48. Erdafitinib, 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, wherein the first and second wall structures are adjacent to each other at two interface edges and together form a tube defining the closed drug reservoir lumen, and the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane, and the second material comprises an aliphatic polyether-based thermoplastic polyurethane. A drug delivery system comprising a drug formulation disposed within the lumen of a closed drug reservoir, the drug formulation comprising erdafitinib, (i) the second wall structure, or both the first and second wall structures, is permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby delivering erdafitinib locally in the form of a drug delivery system that can be released in vivo by diffusion through the second material forming the second wall structure, the method according to any one of Embodiments 1 to 15, erdafitinib for use, or use. 49. Erdafitinib, 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, wherein the first and second wall structures are adjacent to each other at two interface edges and together form a tube defining the closed drug reservoir lumen, and the first material comprises an aromatic polyester hydrocarbon-based thermoplastic polyurethane, and the second material comprises an aliphatic polyether-based thermoplastic polyurethane. A drug delivery system comprising a drug formulation disposed within the lumen of a closed drug reservoir, the drug formulation comprising erdafitinib, (i) the second wall structure, or both the first and second wall structures, is permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby delivering erdafitinib locally in the form of a drug delivery system that can be released in vivo by diffusion through the second wall structure, the method according to any one of Embodiments 1 to 15, erdafitinib for use, or use. 50. The method according to Embodiment 48 or 49, erdafitinib for use, or use, wherein the second wall structure forms a longitudinal strip extending along the length of the tube. 51. The method according to any one of Embodiments 48-50, erdafitinib for use, or use, wherein the drug delivery system is configured to release erdafitinib over a period of 2 days to 6 months. 52. A method for use, erdafitinib for use, or use according to any one of embodiments 48 to 51, wherein two interface edges are arranged at an arc angle of 15 to 270 degrees around the circumference of the pipe in a cross section perpendicular to the longitudinal axis of the pipe. 53. The method according to any one of Embodiments 48 to 52, erdafitinib for use, or use, wherein the drug delivery system is configured to release erdafitinib at an average rate of 1 mg / day to 10 mg / day. 54. The method for use, erdafitinib for use, or use according to Embodiment 53, wherein two interface edges are arranged at an arc angle of 45 to 90 degrees around the circumference of the pipe in a cross section perpendicular to the longitudinal axis of the pipe. 55. The method for use, erdafitinib for use, or use according to Embodiment 53, wherein two interface edges are arranged at an arc angle of 150 to 270 degrees around the circumference of the pipe in a cross section perpendicular to the longitudinal axis of the pipe. 56. The method according to any one of Embodiments 48 to 52, erdafitinib for use, or use, wherein the system is configured to release erdafitinib at an average rate of 2 mg / day. 57. The method for use, erdafitinib for use, or use according to Embodiment 56, wherein two interface edges are arranged at an arc angle of approximately 90 degrees around the circumference of the pipe in a cross section perpendicular to the longitudinal axis of the pipe. 58. The method according to any one of Embodiments 48 to 52, erdafitinib for use, or use, wherein the system is configured to release erdafitinib at an average rate of 4 mg / day. 59. The method for use, erdafitinib for use, or use according to Embodiment 58, wherein two interface edges are arranged at an arc angle of approximately 180 degrees around the circumference of the pipe in a cross section perpendicular to the longitudinal axis of the pipe. 60. The method according to any one of Embodiments 48 to 59, comprising a system containing 500 mg of erdafitinib, erdafitinib for use, or use. 61. Erdafitinib for use, or use according to any one of Embodiments 48-60, wherein the release profile of erdafitinib is substantially pH-independent over a pH range of 5-7. 62. The method, use, or use of erdafitinib according to any one of embodiments 48 to 61, wherein the second wall structure constitutes less than 50 percent of the cross-sectional area of ​​the pipe in a section perpendicular to the longitudinal axis of the pipe. 63. The method, use, or use of erdafitinib according to any one of embodiments 48 to 62, wherein the second wall structure constitutes less than 25 percent of the cross-sectional area of ​​the pipe in a section perpendicular to the longitudinal axis of the pipe. 64. The method according to any one of embodiments 48 to 63, erdafitinib for use, or use, wherein the tube has a substantially constant thickness around its circumference. 65. The method according to any one of embodiments 48 to 64, further comprising a pair of end plugs and / or adhesive material for sealing the ends of the pipe, erdafitinib for use, or use. 66. The method according to any one of embodiments 48 to 65, erdafitinib for use, or use, wherein the first wall structure and the second wall structure are integrally formed. 67. The method according to any one of embodiments 48 to 66, erdafitinib for use, or use, wherein the system is elastically deformable between a relatively straightened unfolded shape suitable for insertion into the patient's bladder through the patient's urethra and a retaining shape suitable for holding the system in the bladder. 68. The method according to any one of embodiments 48 to 67, erdafitinib for use, or use, wherein the system is elastically deformable and comprises overlapping curls formed by a tube, the tube having two opposing free ends, the two opposing free ends being oriented away from each other when the system is in a low-profile unfolded shape and toward each other when the system is in a relatively expanded retained shape. 69. The method, use, or use of erdafitinib according to any one of embodiments 48 to 68, wherein the system is elastically deformable and has a double elliptical retaining shape, and the tube has two opposing free ends located within the outer boundary of the double elliptical retaining shape. 70. The method according to any one of embodiments 48 to 69, further comprising a retaining frame lumen, erdafitinib for use, or use. 71. The method, use, or use of erdafitinib according to any one of embodiments 48 to 70, wherein the first material has a Shore durometer value of 70A to 80A. 72. The method according to any one of Embodiments 48 to 71, erdafitinib for use, or use, wherein the drug formulation comprises the solid pharmaceutical composition described in any one of Embodiments 16 to 47. 73. The method according to any one of embodiments 48 to 72, erdafitinib for use, or use, wherein the drug formulation is in the form of multiple mini-tablets arranged in a drug lumen. 74. Erdafitinib for use, or use according to Embodiment 73, wherein the multiple minitablets include the minitablet described in any one of Embodiments 43 to 45. 75. Erdafitinib, 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, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane, A drug delivery system comprising a drug formulation disposed within the lumen of a drug reservoir, the drug formulation comprising erdafitinib, (i) the second wall structure, or both the first and second wall structures, is permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby delivering erdafitinib locally in the form of a drug delivery system that can be released in vivo by diffusion through the second material forming the second wall structure, the method according to any one of Embodiments 1 to 15, erdafitinib for use, or use. 76. The method according to Embodiment 75, erdafitinib for use, or use, wherein the first wall structure and the second wall structure are adjacent to each other at two interface edges, forming a tube together, and (i) the drug delivery system is configured to release erdafitinib at an average rate of 2 mg / day, with the two interface edges arranged at an arc angle of approximately 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 erdafitinib at an average rate of 4 mg / day, with the two interface edges arranged at an arc angle of approximately 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 erdafitinib at an average rate of 6 mg / day, with the two interface edges arranged at an arc angle of 240 degrees. 77. The method according to Embodiment 75 or 76, Eldafitinib for use, or use, wherein the system is elastically deformable and comprises overlapping curls formed by a tube, the tube having two opposing free ends, the two opposing free ends being oriented away from each other when the system is in a low-profile unfolded shape, and oriented toward each other when the system is in a relatively expanded retained shape. 78. Erdafitinib, 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, wherein the first and second wall structures are adjacent to each other at two interface edges and together form a tube defining the closed drug reservoir lumen, the second wall structure forms a longitudinal strip extending along the length of the tube, the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane, and the second material comprises an aliphatic polyether-based thermoplastic polyurethane, A drug delivery system comprising a drug formulation disposed within the lumen of a closed drug reservoir, the drug formulation comprising a solid pharmaceutical composition according to any one of embodiments 16 to 47, (i) The second wall structure, or both the first and second wall structures, is permeable to water, and (ii) the first wall structure is impermeable to erdafitinib, and the second wall structure is permeable to erdafitinib, thereby allowing erdafitinib to be released in vivo by diffusion through the second material forming the second wall structure. The drug delivery system is configured to deliver a therapeutically effective dose of erdafitinib at a substantially zero-order release rate over at least three days. (i) The drug delivery system is configured to release erdafitinib at an average rate of 2 mg / day, with two interface edges positioned at an arc angle of approximately 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 erdafitinib at an average rate of 4 mg / day, with two interface edges positioned at an arc angle of approximately 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 erdafitinib at an average rate of 6 mg / day, with two interface edges positioned at an arc angle of 240 degrees, and the drug is delivered locally in the form of a drug delivery system, according to any one of Embodiments 1 to 15, erdafitinib for use, or use. 79. Erdafitinib, 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, wherein the first and second wall structures are adjacent to each other at two interface edges and together form a tube defining the closed drug reservoir lumen, the second wall structure forms a longitudinal strip extending along the length of the tube, the first material comprises an aromatic polyester hydrocarbon-based thermoplastic polyurethane, and the second material comprises an aliphatic polyether-based thermoplastic polyurethane, A drug delivery system comprising a drug formulation disposed within the lumen of a closed drug reservoir, the drug formulation comprising a solid pharmaceutical composition according to any one of embodiments 16 to 47, (i) The second wall structure, or both the first and second wall structures, is permeable to water, and (ii) the first wall structure is impermeable to erdafitinib, and the second wall structure is permeable to erdafitinib, thereby allowing erdafitinib to be released in vivo by diffusion through the second wall structure. The drug delivery system is configured to deliver a therapeutically effective dose of erdafitinib at a substantially zero-order release rate over at least three days. (i) The drug delivery system is configured to deliver erdafitinib at an average rate of 2 mg / day, with two interface edges positioned at an arc angle of approximately 90 degrees of the tube in a cross section perpendicular to the longitudinal axis of the tube, or (ii) The drug delivery system is configured to deliver erdafitinib at an average rate of 4 mg / day, with two interface edges positioned at an arc angle of approximately 180 degrees of the circumference of the circumferential tube in a cross section perpendicular to the longitudinal axis of the tube, the method according to any one of Embodiments 1 to 15, erdafitinib for use, or use. 80. The method according to any one of Embodiments 73 to 79, comprising a drug delivery system comprising 44 to 46 erdafitinib minitablets, erdafitinib for use, or use. 81. The method according to any one of Embodiments 73 to 80, erdafitinib for use, or use, wherein the drug formulation includes the solid pharmaceutical formulation described in Embodiment 46. 82. The method according to any one of Embodiments 73 to 80, erdafitinib for use, or use, wherein the drug formulation includes the solid pharmaceutical formulation of Embodiment 47. 83. The method according to any one of Embodiments 48 to 82, erdafitinib for use, or use, wherein the first material comprises AC-4075A-B20 or AR-75A, and the second material comprises EG-80A. 84. Eldafitinib for use, or use according to any one of Embodiments 48 to 83, wherein the first material has a Shore hardness of about 78A; a specific gravity of about 1.38; a maximum tensile strength (psi) of about 8300; a maximum 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 / or a forming shrinkage (inches / inch) of about 0.011 (1 inch × 0.25 inch × 6 inch bar) (ASTM D955). 85. Eldafitinib for use, or use according to any one of embodiments 48 to 84, wherein the second material has a Shore hardness of about 72A; a specific gravity of about 1.04; a flexural modulus (psi) of 1,000; a maximum tensile strength (psi) of about 5,800; a maximum elongation (%) of about 660 (D412); a tensile modulus (psi) (ASTM D412) of about 300 at 100% elongation, about 500 at 200% elongation, and about 800 at 300% elongation; and a forming shrinkage (inches / inch) of about 0.008 to 0.0012. 86. Eldafitinib for use, or use according to any one of Embodiments 48 to 85, wherein the first material has a Shore hardness of about 79A; a specific gravity of about 1.03; a maximum tensile strength (psi) of about 2000; a maximum elongation (%) of about 530; a tensile modulus (psi) of about 730 at 100% elongation, about 1000 at 200% elongation, and about 1300 at 300% elongation; a flexural modulus (psi) of about 2500 (ASTM 790); a Vicat softening point (°C) of about 75; and a forming shrinkage (inches / inch) of about 0.08 (1 inch × 0.25 inch × 6 inch bar). 87. One or more FGFR gene alterations are selected from FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3, particularly FGFR3-TACC3 V1 or FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof, and in particular, the FGFR2 gene alteration ...

Claims

1. Erdafitinib for use in the treatment of bladder cancer in a patient having one or more FGFR gene mutations, wherein erdafitinib is delivered locally to the patient's bladder, and the one or more FGFR gene mutations are detected in a urine sample from the patient.

2. Erdafitinib for use according to claim 1, wherein one or more FGFR gene mutations are detected in a urine sample from the patient using a urine-based PCR assay or NGS assay.

3. Erdafitinib for use in the treatment of bladder cancer having one or more FGFR gene mutations in a patient, comprising, consisting of, or essentially consisting of: (a) evaluating a urine sample from a patient having bladder cancer for the presence of one or more FGFR gene mutations; and (b) if the one or more FGFR gene mutations are present in the sample, delivering erdafitinib topically to the patient.

4. Erdafitinib for use according to claim 3, wherein the use comprises evaluating a urine sample from a patient with bladder cancer for the presence of one or more FGFR gene alterations using a urine-based PCR assay or NGS assay.

5. Erdafitinib for use in the treatment of bladder cancer having one or more FGFR gene mutations in a patient, wherein erdafitinib is delivered locally to the bladder of the patient, and the patient is selected for the treatment based on the detection of the one or more FGFR gene mutations in a urine sample from the patient.

6. Erdafitinib for use according to claim 5, selected for the treatment based on the detection of one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR assay or NGS assay.

7. Erdafitinib for use in the treatment of bladder cancer in a patient having one or more FGFR gene mutations, wherein erdafitinib is delivered locally to the bladder of the patient, and the patient's eligibility for the treatment is determined by detecting the one or more FGFR gene mutations in a urine sample from the patient.

8. The patient's eligibility for the treatment is determined by detecting one or more FGFR gene mutations in a urine sample from the patient using a urine-based PCR assay or NGS assay, erdafitinib for use according to claim 7.

9. Erdafitinib for use according to any one of claims 1 to 8, wherein the one or more FGFR gene alterations comprise one or more FGFR2 gene alterations or FGFR3 gene alterations.

10. Erdafitinib for use according to any one of claims 1 to 9, wherein the one or more FGFR gene mutations include one or more FGFR two-point mutations or fusions, or FGFR three-point mutations or fusions.

11. Erdafitinib for use according to any one of claims 1 to 10, wherein the one or more FGFR gene mutations are detected in a urine sample from the patient before local delivery of erdafitinib.

12. Erdafitinib for use according to any one of claims 1 to 11, wherein the one or more FGFR gene alterations are selected from FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3 (where FGFR3-TACC3 is FGFR3-TACC3 variant 1 (FGFR3-TACC3 V1) or FGFR3-TACC3 variant 3 (FGFR3-TACC3 V3)), FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof.

13. Erdafitinib for use according to claim 12, wherein the FFFR2 gene alteration and / or the FFFR3 gene alteration is selected from FFFR3-TACC3 variant 1 (FFFR3-TACC3 V1), FFFR3 G370C, FFFR3 S249C, FFFR3 Y373C, and FFFR3 R248C.

14. Erdafitinib is a solid pharmaceutical composition, (a) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(l-methyl-1H-pyrazole-4-yl)quinoxaline-6-yl]ethane-1,2-diamine) at a concentration of at least 45% by weight of the solid pharmaceutical composition, (b) Erdafitinib for use according to any one of claims 1 to 13, which is delivered topically in the form of a solid pharmaceutical composition comprising at least one pharmaceutical excipient.

15. Erdafitinib for use according to claim 14, wherein the at least one pharmaceutical excipient comprises a solubilizer, a binder, a diluent (filler), a wetting agent, a disintegrant, a flow promoter, a lubricant, a formaldehyde scavenger, or any combination thereof.

16. Erdafitinib for use according to claim 14 or 15, wherein the free erdafitinib base 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 solid pharmaceutical composition comprises an intragranular solid composition containing at least one intragranular pharmaceutical excipient and an extragranular solid composition containing at least one extragranular pharmaceutical excipient, wherein the at least one extragranular pharmaceutical excipient comprises microcrystalline cellulose and vinylpyrrolidone-vinyl acetate copolymer.

17. Erdafitinib for use according to any one of claims 14 to 16, wherein the at least one extragranular pharmaceutical excipient comprises microcrystalline cellulose and vinylpyrrolidone-vinyl acetate copolymer in a weight ratio of 50:

50.

18. Erdafitinib for use according to any one of claims 14 to 17, wherein the solid pharmaceutical composition further comprises a formaldehyde scavenger selected from the group consisting of 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, their conjugates, pharmaceutically acceptable salts thereof, or any combination thereof.

19. The erdafitinib for use according to claim 18, wherein the formaldehyde scavenger is meglumine.

20. Erdafitinib for use according to claim 18 or 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. Erdafitinib for use according to any one of claims 14 to 20, 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, sulfobutyl ether-beta-cyclodextrin sodium salt, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose E5 (HPMC-E5), or any combination thereof.

22. The erdafitinib for use according to claim 21, wherein the solubilizing agent is hydroxypropyl-beta-cyclodextrin.

23. Erdafitinib for use according to claim 21 or 22, wherein the total concentration of the solubilizer in the solid pharmaceutical composition is 1% to 20% by weight, 5% to 15% by weight, 7% to 12% by weight, or about 10% by weight.

24. Erdafitinib for use according to any one of claims 14 to 23, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient, or the at least one extragranular pharmaceutical excipient comprises or further comprises at least one binder selected from the group consisting of 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, and combinations thereof.

25. Erdafitinib for use according to claim 24, wherein the total concentration of the at least one binder in the solid pharmaceutical composition is 5% to 30% by weight, 10% to 25% by weight, 12% to 22% by weight, or 14% to 19% by weight.

26. Erdafitinib for use according to any one of claims 14 to 25, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient, or the at least one extragranular pharmaceutical excipient comprises or further comprises a wetting agent.

27. Erdafitinib for use according to claim 26, wherein the wetting agent comprises sodium lauryl sulfate, sodium stearyl fumarate, polysorbate 80, sodium docusate, or any combination thereof.

28. Erdafitinib for use according to claim 26 or 27, 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.

29. Erdafitinib for use according to any one of claims 14 to 28, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient, or the at least one extragranular pharmaceutical excipient comprises or further comprises a disintegrant.

30. Erdafitinib for use according to claim 29, wherein the disintegrant comprises hydroxypropyl methylcellulose, low-substituted hydroxypropylcellulose, crospovidone (cross-linked polyvinylpyrrolidone), croscarmellose sodium (cross-linked carboxymethylcellulose sodium), sodium starch glycolate, or any combination thereof.

31. Erdafitinib for use according to claim 29 or 30, 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.

32. Erdafitinib for use according to any one of claims 14 to 31, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient, or the at least one extragranular pharmaceutical excipient comprises or further comprises a diluent.

33. Erdafitinib for use according to claim 32, wherein the diluent comprises lactose, dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium carbonate, sucrose, or any combination thereof.

34. Erdafitinib for use according to claim 32 or 33, wherein the total concentration of the diluent in the solid pharmaceutical composition is 12% to 30% by weight, 15% to 25% by weight, or 18% to 22% by weight.

35. Erdafitinib for use according to any one of claims 14 to 34, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient, or the at least one extragranular pharmaceutical excipient comprises or further comprises a flow promoter.

36. Eldafitinib for use according to claim 35, wherein the flow promoter comprises colloidal silicon dioxide, colloidal anhydrous silicon dioxide, talc, or any combination thereof.

37. Erdafitinib for use according to claim 35 or 36, wherein the total concentration of the flow promoter 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.

38. Erdafitinib for use according to any one of claims 14 to 37, wherein the at least one pharmaceutical excipient, the at least one intragranular pharmaceutical excipient, or the at least one extragranular pharmaceutical excipient comprises or further comprises a lubricant.

39. Eldafitinib for use according to claim 38, wherein the lubricant comprises magnesium stearate, stearic acid, magnesium silicate, aluminum silicate, isopropyl myristate, sodium oleate, sodium stearoyl lactate, sodium stearoyl fumarate, titanium dioxide, or a combination thereof.

40. Erdafitinib for use according to claim 38 or 39, 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.

41. Erdafitinib for use according to any one of claims 14 to 40, wherein the solid pharmaceutical composition is a minitablet.

42. Erdafitinib for use according to claim 41, wherein the mini-tablet is in the form of a solid cylinder having a cylindrical axis, a cylindrical side surface, a circular end surface perpendicular to the cylindrical axis, a diameter across the circular end surface, and a length along the cylindrical side surface.

43. Erdafitinib for use according to claim 42, wherein the length of the mini-tablet exceeds the diameter of the mini-tablet to provide the mini-tablet having an aspect ratio (length:diameter) greater than 1:

1.

44. The erdafitinib for use according to claim 42 or 43, wherein the mini-tablet has a diameter of 1.0 mm to 3.2 mm or 1.5 mm to 3.1 mm.

45. The solid pharmaceutical composition (a) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(l-methyl-1H-pyrazole-4-yl)quinoxaline-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition, (b) Hydroxypropyl-beta-cyclodextrin, (c) Megurumin and, (d) Microcrystalline cellulose and (e) Silicified microcrystalline cellulose, (f) Vinylpyrrolidone-vinyl acetate copolymer, (g) Colloidal silicon dioxide and (h) Hydroxypropyl methylcellulose and (i) Magnesium stearate, comprising erdafitinib for use according to any one of claims 14 or 41 to 44.

46. The solid pharmaceutical composition (a) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(l-methyl-1H-pyrazole-4-yl)quinoxaline-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 the solid pharmaceutical composition, (c) Meglumine at a concentration of 1% by weight of the solid pharmaceutical composition, (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) A 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, (h) Hydroxypropyl methylcellulose at a concentration of 1.5% by weight of the solid pharmaceutical composition, (i) Erdafitinib for use according to any one of claims 14 or 41 to 44, comprising essentially magnesium stearate at a concentration of 1.5% by weight of the solid pharmaceutical composition.

47. The solid pharmaceutical composition (a) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(l-methyl-1H-pyrazole-4-yl)quinoxaline-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition, (b) Hydroxypropyl-beta-cyclodextrin, (c) Microcrystalline cellulose and (d) Silicified microcrystalline cellulose and (e) vinylpyrrolidone-vinyl acetate copolymer, (f) Colloidal silicon dioxide and (g) Hydroxypropyl methylcellulose and (h) Erdafitinib for use according to any one of claims 14 or 41 to 44, comprising magnesium stearate.

48. The solid pharmaceutical composition (a) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(l-methyl-1H-pyrazole-4-yl)quinoxaline-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 the solid pharmaceutical composition, (c) Microcrystalline cellulose at a concentration of 17.5% by weight of the solid pharmaceutical composition, (d) Silicified microcrystalline cellulose at a concentration of 11.75% by weight of the solid pharmaceutical composition, (e) A vinylpyrrolidone-vinyl acetate copolymer at a concentration of 7.5% by weight of the solid pharmaceutical composition, (f) Colloidal silicon dioxide at a concentration of 0.25% by weight of the solid pharmaceutical composition, (g) Hydroxypropyl methylcellulose at a concentration of 1.5% by weight of the solid pharmaceutical composition, (h) Erdafitinib for use according to any one of claims 14 or 41 to 44, comprising magnesium stearate at a concentration of 1.5% by weight of the solid pharmaceutical composition.

49. Erdafitinib, 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, wherein the first and second wall structures are adjacent to each other at two interface edges and together form a tube defining the closed drug reservoir lumen, and the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane. A drug delivery system comprising a drug formulation disposed within the lumen of a closed drug reservoir, the drug formulation comprising erdafitinib, Erdafitinib for use according to any one of claims 1 to 13, 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, thereby being delivered locally in the form of a drug delivery system that allows erdafitinib to be released in vivo by diffusion through the second material forming the second wall structure.

50. Erdafitinib, 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, wherein the first and second wall structures are adjacent to each other at two interface edges and together form a tube defining the closed drug reservoir lumen, the housing comprising an aromatic polyester hydrocarbon-based thermoplastic polyurethane and an aliphatic polyether-based thermoplastic polyurethane, A drug delivery system comprising a drug formulation disposed within the lumen of a closed drug reservoir, the drug formulation comprising erdafitinib, Erdafitinib for use according to any one of claims 1 to 13, 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, thereby being delivered locally in the form of a drug delivery system that allows erdafitinib to be released in vivo by diffusion through the second wall structure.

51. Eldafitinib for use according to claim 49 or 50, wherein the second wall structure forms a longitudinal strip extending along the length of the pipe.

52. Erdafitinib for use according to any one of claims 49 to 51, wherein the drug delivery system is configured to release erdafitinib over a period of 2 days to 6 months.

53. Eldafitinib for use according to any one of claims 49 to 52, wherein the two boundary surface edges are arranged at an arc angle of 15 to 270 degrees around the circumference of the pipe in a cross section perpendicular to the longitudinal axis of the pipe.

54. The erdafitinib for use according to any one of claims 49 to 53, wherein the drug delivery system is configured to release the erdafitinib at an average rate of 1 mg / day to 10 mg / day.

55. Eldafitinib for use according to claim 54, wherein the two boundary surface edges are arranged at an arc angle of 45 to 90 degrees around the circumference of the pipe in a cross section perpendicular to the longitudinal axis of the pipe.

56. Eldafitinib for use according to claim 54, wherein the two boundary surface edges are arranged at an arc angle of 150 to 270 degrees around the circumference of the pipe in a cross section perpendicular to the longitudinal axis of the pipe.

57. Eldafitinib for use according to claim 54, wherein the two boundary surface edges are arranged at an arc angle of 90 to 180 degrees around the circumference of the pipe in a cross section perpendicular to the longitudinal axis of the pipe.

58. The system is configured to release the erdafitinib at an average rate of 2 mg / day to 4 mg / day, the erdafitinib for use according to any one of claims 49 to 53 or 57.

59. The erdafitinib for use according to any one of claims 49 to 53, wherein the system is configured to release the erdafitinib at an average rate of 2 mg / day.

60. The erdafitinib for use according to claim 59, wherein the two boundary edges are arranged at an arc angle of approximately 90 degrees around the circumference of the pipe in a cross section perpendicular to the longitudinal axis of the pipe.

61. The erdafitinib for use according to any one of claims 49 to 53, wherein the system is configured to release the erdafitinib at an average rate of 4 mg / day.

62. The erdafitinib for use according to claim 61, wherein the two boundary edges are arranged at an arc angle of approximately 180 degrees around the circumference of the pipe in a cross section perpendicular to the longitudinal axis of the pipe.

63. The system comprises 500 mg of erdafitinib for use according to any one of claims 49 to 62.

64. Erdafitinib for use according to any one of claims 49 to 63, wherein the release profile of erdafitinib is substantially pH-independent over a pH range of 5 to 7.

65. Eldafitinib for use according to any one of claims 49 to 64, wherein the second wall structure constitutes less than 50 percent of the cross-sectional area of ​​the pipe in a section perpendicular to the longitudinal axis of the pipe, or the second wall structure constitutes less than 25 percent of the cross-sectional area of ​​the pipe in a section perpendicular to the longitudinal axis of the pipe.

66. Eldafitinib for use according to any one of claims 49 to 65, wherein the tube has a substantially constant thickness over its circumference, or the tube further includes a pair of end plugs and / or adhesive material for sealing the ends of the tube, or the first wall structure and the second wall structure are integrally formed.

67. Eldafitinib for use according to any one of claims 49 to 66, wherein the system is elastically deformable between a relatively straightened unfolded shape suitable for insertion into the patient's bladder through the patient's urethra and a retaining shape suitable for holding the system within the bladder.

68. Eldafitinib for use according to any one of claims 49 to 67, wherein the system is elastically deformable and comprises overlapping curls formed by the tube, the tube having two opposing free ends, the two opposing free ends being oriented away from each other when the system is in a low-profile unfolded shape, and toward each other when the system is in a relatively expanded retained shape.

69. Eldafitinib for use according to any one of claims 49 to 68, wherein the system is elastically deformable and has a double elliptical retaining shape, and the tube has two opposing free ends located within the outer boundary of the double elliptical retaining shape.

70. Eldafitinib for use according to any one of claims 49 to 69, further comprising a retaining frame lumen.

71. Eldafitinib for use according to any one of claims 49 to 70, wherein the first material has a Shore durometer value of 70A to 80A.

72. Erdafitinib for use according to any one of claims 49 to 71, wherein the drug formulation comprises the solid pharmaceutical composition according to any one of claims 14 to 48.

73. Erdafitinib for use according to any one of claims 49 to 72, wherein the drug formulation is in the form of a plurality of minitablets arranged in a continuous manner within the drug lumen.

74. Erdafitinib for use according to claim 73, wherein the plurality of minitablets include the minitablets described in any one of claims 42 to 44.

75. Erdafitinib, 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, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane, A drug delivery system comprising a drug formulation disposed within the lumen of the drug reservoir, the drug formulation comprising erdafitinib, Erdafitinib for use according to any one of claims 1 to 13, 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, thereby being delivered locally in the form of a drug delivery system that allows the erdafitinib to be released in vivo by diffusion through the second material forming the second wall structure.

76. Erdafitinib for use according to claim 75, 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 arranged 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, 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 arranged 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, 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 arranged at an arc angle of 240 degrees.

77. Eldafitinib for use according to claim 75 or 76, wherein the system is elastically deformable and comprises overlapping curls formed by the tube, the tube having two opposing free ends, the two opposing free ends being oriented away from each other when the system is in a low-profile unfolded shape, and toward each other when the system is in a relatively expanded retained shape.

78. Erdafitinib, 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, wherein the first and second wall structures are adjacent to each other at two interface edges and together form a tube defining the closed drug reservoir lumen, the second wall structure forms a longitudinal strip extending along the length of the tube, the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane, and the second material comprises an aliphatic polyether-based thermoplastic polyurethane, A drug delivery system comprising a drug preparation disposed within the lumen of the closed drug reservoir, the drug preparation comprising a solid pharmaceutical composition according to any one of claims 14 to 48, (i) the second wall structure, or both the first and second wall structures, 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, thereby allowing the erdafitinib to be released in vivo by diffusion through the second material forming the second wall structure. The drug delivery system is configured to deliver a therapeutically effective dose of erdafitinib at a substantially zero-order release rate over at least three days. (i) the drug delivery system is configured to release the erdafitinib at an average rate of 2 mg / day, with the two interface edges arranged at an arc angle of approximately 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, with the two interface edges arranged at an arc angle of approximately 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, with the two interface edges arranged at an arc angle of 240 degrees, to deliver locally in the form of a drug delivery system, according to any one of claims 1 to 13.

79. Erdafitinib, 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, wherein the first and second wall structures are adjacent to each other at two interface edges to together form a tube defining the closed drug reservoir lumen, the second wall structure forms a longitudinal strip extending along the length of the tube, the first material comprises an aromatic polyester hydrocarbon-based thermoplastic polyurethane, and the second material comprises an aliphatic polyether-based thermoplastic polyurethane, A drug delivery system comprising a drug preparation disposed within the lumen of the closed drug reservoir, the drug preparation comprising a solid pharmaceutical composition according to any one of claims 14 to 48, (i) the second wall structure, or both the first and second wall structures, are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby allowing erdafitinib to be released in vivo by diffusion through the second wall structure. The drug delivery system is configured to deliver a therapeutically effective dose of erdafitinib at a substantially zero-order release rate over at least three days. Erdafitinib for use according to any one of claims 1 to 13, wherein the drug delivery system is configured to release the erdafitinib at an average rate of 2 mg / day, and the two interface edges are arranged 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, 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 arranged 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.

80. Erdafitinib for use according to any one of claims 73 to 79, wherein the drug delivery system comprises 44 to 46 erdafitinib minitablets.

81. Erdafitinib for use according to any one of claims 73 to 80, wherein the drug formulation comprises the solid pharmaceutical formulation according to any one of claims 45 to 46.

82. Erdafitinib for use according to any one of claims 73 to 80, wherein the drug formulation comprises the solid pharmaceutical formulation according to any one of claims 47 to 48.

83. Eldafitinib for use according to any one of claims 49 to 82, wherein the first material comprises AC-4075A-B20 or AR-75A, and the second material comprises EG-80A.

84. Eldafitinib for use according to any one of claims 49 to 83, wherein the first material has a Shore hardness of about 78A; a specific gravity of about 1.38; a maximum tensile strength (psi) of about 8300; a maximum 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 / or a forming shrinkage (inches / inch) of about 0.011 (1 inch × 0.25 inch × 6 inch bar) (ASTM D955).

85. Eldafitinib for use according to any one of claims 49 to 84, wherein the second material has a Shore hardness of about 72A; a specific gravity of about 1.04; a flexural modulus (psi) of 1,000; a maximum tensile strength (psi) of about 5,800; a maximum elongation (%) of about 660 (D412); tensile moduli (psi) of about 300 at 100% elongation, about 500 at 200% elongation, and about 800 at 300% elongation (ASTM D412); and a forming shrinkage (inches / inch) of about 0.008 to 0.0012.

86. Eldafitinib for use according to any one of claims 49 to 83, wherein the first material has a Shore hardness of about 79A; a specific gravity of about 1.03; a maximum tensile strength (psi) of about 2000; a maximum elongation (%) of about 530; tensile modulus (psi) of about 730 at 100% elongation, about 1000 at 200% elongation, and about 1300 at 300% elongation; flexural modulus (psi) of about 2500 (ASTM 790); a Vicat softening point (°C) of about 75; and a molding shrinkage (inches / inch) of about 0.08 (1 inch × 0.25 inch × 6 inch bar).

Images