Intravesical administration of erdatinib for treatment of bladder cancer

Abstract

Provided herein are methods of treatment, Erdatinib for use, the use of Erdatinib for the treatment of bladder cancer with one or more FGFR alterations, comprising topical delivery of Erdatinib into the bladder of a patient.

Description

Technical Field

[0001] The present disclosure generally pertains to the field of methods of treating bladder cancer, including methods of treating bladder cancer having one or more FGFR alterations.

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS

[0003] This application claims priority to U.S. Provisional Application No. 63 / 484,591, filed February 13, 2023, and U.S. Provisional Application No. 63 / 623,193, filed January 19, 2024, the contents of which are incorporated by reference in their entirety.

[0004] Reference to an electronic sequence listing

[0005] 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 Art

[0006] Erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) is a potent pan-FGFR kinase inhibitor that binds to FGFR1, FGFR2, FGFR3, and FGFR4 and inhibits their enzymatic activity. The synthetic preparation of erdafitinib is described in WO2011 / 135376. Erdafitinib has been found to inhibit FGFR phosphorylation and signaling and reduce cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions. Erdafitinib has demonstrated antitumor activity in FGFR-expressing cell lines and xenograft models derived from tumor types, including bladder cancer.

[0007] Currently, erdafitinib It is available as a film-coated tablet for oral administration and is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who have a susceptible fibroblast growth factor receptor (FGFR) 3 or FGFR2 genetic alteration and have progressed during or after at least one line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.

[0008] U.S. Patent No. 10,898,482 to Broggini and International Patent Application Publication No. WO 2020 / 201138 to De Porre describe certain erdafitinib formulations and treatment methods.

[0009] Examples of intravesical drug delivery systems are described in U.S. Pat. No. 8,679,094 to Cima et al., U.S. Pat. No. 9,017,312 to Lee et al., U.S. Pat. No. 9,107,816 to Lee et al., and U.S. Pat. No. 9,457,176 to Lee et al. In some embodiments, the intravesical system includes a water-permeable housing that defines a drug reservoir lumen containing a solid or semisolid drug formulation, and in vivo release of the drug occurs by diffusion of water from the bladder into the drug reservoir lumen to dissolve the drug, and then osmotic pressure buildup in the drug reservoir lumen drives the dissolved drug out of the drug reservoir lumen through a release pore.

[0010] U.S. Patent No. 10,286,199 to Lee et al. discloses a system in which a drug is released from a housing made of a first wall structure that is impermeable to the drug and a hydrophilic second wall structure that is permeable to the drug. U.S. Patent No. 10,894,150 to Lee also discloses a system in which a drug is released from a housing made of a first wall structure that is impermeable to the drug and a second wall structure that is permeable to the drug. Summary of the Invention

[0011] The present disclosure is generally in the field of methods of treatment with erdafitinib, erdafitinib for use, and uses of erdafitinib for treating bladder cancer having one or more FGFR alterations, including local delivery of erdafitinib to the bladder of a patient, and such methods and uses include erdafitinib-based pharmaceutical formulations and drug-device combination products, and more particularly relates to erdafitinib-based formulations and systems for intravesical administration of such formulations.

[0012] In a certain embodiment, a method of treating bladder cancer having one or more FGFR gene alterations is provided, the method comprising locally delivering to the bladder of a patient in need thereof an amount of erdafitinib effective to treat the bladder cancer, wherein the one or more FGFR gene alterations are detected in a urine sample from the patient, in particular wherein the one or more FGFR gene alterations are detected in a urine sample from the patient using a urine-based PCR or NGS assay. In a certain embodiment, a method of treating bladder cancer having one or more FGFR gene alterations is provided, the method comprising, consisting of, or consisting essentially of: (a) assessing a urine sample from a bladder cancer patient for the presence of the one or more FGFR gene alterations, in particular assessing a urine sample from a bladder cancer patient for the presence of the one or more FGFR gene alterations using a urine-based PCR or NGS assay; and (b) in the presence of the one or more FGFR gene alterations in the sample, locally delivering erdafitinib. In a certain embodiment, a method of treating bladder cancer having one or more FGFR gene alterations is provided, the method 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 detecting the one or more FGFR gene alterations in a urine sample from the patient, particularly wherein the patient is selected for treatment based on detecting the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR or NGS assay.

[0013] In a certain embodiment, a method of treating bladder cancer having one or more FGFR gene alterations is provided, the method 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 the one or more FGFR gene alterations in a urine sample from the patient, particularly wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR or NGS assay.

[0014] In a certain embodiment, erdafitinib is provided for use in treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is delivered locally to the bladder of the patient, and wherein the one or more FGFR gene alterations are detected in a urine sample from the patient, particularly wherein the one or more FGFR gene alterations are detected in a urine sample from the patient using a urine-based PCR or NGS assay.

[0015] In a certain embodiment, erdafitinib is provided for use in treating bladder cancer having one or more FGFR gene alterations in a patient, the use comprising, consisting of, or consisting essentially of: (a) assessing a urine sample from a bladder cancer patient for the presence of the one or more FGFR gene alterations, particularly assessing a urine sample from a bladder cancer patient for the presence of the one or more FGFR gene alterations using a urine-based PCR or NGS assay; and (b) locally delivering erdafitinib to the patient in the presence of the one or more FGFR gene alterations in the sample.

[0016] In a certain embodiment, erdafitinib is provided for use in treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is to be delivered locally to the bladder of the patient, and wherein the patient is selected for treatment based on detection of the one or more FGFR gene alterations in a urine sample from the patient, in particular wherein the patient is selected for treatment based on detection of the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR or NGS assay. In a certain embodiment, erdafitinib is provided for use in treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is to be delivered locally to the bladder of the patient, and wherein the patient's eligibility for treatment is determined by detection of the one or more FGFR gene alterations in a urine sample from the patient, in particular wherein the patient's eligibility for treatment is determined by detection of the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR or NGS assay. In a certain embodiment, there is provided use of erdafitinib in the preparation of a medicament for treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is to be delivered locally to the bladder of the patient, and wherein the one or more FGFR gene alterations are detected in a urine sample from the patient, in particular wherein the one or more FGFR gene alterations are detected in a urine sample from the patient using a urine-based PCR or NGS assay.

[0017] In a certain embodiment, erdafitinib is provided for use in the preparation of a medicament for treating bladder cancer having one or more FGFR gene alterations in a patient, the use comprising, consisting of, or consisting essentially of: (a) assessing a urine sample from a bladder cancer patient for the presence of the one or more FGFR gene alterations, particularly assessing a urine sample from a bladder cancer patient for the presence of the one or more FGFR gene alterations using a urine-based PCR or NGS assay; and (b) locally delivering erdafitinib in the presence of the one or more FGFR gene alterations in the sample.

[0018] In a certain embodiment, there is provided use of erdafitinib in the preparation of a medicament for treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is to be delivered locally to the bladder of the patient, and wherein the patient is selected for treatment based on detection of the one or more FGFR gene alterations in a urine sample from the patient, in particular wherein the patient is selected for treatment based on detection of the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR or NGS assay.

[0019] In a certain embodiment, there is provided the use of Erdafitinib in the preparation of a drug for treating bladder cancer having one or more FGFR gene changes in a patient, wherein Erdafitinib is delivered locally to the patient's bladder, and wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene changes in a urine sample from the patient, particularly by determining the one or more FGFR gene changes in a urine sample from the patient using urine-based PCR or NGS. The method or use may include locally delivering or topically administering Erdafitinib (such as in any formulation described herein) to the bladder of a patient (particularly a cancer patient) in need of treatment in an amount effective to treat bladder cancer (e.g., as described herein, about 1 mg / day to 10 mg / day). For example, the treatment can effectively treat muscle-invasive bladder cancer (MIBC), non-muscle-invasive bladder cancer (NMIBC) and / or Bacillus Calmette-Guérin (BCG) juvenile bladder cancer. In one aspect, the patient (particularly a human) is a bladder cancer or NMIBC or MIBC cancer patient who has undergone BCG. In one aspect, patient (particularly mankind) is bladder cancer or NMIBC or MIBC cancer patient who does not experience BCG. In one aspect, patient (particularly mankind) is high-risk only papillary NMIBC (high-grade Ta / T1) cancer patient who is recurrent, experiences BCG (BCG), refuses or is not qualified to carry out radical cystectomy (RCy). In one aspect, patient (particularly mankind) is high-risk only papillary NMIBC (high-grade Ta / T1) cancer patient who is recurrent, experiences BCG, and plans to carry out RCy. In one aspect, patient (particularly mankind) is NMIBC (Ta and T1) cancer patient who is recurrent, intermediate risk, and it only has the past medical history of low-grade disease. In one aspect, patient (particularly mankind) is MIBC cancer patient who plans to carry out RCy, and it has refused or is not qualified to carry out the neoadjuvant chemotherapy based on cisplatin.

[0020] In a certain embodiment, a method of treating bladder cancer having one or more FGFR gene alterations is provided, the method comprising locally delivering erdafitinib to the bladder of a patient in need thereof in an amount effective to treat bladder cancer, wherein the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient, particularly wherein the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient using a tissue-based PCR or NGS assay, or wherein the one or more FGFR gene alterations are detected in a histopathology image of the tumor tissue by digital histopathology analysis.

[0021] In a certain embodiment, a method of treating bladder cancer having one or more FGFR gene alterations is provided, the method comprising, consisting of, or consisting essentially of: (a) assessing the presence of the one or more FGFR gene alterations in a tumor tissue sample from a bladder cancer patient, particularly assessing the presence of the one or more FGFR gene alterations in a tumor tissue sample from a bladder cancer patient using a tissue-based PCR or NGS assay, or assessing the presence of the one or more FGFR gene alterations in a histopathology image of a tumor tissue from a bladder cancer patient by digital histopathology analysis; and (b) locally delivering erdafitinib in the presence of the one or more FGFR gene alterations in the sample. In a certain embodiment, a method of treating bladder cancer having one or more FGFR gene alterations is provided, the method 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 detecting the one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly wherein the patient is selected for treatment based on detecting the one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR or NGS assay, or wherein the patient is selected for treatment based on detecting the one or more FGFR gene alterations in a histopathological image of the tumor tissue by digital histopathological analysis.

[0022] In a certain embodiment, a method of treating bladder cancer having one or more FGFR gene alterations is provided, the method 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 the one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR or NGS assay, or wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a histopathological image of the tumor tissue by digital histopathological analysis.

[0023] In a certain embodiment, erdafitinib is provided for use in treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is delivered locally to the bladder of the patient, and wherein the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient, particularly wherein the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient using a tissue-based PCR or NGS assay, or wherein the one or more FGFR alterations are detected in a histopathology image of the tumor tissue by digital histopathology analysis.

[0024] In a certain embodiment, erdafitinib is provided for use in treating bladder cancer having one or more FGFR gene alterations in a patient, the use comprising, consisting of, or consisting essentially of: (a) assessing the presence of the one or more FGFR gene alterations in a tumor tissue sample from the bladder cancer patient, particularly assessing the presence of the one or more FGFR gene alterations in a tumor tissue sample from the bladder cancer patient using a tissue-based PCR or NGS assay, or assessing the presence of the one or more FGFR gene alterations in a histopathology image of a tumor tissue from the bladder cancer patient by digital histopathology analysis; and (b) locally delivering erdafitinib to the patient in the presence of the one or more FGFR gene alterations in the sample.

[0025] In a certain embodiment, erdafitinib is provided for use in treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is to be delivered locally to the bladder of the patient, and wherein the patient is selected for treatment based on detection of the one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly wherein the patient is selected for treatment based on detection of the one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR or NGS assay, or wherein the patient is selected for treatment based on detection of the one or more FGFR gene alterations in a histopathology image of the tumor tissue by digital histopathology analysis.

[0026] In a certain embodiment, erdafitinib is provided for use in treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is to be delivered locally to the bladder of the patient, and wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR or NGS assay, or wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a histopathological image of the tumor tissue by digital histopathological analysis.

[0027] In a certain embodiment, there is provided use of erdafitinib in the preparation of a medicament for treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is delivered locally to the bladder of the patient, and wherein the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient, in particular wherein the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient using a tissue-based PCR or NGS assay, or wherein the one or more FGFR alterations are detected in a histopathology image of the tumor tissue by digital histopathology analysis.

[0028] In a certain embodiment, there is provided a use of erdafitinib in the preparation of a medicament for treating bladder cancer having one or more FGFR gene alterations in a patient, comprising, consisting of, or consisting essentially of: (a) assessing the presence of the one or more FGFR gene alterations in a tumor tissue sample from the bladder cancer patient, particularly assessing the presence of the one or more FGFR gene alterations in a tumor tissue sample from the bladder cancer patient using a tissue-based PCR or NGS assay, or assessing the presence of the one or more FGFR gene alterations in a histopathology image of a tumor tissue from a bladder cancer patient by digital histopathology analysis; and (b) locally delivering erdafitinib in the presence of the one or more FGFR gene alterations in the sample.

[0029] In a certain embodiment, there is provided the use of erdafitinib in the preparation of a medicament for treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is to be delivered locally to the bladder of the patient, and wherein the patient is selected for treatment based on detection of the one or more FGFR gene alterations in a tumor tissue sample from the patient, in particular wherein the patient is selected for treatment based on detection of the one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR or NGS assay, or wherein the patient is selected for treatment based on detection of the one or more FGFR gene alterations in a histopathological image of the tumor tissue by digital histopathological analysis.

[0030] In a certain embodiment, there is provided the use of erdafitinib in the preparation of a medicament for treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is to be delivered locally to the bladder of the patient, and wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR or NGS assay, or wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a histopathological image of the tumor tissue by digital histopathological analysis. The method or use may comprise locally delivering or topically administering erdafitinib (such as in any formulation described herein) to the bladder of a patient (particularly a cancer patient) in need of treatment in an amount effective to treat bladder cancer (e.g., as described herein, about 1 mg / day to 10 mg / day). In one aspect, the present invention relates to a bladder cancer that is not treated with BCG or a bladder cancer that is not treated with BCG. In one aspect, the present invention relates to a bladder cancer that is not treated with BCG or ... or a bladder cancer that is not treated with BCG or a bladder cancer that is not treated with BCG or a bladder cancer that is not treated with BCG or a bladder cancer that is not treated with BCG or a bladder cancer that is not treated with BCG or a bladder cancer that is not treated with BCG or a bladder cancer that is not treated with BCG or a bladder cancer that is not treated with BCG or a bladder cancer that is not treated with BCG or a bladder cancer that is not treated with BCG or a bladder cancer that is not treated with In one aspect, the patient (particularly a human) is a MIBC cancer patient planned for RCy who has refused or is ineligible for cisplatin-based neoadjuvant chemotherapy. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] Detailed description of the invention is set forth with reference to the accompanying drawings. The use of the same reference numerals may indicate similar or identical items. Various embodiments may utilize elements and / or components other than those shown in the drawings, and some elements and / or components may not be present in various embodiments. The elements and / or components in the drawings are not necessarily drawn to scale.

[0032] Figure 1 is a longitudinal cross-sectional view of one embodiment of a drug delivery system according to the present disclosure in a curled, retained shape.

[0033] Figure 2 is a transverse cross-sectional view of one embodiment of a drug delivery system according to the present disclosure.

[0034] Figure 3 is a transverse cross-sectional view of one embodiment of a drug delivery system according to the present disclosure.

[0035] Figure 4 is a photograph of one embodiment of a drug delivery system according to the present disclosure loaded with an erdafitinib drug tablet.

[0036] Figure 5 is a longitudinal cross-sectional view of one embodiment of a drug delivery system according to the present disclosure in a curled, retained shape with an elastic retention frame and prior to being loaded with a drug tablet.

[0037] Figure 6A is a longitudinal cross-sectional view of one embodiment of a resilient retention frame in a curled, retained shape according to the present disclosure.

[0038] Figure 6B yes Figure 6A A partially enlarged view of one end of the retaining frame.

[0039] Figure 7A is a perspective view of one embodiment of a drug delivery system according to the present disclosure in a relatively straightened shape without a drug disposed therein or without an elastic retention frame.

[0040] Figure 7B yes Figure 7A A longitudinal cross-sectional view of the drug delivery system shown in FIG. 7 is taken along line 7B-7B.

[0041] Figure 7C yes Figure 7A A transverse cross-sectional view of the drug delivery system shown in FIG. 7 is taken along line 7C-7C.

[0042] Figure 8 is a photograph showing a cross-section of a drug reservoir lumen of a drug delivery system according to the present disclosure without a drug disposed therein.

[0043] Figure 9 Single-dose erdafitinib exposure in plasma from nude rats bearing subcutaneous or orthotopic UM-UC-1 tumors is shown. Exposure levels were measured in plasma from naive nude rats and nude rats bearing orthotopic bladder or subcutaneous UM-UC-1 tumors. Rats were administered a single IVES (1-hour infusion) or oral dose of erdafitinib at the indicated dose levels. Individual data points are shown, with the mean at each time point represented by a horizontal line. IVES, intravesical; PO or po, oral; sc, subcutaneous.

[0044] Figure 10 The effect of erdafitinib on ERK1 / 2 phosphorylation in orthotopic bladder UM-UC-1 tumors is shown. Individual pERK and total ERK levels were measured in UM-UC-1 orthotopic bladder tumors from nude rats treated with vehicle or a single IVES (1-hour instillation) or oral dose of erdafitinib at the indicated dose levels. pERK and total ERK levels are reported as a ratio (pERK / ERK) relative to the mean of the vehicle group at the corresponding time point, with the exception of the 120-hour time point, where values ​​were normalized to the 48-hour vehicle group. Individual data points are shown, with the mean at each time point represented by a line. N = 2-6 / group; ERK, extracellular signal-regulated kinase; IVES, intravesical; pERK, phosphorylated extracellular signal-regulated kinase; PO or po, oral.

[0045] Figure 11 Figure 14 shows the size of an orthotopic bladder UC tumor relative to a control bladder at day 14 post-implantation. Tissue samples were fixed in formalin after necropsy. UC, urothelial carcinoma; NBTII, rat Nara Bladder Tumor No. 2 cell line; T24, human bladder cancer cell line.

[0046] Figure 12 Schematic diagram of perfusion experiments in athymic rats with UM-UC-1 implanted into the bladder wall.

[0047] Figure 13 The percent body weight change of athymic, bladder-catheterized rats bearing orthotopic UM-UC-1 bladder tumors is shown. The values ​​in the figure are expressed as mean ± SEM of 10 to 13 animals in each group. The concentrations quoted in the legend are nominal target urine concentrations. Statistical analysis was performed using Graph Pad Prism (version 8.3.0) by two-way ANOVA followed by Bonferroni multiple comparison test. There were no statistically significant differences when the percent body weight change of the erdafitinib (0.5 μg / mL, 1.0 μg / mL, and 5.0 μg / mL)-treated groups was compared to the percent body weight change of the vehicle control group. SEM, standard error of the mean.

[0048] Figure 14 Shown are the mean percentage reductions in tumor weight after calculation of tumor-free bladder weight. Values ​​(Groups 1-4) are expressed as mean ± SEM of 10 to 13 animals per group. Statistical analysis was performed using GraphPad Prism (version 8.3.0) by one-way ANOVA followed by Dunnett's multiple comparison test. Conc, concentration; SEM, standard error of the mean.

[0049] Figure 15 The percentage change in body weight of athymic, bladder-catheterized nude rats bearing orthotopic RT-112 bladder tumors is shown. Values ​​are expressed as mean ± SEM of 2 to 14 animals in each group. The concentrations cited in the legend are nominal target urine concentrations. Statistical analysis was performed using Graph Pad Prism (version 8.3.0) by two-way ANOVA followed by Bonferroni multiple comparison test. When the percentage change in body weight of the erdafitinib (0.5 μg / mL, 1.0 μg / mL, and 5.0 μg / mL) treatment groups was compared to the percentage change in body weight of the vehicle control group except Group 4 on Day 11, there was no statistically significant difference (*p < 0.05). SEM, standard error of the mean.

[0050] Figure 16 Shown are the average bladder weights of athymic nude rats bearing orthotopic RT-112 bladder tumors. Values ​​(Groups 1-5) are expressed as mean ± SEM of 2 to 14 animals per group. Statistical analysis was performed using GraphPad Prism (version 8.3.0) by one-way ANOVA followed by Dunnett's multiple comparison test. *p < 0.05. Conc, concentration; SEM, standard error of the mean; ns, not significant.

[0051] Figure 17A and Figure 17B Shown are the plasma levels in rats after intravesical instillation of erdafitinib ( Figure 17A ) and intravesical ( Figure 17B ) concentration. Erdafitinib solution (0.1 mg / mL, 0.1 mL / hour, cumulative dose 0.72 mg) was administered intravesically over 72 hours. Concentrations are expressed as the mean daily urine concentration in ng / mL.

[0052] Figure 18 Shown are the mean urinary concentrations of erdafitinib in pigs 7 days after intravesical instillation of erdafitinib. Conc., concentration; SD, standard deviation.

[0053] Figure 19 Shown are the mean erdafitinib plasma concentrations in pigs 7 days after intravesical instillation of erdafitinib. SD, standard deviation.

[0054] Figure 20 Screening results for material permeation are shown. O, permeable; Δ, barely permeable; X, impermeable. a High variability between replicates.

[0055] Figure 21 Shown are the predicted (from the short core) and actual (from the full length) mean release rate profiles for the osmotic prototypes. Erda, erdafitinib-releasing intravesical system; HPbCD, hydroxypropyl β-cyclodextrin.

[0056] Figure 22 Shown are the average release rate profiles of the erdafitinib free base + HP-β-CD osmotic prototype (EG-80A strip material). Erda, erdafitinib; HP-β-CD, hydroxypropyl β-cyclodextrin; SU, simulated urine.

[0057] Figure 23 Shown are the average release rate profiles of erdafitinib free base osmotic prototypes with and without HP-β-CD (HP-60D-35 strip material). Erda, erdafitinib; HP-β-CD or HPbCD, hydroxypropyl β-cyclodextrin; SU, simulated urine.

[0058] Figure 24 The IVR (in vitro release) profile of prototype 1 (permeation, erdafitinib free base, tablet, wire form) is shown. Erda, erdafitinib; IVR, in vitro release.

[0059] Figure 25 The IVR curve of Prototype 2 is shown (Permeation, Erdafitinib free base + HP-β-CD (10% w / w), tablet, strand form). Erda, Erdafitinib; HP-β-CD, hydroxypropyl β-cyclodextrin; IVR, in vitro release.

[0060] Figure 26 The in vivo release rate versus time curves of Prototypes 1 and 2 in minipigs are summarized.

[0061] Figure 27 Summarized are the mean urine concentration versus time curves for Prototypes 1 and 2 in minipigs.

[0062] Figure 28A is a diagram of an exemplary permeation system in which the base material is impermeable TPU and the strip material is permeable TPU.

[0063] Figure 28B An overview of an exemplary permeation design is shown. TPU or tPU, thermoplastic polyurethane; API, active pharmaceutical ingredient; HP-β-CD, hydroxypropyl β-cyclodextrin.

[0064] Figure 29 An overview of the solubility of erdafitinib free base drug substance as a function of pH at 20°C is provided. a USP / EP terminology.

[0065] Figure 30 Shown is the solubility of erdafitinib free base drug as a function of pH when the pH is adjusted using HCl at 37°C. Expon., index.

[0066] Figure 31A-Figure 31BThe solubility of erdafitinib free base drug and erdafitinib HCl salt Form 1 in simulated urine at 37°C is shown as a function of pH ( Figure 31A ), and the solubility of erdafitinib free base drug in simulated urine at 37°C as a function of pH (in mg / mL) ( Figure 31B ). HP-β-CD, hydroxypropyl β-cyclodextrin; Sim urine, simulated urine.

[0067] Figure 32 Schematic overview of a concordance study between tissue and urine assays using paired samples from bladder cancer patients from the Bladder BRIDGister clinical trial in Germany.

[0068] Figure 33 Figure 2 is a heat map of identified gene alterations from matched urine NGS and FFPE tissue RT-PCR samples from bladder cancer patients from the German Bladder BRIDGister clinical trial.

[0069] Figure 34A Figure 2 is a scatter plot of variant allele frequencies (VAFs) between matched urine NGS (X-axis) and tissue ("FFPE") RT-PCR (Y-axis) variants for all identified gene alterations, including somatic and germline variants.

[0070] Figure 34B is a scatter plot of variant allele frequencies (VAFs) between matched urine NGS (X-axis) and tissue ("FFPE") RT-PCR (Y-axis) variants for somatic FGFR3 alterations.

[0071] Figure 35 A flow chart comparing the performance of urine and tissue tests from all screened NMIBC patients (N=178) at the cutoff date is shown. Patients were from the first-in-human study described in Example 9.

[0072] Figure 36A The figure is a swim lane graph showing clinical efficacy data (treatment duration and response) for patients with HR-NMIBC in Cohort 1 who were evaluable for disease and 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 erdafitinib) or TAR-210-D (approximately 4 mg / day erdafitinib). The patients were from the first-in-human study described in Example 9. The legend describing patient recruitment ("Recruitment Method"; left side of the figure) by tumor tissue sample assay (left side of the figure) or urine sample assay (right side of the figure) is marked with the relevant check mark. Another legend describing patient treatment status and milestones is also included (right side of the figure).

[0073] Figure 36BThe figure is a swim lane graph showing clinical efficacy data (treatment duration and response) for patients with IR-NMIBC in cohort 3 who were evaluable for disease and 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 erdafitinib) or TAR-210-D (approximately 4 mg / day erdafitinib). The patients were from the first-in-human studies described in the Examples. The legend describing patient recruitment ("Recruitment Method"; left side of the figure) by tumor tissue sample assay (left side of the legend) or urine sample assay (right side of the legend) is marked with the relevant check mark. Another legend describing patient treatment status and milestones is also included (right side of the figure).

[0074] Figure 37 Depicted are the profiles of pathogenic somatic variants in the 15 most prevalent genes detected in urine from all evaluable samples. Del = deletion; UTR = untranslated region; Ins = insertion; CNV = copy number variation. DETAILED DESCRIPTION

[0075] In some embodiments, a solid formulation of Erdafitinib containing a high concentration of Erdafitinib is provided, which is designed for intravesical drug delivery and controlled and prolonged drug release when deployed in the bladder. In some embodiments, when used in an intravesical drug delivery system, the solid Erdafitinib formulation is further customized for large-scale manufacturing and provides the structural and chemical integrity of the solid formulation (particularly a tablet). Also provided are improved intravesical drug delivery systems, methods for manufacturing the same, and methods for drug delivery. In specific embodiments, the system is configured for intravesical insertion and sustained drug delivery, preferably providing a zero-order release rate of a therapeutically effective amount of a drug (particularly Erdafitinib).

[0076] This article describes the development of a formulation and release system for erdafitinib tailored for intravesical drug delivery to exploit this route of administration. When formulated into a solid form and administered in a suitable intravesical drug delivery system, such a formulation can provide a controlled drug release rate and a prolonged drug release profile. Further provided is a system capable of delivering erdafitinib at an effective release rate for the localized treatment of bladder cancer.

[0077] Erdafitinib exhibits pH-dependent solubility within the normal urine pH range of 5.5 to 7. In some embodiments, the formulation and release system are tailored to minimize the effects of urine pH and composition on systemic release rate.

[0078] In specific embodiments, the drug delivery system described herein is a drug-device combination consisting of a device component (particularly an intravesical device) and a drug component (particularly an erdafitinib formulation, such as an erdafitinib tablet).

[0079] Certain terms

[0080] Recurrence-free survival (RFS) was defined as the time from randomization to the first detection of high-grade Ta or T1 bladder cancer or positive urine cytology.

[0081] Complete response (CR) was defined as the absence of urothelial carcinoma confirmed pathologically by cystoscopy at the time of the initial evaluation and negative urine cytology.

[0082] Duration of CR was defined as the time from the first record of CR until the date of recorded relapse or progression or death, whichever occurred first.

[0083] The pathological complete response (pCR) rate was defined as the percentage of participants with no pathological evidence of intravesical disease (pT0) and no pathological evidence of lymph node involvement (pN0).

[0084] The no pathological evidence of intravesical disease (pT0) rate was defined as the percentage of participants without pathological evidence of intravesical disease.

[0085] The rate of stage reduction to less than (<) pT2 was defined as the percentage of participants with a pT stage <2.

[0086] Unless otherwise indicated, when used herein, weight % relative to a drug or excipient refers to weight % based on the total weight of the formulation in question.

[0087] Erdafitinib formulations and tablets

[0088] In one aspect, the present disclosure provides erdafitinib formulations, particularly erdafitinib tablets suitable for use in the disclosed intravesical drug delivery systems. In particular, pharmaceutical tablets comprising erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) are provided. As another example, pharmaceutical tablets comprising erdafitinib HCl salt are provided. After the drug delivery system is inserted into the bladder, the drug is released from the system into the bladder. In one aspect, for example, the drug delivery system can operate by diffusion, whereby the diffusion produces a continuous release of the drug into the bladder over an extended period of time as the drug is released from the tablet in the system.

[0089] In order to increase or maximize the amount of drug that can be stored in and released from the disclosed drug delivery system, the pharmaceutical tablet may have a relatively high erdafitinib content (by weight). This relatively high weight portion of erdafitinib in the pharmaceutical tablet is accompanied by a reduced or low weight portion of excipients, which may be necessary for tablet manufacturing and system assembly and drug use considerations. For the purposes of this disclosure, terms such as "weight portions," "weight percent," and "percentage by weight" with respect to any drug or API (active pharmaceutical ingredient) are directed to the drug or API in the form in which it is employed (whether in free base form, free acid form, salt form, or hydrate form). For example, a pharmaceutical tablet having 90% (90 wt %) of a drug or excipient in salt form by weight may include less than 90 wt % of the drug in free base form. Unless otherwise indicated, weight percentages are relative to the entire solid pharmaceutical composition.

[0090] The erdafitinib pharmaceutical tablets disclosed herein include an erdafitinib content and an excipient content. The pharmaceutical content may include one or more forms of erdafitinib, such as a free base or a salt form, and the excipient content may include one or more excipients. Specific embodiments include erdafitinib free base API, and exemplary formulations presented herein include erdafitinib free base API. The term "excipient" is known in the art, and representative examples of excipients that can be used in the disclosed pharmaceutical tablets may include, but are not limited to, ingredients such as binders, lubricants, glidants, disintegrants, solubilizers, colorants, fillers or diluents, wetting agents, stabilizers, formaldehyde scavengers, coatings, and preservatives, or any combination thereof, as well as other ingredients that facilitate the manufacture, storage, or administration of the pharmaceutical tablets.

[0091] Another aspect of the present disclosure provides a method for preparing a solid pharmaceutical composition, wherein the method may include: (a) preparing an intragranular solid composition comprising or consisting essentially of: (i) erdafitinib free base and (ii) at least one intragranular pharmaceutical excipient; (b) combining the intragranular solid composition with at least one extragranular pharmaceutical excipient to form a blend; and (c) tableting the blend to form a solid pharmaceutical composition. In an embodiment, erdafitinib free base may be present at 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 (mutually present) pharmaceutical excipient, or there may be no common (mutually present) pharmaceutical excipient between the intragranular excipient and the extragranular pharmaceutical excipient. The solid pharmaceutical composition may be prepared by a method comprising an intragranular solid composition prepared by a roller compaction method or by a fluidized bed granulation method. In some embodiments, the step of (a) preparing the intragranular solid composition comprises: (1) preparing a pre-blend comprising erdafitinib free base and one or more excipients; (2) preparing a binder solution; and (3) preparing the intragranular solid composition by combining the pre-blend with the binder solution. In some embodiments, the step of (a) preparing the intragranular solid composition comprises: (1) preparing a pre-blend comprising erdafitinib free base and one or more excipients; (2) preparing a binder solution; and (3) combining the pre-blend with the binder solution by a fluidized bed granulation method to prepare the intragranular solid composition. In some embodiments, the step of (a) preparing the intragranular solid composition comprises: (1) preparing a pre-blend comprising erdafitinib free base and a stabilizer, a solubilizer, and a filler; (2) preparing a binder solution comprising a binder and a solvent; and (3) combining the pre-blend with the binder solution by a fluidized bed granulation method to prepare the intragranular solid composition. In some embodiments, the step of (a) preparing the intragranular solid composition comprises: (1) preparing a pre-blend comprising erdafitinib free base, meglumine, hydroxypropyl-β-cyclodextrin, and microcrystalline cellulose; (2) preparing a binder solution comprising hydroxypropyl methylcellulose and purified water; and (3) combining the pre-blend with the binder solution by a fluidized bed granulation method to prepare the intragranular solid composition. In some embodiments, the step of (a) preparing the intragranular solid composition comprises: (1) preparing a pre-blend comprising erdafitinib free base with a solubilizer and a filler; (2) preparing a binder solution comprising a binder and a solvent; and (3) combining the pre-blend with the binder solution by a fluidized bed granulation method to prepare the intragranular solid composition.In some embodiments, the step of (a) preparing the intragranular solid composition comprises: (1) preparing a preblend of erdafitinib free base, hydroxypropyl-β-cyclodextrin, and microcrystalline cellulose; (2) preparing a binder solution comprising hydroxypropyl methylcellulose and purified water; and (3) combining the preblend with the binder solution by a fluidized bed granulation method to prepare the intragranular solid composition.

[0092] Another aspect of the present disclosure provides a method for preparing a solid pharmaceutical composition, wherein the method may include: (a) preparing an intragranular solid composition comprising or consisting essentially 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) tableting the blend to form a solid pharmaceutical composition. In an embodiment, Erdafitinib HCl salt form may be present at 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 (mutually present) pharmaceutical excipient, or there may be no common (mutually present) pharmaceutical excipient between the intragranular excipient and the extragranular pharmaceutical excipient. The solid pharmaceutical composition may be prepared by a method comprising an intragranular solid composition prepared by a roller compaction method or by a fluidized bed granulation method.

[0093] In an embodiment, the erdafitinib pharmaceutical tablet comprises erdafitinib in its free base form. Other embodiments of the erdafitinib pharmaceutical tablet may comprise erdafitinib in a salt form. In one aspect, the erdafitinib pharmaceutical tablet may comprise greater than or equal to 40% by weight of erdafitinib free base, with the remainder by weight comprising excipients that facilitate the preparation and use of the pharmaceutical tablet, such as lubricants, binders, and stabilizers. Alternatively, the erdafitinib pharmaceutical tablet may comprise greater than or equal to 45% by weight, greater than or equal to 50% by weight, greater than or equal to 55% by weight, or greater than or equal to 60% by weight of erdafitinib free base. In each of these weight percentage embodiments, a practical upper limit of erdafitinib free base in the tablet formulation is about 65% or 70% by weight. Thus, in one aspect, the pharmaceutical tablet may comprise 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 embodiments of the foregoing, the pharmaceutical tablet may comprise between about 5% and about 15% by weight of hydroxypropyl-β-cyclodextrin (HP-β-CD). In some embodiments of the foregoing, the pharmaceutical tablet may comprise about 10% by weight of hydroxypropyl-β-cyclodextrin (HP-β-CD). In embodiments, the pharmaceutical tablet may comprise 50% by weight of the free base form of erdafitinib, based on the total weight of the tablet. In embodiments, the pharmaceutical tablet may comprise 50% by weight of the free base form of erdafitinib, and between about 5% and about 15% by weight of hydroxypropyl-β-cyclodextrin (HP-β-CD), based on the total weight of the tablet. In embodiments, the pharmaceutical tablet may comprise 50% by weight of the free base form of erdafitinib and 10% by weight of hydroxypropyl-β-cyclodextrin (HP-β-CD), based on the total weight of the tablet.

[0094] In an embodiment, the erdafitinib pharmaceutical tablet comprises erdafitinib in the form of its HCl salt. In one aspect, the erdafitinib pharmaceutical tablet may comprise greater than or equal to 40% by weight of the HCl salt form of erdafitinib, with the remainder by weight comprising excipients that facilitate the preparation and use of the pharmaceutical tablet, such as lubricants, binders, and stabilizers. Alternatively, the erdafitinib pharmaceutical tablet may comprise greater than or equal to 45% by weight, greater than or equal to 50% by weight, greater than or equal to 55% by weight, or greater than or equal to 60% by weight of the HCl salt form of erdafitinib. In each of these weight percentage embodiments, the practical upper limit of the erdafitinib salt form in the tablet formulation is about 65% or 70% by weight. Thus, in one aspect, the pharmaceutical tablet may comprise 40% to 60% by weight of the HCl salt form of erdafitinib, or 45% to 55% by weight of the HCl salt form of erdafitinib. In an embodiment, the pharmaceutical tablet may comprise 50% by weight of the HCl salt form of erdafitinib, based on the total weight of the tablet.

[0095] In one embodiment, the erdafitinib drug and excipients are selected and formulated to allow release of the drug from the tablet. In some embodiments, the erdafitinib drug and excipients are selected and formulated to allow solubilization of the drug from the tablet. In embodiments, erdafitinib is formulated in a pharmaceutical composition to be sterilized, within or outside the drug delivery system, without causing substantial or deleterious changes in the chemical or physical composition of the drug tablet, which would otherwise render the drug tablet unsuitable for delivery of erdafitinib as described herein. In one aspect, the erdafitinib drug and excipients are selected for their suitability for a 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.

[0096] In one aspect, the erdafitinib drug tablet can be of a size and shape for use with an implantable drug delivery system including the intravesical drug delivery system disclosed herein. For example, the erdafitinib drug tablet can be a "microtablet" that is generally smaller in size than a conventional tablet, which can allow the drug tablet contained in the system to be inserted into a cavity (such as the bladder) through a lumen (such as the urethra). The erdafitinib tablet can be coated or uncoated. In particular, it has been found that uncoated tablets formulated according to the present disclosure perform well in combination with this system.

[0097] In an embodiment, the drug tablet for intravesical insertion or other in vivo implantation can be in the form of a solid cylinder having a cylindrical axis, a cylindrical side, a circular end face perpendicular to the cylindrical axis, a diameter passing through the circular end face, and a length along the cylindrical side face. In a cylindrical form, each mini-tablet can have a length (L) exceeding its diameter (D) such that the mini-tablet has an aspect ratio (L:D) greater than 1:1. For example, the aspect ratio (L:D) of each mini-tablet can be 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, or a range of values ​​between these aspect ratios. The embodiment of the mini-tablet can have a cylindrical diameter of 1.0 mm to 3.2 mm, or 1.5 mm to 3.1 mm, or 2.0 mm to 2.7 mm, or 2.5 mm to 2.7 mm. In some aspects, the minitablets may have a length of 1.7 mm to 4.8 mm, or 2.0 mm to 4.5 mm, or 2.8 mm to 4 mm, or 3 mm to 3.5 mm.

[0098] The API used in the solid tablet formulation can be erdafitinib, which is N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, and its chemical structure is shown below. The erdafitinib tablet used in the disclosed intravesical system can be formulated using erdafitinib free base or a salt thereof. In one aspect, the erdafitinib tablet used in the disclosed intravesical system can include erdafitinib free base. In one aspect, the erdafitinib tablet used in the disclosed intravesical system can include the HCl salt of erdafitinib, particularly the crystalline form of the HCl salt of erdafitinib. In some embodiments of the foregoing, the erdafitinib tablet used in the disclosed intravesical system can include the crystalline form of the free base of erdafitinib. As described herein, the inclusion of certain stabilizers, solubilizers, and excipients in erdafitinib free base formulations can provide advantageous stability and solubility properties for effective use of the free base formulations in the disclosed intravesical systems.

[0099]

[0100] In an embodiment, the erdafitinib pharmaceutical tablet may be incorporated with various excipients, including but not limited to at least one solubilizer, at least one binder, at least one wetting agent, at least one disintegrant, at least one stabilizer, at least one diluent, at least one glidant, at least one lubricant, or the like, 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 solid composition and the extragranular solid composition. In one aspect, the at least one intragranular pharmaceutical excipient and the at least one extragranular pharmaceutical excipient may be the same, i.e., may be selected from at least one common (mutually present) pharmaceutical excipient. In another aspect, the intragranular pharmaceutical excipient and the extragranular pharmaceutical excipient do not include a common (mutually present) pharmaceutical excipient, such that the intragranular excipient and the extragranular excipient are mutually exclusive. In an embodiment, the erdafitinib pharmaceutical tablet (particularly an erdafitinib pharmaceutical tablet comprising 40% to 70% by weight, or 40% to 60% by weight, or 45% to 55% by weight (e.g., 50% by weight) of erdafitinib) comprises at least one solubilizer, at least one binder, at least one stabilizer, at least one diluent, at least one glidant, at least one lubricant, etc., or any combination thereof. In an embodiment, the erdafitinib pharmaceutical tablet (particularly an erdafitinib pharmaceutical tablet comprising 40% to 70% by weight, or 40% to 60% by weight, or 45% to 55% by weight (e.g., 50% by weight) of erdafitinib) comprises at least one solubilizer, at least one binder, at least one diluent, at least one glidant, at least one lubricant, etc., or any combination thereof.

[0101] It should be understood that these functional descriptions of various excipients are generally used as follows. Once the API is released from the system, a solubilizer can improve or enhance the solubility of the API (such as erdafitinib free base) in the drug lumen of the disclosed system or in a body cavity (such as the bladder). A binder can hold the solid particles of the composition together to achieve physical stability. A wetting agent can reduce the surface tension between the drug and the medium in which it is located and help maintain the solubility of the drug. A disintegrant can assist in the disintegration of the microtablet when exposed to water to release the drug substance. A stabilizer can improve the chemical stability of the formulation (including the API), such as thermal stability, or protect the API from degradation. A diluent can be used as a filler to increase the volume or weight of the composition, which can help provide a tablet of the desired size or can assist in the tabletability of the API-excipient blend. A glidant can improve the flow characteristics of the (granular) particles of the tablet components or the powder blend to be compressed. A lubricant can prevent the particles of the composition from adhering to components of the manufacturing equipment, such as the die and punch of the tablet press. In one aspect, the excipient can be water-soluble. In another aspect, the excipient can be colloidal in water. According to another aspect, the excipient can be soluble under the conditions in which it is deployed in the patient's body (such as in the bladder). These and other excipients are described in more detail below.

[0102] Stabilizers such as formaldehyde scavengers

[0103] In one aspect, the erdafitinib API may be susceptible to degradation under certain conditions when incorporated into a solid dosage form. For example, erdafitinib can degrade or transform in the presence of formaldehyde to form the cyclized product 6,8-dimethoxy-4-(1-methylethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine. Formaldehyde from various sources in the environment, such as from packaging materials or as a contaminant in excipients or other components of the formulation, can come into contact with erdafitinib.

[0104] Thus, in one aspect, an erdafitinib pharmaceutical formulation may include a formaldehyde scavenger to improve the stability or shelf life of the formulation. Various formaldehyde scavengers can be used, and when erdafitinib comes into contact with formaldehyde, the formaldehyde scavenger can prevent, slow, reduce, or delay the formation of degradation products. Thus, the presence of a formaldehyde scavenger can increase the stability, such as chemical stability, of the erdafitinib pharmaceutical formulation compared to an erdafitinib pharmaceutical formulation in the absence of the formaldehyde scavenger. In one aspect, the formaldehyde scavenger can be present in the solid pharmaceutical composition as a component of the intragranular solid composition, the extragranular solid composition, or both the intragranular and extragranular solid compositions. In one aspect, the formaldehyde scavenger, particularly meglumine, is present in the solid pharmaceutical composition as a component of the intragranular solid composition.

[0105] The formaldehyde scavenger may include or may be selected from compounds containing reactive nitrogen centers, such as compounds containing amine or amide groups. Without being bound by theory, it is believed that these compounds may react with formaldehyde to form Schiff base imines (R 1 R 2 C=NR 3 , where R 3 (not hydrogen), which itself can bind formaldehyde. Examples of such formaldehyde scavengers include, but are not limited to, amino acids, amino sugars, α-(α-)amine compounds, their conjugates and derivatives, and mixtures thereof. Such formaldehyde scavenger compounds may contain two or more amine and / or amide moieties that can scavenge formaldehyde.

[0106] In one aspect, the formaldehyde scavenger may include or may be selected from, for example, meglumine, glycine, alanine, serine, threonine, cysteine, valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, aspartic acid, glutamic acid, arginine, lysine, ornithine, taurine, histidine, aspartame, proline, tryptophan, citrulline, pyrrolysine, asparagine, glutamine, tris(hydroxymethyl)aminomethane, their conjugates, their pharmaceutically acceptable salts, or any combination thereof. According to one aspect, the formaldehyde scavenger may include or may be selected from meglumine or a pharmaceutically acceptable salt thereof, particularly meglumine base.

[0107] Thus, one aspect of the present disclosure is the use of a formaldehyde scavenger, particularly meglumine, in an erdafitinib pharmaceutical formulation, such as a pharmaceutical tablet formulation, to increase the stability of erdafitinib in any form thereof, including erdafitinib free base, a salt thereof, or a solvate thereof. The chemical stability of the erdafitinib pharmaceutical formulation is increased compared to an erdafitinib pharmaceutical formulation or composition that does not contain the formaldehyde scavenger. One aspect of the present disclosure is a method for preventing, slowing, reducing, or delaying the formation of degradation products, such as the following compounds, that may be formed from erdafitinib in the presence of formaldehyde:

[0108]

[0109] In one aspect, degradation products, such as the above-mentioned substances, may be present in solid tablet compositions such as minitablet formulations, particularly minitablets as disclosed herein.

[0110] When present in the erdafitinib solid pharmaceutical composition, the formaldehyde scavenger can be present in 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 of the solid pharmaceutical composition. In some embodiments, when present in the erdafitinib solid pharmaceutical composition, the formaldehyde scavenger can be present in a concentration of about 1% by weight. When present in the erdafitinib solid pharmaceutical composition, the formaldehyde scavenger can be present in a concentration of, for example, 5% to 10% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight of the solid pharmaceutical composition. 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 comprises erdafitinib free base, and 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. In some embodiments, the erdafitinib solid pharmaceutical composition comprises erdafitinib free base, and the formaldehyde scavenger is present in the solid pharmaceutical composition at a concentration of about 1% by weight. In some embodiments of any of the foregoing, the formaldehyde scavenger is meglumine.

[0111] In some embodiments, the pharmaceutical compositions described herein (particularly erdafitinib pharmaceutical tablets) do not contain stabilizers or formaldehyde scavengers.

[0112] solubilizer

[0113] In one aspect, the erdafitinib formulation may include a solubilizing agent. The solubilizing agent may be an intragranular component, an extragranular component, or both the intragranular component and the extragranular component of the formulation. In embodiments, the solubilizing agent may include or may be selected from, for example, (a) a cyclic oligosaccharide, (b) a cellulose functionalized with a methoxy, 2-hydroxypropoxy, acetyl, or succinyl moiety, or a combination thereof, or (c) a salt thereof. In one embodiment, the solubilizing agent is present as an intragranular component.

[0114] In an embodiment, the solubilizing agent for the erdafitinib tablet formulation may include or may be selected from oligosaccharides. In an embodiment, the solubilizing agent may include or may be selected from cyclic oligosaccharides such as cyclodextrins. Suitable cyclodextrin solubilizing agents for the erdafitinib tablet formulation include, but are not limited to, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutyl ether-β-cyclodextrin sodium salt, or any combination thereof. In other embodiments, the solubilizing agent may include or may be hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose E5 (HPMC-E5), or a combination thereof.

[0115] The oligosaccharide solubilizing agent may be present in the erdafitinib tablet formulation (e.g., erdafitinib free base formulation) at a concentration of 1% to 20% by weight, alternatively 3% to 18% by weight, alternatively 5% to 15% by weight, alternatively 7% to 12% by weight, or alternatively 10% by weight or about 10% by weight. The cyclodextrin solubilizing agent may be present in the erdafitinib tablet formulation (e.g., erdafitinib free base formulation) at a concentration of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% by weight, or any range of weight percentages between any of these weight percentages.

[0116] In one aspect, the solubilizer for the erdafitinib tablet formulation disclosed herein may comprise or may be hydroxypropyl-β-cyclodextrin (HP-β-CD). One embodiment of the erdafitinib free base formulation includes a hydroxypropyl-β-cyclodextrin solubilizer, particularly an erdafitinib free base formulation comprising 8% to 12% by weight, or alternatively 10% or about 10% by weight of hydroxypropyl-β-cyclodextrin. In some embodiments, the formulation comprises a concentration of about 10% by weight of hydroxypropyl-β-cyclodextrin. 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 (e.g., 50% by weight). In one embodiment, the hydroxypropyl-β-cyclodextrin is present in the intragranular solid composition. In an embodiment, the pharmaceutical tablet may comprise 50% by weight of the free base form of erdafitinib, 1% by weight of meglumine, and 8% to 12% by weight, or alternatively, at a concentration of 10% or about 10% by weight of hydroxypropyl-β-cyclodextrin. In an embodiment, based on the total weight of the tablet, the pharmaceutical tablet may comprise 50% by weight of the free base form of erdafitinib, 10% by weight of hydroxypropyl-β-cyclodextrin (HP-β-CD), and 1% by weight of meglumine. In an embodiment, based on the total weight of the tablet, the pharmaceutical tablet may comprise at least about 45% by weight of the free base form of erdafitinib, 10% by weight of hydroxypropyl-β-cyclodextrin (HP-β-CD), and 0% by weight of meglumine. In an embodiment, based on the total weight of the tablet, the pharmaceutical tablet may comprise 50% by weight of the free base form of erdafitinib, 10% by weight of hydroxypropyl-β-cyclodextrin (HP-β-CD), and 0% by weight of meglumine.

[0117] Adhesives

[0118] The pharmaceutical excipients for the solid pharmaceutical composition of erdafitinib may include one or more binders. One or more binders may be present in the solid pharmaceutical composition as a component of the intragranular solid composition, the extragranular solid composition, or both the intragranular solid composition and the extragranular solid composition. Suitable binders may be water-soluble, water-insoluble, or slightly water-soluble, or a combination thereof. In one aspect, the binder may include a polymeric binder, such as a water-soluble polymeric binder, a slightly water-soluble polymeric binder, a water-insoluble polymeric binder, or any combination thereof. The polymeric binder may include a nonionic polymer.

[0119] It will be understood by those of ordinary skill that binders can also act as diluents (also known as fillers) in pharmaceutical compositions. Therefore, as the case may be and unless otherwise stated, the binders provided in this disclosure can also be used for their diluting function.

[0120] In one aspect, suitable binders may include or be selected from polyvinylpyrrolidone (PVP, also known as polyvidone, povidone or poly(1-vinyl-2-pyrrolidone)), 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 aspect, suitable binders may include or may be selected from polyvinyl pyrrolidone (PVP, also known as povidone or poly (1-vinyl-2-pyrrolidone)), poly (vinyl acetate) (PVA), vinyl pyrrolidone-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), or a combination thereof. In one aspect, suitable binders may include or may be selected from hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, vinyl pyrrolidone-vinyl acetate copolymer, or a combination thereof. In one aspect, suitable binders may include or may be selected from hydroxypropyl methylcellulose (HPMC), vinyl pyrrolidone-vinyl acetate copolymer (copovidone), or a combination thereof. In some embodiments, the binder may be hydroxypropyl methylcellulose (HPMC). In some embodiments, the binder may be hydroxypropyl methylcellulose (HPMC) at a concentration of about 1.5% by weight of the solid composition. In some embodiments, the binder may be hydroxypropyl methylcellulose (HPMC) at 1.5% by weight of the solid composition and is present in the intragranular solid composition.

[0121] In a further aspect, suitable binders may include or may be selected from polymers or copolymers of vinyl pyrrolidone (VP, also known as 1-vinyl-2-pyrrolidone) and vinyl acetate (VA). Such copolymers of VP and VA may also be referred to as "copovidones". Suitable binders may also include or may be selected from polymers or copolymers of ethylene oxide (EO) and propylene oxide (PO). In addition, these binders may be used in combination with other binders, such as microcrystalline cellulose, hydroxypropyl cellulose (HPC) or hydroxypropyl methylcellulose (HPMC).

[0122] In one aspect, the total concentration of the at least one binder in the solid pharmaceutical composition can be 1 wt % to 30 wt %, 2 wt % to 30 wt %, 5 wt % to 30 wt %, 5 wt % to 25 wt %, 10 wt % to 25 wt %, 10 wt % to 22 wt %, 12 wt % to 22 wt %, 14 wt % to 19 wt %, or 12 wt % to 19 wt %.

[0123] According to another aspect, suitable polymeric binders may include or may be selected from copolymers of vinyl pyrrolidone and vinyl acetate, which may be referred to as poly(vinyl pyrrolidone-co-vinyl acetate) or poly(VP-co-VA). Examples of suitable poly(vinyl pyrrolidone-co-vinyl acetate) binders include VA64 and VA64 Fine (BASF, Ludwigshafen am Rhein, Germany), which have molecular weights (Mw) ranging from 45,000 g / mol to 70,000 g / mol based on light scattering measurements of the solutions. Another suitable binder is K30.

[0124] In embodiments, a polymer binder such as vinyl pyrrolidone-vinyl acetate copolymer can be present in the disclosed erdafitinib tablet formulations at a concentration 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 vinyl pyrrolidone-vinyl acetate copolymer binder can be present in the erdafitinib tablet formulation (e.g., erdafitinib free base formulation) at a concentration of 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, or any range of weight percentages between any of these weight percentages (e.g., 7.5%). In one aspect, the vinyl pyrrolidone-vinyl acetate copolymer is present at a concentration of 8% by weight of the solid composition. In one aspect, the vinyl pyrrolidone-vinyl acetate copolymer is present in the intragranular solid composition. In one aspect, the vinyl pyrrolidone-vinyl acetate copolymer is present in a solid composition within the granules, and the solid composition within the granules is prepared by roller compaction. In one aspect, the vinyl pyrrolidone-vinyl acetate copolymer is present in a solid composition within the granules, and the solid composition within the granules is prepared by fluidized bed granulation. In one aspect, the vinyl pyrrolidone-vinyl acetate copolymer is present in an extragranular solid composition. In one aspect, the vinyl pyrrolidone-vinyl acetate copolymer is present at a concentration of about 7.5% by weight of the solid composition. In one aspect, the vinyl pyrrolidone-vinyl acetate copolymer is present at a concentration of about 7.5% by weight of the solid composition and is in an extragranular solid composition.

[0125] In one aspect, binding agent may include or may be microcrystalline cellulose. For example, microcrystalline cellulose may be present in the solid pharmaceutical composition at a concentration of 5% by weight to 30% by weight, 10% by weight to 20% by weight, 5% by weight to 20% by weight, 6% by weight to 15% by weight, or 7% by weight to 12% by weight. For example, microcrystalline cellulose may be present in the solid pharmaceutical composition at a concentration of approximately 17.5% by weight as a filler and / or as a binding agent. For example, microcrystalline cellulose may be present in the solid pharmaceutical composition at a concentration of approximately 17.5% by weight of the solid composition, and may be present in the solid composition and the extragranular solid composition. For example, microcrystalline cellulose may be present in the solid pharmaceutical composition at a concentration of approximately 10% by weight of the solid composition as a filler in the intragranular composition, and may be present in the solid pharmaceutical composition at a concentration of approximately 7.5% by weight of the solid composition as a binding agent in the extragranular composition.

[0126] According to another aspect, the binder may comprise or may be silicified microcrystalline cellulose.For example, the silicified microcrystalline cellulose may be present in the solid pharmaceutical composition at a concentration of 3% to 18%, 4% to 15%, or 5% to 12% by weight.

[0127] In another aspect, the binder may include or may be hydroxypropyl methylcellulose (HPMC). For example, hydroxypropyl methylcellulose (HPMC) may be present in the solid pharmaceutical composition at a concentration of 0.25% to 5% by weight, 0.5% to 4% by weight, or 0.75% to 3% by weight. In one aspect, the HPMC binder may be present in the solid pharmaceutical composition in the intragranular solid composition.

[0128] Wetting agent

[0129] The pharmaceutical excipients for the solid pharmaceutical composition of Erdafitinib may include one or more wetting agents. One or more wetting agents may be present in the solid pharmaceutical composition in the intragranular solid composition, the extragranular solid composition, or both the intragranular solid composition and the extragranular solid composition. In an exemplary embodiment, the wetting agent may include or may be independently selected from an anionic surfactant or a nonionic surfactant, particularly an anionic surfactant. For example, the wetting agent may include or may be independently selected from sodium lauryl sulfate, sodium stearyl fumarate, polysorbate (e.g., polysorbate 80), docusate sodium, or any combination thereof. In an embodiment, the total concentration of the wetting agent in the solid pharmaceutical composition may be 0.01% to 2.5% by weight, 0.05% to 1.0% by weight, or 0.1% to 0.5% by weight. In one embodiment, the wetting agent is present in the intragranular solid composition. In one embodiment, the wetting agent is sodium lauryl sulfate.

[0130] In one embodiment, the erdafitinib solid pharmaceutical composition does not include one or more wetting agents.

[0131] disintegrants

[0132] The pharmaceutical excipients for the solid pharmaceutical composition of erdafitinib may include one or more disintegrants. The one or more disintegrants may be present in the solid pharmaceutical composition in the intragranular solid composition, the extragranular solid composition, or both the intragranular solid composition and the extragranular solid composition. In one embodiment, the disintegrant is present in the intragranular solid composition. In one embodiment, the disintegrant is present in the intragranular solid composition, and the intragranular solid composition is prepared by roller compaction.

[0133] In exemplary embodiments, the disintegrant may comprise or may be independently selected from a functionalized polysaccharide or a cross-linked polymer. For example, in one aspect, the disintegrant may comprise or may be selected from, for example, (a) a cellulose functionalized with a methoxy, 2-hydroxypropoxy or carboxymethoxy moiety, a salt thereof, or a combination thereof, (b) a carboxymethylated starch, or (c) a cross-linked polymer.

[0134] In an embodiment, the disintegrant may comprise or may be independently selected from hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, crospovidone (cross-linked polyvinyl pyrrolidone), croscarmellose sodium (cross-linked sodium carboxymethyl cellulose), sodium starch glycolate, or any combination thereof.

[0135] When present, the disintegrant can be present in a range of concentrations. In embodiments, the total concentration of disintegrant in the solid pharmaceutical composition can be 0.1 wt % to 3 wt %, 0.5 wt % to 2.5 wt %, 1 wt % to 2 wt %, or about 1.5 wt %.

[0136] In one embodiment, the erdafitinib solid pharmaceutical composition does not comprise one or more disintegrants.

[0137] diluent or filler

[0138] The pharmaceutical excipients for the solid pharmaceutical composition of Erdafitinib may include one or more diluents. The one or more diluents may be present in the solid pharmaceutical composition as a component of the intragranular solid composition, the extragranular solid composition, or both the intragranular solid composition and the extragranular solid composition.

[0139] In exemplary embodiments, the diluent may comprise or may be selected from sugar, starch, microcrystalline cellulose, sugar alcohol, hydrogen phosphate, dihydrogen phosphate, carbonate or a combination thereof. In one aspect, the diluent may comprise or may 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.

[0140] In an embodiment, the total concentration of the diluent in the solid pharmaceutical composition can be 10% to 60% by weight, 10% to 50% by weight, 10% to 40% by weight, 12% to 30% by weight, 15% to 25% by weight, or 18% to 22% by weight, or 20% to 40% by weight, or 20% to 30% by weight, or 25% to 30% by weight. For example, in some aspects, the diluent can include or can be selected from microcrystalline cellulose with a concentration of 15% to 25% by weight, or 20% to 22% by weight, or 15% to 20% by weight. In another aspect, the diluent can include or can be selected from anhydrous calcium hydrogen phosphate with a concentration of from 18% to 20% by weight. In another aspect, the diluent can include or can be anhydrous calcium hydrogen phosphate with a concentration of about 19% by weight. In another aspect, the diluent can include or can be anhydrous calcium hydrogen phosphate with a concentration of about 19% by weight, which is present in the extragranular solid composition. In another aspect, the diluent may comprise 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 comprise silicified microcrystalline cellulose at a concentration of about 10.75% or 11.75% by weight of the solid composition. For example, the diluent may comprise silicified microcrystalline cellulose at a concentration of about 10.75% or 11.75% by weight of the solid composition and be present in the extragranular composition. For example, the diluent may comprise silicified microcrystalline cellulose at a concentration of about 10.75% by weight of the solid composition and be present in the extragranular composition. For example, the diluent may comprise silicified microcrystalline cellulose at a concentration of about 11.75% by weight of the solid composition and be present in the extragranular composition. In another aspect, the diluent does not comprise silicified microcrystalline cellulose. In another aspect, the diluent may comprise microcrystalline cellulose and silicified microcrystalline cellulose. In another aspect, the diluent may comprise microcrystalline cellulose or silicified microcrystalline cellulose. In another aspect, the diluent may comprise microcrystalline cellulose at a concentration of about 10% by weight. In another aspect, the diluent may comprise microcrystalline cellulose at a concentration of about 10% by weight, which is present in the intragranular composition. For example, microcrystalline cellulose may be present in the solid pharmaceutical composition as a filler and / or as a 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 intragranular solid composition and the extragranular solid composition. For example, microcrystalline cellulose may be present in the solid pharmaceutical composition as a filler in the intragranular composition at a concentration of about 10% by weight of the solid composition, and may be present in the solid pharmaceutical composition as a binder in the extragranular composition at a concentration of about 7.5% by weight of the solid composition.

[0141] It will be understood by those skilled in the art that some of the diluents / fillers disclosed herein may also function as binders in pharmaceutical compositions. Thus, some compounds or materials may be described herein as providing both binder functionality and diluent / filler functionality.

[0142] glidants

[0143] The pharmaceutical excipients used in the solid pharmaceutical composition of Erdafitinib may include one or more glidants. The one or more glidants may be present in the solid pharmaceutical composition as a component of the intragranular solid composition, the extragranular solid composition, or both the intragranular solid composition and the extragranular solid composition. In one aspect, the glidant is present in the extragranular solid composition. As used in this disclosure, a glidant refers to a pharmaceutical excipient that improves or optimizes the particle flow characteristics of a granular or powdered tablet component in granular form by reducing interactions, attractive forces, cohesive forces, or friction between particles. A pharmaceutically acceptable glidant is a non-toxic and pharmacologically inactive substance. In addition, the glidant may be water-soluble or water-insoluble.

[0144] In one aspect, the glidant may include or may be selected from colloidal silicon dioxide, colloidal anhydrous silicon dioxide, talc, or any combination thereof. In an embodiment, the total concentration of the glidant in the solid pharmaceutical composition may be 0.01% to 5% by weight, 0.05% to 3% by weight, 0.1% to 1% by weight, or about 0.2% by weight, or about 0.25% by weight, or about 0.3% by weight, about 0.35% by weight, or about 0.4% by weight, or about 0.45% by weight, or about 0.5% by weight. In one embodiment, the glidant is colloidal silicon dioxide. In some embodiments, the glidant is about 0.5% by weight of the solid composition. In some embodiments, the glidant is about 0.5% by weight of the colloidal silicon dioxide and is present in the extragranular composition. In some embodiments, the glidant is about 0.25% by weight of the solid composition. In some embodiments, the glidant is colloidal silicon dioxide at about 0.25% by weight of the solid composition and is present in the extragranular composition.

[0145] lubricant

[0146] The pharmaceutical excipients used in the solid pharmaceutical composition of erdafitinib may include one or more lubricants. The one or more lubricants may be present in the solid pharmaceutical composition as a component of the intragranular solid composition, the extragranular solid composition, or both the intragranular solid composition and the extragranular solid composition. In one aspect, the lubricant is present in the extragranular solid composition. In one aspect, the lubricant is present in the intragranular solid composition, and the intragranular solid composition is prepared by roller compaction. As used in this disclosure, a lubricant refers to a pharmaceutical excipient added to a tablet formulation that reduces friction on the tablet surface. In embodiments, the lubricant can reduce friction between the tablet surface and processing equipment, such as friction between the tablet surface and the wall of the mold cavity in which the tablet is formed. Thus, when the tablet is formed and ejected, the lubricant can reduce friction between the mold wall and the formulation particles. Pharmaceutically acceptable lubricants are non-toxic and pharmacologically inactive substances. In addition, the lubricant can be water-soluble or water-insoluble.

[0147] In one aspect, the lubricant may include or may be selected from, for example, fatty acids, fatty acid salts, fatty acid esters, talc, glycerides, metal silicates, or any combination thereof. In an embodiment, the lubricant may include or may be selected from magnesium stearate, stearic acid, magnesium silicate, aluminum silicate, isopropyl myristate, sodium oleate, sodium stearoyl lactylate, sodium stearyl fumarate, titanium dioxide, or a combination thereof. Examples of lubricants include, but are not limited to, leucine, sodium lauryl sulfate, sucrose stearate, boric acid, sodium acetate, sodium oleate, sodium stearyl fumarate, and PEG. In another aspect, the total concentration of 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 intragranular composition or the extragranular composition. In some embodiments, the lubricant is magnesium stearate and is present in both the intragranular composition and the extragranular composition. In some embodiments, the lubricant is magnesium stearate at about 1.5% by weight of the solid composition. In some embodiments, the lubricant is magnesium stearate at about 1.5% by weight of the solid composition and is present in the intragranular composition. In some embodiments, the lubricant is magnesium stearate at about 1.5% by weight of the solid composition and is present in the extragranular composition. In some embodiments, the lubricant is magnesium stearate at about 1.5% by weight of the solid composition and is present in both the intragranular and extragranular compositions.

[0148] Formulation Development

[0149] Provided herein are erdafitinib formulations (particularly erdafitinib tablets) that (a) comprise a high erdafitinib drug load, such as in the range of 40 wt% to 70 wt%, or 40 wt% to 60 wt%, or 45 wt% to 55 wt%, or about 50 wt%, or in the range of 45 wt% to 55 wt%, or about 50 wt%, (b) provide acceptable chemical stability of erdafitinib, (c) support high production speeds for tablet production, e.g., on an industrial scale, particularly where the length (L) exceeds its diameter (D), such that the tablet The invention relates to tablets having an aspect ratio (L:D) greater than 1:1, in particular 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, or 2.5 mm to 2.7 mm, in particular on an industrial scale, in particular for miniature tablets, (d) providing a tablet that is physically sufficiently strong (in particular suitable for inclusion in a drug delivery system as described herein, in particular an osmotic system), and / or (e) exhibiting desirable disintegration and / or dissolution characteristics.

[0150] Formulations of erdafitinib with a range of excipient combinations (both intragranular and extragranular) are provided in Table 1 of the Examples, which lists Formulations 4A, 4B, 4C, and 4D. Additional formulations of erdafitinib with a range of excipient combinations are provided in Table 3 and the Examples, which list Formulations 3.2, 3.3, 3.4, and 4.1.

[0151] Provided herein are solid formulations of erdafitinib, particularly erdafitinib mini-tablets, particularly with a high erdafitinib drug loading, such as 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 can be obtained by a process comprising fluidized bed granulation. In one embodiment, the tablets can be obtained by a process comprising roller compaction. In one embodiment, the intragranular solid composition comprises cyclodextrin, particularly hydroxypropyl-β-cyclodextrin. In one embodiment, the formulation does not comprise mannitol in the intragranular solid composition. In one embodiment, the intragranular solid composition does not comprise a water-soluble filler. In one embodiment, the formulation comprises a water-insoluble filler, such as microcrystalline cellulose.

[0152] In one embodiment, a fluidized bed granulation method for preparing granules comprising erdafitinib and hydroxypropyl-β-cyclodextrin is provided. In one aspect, the method does not include the use of a water-soluble filler (such as mannitol).

[0153] Provided herein are erdafitinib solid formulations, particularly erdafitinib mini-tablets, particularly with high erdafitinib drug loading (such as in the range of 45% to 55% by weight, or about 50% by weight), comprising vinyl pyrrolidone-vinyl acetate copolymer and microcrystalline cellulose, particularly in a weight ratio ranging from 1:99 to 99:1, or 5:95 to 95:5, or 10:90 to 90:10, or 20:80 to 80:20, or 30:70 to 70:30, or 40:60 to 60:40, or 50:50. It was unexpectedly found that in the presence of this mixture, the ejection force during tableting, particularly in the tableting of mini-tablets such as those described herein, was reduced. Powder formulations comprising this mixture were found to have good flow properties. In one aspect, the formulation further comprises hydroxypropyl-β-cyclodextrin. In one aspect, the formulation does not comprise mannitol.

[0154] In one embodiment, a process for preparing tablets, in particular minitablets as described herein, is provided, wherein the powder blend to be tableted comprises vinyl pyrrolidone-vinyl acetate copolymer and microcrystalline cellulose, in particular in a weight ratio ranging from 1:99 to 99:1, or 5:95 to 95:5, or 10:90 to 90:10, or 20:80 to 80:20, or 30:70 to 70:30, or 40:60 to 60:40, or 50:50. In one aspect, a method for preparing a tablet, in particular a minitablet as described herein, is provided, wherein the powder blend to be tableted comprises erdafitinib, vinylpyrrolidone-vinyl acetate copolymer and microcrystalline cellulose, in particular wherein the weight ratio of vinylpyrrolidone-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 aspect, the powder blend to be tableted further comprises hydroxypropyl-β-cyclodextrin. In one aspect, the powder blend to be tableted does not comprise mannitol.

[0155] Provided herein are erdafitinib solid formulations, particularly erdafitinib powder formulations or erdafitinib minitablets, particularly with a high erdafitinib drug load, such as 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, with a low fine particle content, such as a fine particle content of less than 20%, or less than 10%, or less than 5%, or about or less than 3%, or about or less than 2%. Fine particles can increase the ejection force during tableting, particularly during tableting of minitablets as described herein, particularly when tableting at high speeds (e.g., 2500 tablets / minute).

[0156] In one embodiment, provided herein are formulations (particularly tablets or minitablets) comprising erdafitinib (particularly having a high erdafitinib drug load, such as 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-β-cyclodextrin, vinylpyrrolidone-vinyl acetate copolymer, and microcrystalline cellulose. In one aspect, the formulation further comprises meglumine. In one aspect, the formulation does not comprise mannitol. In one aspect, the formulation further comprises at least one or all of a glidant (e.g., colloidal silicon dioxide), a lubricant (e.g., magnesium stearate), a binder (e.g., a cellulose derivative such as hydroxypropyl methylcellulose), a filler (e.g., silicified microcrystalline cellulose).

[0157] In one embodiment, provided herein are formulations (particularly tablets or minitablets) comprising erdafitinib (particularly with a high erdafitinib drug load, such as 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-β-cyclodextrin, vinylpyrrolidone-vinyl acetate copolymer, and microcrystalline cellulose. In one aspect, the formulation further comprises at least one or all of a glidant (e.g., colloidal silicon dioxide), a lubricant (e.g., magnesium stearate), a binder (e.g., a cellulose derivative such as hydroxypropyl methylcellulose), a filler (e.g., silicified microcrystalline cellulose). In one aspect, the formulation does not comprise a stabilizer such as meglumine. In one aspect, the formulation does not comprise mannitol.

[0158] In one embodiment, the formulation is formula 4A. In one embodiment, the formulation is formula 4B. In one embodiment, the formulation is formula 4C. In one embodiment, the formulation is formula 4D.

[0159] Thus, the present disclosure encompasses the formulation of Formulation 4D, wherein the solid pharmaceutical composition comprises: (a) 50 weight percent erdafitinib free base; (b) 10 weight percent hydroxypropyl-β-cyclodextrin; (c) 1 weight percent meglumine; (d) 17.5 weight percent microcrystalline cellulose; (e) 10.75 weight percent silicified microcrystalline cellulose; (f) 7.5 weight percent vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25 weight percent colloidal silicon dioxide; (h) 1.5 weight percent hydroxypropyl methylcellulose; and (i) 1.5 weight percent magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In one aspect, the formulation can be prepared by a method comprising the following steps: (a) preparing an intragranular solid composition by a fluidized bed granulation method, wherein the intragranular solid composition consists essentially of: (i) erdafitinib free base at a concentration of 50% by weight of the solid pharmaceutical composition; (ii) hydroxypropyl-β-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; (b) mixing the intragranular solid composition with a mixture of the granular solid composition and the mixture. The invention relates to a pharmaceutical composition comprising: ...

[0160] Thus, the present disclosure encompasses the formulation of Formulation 4C, wherein the solid pharmaceutical composition comprises: (a) 50 weight percent erdafitinib free base; (b) 10 weight percent hydroxypropyl-β-cyclodextrin; (c) 1 weight percent meglumine; (d) 1.5 weight percent hydroxypropyl methylcellulose; (e) 21.0 weight percent mannitol; (f) 0.25 weight percent sodium lauryl sulfate; (g) 7.25 weight percent microcrystalline cellulose; (h) 7.25 weight percent vinylpyrrolidone-vinyl acetate copolymer; (i) 0.25 weight percent colloidal silicon dioxide; and (j) 1.50 weight percent magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In one aspect, the formulation can be prepared by a method comprising the steps of: (a) preparing an intragranular solid composition by a fluidized bed granulation method; (b) combining the intragranular solid composition with an extragranular component to form a blend; and (c) tableting the blend to form a solid pharmaceutical composition in the form of a mini-tablet, wherein the intragranular component and the extragranular component are listed in Table 1 in the Examples. In one embodiment, the tablet contains 11.5 mg of erdafitinib.

[0161] Thus, the present disclosure encompasses a formulation of Formulation 4B, wherein the solid pharmaceutical composition comprises: (a) 50% by weight of erdafitinib free base; (b) 10% by weight of hydroxypropyl-β-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, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In one aspect, the formulation can be prepared by a process comprising the steps of: (a) preparing an intragranular solid composition by a fluidized bed granulation process; (b) combining the intragranular solid composition with an extragranular component to form a blend; and (c) compressing the blend to form a solid pharmaceutical composition in the form of a minitablet, wherein the intragranular component and the extragranular component are listed in Table 1 in the Examples. In one aspect, the formulation can be prepared by a process comprising the steps of: (a) preparing an intragranular solid composition by roller compaction; (b) combining the intragranular solid composition with an extragranular component to form a blend; and (c) tableting the blend to form a solid pharmaceutical composition in the form of a mini-tablet, wherein the intragranular component and the extragranular component are listed in Table 1 in the Examples. In one embodiment, the tablet contains 11.5 mg of erdafitinib.

[0162] Thus, the present disclosure encompasses formulations of Formulation 4A, wherein the solid pharmaceutical composition comprises: (a) 50% by weight of erdafitinib free base; (b) 10% by weight of hydroxypropyl-β-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, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In one aspect, the formulation can be prepared by a process comprising the steps of: (a) preparing an intragranular solid composition by a fluidized bed granulation process; (b) combining the intragranular solid composition with an extragranular component to form a blend; and (c) compressing the blend to form a solid pharmaceutical composition in the form of a minitablet, wherein the intragranular component and the extragranular component are listed in Table 1 in the Examples. In one aspect, the formulation can be prepared by a process comprising the steps of: (a) preparing an intragranular solid composition by roller compaction; (b) combining the intragranular solid composition with an extragranular component to form a blend; and (c) tableting the blend to form a solid pharmaceutical composition in the form of a mini-tablet, wherein the intragranular component and the extragranular component are listed in Table 1 in the Examples. In one embodiment, the tablet contains 11.5 mg of erdafitinib.

[0163] Accordingly, the present disclosure encompasses Formulation 4.1, wherein the solid pharmaceutical composition comprises: (a) 50 weight percent erdafitinib free base; (b) 10 weight percent hydroxypropyl-β-cyclodextrin; (c) 17.5 weight percent microcrystalline cellulose; (d) 11.75 weight percent silicified microcrystalline cellulose; (e) 7.5 weight percent vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 weight percent colloidal silicon dioxide; (g) 1.5 weight percent hydroxypropyl methylcellulose; and (h) 1.5 weight percent magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In one aspect, the formulation can be prepared by a method comprising the steps of: (a) preparing an intragranular solid composition by a fluidized bed granulation method, the intragranular solid composition consisting essentially of: (i) erdafitinib free base at a concentration of 50% by weight of the solid pharmaceutical composition; (ii) hydroxypropyl-β-cyclodextrin at a concentration of 10% by weight of the solid pharmaceutical composition; (iii) microcrystalline cellulose at a concentration of 10% by weight of the solid pharmaceutical composition; and (iv) hydroxypropyl methylcellulose at a concentration of 1.5% by weight of the solid pharmaceutical composition; (b) combining the intragranular solid composition with extragranular components to form A blend wherein the extragranular component consists essentially of: (i) microcrystalline cellulose at a concentration of 7.5% by weight of the solid pharmaceutical composition; and (ii) vinyl pyrrolidone-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) tableting the blend to form a solid pharmaceutical composition in the form of a mini-tablet. In one embodiment, the tablet contains 11.5 mg of erdafitinib.

[0164] Diffusion-based drug delivery systems

[0165] Described herein are drug delivery systems that are particularly suitable for effectively releasing drug formulations containing erdafitinib, such as those described in detail above or below. These specific systems have been developed in which drug release is not a permeable drug release mechanism, but rather is controlled by drug diffusion through a drug-permeable polymer component that defines a portion of the system housing.

[0166] In certain embodiments, the system includes a drug-permeable polymeric component or portion that forms part of the housing. For example, the drug-permeable component or portion of the system can be a portion of the housing formed from a different material than the rest of the housing (e.g., one or more strips of material extending along at least a portion of the length of the housing), such that the size, shape (e.g., arc angle), thickness, and material properties of the drug-permeable wall structure can be selected to achieve a desired drug release rate. In certain embodiments, the drug-permeable portion, the drug-impermeable portion, or both the drug-permeable and drug-impermeable portions are formed from a thermoplastic polyurethane composition to provide (i) controlled diffusion of the drug from the system, (ii) desired mechanical properties (e.g., ability to straighten for insertion / removal, sufficiently flexible to be well tolerated during indwelling, tubing that remains intact with small compressions / extensions, elastic deformability (compliance) in response to detrusor contraction), (iii) a system that can be heat-set to have a desired shape retention, and / or (iv) a system that can be manufactured in a co-extrusion process.

[0167] In some embodiments, the drug permeable portion is permeable to erdafitinib free base. In some embodiments, the drug permeable portion is permeable to erdafitinib free base and erdafitinib free base formulated with HP-β-CD. In some embodiments, the drug permeable portion is permeable to erdafitinib free base, erdafitinib HCl salt, and erdafitinib free base formulated with HP-β-CD. In some embodiments of any of the foregoing, the material of the drug permeable portion is an aliphatic polyether-based TPU. In some embodiments of the foregoing, the material of the drug permeable portion is an aliphatic polyether-based TPU that is Lubrizol Tecophilic HP-60D-35 or HP-93A-100.

[0168] In some embodiments, the drug permeable portion is permeable to erdafitinib free base formulated with HP-β-CD. In some embodiments, the drug permeable portion is permeable to erdafitinib free base formulated with HP-β-CD and is impermeable or substantially impermeable to erdafitinib free base formulated without HP-β-CD. In some embodiments of any of the foregoing, the material of the drug permeable portion is aliphatic polyether-based TPU. In some embodiments of the foregoing, the material of the drug permeable portion is Lubrizol Tecoflex EG-80A.

[0169] Exemplary materials for the drug permeable portion (e.g., the "strip" material of the osmotic 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 of the drug permeable portion is Lubrizol Tecophilic HP-60D-35, Tecophilic HP-93A-100, or Tecoflex EG-80A. In some embodiments, the material of the drug permeable portion is Lubrizol Tecoflex EG-80A. In some embodiments, the drug is erdafitinib free base, and the material of 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.

[0170] Exemplary materials for the drug-impermeable portion (e.g., the "base" material of the osmotic system) include, but are not limited to, silicone elastomeric materials such as NuSil MED-4750; TPUs such as Lubrizol Carbothane Aliphatic PC-3575A, Tecothane Soft AR-62A, AR-75A-B20, AC-4075A-B20, Carbothane Aromatic AC-4075A, Tecothane TT-1074A, Tecoflex EG-80A; and ethylene vinyl acetate such as 3M CoTran 9712. In some embodiments, the material of the drug-impermeable portion is selected from MED-4750, PC-3575A, PC-3575A, AR-62A, AR-75A-B20, AC-4075A-B20, AC-4075A, TT-1074A, EG-80A, and CoTran 9712. In some embodiments, the material of the drug-impermeable portion is selected from the group consisting of MED-4750, PC-3575A, PC-3575A, AR-62A, AR-75A-B20, AC-4075A-B20, AC-4075A, TT-1074A, and CoTran 9712. In some embodiments, the material of the drug-impermeable portion is AR-75A-B20. In some embodiments, the material of the drug-impermeable portion is AC-4075A-B20.

[0171] 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.

[0172] It should be understood that the Lubrizol Tecophilic HP series materials are TPUs based on aliphatic polyethers that are formulated to absorb an equilibrium water content of up to 100% of the dry resin weight and are designed for extrusion but can also be processed by injection molding. HP-60D-35 has a Shore hardness of about 42D (ASTM D2240), a specific gravity of about 1.12 (ASTM D792), a flexural modulus (psi) of 4000 (ASTM D790), an ultimate tensile (psi) of about 7,800 dry and 4900 wet (ASTM D412), an ultimate elongation (%) of about 450 dry and 390 wet (D412); and a water absorption of about 35 (% measured by the Lubrizol method). HP-93A-100 has a Shore hardness of about 83A (ASTM D2240), a specific gravity of about 1.13 (ASTM D792), a flexural modulus (psi) of 2900 (ASTM D790), an ultimate tensile (psi) of about 2200 dry and 1400 wet (ASTM D412), an ultimate elongation (%) of about 1040 dry and 620 wet (D412); and a water absorption (% measured by the Lubrizol method) of about 100.

[0173] 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 A hardness of about 72A (ASTM D2240), a specific gravity of about 1.04 (ASTM D792), a flexural modulus (psi) of 1,000 (ASTM D790), an ultimate tensile (psi) of about 5,800 (ASTM D412), an ultimate elongation (%) of about 660 (D412); a tensile modulus (psi) of about 300 at 100% elongation, about 500 at 200% elongation, and about 800 at 300% elongation (ASTM D412); and a mold shrinkage (in / in) of about 0.008-0.012 (ASTM D955).

[0174] It should be understood that Lubrizol Aromatic Carbothane 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 A hardness of about 78A (ASTM D2240), a specific gravity of about 1.38 (ASTM D792), an ultimate tensile tensile (psi) of about 8300 (ASTM D412), an ultimate elongation (%) of about 400 (D412); a tensile modulus (psi) of about 560 at 100% elongation, about 1300 at 200% elongation, and about 3400 at 300% elongation (ASTM D412); a flexural modulus (psi) of about 1800, a Vicat temperature (°C) of about 55, and a mold shrinkage (in / in) of about 0.011 (1" x 0.25" x 6" bar) (ASTM D955).

[0175] It will be appreciated 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 A hardness of about 79A (ASTM D785), a specific gravity of about 1.03 (ASTM D792), an ultimate tensile (psi) of about 2000 (ASTM D412), an ultimate elongation (%) of about 530 (ASTM D412), a tensile modulus (psi) of about 730 at 100% elongation, about 1000 at 200% elongation, and about 1300 at 300% elongation (ASTM D412); a flexural modulus (psi) of about 2500 (ASTM 790); a Vicat softening point (° C.) of about 75; and a mold shrinkage (in / in) of about 0.08 (1" x 0.25" x 6" bar) (ASTM D955). AR-75A-B20 is AR-75A filled with 20% BaSO4 and can be manufactured, for example, by Compounding Solutions.

[0176] It should be further understood that the above test results for Lubrizol Tecophilic HP, Tecoflex, Aromatic Carbothane AC, and Tecothane Soft materials were approximated based on small samples of TPU; therefore, the properties of these materials may exhibit slight differences from those listed herein.

[0177] In one aspect, as Figure 1As shown in , a drug delivery system 100 is provided, which includes a tubular housing having a drug reservoir lumen 106 defined by a wall structure 104, wherein (i) at least a portion of the wall structure 104 is water-permeable, and (ii) at least a portion of the wall structure is permeable to a drug (contained in a drug unit 108) such that the drug can be released in vivo by diffusion through the drug-permeable portion of the wall structure 104. In certain embodiments, as discussed in further detail below, the wall structure includes a first wall structure and a second wall structure that together form the housing. As used herein, the phrase "diffusion through the drug-permeable portion" (e.g., through the "second wall structure") refers to the release of a drug by molecular diffusion through the material forming the wall, rather than by passing through a hole or open structure extending through the wall.

[0178] In one aspect, as Figure 2 As shown in FIG, a drug delivery system 200 is provided that includes a housing having a first wall structure 206 formed of a first material and a second wall structure 205 formed of a second material, the first wall structure and the second wall structure being adjacent to each other and together forming 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 the drug and the second wall structure 205 is permeable to the drug, such that the drug can be released in vivo by diffusion through the second wall structure 205. As used herein, the term "impermeable to the drug" means that the wall is substantially impermeable to dissolved drug, such that no substantial amount of dissolved drug can diffuse through the wall during treatment when the system is in vivo.

[0179] In certain embodiments, the tube is cylindrical or another suitable shape or design. As used herein, the term "cylindrical" when used to refer to a tubular housing refers to a housing having a substantially cylindrical outer wall. In some embodiments, the system is "closed" and therefore does not include pores; drug release occurs solely by diffusion through the second wall structure.

[0180] In some embodiments, as Figure 2 and Figure 3 As shown in FIG, 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 can be formed in a co-extrusion or 3D printing process so that the first wall structure and the second wall structure are integrally formed. In one embodiment, the co-extruded first and second wall structures are thermoplastic polymers having desired properties.

[0181] like Figure 3As shown in FIG, first wall structure 306 and second wall structure 305 together form a cylindrical tube having a lumen 308 in which the drug formulation is contained. Second wall structure 305 is in the form of a longitudinal strip extending along at least a portion of the length of first wall structure 306 and is permeable to the drug, while first wall structure 306 is impermeable to the drug. In certain embodiments, multiple drug permeable strips can be used in a single system. In certain embodiments, one permeable strip can be used in a single system. Therefore, the size, shape, thickness, and material properties of the second wall structure can be selected to achieve a desired drug release rate.

[0182] In a preferred embodiment, as discussed in further detail below, the system is capable of elastically deforming between a low-profile deployment shape (e.g., a relatively straight shape) suitable for insertion through the patient's urethra and into the patient's bladder, and a relatively expanded retention shape (e.g., a pretzel shape, a bi-oval curled shape, an S-shape, etc.) suitable for retention within the bladder.

[0183] In some embodiments, as Figures 7A-7C As shown in , the system also includes a retention frame lumen 734. In certain embodiments, the retention frame lumen includes an elastic wire, such as a nitinol wire. In certain other embodiments, the retention frame lumen is filled with a shape-setting elastic polymer.

[0184] In other embodiments, Figure 11-Figure 3 and Figure 8 As shown in , the system does not include a retention frame lumen or a retention frame or wire. Instead, the material of the shell is configured to be able to elastically deform between a straight shape and a retention shape in the absence of a retention frame or wire. In certain embodiments, the tubular shell is heat-set to have a curled or other retention shape. Therefore, in such embodiments, the design and manufacture of the system is simplified, and the overall size of the system is minimized (or if the size of the system remains constant, the drug payload can be increased). In embodiments without a retention frame, the tubular shell material serves the following functions: (i) forming a drug reservoir lumen, (ii) controlling drug release, and (iii) keeping the system in the bladder during deployment.

[0185] In one embodiment, Figures 7A-7C, a drug delivery system 700 is provided that includes an elongated elastomeric housing 702 having a drug reservoir lumen 704 extending between a first end 706 and a second end 708. The elastomeric housing 702 is formed of a tubular wall structure 710 that includes a first wall structure 716 and a second wall structure 724 that are adjacent to each other and together form a tube that defines the drug reservoir lumen 704, wherein (i) the second wall structure 724 or both the first wall structure 716 and the second wall structure 724 are permeable to water, and (ii) the first wall structure 716 is impermeable to the drug and the second wall structure 724 is permeable to the drug, such that the drug can be released in vivo by diffusion through the second wall structure 724.

[0186] In embodiments where the first and second wall structures together form a cylindrical tube, any suitable end plugs or closures or heat-formed seals may be used to seal the ends of the tube after the drug has been loaded. These end plugs / closures ensure that the drug-permeable polymer portion forming part of the outer tube is the only path for drug release.

[0187] In some embodiments, as Figure 2 and Figure 3 As shown in FIG, 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 and second wall structures 206, 205 / 306, 305 (which together form a cylindrical tube) are the same. In other embodiments, the walls may have a varying thickness around the circumference of the wall.

[0188] Thus, for the systems described herein, drug release is controlled by diffusion of the drug through a drug permeable component that defines a portion of the system housing. The drug permeable wall structure can be positioned, sized, and have material properties to provide a desired rate of controlled diffusion of the drug from the system.

[0189] The specific materials and arc angles of the drug permeable portion or wall structure can be selected to achieve a specific drug release profile, i.e., water and drug permeation rates. As used herein, the phrase "arc angle" refers to the angular dimension of the arc of the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube.

[0190] For example, in certain embodiments, Figure 2 and Figure 3As shown in , the second wall structure 205 / 305 occupies less than 90% of the cross-sectional area of ​​the tube in a cross section perpendicular to the longitudinal axis of the tube. In one embodiment, the second wall structure occupies less than 50% of the cross-sectional area of ​​the tube in a cross section perpendicular to the longitudinal axis of the tube. In one embodiment, the second wall structure occupies less than 25% of the cross-sectional area of ​​the tube in a cross section perpendicular to the longitudinal axis of the tube.

[0191] In certain embodiments, such as Figure 2 、 Figure 3 、 Figures 7A-7C and Figure 8 As shown in , a first wall structure and a second wall structure forming a tube defining a drug reservoir lumen are adjacent to each other at two interface edges, such that the wall structures together form a tube defining the drug reservoir lumen. In these embodiments, the two interface edges are arranged at an arc angle of about 15 degrees to about 270 degrees of the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube. As used herein, the phrase "about" with respect to the arc angle of the second wall structure refers to an arc angle of plus or minus 3 degrees.

[0192] In one embodiment, Figure 2 As shown in FIG, the second wall structure 205 has an arc angle 214 of about 60 degrees of the circumference of the cylindrical tube 200 in cross section. In one embodiment, as shown in FIG. Figure 3 , the second wall structure 305 has an arc angle 314 of about 30 degrees of the circumference of the cylindrical tube 300 in a 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 (such as about 45 degrees, about 90 degrees, about 180 degrees and about 240 degrees). In certain embodiments, the second wall structure has an arc angle of about 45 degrees, about 90 degrees, about 180 degrees, about 240 degrees or about 270 degrees.

[0193] When the system is formed to have Figure 1 When the shape is maintained as shown in , the second wall structure can be located on the inner curvature (0 degrees), the outer curvature (180 degrees), the top (90 degrees), or therebetween. The top (90 degrees) position may be preferred when the second wall structure is formed of a material that expands significantly after absorbing water.

[0194] Therefore, tubular systems have been developed that are designed to reduce or control drug release rates without negatively altering mechanical properties and the appropriate size and tolerance for system deployment. In some embodiments, this design reduces drug release rates by reducing the length of the drug-permeable zone so that it extends along only a portion of the system's total length. Consequently, a larger drug-permeable zone arc angle can be employed to tailor the rate of drug release from the system. Furthermore, by reducing the length of the drug-permeable zone, a smaller amount of drug-permeable material can be used to achieve the reduced drug release rate compared to conventional systems.

[0195] Once the drug is loaded into the drug reservoir lumen, any suitable end plug or closure or heat-formed seal may be used to seal / close the first and second ends of the drug reservoir lumen. These end plugs / closures ensure that the second material forming part of the elastomeric shell is the only path for drug release. In certain embodiments, the end plugs are formed from a first material (i.e., the material forming the first wall structure) that is impermeable to the drug.

[0196] In the aforementioned embodiments, the first material or the first wall structure, the second material or the first wall structure, or both are formed of a water-permeable material. In a preferred embodiment, as described above for the solid formulation of Erdafitinib, the drug is in solid form (e.g., one tablet or multiple tablets), and at least a portion of the tubular body is water-permeable to allow the drug to dissolve in vivo when in the drug reservoir lumen. In an embodiment, the first material or the first wall structure may be the only water-permeable portion. In other embodiments, both the first material / wall structure and the second material / wall structure may be water-permeable.

[0197] The material for the wall structure of the system of the present invention 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., the material that is impermeable to the drug contained in the drug reservoir) can be a polycarbonate-based aromatic thermoplastic polyurethane (e.g., CARBOTHANE TM TPU, such as AC-4075A, commercially available from Lubrizol) or thermoplastic polyurethanes based on aromatic polyester hydrocarbons (e.g., TECOTHANE TM TPU, such as AR-75A, is commercially available from Lubrizol. For example, CARBOTHANE polyurethane is a cycloaliphatic polymer and is of the type produced from polycarbonate-based polyols. The general structure of the polyol segment is represented by O--[(CH2)6--CO3] n--(CH2)--O--. AC-4075A has a Shore durometer hardness of 77A, a specific gravity of 1.19, a flexural modulus of 1500 psi, and an ultimate elongation of 400%. AR-75A has a Shore durometer hardness of 79A, a specific gravity of 1.03, a flexural modulus of 2500 psi, and an ultimate elongation of 530%. In particular, the second material forming the second wall structure (i.e., the material permeable to the drug contained in the drug reservoir) can be a thermoplastic polyurethane based on an aliphatic polyether (e.g., TECOFLEX TM TPU, such as EG-80A, is commercially available from Lubrizol. For example, TECOFLEX polyurethane is a cycloaliphatic polymer and is of the type produced from polyether-based polyols. The general structure of a polyol segment is represented by O--(CH2--CH2--CH2--CH2) x --O--. EG-80A has a Shore durometer hardness of 72A, a specific gravity of 1.04, a flexural modulus of 1000 psi, and an ultimate elongation of 660%. The TPU may also include 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 loading.

[0198] In one embodiment, the inner diameter of the cylindrical tube can be from about 1.0 mm to about 2.5 mm. In one embodiment, the outer diameter of the cylindrical tube is from about 2.0 mm to about 4.1 mm. In one embodiment, the thickness of the first wall structure, the second wall structure, or both is from about 0.2 mm to about 1.0 mm.

[0199] Therefore, compared with the drug delivery system that utilizes homogeneous material (for example, permeable and impermeable thermoplastic material blend) to form drug permeable tube, the mechanical properties of the tube utilizing double-wall structure (for example, drug permeable strip embodiment) can be unrelated to the drug release (for example, diffusion) characteristics of tube.For example, in a single material tube, changing the material of the tube inherently affects both the mechanical properties and diffusion characteristics of the system. Being able to control the release rate with the strip angle can have the additional benefit of not changing the outer diameter of the system; By contrast, controlling by changing the wall thickness may become too large to be suitable for passing through the urethra, or too thin to provide the mechanical strength required for the system. In addition, the drug release characteristics of the blended polymer may not be easy to predict. In addition, when mixing two thermoplastics, obtaining a truly homogeneous blend is generally challenging. Therefore, in the case of such a tubular drug delivery system, experiments are needed to regulate the drug release rate. By contrast, the double-wall structure described herein can provide enhanced flexibility in terms of the release rate of a custom specific drug from a delivery system.

[0200] For use in the bladder, it is important that the system be compliant (i.e., bend easily, feel soft) during detrusor contraction in order to avoid or reduce discomfort and irritation to the patient. Therefore, it is worth noting that the durometer of the first and second materials of construction is important, and the proportion of high durometer materials can be limited in the process of constructing a system housing of a given size while maintaining its proper compliance in the bladder. For example, a suitable first wall material (such as TECOTHANE or CARBOTHANE) may have a Shore durometer greater than 70A (such as 77A to 65D), while a suitable second wall material (such as TECOFLEX) may have a Shore durometer less than 90A or less than 80A (such as 72A). In some embodiments, the first material has a Shore durometer value of 70A to 80A, while the second material has a Shore durometer value of 70A to 75A. Thus, in certain embodiments, the second wall material has a Shore durometer less than the Shore durometer of the first wall material, with both wall materials having a Shore durometer value of less than 80A. Therefore, rather than making the system housing entirely of a second water-swellable, hydrophilic, drug-permeable material, it may be advantageous to utilize a combination of two different polymeric materials to achieve the desired mechanical properties of the tubing.

[0201] In embodiments, system as herein described is configured to release the medicine of therapeutically effective amount, wherein the medicine is zero order from the rate of release of drug delivery system in at least 36 hours.In one embodiment, the medicine is zero order substantially from the rate of release of drug delivery system in at least 7 days.In embodiments, system is configured to release the medicine of therapeutically effective amount in the time period of 2 days to 6 months (for example, 2 days to 90 days, 7 days to 30 days or 7 days to 14 days).Ideally, the medicine is zero order from the rate of release of drug delivery system in at least 7 days (for example, 7 to 14 days) or longer time (such as reaching 3 months or 90 days).In certain embodiments, system is configured to start releasing medicine after lag time.In certain embodiments, lag time can be at least about 30 minutes, about 12 hours to about 24 hours or reach about 2 days.These systems can effectively release the medicine of therapeutically effective amount for 6 months or for 3 months (90 days) time period.

[0202] As will be discussed in more detail below, a drug formulation (such as those described throughout the present disclosure) is disposed in a drug reservoir lumen defined by the first and second wall structures. In particularly preferred embodiments, the drug is an erdafitinib-based drug 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 according to the desired treatment regimen. In some embodiments, the system is configured to release erdafitinib at an average rate of 1 mg / day to 2 mg / day. In such embodiments, the two interface edges can be arranged at an arc angle of 45 degrees to 90 degrees. In some embodiments, the system is configured to release erdafitinib at an average rate of 4 mg / day to 6 mg / day. In such embodiments, the two interface edges can be arranged at an arc angle of 150 degrees to 270 degrees.

[0203] In one embodiment, the system is configured to release erdafitinib at an average rate of 1 mg / day, and the two interface edges are 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, and the two interface edges are arranged at an arc angle of approximately 90 degrees. In another embodiment, the system is configured to release erdafitinib at an average rate of 4 mg / day, and the two interface edges are 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, and the two interface edges are arranged at an arc angle of 240 degrees. In certain embodiments, the drug release profile is substantially independent of pH within the pH range of 5 to 7. In certain embodiments, the drug release profile is substantially independent of pH within the pH range of 5.5 to 7. In certain embodiments, the drug release profile is substantially independent of pH within the pH range of 5.5 to 8. In certain embodiments, the release rate is maintained for a period of up to 6 months (particularly up to 3 months or 90 days).

[0204] In some embodiments, the system is configured to release erdafitinib at a rate of about 2 mg / day or about 4 mg / day. In some embodiments, the system comprises two interface edges disposed at an angle of about 90 degrees to about 180 degrees. In some embodiments, the system is configured to release erdafitinib at an average rate of about 2 mg / day to about 4 mg / day, and the two interface edges are disposed at an arc angle of about 90 degrees to about 180 degrees.

[0205] In one embodiment, a drug delivery system is provided having (i) a housing defining a drug reservoir lumen and a retaining frame lumen, (ii) a plurality of tablets comprising erdafitinib disposed in the drug reservoir lumen, and (iii) a nitinol wire form (retaining frame) disposed in the retaining frame lumen. The drug reservoir lumen is defined / delimited by a first wall structure (base) formed of a first material, a thermoplastic polyurethane based on an aromatic polyester hydrocarbon (particularly AC-4075A-B20), and a second wall structure (strip), the first wall structure being formed of a second material, the second material being made of a thermoplastic polyurethane based on an aliphatic polyether (particularly EG-80A), wherein the first wall structure and the second wall structure are adjacent to each other at two interface edges and together form a tube defining a closed drug reservoir lumen. In one embodiment, the closed drug reservoir lumen contains a plurality of tablets, particularly a plurality of miniature tablets, particularly erdafitinib miniature tablets as described herein. In one embodiment, the amount of erdafitinib in the drug reservoir lumen is about 500 mg. In one embodiment, the drug reservoir lumen contains about 44 erdafitinib mini-tablets, in particular erdafitinib tablets as described herein. In one embodiment, the plurality of tablets consists of 44 mini-tablets, having a total of about 500 mg of erdafitinib. In one embodiment, the strip angle is 90 degrees, and the average release rate of erdafitinib from the system is about 2 mg / day. In one embodiment, the strip angle is 180 degrees, and the average release rate of erdafitinib from the system is about 4 mg / day. In one embodiment, the strip angle is 210 to 270 degrees, and the average release rate of erdafitinib from the system is about 6 mg / day. In one embodiment, the strip angle is 45 degrees, and the average release rate of erdafitinib from the system is about 1 mg / day. In one embodiment, the strip angle is 90 degrees, and the average release rate of erdafitinib from the system is about 2 mg / day. In one embodiment, the strip angle is 90 degrees, and the average release rate of erdafitinib from the system is about 2 mg / day at a pH between about 5 and about 6.8, and about 1 mg / day at a pH of about 8. In one embodiment, the strip angle is 180 degrees, and the average release rate of erdafitinib from the system is about 4 mg / day. In one embodiment, the strip angle is 180 degrees, and the average release rate of erdafitinib from the system is about 4 mg / day at a pH between about 5 and about 6.8, and about 2 mg / day at a pH of about 8. In one embodiment, the strip angle is 210 to 270 degrees, particularly 270 degrees, and the average release rate of erdafitinib from the system is about 6 mg / day.In one embodiment, the strip angle is 210 to 270 degrees, particularly 270 degrees, and the average release rate of erdafitinib from the system is about 6 mg / day at a pH between about 5 and about 6.8, and about 3 mg / day at a pH of about 8. In one embodiment, the strip angle is 45 degrees, and the average release rate of erdafitinib from the system is about 1 mg / day. In one embodiment, the strip angle is 45 degrees, and the average release rate of erdafitinib from the system is about 1 mg / day at a pH between about 5 and about 6.8, and about 0.5 mg / day at a pH of about 8. In one embodiment, the tablet has a formulation 4D as described herein. In one embodiment, the tablet has a formulation 4C as described herein. In one embodiment, the tablet has a formulation 4B as described herein. In one embodiment, the tablet has a formulation 4A as described herein.

[0206] Other aspects of drug delivery systems

[0207] In certain embodiments, the system is configured for intravesical insertion and retention within a patient. For example, the system can be in a relatively low-profile (e.g., straight) shape (such as a Figure 7A-7B ) and a relatively expanded retention shape (such as Figure 1 、 Figure 4 、 Figure 5 and Figure 6A The relatively expanded shape may include a pair of overlapping curls, sometimes referred to as a "German loaf" shape. In specific embodiments, the ends of the elongated system are generally located within the boundaries of the biovoid shape.

[0208] For example, when in an expanded, retained shape after deployment in the bladder, the system can resist excretion in response to urination or other forces. After drug release, the system can be removed, for example, by cystoscope and forceps, or can be bioerodible (at least partially) to avoid a retrieval procedure.

[0209] The system can be loaded with at least one drug in the form of one or more drug units, such as tablets described throughout the present disclosure. Solid drug composition forms (such as tablets) can provide a relatively large drug payload volume relative to the total system volume, and potentially enhance the stability of the drug during transportation, storage, before use, or before drug release. However, solid drugs may need to be soluble in the body so that they can diffuse through the drug permeable components and enter the patient's surrounding tissue or cavity with a therapeutically effective amount. The drug reservoir lumen can accommodate several disclosed drug tablets in an end-to-end series arrangement in an elongated form. In some embodiments, the system accommodates approximately 10 to 100 cylindrical drug tablets (for example, 44 tablets), such as mini tablets, which can be continuously loaded in the drug reservoir lumen. In one aspect, tablets are those as described herein. In one aspect, tablets are those of formula 4A. In one aspect, tablets are those of formula 4B. In one aspect, tablets are those of formula 4C. In one aspect, tablets are those of formula 4D.

[0210] The system can be inserted into the patient's body using a cystoscope or a catheter or any other suitable or customized insertion 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 an embodiment, a cystoscope can have a working channel with a larger inner diameter (such as an inner diameter of 4 mm or larger). Therefore, the size of the system can be relatively small. For example, when the system is elastically deformed into a relatively straight shape, the system for adult patients can have a total outer diameter less than about 2.6 mm (such as between about 2.0 mm and about 2.4 mm). In addition to allowing insertion, a relatively small-sized system can also reduce the patient's discomfort and trauma to the bladder. In one embodiment, the overall structure of the system improves the in vivo tolerance for most patients. In a specific embodiment, the system is configured to have tolerance based on the bladder characteristics and design considerations described in U.S. Patent No. 11,065,426.

[0211] In the three-dimensional space occupied by the shape-maintaining system, the maximum dimension of the system in any direction is preferably less than 10 cm, i.e., the approximate diameter of the bladder when filled. In some embodiments, the maximum dimension of the system in any direction can be less than about 9 cm, such as 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 a specific embodiment, the maximum dimension of the system in any direction is less than about 7 cm, such as about 6 cm, 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 cm or less. In a preferred embodiment, the maximum dimension of the system in any direction is less than about 6 cm, such as 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 limited by three perpendicular directions. Along one of these directions, the system has its maximum dimension, and along two other directions, the system can have a smaller size. For example, the smaller size in the two other directions can be less than about 4 cm, such as about 3.5 cm, 3 cm, 2.5 cm or less. In a preferred embodiment, the system has a dimension of less than 3 cm in at least one of these directions.

[0212] In some embodiments, the system can have different dimensions in at least two of the three directions, and in some cases different dimensions in each of the three directions, such that the system is non-uniform in shape. Due to the non-uniform shape, the system may be able to achieve an orientation that reduces compression in an empty bladder, which is also non-uniform in shape. In other words, a specific orientation of the system in an empty bladder can allow the system to exert less contact pressure on the bladder wall, making the system more tolerable for the patient.

[0213] The overall shape of the system can enable the system to reorient itself within the bladder to reduce its engagement or contact with the bladder wall. For example, the overall external shape of the system can be curved, and all or most of the external or exposed surfaces of the system can be substantially rounded. The system can also be substantially free of sharp edges, and its external surfaces can be formed from a material that experiences reduced frictional engagement with the bladder wall. This configuration can enable the system to reposition itself within an empty bladder so that the system applies less contact pressure to the bladder wall. In other words, the system can slide or roll against the bladder wall to a lower energy position, meaning a position where the system experiences less compression.

[0214] In one embodiment, even if the system occupies three-dimensional space, the shape of the system is generally planar. Such a system can define a minor axis and a major axis, and the system is substantially symmetrical about the minor axis, and the major axis is substantially perpendicular to the minor axis. The system can have a maximum dimension of no more than about 6 cm and less than 5 cm (such as about 4.5 cm, about 4 cm, about 3.5 cm, about 3 cm or less) in the major axis direction. The system can have a maximum dimension of no more than about 4.5 cm and less than 4 cm (such as about 3.5 cm, about 3 cm or less) in the minor axis direction. The system is substantially curved around its entire periphery in both the main cross-sectional plane and the secondary cross-sectional plane. In other words, the overall external shape of the system is curved, and the cross-sectional shape of the system is circular. Therefore, the system has substantially no edges, except for the edges on the two flat ends, which are fully protected inside the system when the system is located in a plane. These characteristics enable the system to redirect itself to a position where compression is reduced when the bladder is in an empty state.

[0215] The system can also be small enough to allow movement within the bladder when in a retained shape. In particular, the system can be small enough to move within the bladder when deployed, such as moving freely or unimpeded throughout the bladder under most conditions when the bladder is full, thereby promoting patient tolerance of the system. The free movement of the system also promotes uniform drug delivery throughout the bladder.

[0216] The system can also be configured to promote buoyancy, such as by using low-density materials of construction for housing components and / or by incorporating a gas or gas-generating material into the housing, as described, for example, in U.S. Patent No. 9,457,176. Typically, the system in a dry and drug-loaded state can have a density in the range of about 0.5 g / mL to about 1.5 g / mL (such as between about 0.7 g / mL to about 1.3 g / mL). In some embodiments, the system in a dry and drug-loaded state has a density of less than 1 g / mL.

[0217] In one embodiment, the intravesical drug delivery system is non-bioerodible. In another embodiment, the intravesical drug delivery system can be made fully or partially bioerodible so that the system does not need to be removed or retrieved after the drug formulation is released. In some embodiments, the system is partially bioerodible so that the system breaks into non-erodible pieces small enough to be excreted from the bladder when partially eroded. For example, the systems described herein can be designed to conform to the characteristics of those systems described in U.S. Patent No. 8,690,840.

[0218] The drug delivery system is sterilized before being inserted into the patient. In one embodiment, the system is sterilized using a suitable method, such as gamma irradiation or ethylene oxide sterilization, but other sterilization methods may also be used.

[0219] System as described herein may include radiopaque parts or structures to facilitate the medical practitioner to detect or observe (e.g., by X-ray imaging or fluoroscopy) the system when implanting or retrieving a part of a procedure. In one embodiment, the shell is made of following material, and this material includes radiopaque filler material, such as barium sulfate or another radiopaque material known in the art. Some shells can be made radiopaque by blending radiopaque fillers (such as barium sulfate or another suitable material) during the processing of the material forming the shell. In those embodiments comprising a retaining frame, the radiopaque material can be associated with the retaining frame. Ultrasound imaging or fluoroscopy can be used for imaging the system in vivo.

[0220] In some embodiments, the device components of the system include a drug-impermeable base material and a drug-permeable strip material, and the base material is TPU with 20% BaSO4 filler, such as Lubrizol's Carbothane TM AC-4075A-B20 or Tecothane TM AR-75A-B20. (Lubrizol Life Science (Bethlehem, PA)).

[0221] The drug delivery system may also include a retrieval feature, such as a string, loop, or other structure that facilitates removal of the system from the patient. In one embodiment, the system can be removed from the bladder by engaging the string to pull the system through the urethra. When the system is pulled into the lumen of a catheter or cystoscope or into the urethra by the retrieval feature, the system can be configured to assume a relatively narrow or linear shape.

[0222] Maintenance of the system in the body cavity

[0223] The systems described herein can be elastically deformed between a relatively low profile (e.g., straightened or expanded) shape suitable for inserting a patient's bladder (or other body cavity) through a lumen and a relatively expanded retention shape suitable for maintaining the system in the bladder (or other body cavity). In certain embodiments, the drug delivery system can naturally present a retention shape and can be deformed into a relatively straight shape to be inserted into the body manually or with the aid of an external device. Once deployed, the system can spontaneously or naturally return to the initial retention shape to remain in the body.

[0224] For purposes of this disclosure, the terms "retaining shape," "relatively expanded shape," and the like generally refer to any shape suitable for retaining the system in the intended implanted position, including but not limited to shapes such as Figure 1 and Figure 4 Similarly, the terms "deployed shape," "relatively low-profile shape," "relatively straight shape," and the like generally refer to any shape suitable for deploying a drug delivery system into the body, including but not limited to shapes such as Figure 7A-7B , which is suitable for deploying the system through a working channel of a catheter, cystoscope, or other deployment instrument positioned in a body cavity, such as the urethra. For example, the housing or tube of the system may have two opposing free ends that are directed away from each other when the system is in the low-profile deployed shape and directed toward each other when the system is in the relatively expanded retention shape.

[0225] In some embodiments, as Figures 7A-7C As shown in FIG, the system further includes a retention frame lumen 734 and a retention frame (not shown) positioned within the retention frame lumen. For example, the retention frame lumen and retention frame may be as described in U.S. Application Publication No. 2010 / 0331770; U.S. Application Publication No. 2010 / 0060309; U.S. Application Publication No. 2011 / 0202036; and U.S. Application Publication No. 2011 / 0152839, which are incorporated herein by reference. For example, the retention frame lumen may be sealed with a suitable plug or adhesive material (such as a silicone adhesive material).

[0226] Figure 4 The system 300 is shown loaded with a drug tablet 108 in the drug reservoir lumen of the system housing 304. Figure 5 As can be seen in FIG, prior to tablet loading, the retention frame 305 urges the system housing 304 into a different, expanded shape than the retained shape achieved when the system is loaded with the medication tablet 108.

[0227] In certain embodiments where increased payload is desired, additional lengths of drug reservoir lumen / tubing may be provided. In one embodiment, as Figure 6A-6B As shown in , the retention frame has a periphery defined by two overlapping portions (curls) of nitinol wire. Each end portion of the wire points 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 in a circular end cap. In contrast, in Figure 5 In the system shown in , the retaining frame has an outer periphery defined by a single curl. Figure 6A-6B The system of holding the frame enables the Figure 5A relatively longer drug reservoir (eg, to accommodate more tablets) is implemented in a system having the same "footprint" (peripheral shape and size) as the system shown in FIG.

[0228] In other embodiments, Figure 1-Figure 3 As shown in , the system does not include a retention frame lumen or a retention frame or wire. Instead, the material of the housing is configured to be able to elastically deform between a straightened shape and a retained shape in the absence of a retention frame or wire. Thus, in such embodiments, the design and manufacture of the system is simplified, and the overall size of the system is minimized (or the drug payload can be increased while the size of the system remains constant). In embodiments without a retention frame, the tubular housing material serves the following functions: (i) forming a drug reservoir lumen, (ii) controlling drug release, and (iii) retaining the system in the bladder during deployment.

[0229] In some embodiments, the drug delivery system comprises a tubular housing having a closed drug reservoir lumen defined by a wall structure comprising at least one thermoplastic material, wherein at least a portion of (i) the wall structure is water-permeable and at least a portion of the wall structure is drug-permeable, (ii) the tubular housing can be elastically deformed from the holding shape suitable for maintaining the system in the bladder to a relatively straight shape suitable for being inserted into the bladder through the lumen, and (iii) the tubular wall is thermoformed to have the holding shape.

[0230] In certain embodiments, the first wall structure and the second wall structure are each thermoplastic polyurethane, and the tubular housing is thermoformed to have a shape-retaining structure. In one embodiment, the tubular wall has a spring constant that effectively prevents the system from assuming a relatively straight shape once implanted in the bladder. Thus, the properties of the tubular wall can cause the system to act like a spring, deforming in response to a compressive load but spontaneously returning to its original shape once the load is removed.

[0231] In certain embodiments, the system can naturally present a holding shape, be deformable into a relatively straight shape, and can spontaneously return to the holding shape when inserted into the body. The tubular wall structure in the holding shape can be shaped to be held in a body cavity, and the tubular wall structure in the relatively straight shape can be shaped to be inserted into the body by the working channel of a deployment instrument (such as a catheter or a cystoscope). In order to achieve such a result, the tubular wall structure can have an elastic limit, a modulus and / or a spring constant that is selected to prevent the system from presenting a relatively low profile shape once implanted. This construction can limit or prevent the system from being accidentally discharged from the body under the expected force. For example, the system can remain in the bladder during urination or detrusor contraction.

[0232] In a preferred embodiment, the system is capable of elastically deforming between a relatively straight shape suitable for insertion through a catheter or cystoscope extending through the patient's urethra and a curved or curled shape suitable for retaining the system within the bladder (i.e., preventing it from being expelled from the bladder during urination) after the system is released from the end of the catheter or cystoscope.

[0233] like Figure 1 As shown in , the retaining shape may include a curled or "Grunge" shape. The Grunge shape essentially includes at least two sub-circles, each with its own smaller arch and sharing a common larger arch. When the Grunge shape is first compressed, the larger arch absorbs most of the compression force and begins to deform, but as the compression continues, the smaller arches overlap, and subsequently, all three arches resist the compression force. Once the two sub-circles overlap, the system as a whole increases its resistance to compression, thereby preventing the system from collapsing and draining when the bladder contracts during urination.

[0234] The wall structure in the retaining shape can have a two-dimensional structure confined to a plane; a three-dimensional structure, such as a structure occupying the interior of a spheroid; or some combination thereof. The retaining shape can include one or more rings, curls, or sub-circles that are connected linearly or radially, rotate in the same or alternating directions, and overlap or do not overlap. The retaining shape can include one or more circles or ellipses arranged in a two-dimensional or three-dimensional configuration, which can be closed or open, have the same or different dimensions, overlap or do not overlap, and are connected together at one or more connection points. The retaining shape can also be a three-dimensional structure shaped to occupy or wrap around a spheroid-shaped space, such as a spherical space, a space with a prorate spheroid shape, or a space with an oblate spheroid shape. The wall structure in the retaining shape can be shaped to occupy or wrap around a spherical space. The wall structure in the retaining shape can generally take the shape of two intersecting circles located in different planes, two intersecting circles located in different planes with inwardly curled ends, three intersecting circles located in different planes, or a spherical spiral. In each of these examples, the wall structure can be stretched into a linear shape for deployment by a deployment instrument.The wall structure can be wound around or through a spherical or other spheroid-shaped space in a variety of other ways.

[0235] Drug delivery systems utilizing thermoformed coextruded tubing with drug-permeable and drug-impermeable portions can integrate three functional components (drug reservoir / housing, drug-permeable pathway, and retention features) into a single thermoformed coextruded tubing component, which can simplify system design and the ability to control drug release rate. As discussed herein, in such systems, drug release rate can be relatively easily varied by controlling the angle and thickness of the drug-permeable portion (e.g., stripe) without changing the entire tubing housing material.

[0236] The thermoformed coextruded tubular housing can be loaded with drug tablets and both ends can be heat sealed or sealed with an adhesive (such as with the first wall material). If local tube cross-section deformation or tube kinking occurs, tablet loading will be difficult. Therefore, when the tube is thermoformed, the tube size should be selected to prevent kinking. The critical bending curvature radius (R) of the elastic tube under pure bending conditions is * ) can be estimated using the following formula:

[0237]

[0238] Where v is the Poisson's ratio, r is the mean radius (i.e., (ID + OD) / 4), w is the tube wall thickness, ID is the tube inner diameter, and OD is the tube outer diameter. For polyurethane, a Poisson's ratio v of 0.49 yields an estimated critical radius of 0.5 cm. Thus, in some embodiments, when thermoforming polyurethane tubing, the radius of curvature should preferably be greater than 0.5 cm throughout the length of the tubing to prevent kinking. Thus, in one embodiment, the shape-retaining ring comprises at least one ring having a radius of curvature of at least 0.5 cm.

[0239] Drug tablets

[0240] As discussed herein with respect to the erdafitinib drug formulation, the drug may be provided in a solid form (e.g., a solid mini-tablet) suitable for loading into the drug reservoir lumen of the system. Figure 1 As shown in FIG, the drug formulation is formed into drug units 108, which are loaded into the drug reservoir lumen of the system 100. Each drug unit is a solid discrete object that substantially retains a selectively imparted shape under the temperature and pressure conditions to which the drug units (e.g., tablets) and delivery systems will typically be exposed during handling prior to assembly (e.g., loading into the system drug reservoir), storage, and insertion into the body.

[0241] Each drug unit can have substantially any selected shape and size suitable for use in the systems described herein. In one embodiment, the size and shape of the drug units are set so that the drug reservoir lumen in the housing is substantially filled with a selected number of drug units. Each drug unit can have a cross-sectional shape that substantially corresponds to the cross-sectional shape of the drug reservoir lumen of a particular housing. For example, the drug unit can be substantially cylindrical in shape for positioning in a substantially cylindrical drug reservoir lumen. In some embodiments, once loaded, the drug unit can substantially fill the drug reservoir lumen forming part of the drug housing.

[0242] In one embodiment, drug unit is shaped as and is arranged in a row when system is in its deployment configuration.For example, the cross-sectional shape that each drug unit has can correspond to the cross-sectional shape of the drug reservoir lumen in shell, and the end face shape that each drug unit has can correspond to the end face of adjacent drug unit.The space between drug unit or fracture can adapt to system such as deformation or movement during deployment, while allowing each drug unit to keep its solid form.Therefore, although drug delivery system is loaded with solid drug composition (such as tablet), it can still be relatively flexible or deformable, because each drug unit can be allowed to move relative to adjacent drug unit.

[0243] In embodiments where the drug unit is designed to be inserted into or implanted into a lumen or cavity (such as the bladder) within the body by a drug delivery system, the drug unit can be a "mini tablet" whose size and shape are suitable for insertion through the natural lumen (such as the urethra) of the body. 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 a substantially cylindrical side face. The diameter of the mini tablet along the end face extension is in the range of about 1.0 mm to about 3.2 mm, such as between about 1.5 mm and about 3.1 mm. The length of the mini tablet along the side extension is in the range of about 1.7 mm to about 4.8 mm, such as between about 2.0 mm and about 4.5 mm. The friability of the tablet can be less than about 2%. In one aspect, the tablet is as described herein. In one aspect, the tablet is those of formula 4A. In one aspect, the tablet is those of formula 4B. In one aspect, the tablet is those of formula 4C. In one aspect, the tablet is those of formula 4D.

[0244] Drug delivery methods

[0245] The systems and methods or uses disclosed herein can be suitable for use in humans or in veterinary or livestock applications. Thus, the term "patient" can refer to a human or other mammalian subject. In one embodiment, the patient is a human subject.

[0246] In certain embodiments, provided herein is a method for treating urothelial carcinoma (such as bladder cancer). In certain embodiments, provided herein is the use of a drug delivery system as described herein in the manufacture of a drug for treating urothelial carcinoma (such as bladder cancer). In certain embodiments, provided herein is a drug delivery system as described herein for use in treating urothelial carcinoma (such as bladder cancer). In certain embodiments, provided herein is erdafitinib used in a drug delivery system as described herein for treating urothelial carcinoma (such as bladder cancer). The method or purposes may include locally delivering or administering erdafitinib (such as in any formulation described herein) to the bladder of a patient (particularly a cancer patient) in need of treatment in an amount (e.g., as described herein, about 1 mg / day to 10 mg / day) effective for treating bladder cancer. For example, the treatment can effectively treat muscle-invasive bladder cancer (MIBC), non-muscle-invasive bladder cancer (NMIBC) and / or bacille Calmette-Guérin (BCG) juvenile bladder cancer. In one aspect, the patient (particularly mankind) is a bladder cancer or NMIBC or MIBC cancer patient experiencing BCG. In one aspect, patient (particularly mankind) is bladder cancer or NMIBC or MIBC cancer patient who does not experience BCG. In one aspect, patient (particularly mankind) is high-risk only papillary NMIBC (high-grade Ta / T1) cancer patient who is recurrent, experiences BCG (BCG), refuses or is not qualified to carry out radical cystectomy (RCy). In one aspect, patient (particularly mankind) is high-risk only papillary NMIBC (high-grade Ta / T1) cancer patient who is recurrent, experiences BCG, and plans to carry out RCy. In one aspect, patient (particularly mankind) is NMIBC (Ta and T1) cancer patient who is recurrent, intermediate risk, and it only has the past medical history of low-grade disease. In one aspect, patient (particularly mankind) is MIBC cancer patient who plans to carry out RCy, and it has refused or is not qualified to carry out the neoadjuvant chemotherapy based on cisplatin.

[0247] In a certain embodiment, a method of treating bladder cancer having one or more FGFR gene alterations is provided, the method comprising locally delivering to the bladder of a patient in need thereof an amount of erdafitinib effective to treat the bladder cancer, wherein the one or more FGFR gene alterations are detected in a urine sample from the patient, in particular wherein the one or more FGFR gene alterations are detected in a urine sample from the patient using a urine-based PCR or NGS assay. In a certain embodiment, a method of treating bladder cancer having one or more FGFR gene alterations is provided, the method comprising, consisting of, or consisting essentially of: (a) assessing a urine sample from a bladder cancer patient for the presence of the one or more FGFR gene alterations, in particular assessing a urine sample from a bladder cancer patient for the presence of the one or more FGFR gene alterations using a urine-based PCR or NGS assay; and (b) in the presence of the one or more FGFR gene alterations in the sample, locally delivering erdafitinib. In a certain embodiment, a method of treating bladder cancer having one or more FGFR gene alterations is provided, the method 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 detecting the one or more FGFR gene alterations in a urine sample from the patient, in particular wherein the patient is selected for treatment based on detecting the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR or NGS assay. In a certain embodiment, a method of treating bladder cancer having one or more FGFR gene alterations is provided, the method 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 the one or more FGFR gene alterations in a urine sample from the patient, in particular wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR or NGS assay. In a certain embodiment, erdafitinib is provided for use in treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is delivered locally to the bladder of the patient, and wherein the one or more FGFR gene alterations are detected in a urine sample from the patient, particularly wherein the one or more FGFR gene alterations are detected in a urine sample from the patient using a urine-based PCR or NGS assay.In a certain embodiment, erdafitinib is provided for use in treating bladder cancer having one or more FGFR gene alterations in a patient, the use comprising, consisting of, or consisting essentially of: (a) assessing a urine sample from a bladder cancer patient for the presence of the one or more FGFR gene alterations, particularly assessing a urine sample from a bladder cancer patient for the presence of the one or more FGFR gene alterations using a urine-based PCR or NGS assay; and (b) in the presence of the one or more FGFR gene alterations in the sample, locally delivering erdafitinib to the patient. In a certain embodiment, erdafitinib is provided for use in treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is to be locally delivered to the patient's bladder, and wherein the patient is selected for treatment based on detecting the one or more FGFR gene alterations in a urine sample from the patient, particularly wherein the patient is selected for treatment based on detecting the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR or NGS assay. In a certain embodiment, erdafitinib is provided for use in treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is to be delivered locally to the bladder of the patient, and wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient, in particular wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR or NGS assay. In a certain embodiment, use of erdafitinib in the preparation of a medicament for treating bladder cancer having one or more FGFR gene alterations in a patient is provided, wherein erdafitinib is to be delivered locally to the bladder of the patient, and wherein the one or more FGFR gene alterations are detected in a urine sample from the patient, in particular wherein the one or more FGFR gene alterations are detected in a urine sample from the patient using a urine-based PCR or NGS assay. In a certain embodiment, there is provided a use of erdafitinib in the preparation of a medicament for treating bladder cancer having one or more FGFR gene alterations in a patient, comprising, consisting of, or consisting essentially of: (a) assessing the presence of the one or more FGFR gene alterations in a urine sample from a bladder cancer patient, particularly assessing the presence of the one or more FGFR gene alterations in a urine sample from a bladder cancer patient using a urine-based PCR or NGS assay; and (b) locally delivering erdafitinib in the presence of the one or more FGFR gene alterations in the sample.In a certain embodiment, there is provided the use of erdafitinib in the preparation of a medicament for treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is to be delivered locally to the bladder of the patient, and wherein the patient is selected for treatment based on detecting the one or more FGFR gene alterations in a urine sample from the patient, in particular wherein the patient is selected for treatment based on detecting the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR or NGS assay. In a certain embodiment, there is provided the use of erdafitinib in the preparation of a medicament for treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is to be delivered locally to the bladder of the patient, and wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient, in particular wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR or NGS assay. The method or use may include locally delivering or topically administering erdafitinib (such as in any formulation described herein) to the bladder of a patient (particularly a cancer patient) in need of treatment in an amount (e.g., as described herein, about 1 mg / day to 10 mg / day) effective for treating bladder cancer. For example, the treatment is effective for treating muscle-invasive bladder cancer (MIBC), non-muscle-invasive bladder cancer (NMIBC) and / or bacillus Calmette-Guérin (BCG) juvenile bladder cancer. In one aspect, the patient (particularly human) is a bladder cancer or NMIBC or MIBC cancer patient who has undergone BCG. In one aspect, the patient (particularly human) is a bladder cancer or NMIBC or MIBC cancer patient who has not undergone BCG. In one aspect, the patient (particularly human) is a recurrent, high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient who has undergone BCG (BCG) and refuses or is not eligible for radical cystectomy (RCy). In one aspect, the patient (particularly a human being) is a high-risk papillary NMIBC (high-grade Ta / T1) cancer patient who has undergone recurrent BCG and plans to undergo RCy. In one aspect, the patient (particularly a human being) is a recurrent NMIBC (Ta and T1) cancer patient who has only a history of low-grade disease. In one aspect, the patient (particularly a human being) is a MIBC cancer patient who plans to undergo RCy and has refused or is not eligible for neoadjuvant chemotherapy based on cisplatin.

[0248] In a certain embodiment, a method of treating bladder cancer having one or more FGFR gene alterations is provided, the method comprising locally delivering erdafitinib to the bladder of a patient in need thereof in an amount effective to treat the bladder cancer, wherein the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient, in particular wherein the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient using a tissue-based PCR or NGS assay, or wherein the one or more FGFR gene alterations are detected in a histopathology image of the tumor tissue by digital histopathology analysis. In a certain embodiment, a method of treating bladder cancer having one or more FGFR gene alterations is provided, the method comprising, consisting of, or consisting essentially of: (a) assessing a tumor tissue sample from a bladder cancer patient for the presence of the one or more FGFR gene alterations, in particular assessing a tumor tissue sample from a bladder cancer patient for the presence of the one or more FGFR gene alterations using a tissue-based PCR or NGS assay, or assessing a histopathology image of a tumor tissue from a bladder cancer patient for the presence of the one or more FGFR gene alterations by digital histopathology analysis; and (b) in the presence of the one or more FGFR gene alterations in the sample, locally delivering erdafitinib. In a certain embodiment, a method of treating bladder cancer having one or more FGFR gene alterations is provided, the method 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 detecting the one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly wherein the patient is selected for treatment based on detecting the one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR or NGS assay, or wherein the patient is selected for treatment based on detecting the one or more FGFR gene alterations in a histopathological image of the tumor tissue by digital histopathological analysis. In a certain embodiment, a method of treating bladder cancer having one or more FGFR gene alterations is provided, the method 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 the one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR or NGS assay, or wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a histopathological image of the tumor tissue by digital histopathological analysis.In a certain embodiment, erdafitinib is provided for use in treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is delivered locally to the bladder of the patient, and wherein the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient, particularly wherein the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient using a tissue-based PCR or NGS assay, or wherein the one or more FGFR alterations are detected in a histopathology image of the tumor tissue by digital histopathology analysis. In a certain embodiment, erdafitinib is provided for use in treating bladder cancer having one or more FGFR gene alterations in a patient, the use comprising, consisting of, or consisting essentially of: (a) assessing the presence of the one or more FGFR gene alterations in a tumor tissue sample from the bladder cancer patient, particularly assessing the presence of the one or more FGFR gene alterations in a tumor tissue sample from the bladder cancer patient using a tissue-based PCR or NGS assay, or assessing the presence of the one or more FGFR gene alterations in a histopathology image of a tumor tissue from the bladder cancer patient by digital histopathology analysis; and (b) locally delivering erdafitinib to the patient in the presence of the one or more FGFR gene alterations in the sample. In a certain embodiment, erdafitinib is provided for use in treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is to be delivered locally to the bladder of the patient, and wherein the patient is selected for treatment based on detection of the one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly wherein the patient is selected for treatment based on detection of the one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR or NGS assay, or wherein the patient is selected for treatment based on detection of the one or more FGFR gene alterations in a histopathology image of the tumor tissue by digital histopathology analysis. In a certain embodiment, erdafitinib is provided for use in treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is to be delivered locally to the bladder of the patient, and wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR or NGS assay, or wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a histopathological image of the tumor tissue by digital histopathological analysis.In a certain embodiment, there is provided use of erdafitinib in the preparation of a medicament for treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is delivered locally to the bladder of the patient, and wherein the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient, in particular wherein the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient using a tissue-based PCR or NGS assay, or wherein the one or more FGFR alterations are detected in a histopathology image of the tumor tissue by digital histopathology analysis. In a certain embodiment, there is provided a use of erdafitinib in the preparation of a medicament for treating bladder cancer having one or more FGFR gene alterations in a patient, comprising, consisting of, or consisting essentially of: (a) assessing the presence of the one or more FGFR gene alterations in a tumor tissue sample from the bladder cancer patient, particularly assessing the presence of the one or more FGFR gene alterations in a tumor tissue sample from the bladder cancer patient using a tissue-based PCR or NGS assay, or assessing the presence of the one or more FGFR gene alterations in a histopathology image of a tumor tissue from a bladder cancer patient by digital histopathology analysis; and (b) locally delivering erdafitinib in the presence of the one or more FGFR gene alterations in the sample. In a certain embodiment, there is provided the use of erdafitinib in the preparation of a medicament for treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is to be delivered locally to the bladder of the patient, and wherein the patient is selected for treatment based on detection of the one or more FGFR gene alterations in a tumor tissue sample from the patient, in particular wherein the patient is selected for treatment based on detection of the one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR or NGS assay, or wherein the patient is selected for treatment based on detection of the one or more FGFR gene alterations in a histopathological image of the tumor tissue by digital histopathological analysis. In a certain embodiment, there is provided use of erdafitinib in the preparation of a medicament for treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is to be delivered locally to the bladder of the patient, and wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a tumor tissue sample from the patient, in particular wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a tumor tissue sample from the patient using a tissue-based PCR or NGS assay, or wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a histopathological image of the tumor tissue by digital histopathological analysis.The method or use may include locally delivering or topically administering erdafitinib (such as in any formulation described herein) to the bladder of a patient (particularly a cancer patient) in need of treatment in an amount (e.g., as described herein, about 1 mg / day to 10 mg / day) effective for treating bladder cancer. For example, the treatment is effective for treating muscle-invasive bladder cancer (MIBC), non-muscle-invasive bladder cancer (NMIBC) and / or bacillus Calmette-Guérin (BCG) juvenile bladder cancer. In one aspect, the patient (particularly human) is a bladder cancer or NMIBC or MIBC cancer patient who has undergone BCG. In one aspect, the patient (particularly human) is a bladder cancer or NMIBC or MIBC cancer patient who has not undergone BCG. In one aspect, the patient (particularly human) is a recurrent, high-risk papillary-only NMIBC (high-grade Ta / T1) cancer patient who has undergone BCG (BCG) and refuses or is not eligible for radical cystectomy (RCy). In one aspect, the patient (particularly a human being) is a high-risk papillary NMIBC (high-grade Ta / T1) cancer patient who has undergone recurrent BCG and plans to undergo RCy. In one aspect, the patient (particularly a human being) is a recurrent NMIBC (Ta and T1) cancer patient who has only a history of low-grade disease. In one aspect, the patient (particularly a human being) is a MIBC cancer patient who plans to undergo RCy and has refused or is not eligible for neoadjuvant chemotherapy based on cisplatin.

[0249] In certain embodiments, a urothelial carcinoma as described herein is susceptible to an FGFR2 gene alteration and / or an FGFR3 gene alteration.

[0250] As used herein, "FGFR gene alteration" refers to the change of wild-type FGFR gene, including but not limited to FGFR fusion gene, FGFR mutation, FGFR amplification or any combination thereof, particularly FGFR fusion gene, FGFR mutation or any combination thereof. In certain embodiments, FGFR2 or FGFR3 gene alteration is FGFR gene fusion. "FGFR fusion" or "FGFR gene fusion" refers to a gene encoding a portion of FGFR (e.g., FGRF2 or FGFR3) and one of or a portion of a fusion partner disclosed herein, which 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 biological sample from a patient can be determined using the disclosed methods or uses or by methods known to those of ordinary skill in the art: FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7 or any combination thereof. In certain embodiments, FGFR3-TACC3 is FGFR3-TACC3 variant 1 (FGFR3-TACC3 V1) or FGFR3-TACC3 variant 3 (FGFR3-TACC3 V3). Table A provides FGFR fusion genes and fused FGFR and fusion partner exons. The sequences of each FGFR fusion gene are disclosed in Table A2. The underlined sequences correspond to FGFR3 or FGFR2, and the sequences represent the fusion partners.

[0251] Table A

[0252] fusion gene FGFR exons Partner exon FGFR2 FGFR2-BICC1 19 3 FGFR2-CASP7 19 4 FGFR3 FGFR3-BAIAP2L1 18 2 FGFR3-TACC3 V1 18 11 FGFR3-TACC3 V3 18 10

[0253] Table A2

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262] FGFR gene changes include FGFR single nucleotide polymorphisms (SNPs). "FGFR single nucleotide polymorphism" (SNP) refers to FGFR2 or FGFR3 genes, and wherein single nucleotides are different between individuals. In certain embodiments, FGFR2 or FGFR3 gene changes are FGFR3 gene mutations. Especially, "FGFR single nucleotide polymorphism" (SNP) refers to FGFR3 genes, and wherein single nucleotides are different between individuals. The presence of one or more following FGFR SNPs from the patient's biological sample can be determined by methods known to those of ordinary skill in the art or disclosed in WO 2016 / 048833, FGFR3 R248C, FGFR3 S249C, FGFR3 G370C, FGFR3 Y373C or any combination thereof. The sequence of FGFR SNPs is provided in Table B.

[0263] Table B

[0264]

[0265]

[0266] The sequence corresponds to nucleotides 920-1510 of FGFR3 (Genebank ID# NM_000142.4).

[0267] Bold underlined nucleotides indicate SNPs.

[0268] *Sometimes incorrectly referred to as Y375C in the literature.

[0269] In certain embodiments, the method or purposes for treating urothelial carcinoma as described herein include the following, are made up of or are essentially made up of: a drug delivery system as described herein is applied to a patient, the patient has been diagnosed with urothelial carcinoma as described herein and has at least one FGFR2 gene change and / or FGFR3 gene change (that is, one or more FGFR2 gene changes, one or more FGFR3 gene changes or a combination thereof). In certain embodiments, the FGFR2 gene change and / or FGFR3 gene change is a FGFR3 gene mutation, FGFR2 gene fusion or FGFR3 gene fusion. In some embodiments, the FGFR3 gene mutation is R248C, S249C, G370C, Y373C or any combination thereof. In still another embodiment, the FGFR2 or FGFR3 gene fusion is FGFR3-TACC3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7 or any combination thereof.

[0270] Also described herein are methods or uses for treating urothelial carcinoma as described herein, comprising, consisting of, or consisting essentially of: (a) evaluating a biological sample from a patient with 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 a drug delivery system as described herein to the patient.

[0271] The following methods for assessing the presence of one or more FGFR gene alterations in a biological sample are also applicable to any of the above-disclosed methods of treatment and uses.

[0272] Suitable methods for evaluating the presence of one or more FGFR gene changes in a biological sample are described herein and in WO 2016 / 048833 and U.S. Patent Application Serial No. 16 / 723,975 (which are incorporated herein in their entirety). For example, and not intended to be limiting, the presence of one or more FGFR gene changes in a biological sample may include any combination of the following steps: isolating RNA from the biological sample; synthesizing cDNA from RNA; and amplifying cDNA (pre-amplification or non-pre-amplification). In some embodiments, the presence of one or more FGFR gene changes in a biological sample may include: amplifying cDNA from a patient with a pair of primers that bind and amplify one or more FGFR gene changes; and determining whether one or more FGFR gene changes are present in the sample. In some aspects, cDNA may be pre-amplified. In some aspects, the assessment step may include isolating RNA from the sample, synthesizing cDNA from the isolated RNA, and pre-amplifying the cDNA.

[0273] Suitable primer pairs for performing the amplification step include, but are not limited to, those disclosed in WO 2016 / 048833, as exemplified in Table C below:

[0274] Table C

[0275]

[0276]

[0277] The presence of one or more FGFR gene alterations can be assessed at any suitable time point, including at diagnosis, after tumor resection, after first-line therapy, during clinical treatment, or any combination thereof.

[0278] The methods and uses may further comprise assessing the biological sample for the presence of one or more FGFR gene alterations prior to the administering step.

[0279] Diagnostic testing and screening are usually performed on a biological sample 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.

[0280] Methods for identifying and analyzing gene alterations and protein upregulation are known to those skilled 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).

[0281] Identification of individuals carrying genetic alterations in FGFR, particularly those described herein, may mean that the patient will be particularly suitable for treatment with erdafitinib. Tumors may be preferentially screened for the presence of FGFR variants prior to treatment. Screening procedures typically include direct sequencing, oligonucleotide microarray analysis, or mutant-specific antibodies. In addition, tumors with such genetic alterations may be diagnosed using techniques known to those skilled in the art and as described herein, such as RT-PCR, FISH, and next-generation sequencing (NGS).

[0282] In addition, for example, genetic alterations in FGFR can be identified by direct sequencing of tumor biopsies, for example, using PCR, and by methods for directly sequencing PCR products as described above. The skilled person will recognize that all such well-known techniques for detecting overexpression, activation, or mutations of the above-mentioned proteins are applicable to the present invention.

[0283] In screening by RT-PCR, by producing a cDNA copy of mRNA, the cDNA is subsequently amplified by PCR to assess the level of mRNA in the tumor. The method of PCR amplification, the selection of primers and the conditions of amplification are well known to those skilled in the art. Nucleic acid manipulation and PCR are performed by standard methods, such as Ausubel, FM et al., (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc., or Innis, MA et al., (1990) PCR Protocols: a guide to methods and applications, Academic Press, San Diego. Reaction and operation related to nucleic acid technology are also described in Sambrook et al., (2001), 3rd edition, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press. Alternatively, commercially available kits for RT-PCR (e.g., Roche Molecular Biochemicals) can be used, or methods as 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, which are incorporated herein by reference. An example of an in situ hybridization technique for assessing mRNA expression is fluorescence in situ hybridization (FISH) (see Angerer (1987) Meth. Enzymol., 152:649).

[0284] Typically, in situ hybridization involves the following major steps: (1) fixing the tissue to be analyzed; (2) subjecting the sample to a prehybridization treatment to increase accessibility of the target nucleic acid and reduce nonspecific binding; (3) hybridizing the nucleic acid mixture to nucleic acids in the biological structure or tissue; (4) post-hybridization washing to remove unbound nucleic acid fragments during hybridization, and (5) detecting the hybridized nucleic acid fragments. Probes used in such applications are typically labeled, for example, with radioisotopes or fluorescent reporter molecules. Preferred probes are sufficiently long, for example, from about 50, 100, or 200 nucleotides to about 1000 or more nucleotides, to enable specific hybridization to the target nucleic acid under stringent conditions. Standard methods for performing FISH are described in Ausubel, FM et al., eds. (2004) Current Protocols in Molecular Biology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization: Technical Overview, John MS, Bartlett in Molecular Diagnosis of Cancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004, pp. 77-88; Series: Methods in Molecular Medicine.

[0285] The method for gene expression profiling is 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 a (dT)24 oligomer (SEQ ID NO:38: ttttttttttt ttttttttttt tttt) by priming first-strand cDNA synthesis followed by second-strand cDNA synthesis using random hexamer primers. The 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 human genome arrays.

[0286] Alternatively, the protein product expressed by the mRNA can be measured by immunohistochemistry of tumor samples, solid phase immunoassay using microtiter plates, Western blot, 2-dimensional SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry and other methods known in the art for detecting specific proteins. Detection methods include the use of site-specific antibodies. The skilled artisan will recognize that all such well-known techniques for detecting FGFR upregulation or detecting FGFR variants or mutants are applicable to the present situation.

[0287] Abnormal levels of proteins such as FGFR can be measured using standard enzyme assays (e.g., those described herein). Activation or overexpression in tissue samples (e.g., tumor tissue) can also be detected by measuring tyrosine kinase activity using assays such as those from Chemicon International. The tyrosine kinase of interest is immunoprecipitated from sample lysates and its activity is measured.

[0288] Alternative methods for measuring overexpression or activation of FGFR (including its isoforms) include measuring microvessel density. This can be measured, for example, using the method described by Orre and Rogers (Int J Cancer (1999), 84 (2): 101-8). Assays also include the use of markers.

[0289] 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.

[0290] According to certain embodiments, commercially available kits (including but not limited to QIAGEN FGFR RGQ RT-PCR Kit) was used to identify FGFR2 and / or FGFR3 gene alterations.

[0291] According to certain embodiments, FGFR2 and / or FGFR3 gene alterations can be identified in a liquid biological sample (eg, a urine sample) from a cancer patient.Urothelial bladder cancer cells can be shed into the urine.

[0292] According to certain embodiments, analytes that can be used for screening or detecting FGFR gene alterations in urine include precipitated DNA, cell-free DNA (cfDNA), non-coding RNA, shed tumor cells, and proteins.

[0293] According to certain embodiments, cfDNA in urine samples can be analyzed by ultracentrifugation or by molecular weight-based DNA separation techniques. For example, DNA can be extracted from urine samples using the QIAamp Blood Genomic DNA Mini Kit (Qiagen, Valencia, CA, USA) according to the manufacturer's instructions. The extracted cfDNA can be amplified and analyzed using various procedures including polymerase chain reaction (PCR) and / or gene sequencing.

[0294] According to certain embodiments, urine-based molecular profiling can be performed using available kits, including but not limited to PCR assays and NGS assays. Non-limiting examples of available kits include: PCR kits, including the mutation assay MASO (“mutant allele-specific oligonucleotide”)-PCR; AssureMDX, a urine-based test that investigates mutations in, for example, FGFR3; PredicineCARE TM , a targeted NGS assay based on urine cfDNA.

[0295] In some embodiments, FGFR gene changes are detected using NGS or PCR assays of urine samples and tumor tissue samples obtained from patients. In some embodiments, there is a high degree of consistency between the FGFR changes detected by urine sample assays and tumor tissue sample assays. In some embodiments, urine sample assays identify bladder cancer patients who have not been identified by tumor tissue sample assays. In some embodiments, patients are identified only by urine sample assays. In some embodiments, patients are identified only by urine sample assays due to the absence of available samples or insufficient tumor tissue. 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 TM (NGS) assay. In one embodiment, the tumor tissue sample assay is a PCR (polymerase chain reaction) assay, particularly a QIAGEN FGFRRGQ RT-PCR Kit.

[0296] In certain embodiments, the method for administering a drug to a patient includes inserting a drug delivery system as described herein into the patient's body and allowing the drug to be released from the system. For example, the system may include any feature or combination of features described herein. In one embodiment, the drug is released from the drug reservoir lumen via diffusion through the second material of the wall structure. In certain embodiments, the release curve of the drug is substantially independent of pH in the pH range of 5 to 7. In certain embodiments, the release curve of the drug is substantially independent of pH in the pH range of 5.5 to 7. In certain embodiments, the release curve of the drug is substantially independent of pH in the pH range of 5.5 to 8.

[0297] In certain embodiments, allowing the drug to be released from the system includes allowing water to be absorbed by the water-permeable wall portion (e.g., only by the second wall structure / second material or by both the first wall structure / material and the second wall structure / material to dissolve the drug), and allowing the dissolved drug to be released from the system by diffusion through the second wall structure / material. That is, in certain embodiments, the elution of the drug from the system occurs after the drug is dissolved in the system. Body fluid enters the system, contacts the drug and dissolves the drug, after which the dissolved drug diffuses out of the system. For example, in the case where the system is inserted into the bladder, the drug can dissolve when in contact with urine. In one embodiment, releasing the drug from the system includes dissolving the drug with water or an aqueous medium (e.g., urine), absorbing it by the second wall structure / material or both the first wall structure / material and the second wall structure / material.

[0298] In some embodiments, the device components of the system include a base material that is water permeable and drug impermeable, and a strip material that is water permeable and drug permeable. For example, the base material can be TPU, such as Lubrizol's Carbothane TM AC-4075A or Tecothane TM AR-75A, and the strip material can be TPU, such as Lubrizol TECOFLEX TM TPU, such as EG-80A. (Lubrizol Life Science (Bethlehem, PA)).

[0299] In certain embodiments, the insertion includes deploying the system through the patient's urethra and into the patient's bladder. The system can release the drug for several days, weeks, months or longer after the implantation procedure ends. In one embodiment, deploying the drug delivery system in the patient's body includes inserting the system into the patient's body cavity or lumen via a deployment device. For example, the system can be deployed by a deployment device (such as a catheter or cystoscope) positioned in the natural lumen of the body (such as the urethra), or deployed in a body cavity (such as the bladder). The deployment device is usually removed from the body cavity, while the drug delivery system remains in the bladder or other body cavities for a continuous prescribed treatment period.

[0300] 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 (e.g., a body cavity (such as a bladder)). In an embodiment, once the system emerges from the deployment device into the cavity, the system assumes a retaining shape, such as an expanded or higher profile shape. The deployment device can be a commercially available system or a system particularly suitable for the drug delivery system of the present invention. In one embodiment, deploying the drug delivery system in the patient's body includes (i) elastically deforming the system into a relatively straight shape; (ii) inserting the system through the patient's urethra; and (iii) releasing the system into the patient's bladder so that it assumes a curled retaining shape.

[0301] The drug delivery system may be passed through the deployment device, for example driven by a stylet, typically with the aid of a lubricant, until the drug delivery system exits the lumen of the device and enters the bladder.

[0302] In a specific embodiment, the drug delivery system described herein is deployed transurethrally into the patient's bladder using a urinary placement catheter comprising two components: a catheter-like shaft and a stylet mounted inside the shaft. The shaft may comprise a single lumen extrusion with an atraumatic distal tip comprising a Coudé elbow, an outlet proximal to the distal tip, and an internal lumen extending from the outlet to an open proximal end. Depth markings on the shaft indicate the insertion depth and orientation of the Coudé tip to assist in the intravesical drug delivery system insertion procedure. The stylet is a single lumen extrusion and is used to advance the drug delivery system through the transparent shaft lumen and into the bladder.

[0303] Once deployed in vivo, the system then releases a drug (e.g., erdafitinib) locally to the tissue at the deployment site for treating one or more conditions or diseases. The release is controlled to release an effective amount of the drug over an extended period of time. Thereafter, the system can be removed, dissolved, excreted, or some combination thereof. In certain embodiments, the system resides in the bladder and releases the drug over a predetermined period of time, such as two weeks, three weeks, four weeks, one month, two months, three months, or longer.

[0304] The system of deployment releases the medicine of desired amount in the predetermined time period of expectation.In embodiments, system can deliver the medicine of desired dose in the time period of extension, such as 12 hours, 24 hours, 2 days, 3 days, 5 days, 7 days, 10 days, 14 days or 20 days, 25 days, 30 days, 45 days, 60 days or 90 days, 6 months or longer time.Can select the delivery rate and dosage of medicine according to the medicine delivered and the disease treated or illness.In one embodiment, the release rate of medicine from drug delivery system is zero order in at least 36 hours.In one embodiment, the release rate of medicine from drug delivery system is zero order in at least 7 days, two weeks, three weeks, four weeks, one month, two months, three months or longer time basically.

[0305] Subsequently, the system can be retrieved from the body, such as in the case where the system is non-bioerodible or needs to be removed for other reasons. Retrieval systems for this purpose are known in the art or can be specially produced. The system can also be completely or partially bioerodible, dissolvable or biodegradable, so that retrieval is unnecessary because the entire system is dissolved or the system is sufficiently degraded to be discharged from the bladder, for example, during urination. The system can not be retrieved or dissolved until some, or preferably most or all, of the drug has been released. If necessary, the system loaded with new drug can be implanted later during the same procedure as the retrieval or at a later time.

[0306] Methods for preparing drug delivery systems

[0307] The systems described herein are generally formed by forming an elongated, elastomeric housing of the system using a coextrusion or 3D printing process; loading a drug reservoir lumen with an appropriate amount of drug (e.g., with an appropriate number of drug tablets); and closing the ends of the tubular housing.

[0308] In some embodiments, the tubular wall structure may include a holding lumen extending through or along the structure. The holding lumen may optionally be loaded with an elastic holding frame, such as a nitinol wire or other superelastic wire, and then sealed to hold the frame inside the lumen and / or optionally may be filled with a gas (e.g., air) and then sealed at its ends before or after drug loading of the system. In another embodiment, the holding lumen may be filled with a high durometer silicone prior to drug loading of the system, which is then cured into a solid, elastic form to effectively bias the tubular wall structure into a curled bladder holding shape.

[0309] In other embodiments, the method includes heat setting the tubular structure to have a coiled retention shape that is elastically deformable to an expanded shape. In such embodiments, the retention lumen and frame may not be necessary.

[0310] Some steps or sub-steps of the method of preparing a drug delivery system may be performed in another order or simultaneously.

[0311] The present disclosure may be further understood by reference to the following non-limiting examples.

[0312] Implementation Plan

[0313] 1. A solid pharmaceutical composition, comprising:

[0314] (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of at least 45% by weight of the solid pharmaceutical composition; and

[0315] (b) at least one pharmaceutical excipient.

[0316] 2. A solid pharmaceutical composition according to embodiment 1, wherein the at least one pharmaceutical excipient includes or is selected from a solubilizer, a binder, a diluent (filler), a wetting agent, a disintegrant, a glidant, a lubricant, a formaldehyde scavenger or any combination thereof.

[0317] 3. A solid pharmaceutical composition according to embodiment 1, wherein the at least one pharmaceutical excipient comprises or is selected from a solubilizer, a binder, a diluent (filler), a glidant, a lubricant, a formaldehyde scavenger or any combination thereof.

[0318] 4. A method for preparing a solid pharmaceutical composition, comprising:

[0319] (a) preparing an intragranular solid composition comprising or consisting essentially of:

[0320] (i) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine); and

[0321] (ii) at least one intragranular pharmaceutical excipient;

[0322] (b) combining the intragranular solid composition with at least one extragranular pharmaceutical excipient to form a blend; and

[0323] (c) tableting the blend to form the solid pharmaceutical composition, wherein the erdafitinib free base is present in a concentration of at least 45% by weight of the solid pharmaceutical composition.

[0324] 5. The method for preparing a solid pharmaceutical composition according to embodiment 4, wherein the at least one intragranular pharmaceutical excipient and the at least one extragranular pharmaceutical excipient comprise or are selected from at least one common (mutually present) pharmaceutical excipient.

[0325] 6. The method for preparing a solid pharmaceutical composition according to embodiment 4, wherein the at least one intragranular excipient and the at least one extragranular pharmaceutical excipient do not contain a common (mutually present) pharmaceutical excipient.

[0326] 7. The method for preparing a solid pharmaceutical composition according to any one of embodiments 4 to 6, wherein the intragranular solid composition is prepared by roller compaction.

[0327] 8. The method for preparing a solid pharmaceutical composition according to any one of embodiments 4 to 6, wherein the intragranular solid composition is prepared by a fluidized bed granulation method.

[0328] 9. The method for preparing a solid pharmaceutical composition according to any one of embodiments 4 to 8, wherein the at least one extragranular pharmaceutical excipient comprises microcrystalline cellulose and vinylpyrrolidone-vinyl acetate copolymer, particularly in a weight ratio of 50:50.

[0329] 10. The method for preparing a solid pharmaceutical composition according to any one of embodiments 4-6, wherein:

[0330] (a) the intragranular solid composition comprises a solubilizer, at least one binder, and a first amount of a lubricant;

[0331] (b) the extragranular pharmaceutical excipient comprises a diluent, a glidant, and a second amount of a lubricant; and

[0332] (c) The solid composition within the granules is prepared by roller compaction.

[0333] 11. The method for preparing a solid pharmaceutical composition according to embodiment 10, wherein:

[0334] The solubilizing agent is hydroxypropyl-β-cyclodextrin;

[0335] The binder is a combination of microcrystalline cellulose and vinyl pyrrolidone-vinyl acetate copolymer;

[0336] The lubricant is magnesium stearate;

[0337] The diluent is anhydrous calcium hydrogen phosphate; and the glidant is colloidal silicon dioxide.

[0338] 12. The method for preparing a solid pharmaceutical composition according to any one of embodiments 4-5, wherein:

[0339] (a) the intragranular solid composition comprises a solubilizer, a diluent and a disintegrant;

[0340] (b) the extragranular pharmaceutical excipient comprises at least one binder and a lubricant; and

[0341] (c) The solid composition within the granules is prepared by a fluidized bed granulation method.

[0342] 13. The method for preparing a solid pharmaceutical composition according to embodiment 12, wherein:

[0343] The solubilizing agent comprises or is selected from hydroxypropyl-β-cyclodextrin;

[0344] The diluent comprises or is selected from microcrystalline cellulose.

[0345] The disintegrant comprises or is selected from hydroxypropyl methylcellulose;

[0346] The at least one binder comprises or is selected from a combination of microcrystalline cellulose and vinyl pyrrolidone-vinyl acetate copolymer; and

[0347] The lubricant comprises or is selected from magnesium stearate.

[0348] 14. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to any one of embodiments 1-13, wherein the 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.

[0349] 15. The solid pharmaceutical composition or the method for preparing the solid pharmaceutical composition according to any one of embodiments 1-13, wherein the 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 wherein the at least one extragranular excipient comprises microcrystalline cellulose and vinylpyrrolidone-vinyl acetate copolymer, particularly in a weight ratio of 50:50.

[0350] 16. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to any one of embodiments 1 to 15, wherein the solid pharmaceutical composition further comprises a formaldehyde scavenger.

[0351] 17. The solid pharmaceutical composition or the method for preparing the solid pharmaceutical composition according to embodiment 16, wherein the formaldehyde scavenger comprises or is selected from an amino acid, an amino sugar, an α-(α-)amine compound, a conjugate thereof, or any combination thereof.

[0352] 18. The solid pharmaceutical composition or the method for preparing the solid pharmaceutical composition according to embodiment 16, wherein the formaldehyde scavenger comprises or is selected from meglumine, glycine, alanine, serine, threonine, cysteine, valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, aspartic acid, glutamic acid, arginine, lysine, ornithine, taurine, histidine, aspartame, proline, tryptophan, citrulline, pyrrolysine, asparagine, glutamine, tris(hydroxymethyl)aminomethane, a conjugate thereof, a pharmaceutically acceptable salt thereof, or any combination thereof.

[0353] 19. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to embodiment 16, wherein the formaldehyde scavenger is meglumine.

[0354] 20. The solid pharmaceutical composition or method for preparing a solid pharmaceutical composition according to any one of embodiments 16-19, wherein the formaldehyde scavenger is present in the solid pharmaceutical composition at a concentration of 0.01 wt % to 5 wt %, 0.05 wt % to 3 wt %, 0.1 wt % to 2 wt %, 0.5 wt % to 1.5 wt %, or about 1 wt %.

[0355] 21. The solid pharmaceutical composition or the method for preparing the solid pharmaceutical composition according to any one of embodiments 1-20, wherein the solid pharmaceutical composition further comprises

[0356] compounds, their salts, their solvates or combinations thereof.

[0357] 22. The solid pharmaceutical composition or method for preparing a solid pharmaceutical composition according to any one of embodiments 1-21, 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.

[0358] 23. A solid pharmaceutical composition or a method for preparing a solid pharmaceutical composition according to embodiment 22, wherein the solubilizing agent comprises or is selected from (a) a cyclic oligosaccharide, (b) a cellulose functionalized with a methoxy-, 2-hydroxypropoxy-, acetyl- or succinyl-moiety or a combination thereof, or (c) a salt thereof.

[0359] 24. A solid pharmaceutical composition or a method for preparing a solid pharmaceutical composition according to embodiment 22, wherein the solubilizer comprises or is selected from hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutyl ether-β-cyclodextrin sodium salt, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose E5 (HPMC-E5) or any combination thereof.

[0360] 25. A solid pharmaceutical composition or a method for preparing a solid pharmaceutical composition according to embodiment 22, wherein the at least one pharmaceutical excipient or the at least one intragranular pharmaceutical excipient comprises a solubilizer comprising hydroxypropyl-β-cyclodextrin.

[0361] 26. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to any one of embodiments 22-25, wherein the total concentration of the solubilizer in the solid pharmaceutical composition is 1 wt % to 20 wt %, 5 wt % to 15 wt %, 7 wt % to 12 wt %, or about 10 wt %.

[0362] 27. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to any one of embodiments 1 to 26, 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.

[0363] 28. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to embodiment 27, wherein the at least one binder comprises or is independently selected from a water-soluble polymer binder, a slightly water-soluble polymer binder, a water-insoluble polymer binder, or any combination thereof.

[0364] 29. The solid pharmaceutical composition or method for preparing a solid pharmaceutical composition according to embodiment 27, wherein the at least one binder comprises or is independently selected from polyvinylpyrrolidone (PVP), poly(vinyl acetate) (PVA), vinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide (PEO), polypropylene oxide (PPO), ethylene glycol-propylene glycol copolymer, poloxamer, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, silicified microcrystalline cellulose, or a combination thereof.

[0365] 30. A solid pharmaceutical composition or a method for preparing a solid pharmaceutical composition according to embodiment 27, wherein the at least one binder comprises or is selected from vinyl pyrrolidone-vinyl acetate copolymer, silicified microcrystalline cellulose, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC), or any combination thereof.

[0366] 31. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to embodiment 27, wherein the at least one binder comprises or is microcrystalline cellulose.

[0367] 32. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to any one of embodiments 29-30, wherein the vinyl pyrrolidone-vinyl acetate copolymer has a molecular weight (Mw) ranging from 45,000 g / mol to 70,000 g / mol.

[0368] 33. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to any one of embodiments 27-32, wherein the total concentration of the at least one binder in the solid pharmaceutical composition is 5 wt % to 30 wt %, 10 wt % to 25 wt %, 12 wt % to 22 wt %, or 14 wt % to 19 wt %.

[0369] 34. The solid pharmaceutical composition or method for preparing a solid pharmaceutical composition according to any one of embodiments 27-33, wherein the at least one binder comprises or further comprises vinyl pyrrolidone-vinyl acetate copolymer, and the vinyl pyrrolidone-vinyl acetate copolymer is present in the solid pharmaceutical composition at a concentration of 4 wt % to 12 wt %, 6 wt % to 10 wt %, or 7 wt % to 8 wt %.

[0370] 35. The solid pharmaceutical composition or method for preparing a solid pharmaceutical composition according to any one of embodiments 27-34, wherein the at least one binder comprises or further comprises: (a) microcrystalline cellulose, the microcrystalline cellulose being 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, the silicified microcrystalline cellulose being present in a concentration of 3% to 18% by weight;

[0371] wt %, 4 wt % to 15 wt %, or 5 wt % to 12 wt %; or (c) a combination of (a) and (b).

[0372] 36. A solid pharmaceutical composition or a method for preparing a solid pharmaceutical composition according to any one of embodiments 1-35, 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.

[0373] 37. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to embodiment 36, wherein the wetting agent comprises or is an anionic surfactant.

[0374] 38. The solid pharmaceutical composition or the method for preparing the solid pharmaceutical composition according to embodiment 36, wherein the wetting agent comprises or is independently selected from sodium lauryl sulfate, sodium stearyl fumarate, polysorbate 80, docusate sodium, or any combination thereof.

[0375] 39. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to any one of embodiments 36-38, wherein the total concentration of the wetting agent in the solid pharmaceutical composition is 0.01 wt % to 2.5 wt %, 0.05 wt % to 1.0 wt %, or 0.1 wt % to 0.5 wt %.

[0376] 40. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to any one of embodiments 1-39, 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.

[0377] 41. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to embodiment 40, wherein the disintegrant comprises or is independently selected from a functionalized polysaccharide or a cross-linked polymer.

[0378] 42. A solid pharmaceutical composition or a method for preparing a solid pharmaceutical composition according to embodiment 40, wherein the disintegrant comprises or is selected from (a) cellulose functionalized with methoxy-, 2-hydroxypropoxy- or carboxymethoxy moieties, their salts or combinations thereof, (b) carboxymethylated starch, or (c) a cross-linked polymer.

[0379] 43. A solid pharmaceutical composition or a method for preparing a solid pharmaceutical composition according to embodiment 40, wherein the disintegrant comprises or is independently selected from hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, crospovidone (cross-linked polyvinyl pyrrolidone), cross-linked sodium carboxymethylcellulose (cross-linked sodium carboxymethylcellulose), sodium starch glycolate, or any combination thereof.

[0380] 44. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to any one of embodiments 40-43, wherein the total concentration of the disintegrant in the solid pharmaceutical composition is 0.1 wt % to 3 wt %, 0.5 wt % to 2.5 wt %, 1 wt % to 2 wt %, or about 1.5 wt %.

[0381] 45. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to any one of embodiments 1-44, 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.

[0382] 46. ​​The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to embodiment 45, wherein the diluent comprises or is selected from sugar, starch, microcrystalline cellulose, sugar alcohol, hydrogen phosphate, dihydrogen phosphate, carbonate or a combination thereof.

[0383] 47. A solid pharmaceutical composition or a method for preparing a solid pharmaceutical composition according to embodiment 45, wherein the diluent comprises or is selected from lactose (lactose monohydrate), dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium carbonate, sucrose, or any combination thereof.

[0384] 48. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to any one of embodiments 45-47, wherein the total concentration of the diluent in the solid pharmaceutical composition is 12 wt% to 30 wt%, 15 wt% to 25 wt%, or 18 wt% to 22 wt%.

[0385] 49. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to embodiment 47, wherein the diluent comprises or is selected from anhydrous calcium hydrogen phosphate at a concentration of 18% to 20% by weight.

[0386] 50. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to embodiment 47, wherein the diluent comprises or is selected from microcrystalline cellulose at a concentration of 20% to 22% by weight.

[0387] 51. A solid pharmaceutical composition or a method for preparing a solid pharmaceutical composition according to any one of embodiments 1-50, 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 glidant.

[0388] 52. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to embodiment 51, wherein the glidant comprises or is selected from colloidal silicon dioxide, colloidal anhydrous silicon dioxide, talc or any combination thereof.

[0389] 53. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to embodiment 51, wherein the glidant comprises or is colloidal silicon dioxide.

[0390] 54. The solid pharmaceutical composition or method for preparing a solid pharmaceutical composition according to any one of embodiments 51-53, wherein the total concentration of the glidant in the solid pharmaceutical composition is 0.01 wt% to 5 wt%, 0.05 wt% to 3 wt%, 0.1 wt% to 1 wt%, or about 0.5 wt%.

[0391] 55. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to any one of embodiments 1-54, 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.

[0392] 56. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to embodiment 55, wherein the lubricant comprises or is selected from a fatty acid, a fatty acid salt, a fatty acid ester, talc, a glyceride, a metal silicate, or any combination thereof.

[0393] 57. A solid pharmaceutical composition or a method for preparing a solid pharmaceutical composition according to embodiment 55, wherein the lubricant comprises or is selected from magnesium stearate, stearic acid, magnesium silicate, aluminum silicate, isopropyl myristate, sodium oleate, sodium stearoyl lactylate, sodium stearoyl fumarate, titanium dioxide, or a combination thereof.

[0394] 58. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to embodiment 55, wherein the lubricant comprises or is magnesium stearate.

[0395] 59. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to any one of embodiments 55-58, wherein the total concentration of the lubricant in the solid pharmaceutical composition is 0.05 wt % to 5 wt %, 0.1 wt % to 3 wt %, 1 wt % to 2 wt %, or about 1.5 wt %.

[0396] 60. The solid pharmaceutical composition or the method for preparing a solid pharmaceutical composition according to any one of embodiments 1-59, wherein the solid pharmaceutical composition is a minitablet.

[0397] 61. A solid pharmaceutical composition or a method for preparing a solid pharmaceutical composition according to embodiment 60, wherein the microtablet is in the form of a solid cylinder having a cylindrical axis, a cylindrical side, a circular end face perpendicular to the cylindrical axis, a diameter passing through the circular end face, and a length along the cylindrical side face.

[0398] 62. A solid pharmaceutical composition or a method for preparing a solid pharmaceutical composition according to embodiment 61, wherein the length of the microtablet exceeds the diameter of the microtablet to provide a microtablet having an aspect ratio (length:diameter) greater than 1:1.

[0399] 63. The solid pharmaceutical composition or method for preparing a solid pharmaceutical composition according to any one of embodiments 61-62, wherein the minitablet has a diameter of 1.0 mm to 3.2 mm, or 1.5 mm to 3.1 mm.

[0400] 64. The solid pharmaceutical composition or method for preparing a solid pharmaceutical composition according to any one of embodiments 61-63, wherein the minitablet has a length of 1.7 mm to 4.8 mm, or 2.0 mm to 4.5 mm.

[0401] 65. A solid pharmaceutical composition consisting essentially of:

[0402] (a) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition;

[0403] (b) hydroxypropyl-β-cyclodextrin at a concentration of 10% by weight of the solid pharmaceutical composition;

[0404] (c) meglumine at a concentration of 1% by weight of the solid pharmaceutical composition;

[0405] (d) microcrystalline cellulose at a concentration of 10% by weight of the solid pharmaceutical composition;

[0406] (e) anhydrous dibasic calcium phosphate at a concentration of 19% by weight of the solid pharmaceutical composition;

[0407] (f) vinyl pyrrolidone-vinyl acetate copolymer at a concentration of 8% by weight of the solid pharmaceutical composition;

[0408] (g) colloidal silicon dioxide at a concentration of 0.5% by weight of the solid pharmaceutical composition; and

[0409] (h) magnesium stearate at a concentration of 1.50% by weight of the solid pharmaceutical composition; or

[0410] A solid pharmaceutical composition, the solid pharmaceutical composition essentially consisting of:

[0411] (a) Erdafitinib free base (N-

[0412] (3,5-Dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)

[0413] [quinoxalin-6-yl]ethane-1,2-diamine);

[0414] (b) hydroxypropyl-β-cyclodextrin;

[0415] (c) meglumine;

[0416] (d) microcrystalline cellulose;

[0417] (e) anhydrous calcium hydrogen phosphate;

[0418] (f) vinylpyrrolidone-vinyl acetate copolymer;

[0419] (g) colloidal silicon dioxide; and

[0420] (h) Magnesium stearate.

[0421] 66. A solid pharmaceutical composition consisting essentially of:

[0422] (a) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition;

[0423] (b) hydroxypropyl-β-cyclodextrin at a concentration of 10% by weight of the solid pharmaceutical composition;

[0424] (c) meglumine at a concentration of 1% by weight of the solid pharmaceutical composition;

[0425] (d) microcrystalline cellulose at a concentration of 24.5% by weight of the solid pharmaceutical composition;

[0426] (e) silicified microcrystalline cellulose at a concentration of 6.0% by weight of the solid pharmaceutical composition;

[0427] (f) vinyl pyrrolidone-vinyl acetate copolymer at a concentration of 6.0% by weight of the solid pharmaceutical composition;

[0428] (g) colloidal silicon dioxide at a concentration of 0.5% by weight of the solid pharmaceutical composition; and

[0429] (h) magnesium stearate at a concentration of 2.0% by weight of the solid pharmaceutical composition; or

[0430] A solid pharmaceutical composition, the solid pharmaceutical composition essentially consisting of:

[0431] (a) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition;

[0432] (b) hydroxypropyl-β-cyclodextrin;

[0433] (c) meglumine;

[0434] (d) microcrystalline cellulose;

[0435] (e) silicified microcrystalline cellulose;

[0436] (f) vinylpyrrolidone-vinyl acetate copolymer;

[0437] (g) colloidal silicon dioxide; and

[0438] (h) Magnesium stearate.

[0439] 67. A solid pharmaceutical composition consisting essentially of:

[0440] (a) Erdafitinib free base (N-

[0441] (3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine);

[0442] (b) hydroxypropyl-β-cyclodextrin at a concentration of 10% by weight of the solid pharmaceutical composition;

[0443] (c) meglumine at a concentration of 1% by weight of the solid pharmaceutical composition;

[0444] (d) hydroxypropyl methylcellulose at a concentration of 1.5% by weight of the solid pharmaceutical composition;

[0445] (e) mannitol at a concentration of 21.0% by weight of the solid pharmaceutical composition;

[0446] (f) sodium lauryl sulfate at a concentration of 0.25% by weight of the solid pharmaceutical composition;

[0447] (g) microcrystalline cellulose at a concentration of 7.25% by weight of the solid pharmaceutical composition;

[0448] (h) vinyl pyrrolidone-vinyl acetate copolymer at a concentration of 7.25% by weight of the solid pharmaceutical composition;

[0449] (i) colloidal silicon dioxide at a concentration of 0.25% by weight of the solid pharmaceutical composition; and

[0450] (j) magnesium stearate at a concentration of 1.50% by weight of the solid pharmaceutical composition; or

[0451] A solid pharmaceutical composition, the solid pharmaceutical composition essentially consisting of:

[0452] (a) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition;

[0453] (b) hydroxypropyl-β-cyclodextrin;

[0454] (c) meglumine;

[0455] (d) hydroxypropyl methylcellulose;

[0456] (e) mannitol;

[0457] (f) sodium lauryl sulfate;

[0458] (g) microcrystalline cellulose;

[0459] (h) vinylpyrrolidone-vinyl acetate copolymer;

[0460] (i) colloidal silicon dioxide; and

[0461] (j) Magnesium stearate.

[0462] 68. A solid pharmaceutical composition consisting essentially of:

[0463] (a) Erdafitinib free base (N-

[0464] (3,5-Dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)

[0465] [quinoxalin-6-yl]ethane-1,2-diamine);

[0466] (b) hydroxypropyl-β-cyclodextrin at a concentration of 10% by weight of the solid pharmaceutical composition;

[0467] (c) meglumine at a concentration of 1% by weight of the solid pharmaceutical composition;

[0468] (d) microcrystalline cellulose at a concentration of 17.5% by weight of the solid pharmaceutical composition;

[0469] (e) silicified microcrystalline cellulose at a concentration of 10.75% by weight of the solid pharmaceutical composition;

[0470] (f) vinyl pyrrolidone-vinyl acetate copolymer at a concentration of 7.5% by weight of the solid pharmaceutical composition;

[0471] (g) colloidal silicon dioxide at a concentration of 0.25% by weight of the solid pharmaceutical composition;

[0472] (h) hydroxypropyl methylcellulose at a concentration of 1.5% by weight of the solid pharmaceutical composition;

[0473] as well as

[0474] (i) magnesium stearate at a concentration of 1.5% by weight of the solid pharmaceutical composition; or

[0475] A solid pharmaceutical composition, the solid pharmaceutical composition essentially consisting of:

[0476] (a) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition;

[0477] (b) hydroxypropyl-β-cyclodextrin;

[0478] (c) meglumine;

[0479] (d) microcrystalline cellulose;

[0480] (e) silicified microcrystalline cellulose;

[0481] (f) vinylpyrrolidone-vinyl acetate copolymer;

[0482] (g) colloidal silicon dioxide;

[0483] (h) hydroxypropyl methylcellulose; and

[0484] (i) Magnesium stearate.

[0485] 69. A method for preparing a solid pharmaceutical composition, the method comprising:

[0486] (a) preparing an intragranular solid composition by roller compaction, said intragranular solid composition consisting essentially of:

[0487] (i) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition;

[0488] (ii) hydroxypropyl-β-cyclodextrin at a concentration of 10% by weight of the solid pharmaceutical composition;

[0489] (iii) meglumine at a concentration of 1% by weight of the solid pharmaceutical composition;

[0490] (iv) microcrystalline cellulose at a concentration of 10% by weight of the solid pharmaceutical composition;

[0491] (v) vinyl pyrrolidone-vinyl acetate copolymer at a concentration of 8% by weight of the solid pharmaceutical composition; and

[0492] (vi) magnesium stearate at a concentration of 0.75% by weight of the solid pharmaceutical composition;

[0493] (b) combining the intragranular solid composition with an extragranular component to form a blend, wherein the extragranular component consists essentially of:

[0494] (i) anhydrous calcium hydrogen phosphate at a concentration of 19% by weight of the solid pharmaceutical composition;

[0495] (ii) colloidal silicon dioxide at a concentration of 0.5% by weight of the solid pharmaceutical composition; and

[0496] (iii) magnesium stearate at a concentration of 0.75% by weight of the solid pharmaceutical composition; and

[0497] (c) compressing the blend to form a solid pharmaceutical composition in the form of mini-tablets.

[0498] 70. A method for preparing a solid pharmaceutical composition, the method comprising:

[0499] (a) preparing an intragranular solid composition by roller compaction, said intragranular solid composition consisting essentially of:

[0500] (i) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition;

[0501] (ii) hydroxypropyl-β-cyclodextrin at a concentration of 10% by weight of the solid pharmaceutical composition;

[0502] (iii) meglumine at a concentration of 1% by weight of the solid pharmaceutical composition;

[0503] (iv) microcrystalline cellulose at a concentration of 24.5% by weight of the solid pharmaceutical composition;

[0504] (v) colloidal silicon dioxide at a concentration of 0.2% by weight of the solid pharmaceutical composition; and

[0505] (vi) magnesium stearate at a concentration of 0.75% by weight of the solid pharmaceutical composition.

[0506] (b) combining the intragranular solid composition with an extragranular component to form a blend, wherein the extragranular component consists essentially of:

[0507] (i) silicified microcrystalline cellulose at a concentration of 6.0% by weight of the solid pharmaceutical composition;

[0508] (ii) vinyl pyrrolidone-vinyl acetate copolymer at a concentration of 6.0% by weight of the solid pharmaceutical composition;

[0509] (iii) colloidal silicon dioxide at a concentration of 0.3% by weight of the solid pharmaceutical composition; and

[0510] (iv) magnesium stearate at a concentration of 1.25% by weight of the solid pharmaceutical composition; and

[0511] (c) compressing the blend to form a solid pharmaceutical composition in the form of mini-tablets.

[0512] 71. A method for preparing a solid pharmaceutical composition, the method comprising:

[0513] (a) preparing an intragranular solid composition by a fluidized bed granulation process, said intragranular solid composition consisting essentially of:

[0514] (i) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition;

[0515] (ii) hydroxypropyl-β-cyclodextrin at a concentration of 10% by weight of the solid pharmaceutical composition;

[0516] (iii) meglumine at a concentration of 1% by weight of the solid pharmaceutical composition;

[0517] (iv) mannitol at a concentration of 21% by weight of the solid pharmaceutical composition;

[0518] (v) sodium lauryl sulfate at a concentration of 0.25% by weight of the solid pharmaceutical composition; and

[0519] (vi) hydroxypropyl methylcellulose at a concentration of 1.5% by weight of the solid pharmaceutical composition;

[0520] (b) combining the intragranular solid composition with an extragranular component to form a blend, wherein the extragranular component consists essentially of:

[0521] (i) microcrystalline cellulose at a concentration of 7.25% by weight of the solid pharmaceutical composition;

[0522] (ii) vinyl pyrrolidone-vinyl acetate copolymer at a concentration of 7.25% by weight of the solid pharmaceutical composition;

[0523] (iii) colloidal silicon dioxide at a concentration of 0.25% by weight of the solid pharmaceutical composition; and

[0524] (iv) magnesium stearate at a concentration of 1.50% by weight of the solid pharmaceutical composition; and

[0525] (c) compressing the blend to form a solid pharmaceutical composition in the form of mini-tablets.

[0526] 72. A method for preparing a solid pharmaceutical composition, the method comprising:

[0527] (a) preparing an intragranular solid composition by a fluidized bed granulation process, said intragranular solid composition consisting essentially of:

[0528] (i) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition;

[0529] (ii) hydroxypropyl-β-cyclodextrin at a concentration of 10% by weight of the solid pharmaceutical composition;

[0530] (iii) meglumine at a concentration of 1% by weight of the solid pharmaceutical composition;

[0531] (iv) microcrystalline cellulose at a concentration of 10% by weight of the solid pharmaceutical composition; and

[0532] (v) hydroxypropyl methylcellulose at a concentration of 1.5% by weight of the solid pharmaceutical composition;

[0533] (b) combining the intragranular solid composition with an extragranular component to form a blend, wherein the extragranular component consists essentially of:

[0534] (i) microcrystalline cellulose at a concentration of 7.5% by weight of the solid pharmaceutical composition; and

[0535] (ii) vinyl pyrrolidone-vinyl acetate copolymer at a concentration of 7.5% by weight of the solid pharmaceutical composition;

[0536] (iii) silicified microcrystalline cellulose at a concentration of 10.75% by weight of the solid pharmaceutical composition;

[0537] (iv) colloidal silicon dioxide at a concentration of 0.25% by weight of the solid pharmaceutical composition; and

[0538] (iv) magnesium stearate at a concentration of 1.5% by weight of the solid pharmaceutical composition; and

[0539] (c) compressing the blend to form a solid pharmaceutical composition in the form of mini-tablets.

[0540] 73. A drug delivery system, comprising:

[0541] a housing defining an enclosed drug reservoir lumen bounded by a first wall structure formed from a first material and a second wall structure formed from a second material, the first wall structure and the second wall structure being adjacent to each other at two interfacial edges and together forming a tube defining the enclosed drug reservoir lumen, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and

[0542] a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising a drug,

[0543] wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the drug and the second wall structure is permeable to the drug, such that the drug can be released in vivo by diffusion through the second material forming the second wall structure.

[0544] 74. A drug delivery system, comprising:

[0545] a housing defining an enclosed drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, the first wall structure and the second wall structure being adjacent to each other at two interfacial edges and together forming a tube defining the enclosed drug reservoir lumen, wherein the first material comprises an aromatic polyester hydrocarbon-based thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and

[0546] a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising a drug,

[0547] wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the drug and the second wall structure is permeable to the drug, such that the drug can be released in vivo by diffusion through the second wall structure.

[0548] 75. The drug delivery system of any one of embodiments 73 and 74, wherein the second wall structure forms a longitudinal strip extending along the length of the tube.

[0549] 76. The system of any one of embodiments 73-75, wherein the system is configured to release a therapeutically effective amount of the drug at a substantially zero order release rate over at least 36 hours.

[0550] 77. The system of any one of embodiments 73-76, wherein the system is configured to release the drug over a period of 2 days to 6 months.

[0551] 78. The system of any one of embodiments 73-77, wherein the two interface edges are disposed at an arc angle of 15 to 270 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube.

[0552] 79. The system according to any one of embodiments 73-78, wherein the drug comprises erdafitinib, in particular erdafitinib.

[0553] 80. The system of embodiment 79, wherein the system is configured to release the erdafitinib at an average rate of 1 mg / day to 10 mg / day.

[0554] 81. The system of embodiment 79, wherein the system is configured to release the erdafitinib at an average rate of 1 mg / day to 2 mg / day.

[0555] 82. A system according to embodiment 81, wherein the two interface edges are arranged at an arc angle of 45 degrees to 90 degrees of the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube.

[0556] 83. The system of embodiment 79, wherein the system is configured to release the erdafitinib at an average rate of 4 mg / day to 6 mg / day.

[0557] 84. A system according to embodiment 83, wherein the two interface edges are arranged at an arc angle of 150 degrees to 270 degrees of the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube.

[0558] 85. The system of embodiment 79, wherein the system is configured to release the erdafitinib at an average rate of 1 mg / day.

[0559] 86. A system according to embodiment 85, wherein the two interface edges are arranged at an arc angle of approximately 45 degrees of the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube.

[0560] 87. The system of embodiment 79, wherein the system is configured to release the erdafitinib at an average rate of 2 mg / day.

[0561] 88. A system according to embodiment 87, wherein the two interface edges are arranged at an arc angle of approximately 90 degrees of the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube.

[0562] 89. The system of embodiment 79, wherein the system is configured to release the erdafitinib at an average rate of 4 mg / day.

[0563] 90. A system according to embodiment 89, wherein the two interface edges are arranged at an arc angle of approximately 180 degrees of the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube.

[0564] 91. The system of embodiment 79, wherein the system is configured to release the erdafitinib at an average rate of 6 mg / day.

[0565] 92. A system according to embodiment 91, wherein the two interface edges are arranged at an arc angle of 210 degrees to 270 degrees of the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube.

[0566] 93. The system of any one of embodiments 79-92, wherein the system comprises 500 mg of the erdafitinib.

[0567] 94. The system of any one of embodiments 73-93, wherein the release profile of the drug is substantially pH independent within a pH range of 5 to 7.

[0568] 95. The system of any one of embodiments 73-94, wherein the second wall structure comprises less than 50% of the cross-sectional area of ​​the tube in a cross section perpendicular to the longitudinal axis of the tube.

[0569] 96. The system of any one of embodiments 73-94, wherein the second wall structure comprises less than 25% of the cross-sectional area of ​​the tube in a cross section perpendicular to the longitudinal axis of the tube.

[0570] 97. The system of any one of embodiments 73-96, wherein the tube has a substantially constant thickness around its circumference.

[0571] 98. The system of any one of embodiments 73-97, further comprising a pair of end plugs and / or adhesive material sealing the ends of the tube.

[0572] 99. The system of any one of embodiments 73-98, wherein the first wall structure and the second wall structure are integrally formed.

[0573] 100. The system of embodiment 99, wherein the tube is formed in an extrusion process.

[0574] 101. The system of any one of embodiments 73-100, wherein the system is capable of

[0575] The system is elastically deformable between a relatively straightened deployed shape adapted for insertion through a patient's urethra and into the patient's bladder and a retention shape adapted to retain the system within the bladder.

[0576] 102. The system of any one of embodiments 73-101, wherein the system is elastically deformable and comprises overlapping curls formed by the tube, and the tube has two opposing free ends that are directed away from each other when the system is in a low-profile deployed shape and directed toward each other when the system is in a relatively expanded retention shape.

[0577] 103. The system of any one of embodiments 73-102, wherein the system is elastically deformable and has a bi-oval retention shape, and the tube has two opposing free ends that are located within the outer boundaries of the bi-oval retention shape.

[0578] 104. The system of any one of embodiments 73-103, further comprising a retention frame lumen.

[0579] 105. The system of embodiment 104 further comprising a nitinol wire disposed within the retention frame lumen.

[0580] 106. The system of any one of embodiments 73-105, wherein the first material has a Shore durometer value of 70A to 80A.

[0581] 107. The system of any one of embodiments 73-106, wherein the second material has a Shore durometer value of 70A to 75A.

[0582] 108. The system of any one of embodiments 73-107, wherein the drug formulation comprises a solid pharmaceutical composition of any one of embodiments 1, 2, 3, and 14-68.

[0583] 109. The system of any one of embodiments 73-108, wherein the drug formulation is in the form of a plurality of microtablets serially arranged in the drug lumen.

[0584] 110. The system of embodiment 109, wherein the plurality of microtablets comprises the microtablet of any one of embodiments 60-64.

[0585] 111. A drug delivery system, comprising:

[0586] 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; and

[0587] a drug formulation disposed in the lumen of the drug reservoir, the drug formulation comprising erdafitinib,

[0588] wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib can be released in vivo by diffusion through the second material forming the second wall structure.

[0589] 112. The system of embodiment 111, wherein the first wall structure and the second wall structure are adjacent to each other at two interface edges and together form a tube, and (i) the system is configured to release the erdafitinib at an average rate of 2 mg / day, and the two interface edges are disposed at an arc angle of approximately 90 degrees from the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube, (ii) the system is configured to release the erdafitinib at an average rate of 4 mg / day, and the two interface edges are disposed at an arc angle of approximately 180 degrees from 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 the erdafitinib at an average rate of 6 mg / day, and the two interface edges are disposed at an arc angle of 240 degrees.

[0590] 113. A drug delivery system, comprising:

[0591] 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; and

[0592] a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising erdafitinib,

[0593] 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,

[0594] 114. The system of embodiment 113, wherein the first wall structure and the second wall structure are adjacent to each other at two interface edges and together form a tube, and (i) the system is configured to release the erdafitinib at an average rate of 2 mg / day, and the two interface edges are disposed at an arc angle of about 90 degrees to 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 the erdafitinib at an average rate of 4 mg / day, and the two interface edges are disposed at an arc angle of about 90 degrees to the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube.

[0595] The cross section of the longitudinal axis of the tube is arranged at an arc angle of about 180 degrees of the circumference of the tube. 115. The system according to any one of embodiments 111-114, wherein the system is capable of

[0596] The system is elastically deformable and includes overlapping curls formed by the tube, and the tube has two opposing free ends that are directed away from each other when the system is in a low-profile deployed shape and directed toward each other when the system is in a relatively expanded retention shape.

[0597] 116. The system according to any one of embodiments 111-115, wherein the release profile of erdafitinib is substantially pH independent in the pH range of 5 to 7.

[0598] 117. A drug delivery system, comprising:

[0599] a housing defining an enclosed drug reservoir lumen bounded by a first wall structure formed from a first material and a second wall structure formed from a second material, the first and second wall structures being adjacent to one another at two interfacial edges and together forming a tube defining the enclosed drug reservoir lumen, the second wall structure forming a longitudinal strip extending along the length of the tube, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and

[0600] a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising a solid pharmaceutical composition according to any one of embodiments 1, 2, 3, and 14-68,

[0601] wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib can be released in vivo by diffusion through the second material forming the second wall structure,

[0602] wherein the system is configured to release a therapeutically effective amount of erdafitinib at a substantially zero-order release rate over at least 3 days, and

[0603] wherein (i) the system is configured to release the erdafitinib at an average rate of 2 mg / day and the two interfacial edges are disposed at an arc angle of approximately 90 degrees from the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube, (ii) the system is configured to release the erdafitinib at an average rate of 4 mg / day and the two interfacial edges are disposed at an arc angle of approximately 180 degrees from 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 the erdafitinib at an average rate of 6 mg / day and the two interfacial edges are disposed at an arc angle of 240 degrees.

[0604] 118. A drug delivery system, comprising:

[0605] a housing defining an enclosed drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being adjacent to one another at two interfacial edges and together forming a tube defining the enclosed drug reservoir lumen, the second wall structure forming a longitudinal strip extending along the length of the tube, wherein the first material comprises an aromatic polyester hydrocarbon-based thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and

[0606] a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising a solid pharmaceutical composition according to any one of embodiments 1, 2, 3, and 14-68,

[0607] wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib can be released in vivo by diffusion through the second wall structure, wherein the system is configured to release a therapeutically effective amount of the erdafitinib at a substantially zero-order release rate for at least 3 days, and

[0608] wherein (i) the system is configured to release erdafitinib at an average rate of 2 mg / day and the two interfacial edges are disposed at an arc angle of approximately 90 degrees from the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube, or (ii) the system is configured to release erdafitinib at an average rate of 4 mg / day and the two interfacial edges are disposed at an arc angle of approximately 180 degrees from the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube.

[0609] 119. A method of treating bladder cancer, the method comprising locally delivering erdafitinib to the bladder of a patient in need thereof in an amount effective to treat the bladder cancer.

[0610] 120. The method of embodiment 119, wherein the bladder cancer is muscle-invasive bladder cancer.

[0611] 121. The method of embodiment 119, wherein the bladder cancer is non-muscle invasive bladder cancer.

[0612] 122. The method of embodiment 119, wherein the bladder cancer is Bacillus Calmette-Guérin (BCG) naive bladder cancer.

[0613] 123. The method of any one of embodiments 119-122, wherein the erdafitinib is in the form of a solid pharmaceutical composition of any one of embodiments 1, 2, 3, and 14-68.

[0614] 124. A method of intravesically administering erdafitinib, comprising:

[0615] deploying an intravesical system into the bladder of a patient, the system comprising the solid pharmaceutical composition of any one of Embodiments 1, 2, 3, and 14-68; and

[0616] The erdafitinib is released from the system.

[0617] 125. The method of embodiment 124, wherein the intravesical system is a drug delivery system according to any one of embodiments 73-118, and releasing the Erdafitinib from the system comprises releasing the Erdafitinib from the drug reservoir lumen via diffusion through the second wall structure.

[0618] 126. The method of any one of embodiments 124 or 125, wherein the system elasticity

[0619] The device is deformed into a low-profile deployed shape and inserted through the urethra and into the patient's bladder, and then assumes a relatively expanded retention shape within the bladder.

[0620] 127. A drug delivery system comprising:

[0621] a device configured for intravesical deployment; and

[0622] a pharmaceutical formulation disposed within the device and comprising erdafitinib,

[0623] wherein the system is configured to release the erdafitinib from the device after deployment of the drug delivery system within the bladder.

[0624] 128. The drug delivery system of embodiment 127, wherein the drug formulation comprises a plurality of tablets containing erdafitinib.

[0625] 129. The drug delivery system of embodiment 128, wherein the tablet comprises the solid pharmaceutical composition of any one of embodiments 1, 2, 3, and 14-68.

[0626] 130. The drug delivery system according to any one of embodiments 127 to 129, wherein the

[0627] The system is configured to release the erdafitinib by diffusion through the drug permeable portion of the device.

[0628] 131. A drug delivery system according to any one of embodiments 127 to 130, wherein the

[0629] The system is configured to release the erdafitinib at a release rate of about 1 mg / day to about 6 mg / day, such as 2 mg / day to 4 mg / day.

[0630] 132. A method of treating non-muscle invasive bladder cancer (NMIBC) or muscle invasive bladder cancer (MIBC) in a cancer patient, comprising:

[0631] A therapeutically effective amount of erdafitinib is locally delivered into the bladder of the patient.

[0632] 133. The method according to embodiment 132, wherein the locally delivering Erdafitinib comprises systemically releasing the Erdafitinib from the intravesical cavity at a release rate of about 1 mg / day to about 6 mg / day, such as 2 mg / day to 4 mg / day.

[0633] 134. The method of embodiment 133, wherein the intravesical system is maintained in the patient's bladder for up to 90 days and then optionally replaced with another intravesical system that releases erdafitinib.

[0634] 135. A method of treating a cancer patient with (i) recurrent, non-muscle invasive or muscle invasive urothelial bladder cancer, (ii) high-risk or intermediate-risk papillary urothelial bladder cancer, or (iii) muscle invasive urothelial bladder cancer staged cT2-T3a, comprising:

[0635] A therapeutically effective amount of erdafitinib is locally delivered into the bladder of the patient.

[0636] 136. The method of embodiment 131, wherein prior to local delivery of erdafitinib into the bladder, the patient undergoes transurethral resection of bladder tumor (TURBT) to reduce the total tumor size to less than or equal to 3 cm.

[0637] 137. The method according to embodiment 135 or 136, wherein said locally delivering Erdafitinib comprises systemically releasing said Erdafitinib from the intravesical cavity at a release rate of about 1 mg / day to about 6 mg / day, such as 2 mg / day to 4 mg / day.

[0638] 138. The method of embodiment 137, wherein the intravesical system is maintained in the patient's bladder for up to 90 days and then optionally replaced with another intravesical system that releases erdafitinib.

[0639] 139. A method of treating a Bacillus Calmette-Guérin (BCG)-naive patient with recurrent high-grade Ta / T1 urothelial bladder carcinoma within 18 months of completion of prior BCG therapy, the method comprising:

[0640] A therapeutically effective amount of erdafitinib is locally delivered into the bladder of the patient.

[0641] 140. The method according to embodiment 139, wherein the locally delivering erdafitinib comprises systemically releasing the erdafitinib from the intravesical cavity at a release rate of about 1 mg / day to about 6 mg / day, such as 2 mg / day to 4 mg / day.

[0642] 141. The method of embodiment 140, wherein the intravesical system is maintained in the patient's bladder for up to 90 days and then optionally replaced with another intravesical system that releases erdafitinib.

[0643] 142. The method according to any one of embodiments 132 to 141, wherein the erdafitinib

[0644] Local delivery into the bladder from a drug delivery system according to any one of embodiments 127 to 131.

[0645] 143. The method of any one of embodiments 132 to 142, wherein the patient has at least one FGFR2 gene alteration and / or FGFR3 gene alteration.

[0646] Additional Implementation Plans

[0647] 1. A method of treating bladder cancer having one or more FGFR gene alterations, the method comprising locally delivering erdafitinib to the bladder of a patient in need thereof in an amount effective to treat bladder cancer, wherein the one or more FGFR gene alterations are detected in a urine sample from the patient, in particular wherein the one or more FGFR gene alterations are detected in a urine sample from the patient using a urine-based PCR or NGS assay.

[0648] 2. A method of treating bladder cancer having one or more FGFR gene alterations, the method comprising, consisting of, or consisting essentially of: (a) assessing the presence of the one or more FGFR gene alterations in a urine sample from a bladder cancer patient, particularly assessing the presence of the one or more FGFR gene alterations in a urine sample from a bladder cancer patient using a urine-based PCR or NGS assay; and (b) locally delivering erdafitinib in the presence of the one or more FGFR gene alterations in the sample.

[0649] 3. A method of treating bladder cancer having one or more FGFR gene alterations, the method 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 detection of the one or more FGFR gene alterations in a urine sample from the patient, in particular wherein the patient is selected for treatment based on detection of the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR or NGS assay.

[0650] 4. A method of treating bladder cancer having one or more FGFR gene alterations, the method 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 the one or more FGFR gene alterations in a urine sample from the patient, particularly wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR or NGS assay.

[0651] 5. Erdafitinib for use in treating bladder cancer having one or more FGFR gene alterations in a patient, wherein Erdafitinib is delivered locally to the bladder of the patient, and wherein the one or more FGFR gene alterations are detected in a urine sample from the patient, in particular wherein the one or more FGFR gene alterations are detected in a urine sample from the patient using a urine-based PCR or NGS assay.

[0652] 6. Erdafitinib for use in treating bladder cancer having one or more FGFR gene alterations in a patient, said use comprising, consisting of, or consisting essentially of: (a) assessing a urine sample from a bladder cancer patient for the presence of said one or more FGFR gene alterations, particularly assessing a urine sample from a bladder cancer patient for the presence of said one or more FGFR gene alterations using a urine-based PCR or NGS assay; and (b) locally delivering Erdafitinib to said patient in the presence of said one or more FGFR gene alterations in said sample.

[0653] 7. Erdafitinib for use in treating bladder cancer having one or more FGFR gene alterations in a patient, wherein Erdafitinib is to be delivered locally to the bladder of the patient, and wherein the patient is selected for treatment based on detection of the one or more FGFR gene alterations in a urine sample from the patient, in particular wherein the patient is selected for treatment based on detection of the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR or NGS assay.

[0654] 8. Erdafitinib for use in treating bladder cancer having one or more FGFR gene alterations in a patient, wherein Erdafitinib is to be delivered locally to the bladder of the patient, and wherein the patient's eligibility to receive the treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient, in particular wherein the patient's eligibility to receive the treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR or NGS assay.

[0655] 9. Use of erdafitinib in the preparation of a medicament for treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is to be delivered locally to the bladder of the patient, and wherein the one or more FGFR gene alterations are detected in a urine sample from the patient, in particular wherein the one or more FGFR gene alterations are detected in a urine sample from the patient using a urine-based PCR or NGS assay.

[0656] 10. Use of erdafitinib in the preparation of a medicament for treating bladder cancer in a patient having one or more FGFR gene alterations, comprising, consisting of or consisting essentially of: (a) assessing the presence of said one or more FGFR gene alterations in a urine sample from a bladder cancer patient, in particular assessing the presence of said one or more FGFR gene alterations in a urine sample from a bladder cancer patient using a urine-based PCR or NGS assay; and (b) locally delivering erdafitinib in the presence of said one or more FGFR gene alterations in said sample.

[0657] 11. Use of erdafitinib in the preparation of a medicament for treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is to be delivered locally to the bladder of the patient, and wherein the patient is selected for treatment based on detection of the one or more FGFR gene alterations in a urine sample from the patient, in particular wherein the patient is selected for treatment based on detection of the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR or NGS assay.

[0658] 12. Use of erdafitinib in the preparation of a medicament for treating bladder cancer having one or more FGFR gene alterations in a patient, wherein erdafitinib is to be delivered locally to the bladder of the patient, and wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient, in particular wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR or NGS assay.

[0659] 13. The method, erdafitinib for use, or the use according to any one of the preceding embodiments, wherein the one or more FGFR gene alterations comprise one or more FGFR2 or FGFR3 gene alterations.

[0660] 14. The method, erdafitinib for use, or the use according to any one of the preceding embodiments, wherein the one or more FGFR genetic alterations comprise one or more FGFR2 or FGFR3 point mutations or fusions.

[0661] 15. The method, erdafitinib for use or the use according to any one of the preceding embodiments, wherein the one or more FGFR gene alterations are detected in a urine sample of the patient prior to local delivery of erdafitinib.

[0662] 16. The method, erdafitinib for use or use according to any one of the preceding embodiments, wherein erdafitinib is delivered topically in the form of a solid pharmaceutical composition, the solid

[0663] The pharmaceutical composition comprises:

[0664] (a) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole)]) at a concentration of at least 45% by weight of the solid pharmaceutical composition;

[0665] -4-yl)quinoxalin-6-yl]ethane-1,2-diamine); and

[0666] (b) at least one pharmaceutical excipient.

[0667] 17. The method, erdafitinib for use, or use according to embodiment 16, wherein the at least one pharmaceutical excipient comprises a solubilizer, a binder, a diluent (filler), a wetting agent, a disintegrant, a glidant, a lubricant, a formaldehyde scavenger, or any combination thereof.

[0668] 18. The method, erdafitinib for use or the use according to embodiment 16 or 17, wherein the 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 / or wherein the solid pharmaceutical composition comprises an intragranular solid composition comprising at least one intragranular pharmaceutical excipient and an extragranular solid composition comprising at least one extragranular pharmaceutical excipient, and wherein the at least one extragranular pharmaceutical excipient comprises microcrystalline cellulose and vinylpyrrolidone-vinyl acetate copolymer, in particular in a weight ratio of 50:50.

[0669] 19. The method, erdafitinib for use, or the use according to any one of embodiments 16 to 18, 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, pyrrolysine, asparagine, glutamine, tris(hydroxymethyl)aminomethane, a conjugate thereof, a pharmaceutically acceptable salt thereof, or any combination thereof.

[0670] 20. The method, erdafitinib for use or the use according to embodiment 19, wherein the formaldehyde scavenger is meglumine.

[0671] 21. The method, 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 wt% to 5 wt%, 0.05 wt% to 3 wt%, 0.1 wt% to 2 wt%, 0.5 wt% to 1.5 wt%, or about 1 wt%.

[0672] 22. The method, erdafitinib for use, or the use according to any one of embodiments 16 to 21, 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-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutyl ether-β-cyclodextrin sodium salt, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose E5 (HPMC-E5), or any combination thereof.

[0673] 23. The method, erdafitinib for use or the use according to embodiment 22, wherein the solubilizing agent is hydroxypropyl-β-cyclodextrin.

[0674] 24. The method, 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 wt% to 20 wt%, 5 wt% to 15 wt%, 7 wt% to 12 wt%, or about 10 wt%.

[0675] 25. The method, erdafitinib for use, or the use according to any one of embodiments 16 to 24, 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.

[0676] 26. The method, erdafitinib for use, or the use according to embodiment 25, wherein the total concentration of the at least one binder in the solid pharmaceutical composition is 5 wt% to 30 wt%, 10 wt% to 25 wt%, 12 wt% to 22 wt%, or 14 wt% to 19 wt%.

[0677] 27. The method, erdafitinib for use, or the use according to any one of embodiments 16 to 26, 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.

[0678] 28. The method, erdafitinib for use, or the use according to embodiment 27, wherein the wetting agent comprises sodium lauryl sulfate, sodium stearyl fumarate, polysorbate 80, docusate sodium, or any combination thereof.

[0679] 29. The method, 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 wt% to 2.5 wt%, 0.05 wt% to 1.0 wt%, or 0.1 wt% to 0.5 wt%.

[0680] 30. The method, erdafitinib for use, or the use according to any one of embodiments 1 to 29, 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.

[0681] 31. The method, erdafitinib for use, or the use according to embodiment 30, wherein the disintegrant comprises hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, crospovidone (cross-linked polyvinyl pyrrolidone), croscarmellose sodium (cross-linked sodium carboxymethyl cellulose), sodium starch glycolate, or any combination thereof.

[0682] 32. The method, 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 wt% to 3 wt%, 0.5 wt% to 2.5 wt%, 1 wt% to 2 wt%, or about 1.5 wt%.

[0683] 33. The method, erdafitinib for use, or the use according to any one of embodiments 16 to 32, 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.

[0684] 34. The method, erdafitinib for use, or the use according to embodiment 33, wherein the diluent comprises lactose (lactose monohydrate), dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, dibasic calcium phosphate, anhydrous dibasic calcium phosphate, calcium carbonate, sucrose, or any combination thereof.

[0685] 35. The method, erdafitinib for use, or the use according to embodiment 33 or 34, wherein the total concentration of the diluent in the solid pharmaceutical composition is 12 wt% to 30 wt%, 15 wt% to 25 wt%, or 18 wt% to 22 wt%.

[0686] 36. The method, erdafitinib for use, or the use according to any one of embodiments 16 to 35, 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 glidant.

[0687] 37. The method, erdafitinib for use, or the use according to embodiment 36, wherein the glidant comprises colloidal silicon dioxide, colloidal anhydrous silicon dioxide, talc, or any combination thereof.

[0688] 38. The method, erdafitinib for use, or use according to embodiment 36 or 37, wherein the total concentration of the glidant in the solid pharmaceutical composition is 0.01 wt% to 5 wt%, 0.05 wt% to 3 wt%, 0.1 wt% to 1 wt%, or about 0.5 wt%.

[0689] 39. The method, erdafitinib for use, or the use according to any one of embodiments 16 to 38, 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.

[0690] 40. The method, erdafitinib for use, or the use according to embodiment 39, wherein the lubricant comprises magnesium stearate, stearic acid, magnesium silicate, aluminum silicate, isopropyl myristate, sodium oleate, sodium stearoyl lactylate, sodium stearyl fumarate, titanium dioxide, or a combination thereof.

[0691] 41. The method, 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 wt% to 5 wt%, 0.1 wt% to 3 wt%, 1 wt% to 2 wt%, or about 1.5 wt%.

[0692] 42. The method, erdafitinib for use, or the use according to any one of embodiments 16 to 41, wherein the solid pharmaceutical composition is a minitablet.

[0693] 43. The method, erdafitinib for use, or use according to embodiment 42, wherein the minitablet is in the form of a solid cylinder having a cylindrical axis, a cylindrical side, a circular end face perpendicular to the cylindrical axis, a diameter through the circular end face, and a length along the cylindrical side face.

[0694] 44. The method, erdafitinib for use, or use according to embodiment 43, wherein the length of the microtablet exceeds the diameter of the microtablet to provide the microtablet with an aspect ratio (length:diameter) greater than 1:1.

[0695] 45. The method, erdafitinib for use, or the use according to embodiment 43 or 44, wherein the minitablet has a diameter of 1.0 mm to 3.2 mm, or 1.5 mm to 3.1 mm.

[0696] 46. ​​The method, erdafitinib for use, or the use according to any one of embodiments 16, 42 to 45, wherein the solid pharmaceutical composition consists essentially of:

[0697] (a) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition;

[0698] (b) hydroxypropyl-β-cyclodextrin at a concentration of 10% by weight of the solid pharmaceutical composition;

[0699] (c) meglumine at a concentration of 1% by weight of the solid pharmaceutical composition;

[0700] (d) microcrystalline cellulose at a concentration of 17.5% by weight of the solid pharmaceutical composition;

[0701] (e) silicified microcrystalline cellulose at a concentration of 10.75% by weight of the solid pharmaceutical composition;

[0702] (f) vinyl pyrrolidone-vinyl acetate copolymer at a concentration of 7.5% by weight of the solid pharmaceutical composition;

[0703] (g) colloidal silicon dioxide at a concentration of 0.25% by weight of the solid pharmaceutical composition;

[0704] (h) hydroxypropyl methylcellulose at a concentration of 1.5% by weight of the solid pharmaceutical composition; and

[0705] (i) magnesium stearate at a concentration of 1.5% by weight of the solid pharmaceutical composition; or wherein the solid pharmaceutical composition comprises:

[0706] (a) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition;

[0707] (b) hydroxypropyl-β-cyclodextrin;

[0708] (c) meglumine;

[0709] (d) microcrystalline cellulose;

[0710] (e) silicified microcrystalline cellulose;

[0711] (f) vinylpyrrolidone-vinyl acetate copolymer;

[0712] (g) colloidal silicon dioxide;

[0713] (h) hydroxypropyl methylcellulose; and

[0714] (i) Magnesium stearate.

[0715] 47. The method, erdafitinib for use, or the use according to any one of embodiments 16, 42 to 45, wherein the solid pharmaceutical composition comprises:

[0716] (a) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition;

[0717] (b) hydroxypropyl-β-cyclodextrin at a concentration of 10% by weight of the solid pharmaceutical composition;

[0718] (c) microcrystalline cellulose at a concentration of 17.5% by weight of the solid pharmaceutical composition;

[0719] (d) silicified microcrystalline cellulose at a concentration of 11.75% by weight of the solid pharmaceutical composition;

[0720] (e) vinyl pyrrolidone-vinyl acetate copolymer at a concentration of 7.5% by weight of the solid pharmaceutical composition;

[0721] (f) colloidal silicon dioxide at a concentration of 0.25% by weight of the solid pharmaceutical composition;

[0722] (g) hydroxypropyl methylcellulose at a concentration of 1.5% by weight of the solid pharmaceutical composition; and

[0723] (h) magnesium stearate at a concentration of 1.5% by weight of the solid pharmaceutical composition; or wherein the solid pharmaceutical composition comprises:

[0724] (a) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition;

[0725] (b) hydroxypropyl-β-cyclodextrin;

[0726] (c) microcrystalline cellulose;

[0727] (d) silicified microcrystalline cellulose;

[0728] (e) vinylpyrrolidone-vinyl acetate copolymer;

[0729] (f) colloidal silicon dioxide;

[0730] (g) hydroxypropyl methylcellulose; and

[0731] (h) Magnesium stearate.

[0732] 48. The method, erdafitinib for use or the use according to any one of embodiments 1 to 15, wherein erdafitinib is delivered locally in the form of a drug delivery system comprising:

[0733] a housing defining an enclosed drug reservoir lumen bounded by a first wall structure formed from a first material and a second wall structure formed from a second material, the first wall structure and the second wall structure being adjacent to each other at two interfacial edges and together forming a tube defining the enclosed drug reservoir lumen, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and

[0734] a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising erdafitinib,

[0735] wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, such that erdafitinib can be released in vivo by diffusion through the second material forming the second wall structure.

[0736] 49. The method, erdafitinib for use or the use according to any one of embodiments 1 to 15, wherein erdafitinib is delivered locally in the form of a drug delivery system comprising:

[0737] a housing defining an enclosed drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, the first wall structure and the second wall structure being adjacent to each other at two interfacial edges and together forming a tube defining the enclosed drug reservoir lumen, wherein the first material comprises an aromatic polyester hydrocarbon-based thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and

[0738] a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising erdafitinib,

[0739] wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, such that erdafitinib can be released in vivo by diffusion through the second wall structure.

[0740] 50. The method, erdafitinib for use, or the use according to embodiment 48 or 49, wherein the second wall structure forms a longitudinal strip extending along the length of the tube.

[0741] 51. The method, Erdafitinib for use or the use according to any one of embodiments 48 to 50, wherein the drug delivery system is configured to release Erdafitinib over a period of 2 days to 6 months.

[0742] 52. The method, erdafitinib for use, or the use according to any one of embodiments 48 to 51, wherein the two interface edges are disposed at an arc angle of 15 to 270 degrees of the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube.

[0743] 53. The method, erdafitinib for use or the use according to any one of embodiments 48 to 52, wherein the drug delivery system is configured to release the erdafitinib at an average rate of 1 mg / day to 10 mg / day.

[0744] 54. The method, erdafitinib for use, or use according to embodiment 53, wherein the two interface edges are disposed at an arc angle of 45 to 90 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube.

[0745] 55. The method, erdafitinib for use, or use according to embodiment 53, wherein the two interface edges are disposed at an arc angle of 150 to 270 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube.

[0746] 56. The method, erdafitinib for use, or the use according to any one of embodiments 48 to 52, wherein the system is configured to release the erdafitinib at an average rate of 2 mg / day.

[0747] 57. The method, erdafitinib for use, or use according to embodiment 56, wherein the two interface edges are disposed at an arc angle of about 90 degrees of the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube.

[0748] 58. The method, erdafitinib for use, or the use according to any one of embodiments 48 to 52, wherein the system is configured to release the erdafitinib at an average rate of 4 mg / day.

[0749] 59. The method, erdafitinib for use, or use according to embodiment 58, wherein the two interface edges are disposed at an arc angle of about 180 degrees of the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube.

[0750] 60. The method, erdafitinib for use, or the use according to any one of embodiments 48 to 59, wherein the system comprises 500 mg of erdafitinib.

[0751] 61. The method, erdafitinib for use or the use according to any one of embodiments 48 to 60, wherein the release profile of erdafitinib is substantially pH independent in the pH range of 5 to 7.

[0752] 62. The method, erdafitinib for use, or the use according to any one of embodiments 48 to 61, wherein the second wall structure occupies less than 50% of the cross-sectional area of ​​the tube in a cross section perpendicular to the longitudinal axis of the tube.

[0753] 63. The method, erdafitinib for use, or the use according to any one of embodiments 48 to 62, wherein the second wall structure occupies less than 25% of the cross-sectional area of ​​the tube in a cross section perpendicular to the longitudinal axis of the tube.

[0754] 64. The method, erdafitinib for use, or the use according to any one of embodiments 48 to 63, wherein the tube has a substantially constant thickness over its circumference.

[0755] 65. The method, erdafitinib for use, or the use according to any one of embodiments 48 to 64, further comprising a pair of end plugs and / or adhesive material sealing the ends of the tube.

[0756] 66. The method, erdafitinib for use, or the use according to any one of embodiments 48 to 65, wherein the first wall structure and the second wall structure are integrally formed.

[0757] 67. The method, erdafitinib for use, or use of any one of embodiments 48 to 66, wherein the system is elastically deformable between a relatively straightened deployed shape suitable for insertion through a patient's urethra and into the patient's bladder and a retention shape suitable for retaining the system within the bladder.

[0758] 68. The method, erdafitinib for use, or use of any one of embodiments 48 to 67, wherein the system is elastically deformable and comprises overlapping coils formed by the tube, and the tube has two opposing free ends that are directed away from each other when the system is in a low-profile deployed shape and directed toward each other when the system is in a relatively expanded retention shape.

[0759] 69. The method, erdafitinib for use, or use according to any one of embodiments 48 to 68, wherein the system is elastically deformable and has a bi-oval retention shape, and the tube has two opposing free ends that are located within the outer boundary of the bi-oval retention shape.

[0760] 70. The method, erdafitinib for use, or the use according to any one of embodiments 48 to 69, further comprising maintaining the framework lumen.

[0761] 71. The method, erdafitinib for use, or the use according to any one of embodiments 48 to 70, wherein the first material has a Shore durometer value of 70A to 80A.

[0762] 72. The method, erdafitinib for use or the use according to any one of embodiments 48 to 71, wherein the pharmaceutical formulation comprises a solid pharmaceutical composition as defined in any one of embodiments 16 to 47.

[0763] 73. The method, erdafitinib for use, or the use according to any one of embodiments 48 to 72, wherein the drug formulation is in the form of a plurality of mini-tablets arranged serially in the drug lumen.

[0764] 74. The method, erdafitinib for use or use according to embodiment 73, wherein the plurality of minitablets comprises minitablets as defined in any one of embodiments 43 to 45.

[0765] 75. The method, erdafitinib for use or the use according to any one of embodiments 1 to 15, wherein erdafitinib is delivered locally in the form of a drug delivery system comprising:

[0766] 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; and

[0767] a drug formulation disposed in the lumen of the drug reservoir, the drug formulation comprising erdafitinib,

[0768] wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib can be released in vivo by diffusion through the second material forming the second wall structure.

[0769] 76. The method, erdafitinib for use, or use according to embodiment 75, wherein the first wall structure and the second wall structure are adjacent to each other at two interfacial 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 interfacial edges are arranged at an arc angle of about 90 degrees from the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube, (ii) the drug delivery system is configured to release the erdafitinib at an average rate of 4 mg / day, and the two interfacial edges are arranged at an arc angle of about 180 degrees from 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 interfacial edges are arranged at an arc angle of 240 degrees.

[0770] 77. The method, erdafitinib for use, or use according to embodiment 75 or 76, wherein the system is elastically deformable and comprises overlapping curls formed by the tube, and the tube has two opposing free ends that are directed away from each other when the system is in a low-profile deployed shape and directed toward each other when the system is in a relatively expanded retention shape.

[0771] 78. The method, erdafitinib for use or the use according to any one of embodiments 1 to 15, wherein erdafitinib is delivered locally in the form of a drug delivery system comprising:

[0772] a housing defining an enclosed drug reservoir lumen bounded by a first wall structure formed from a first material and a second wall structure formed from a second material, the first and second wall structures being adjacent to one another at two interfacial edges and together forming a tube defining the enclosed drug reservoir lumen, the second wall structure forming a longitudinal strip extending along the length of the tube, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and

[0773] a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising a solid pharmaceutical composition according to any one of embodiments 16 to 47,

[0774] 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,...

Claims

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

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

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

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

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

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

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

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

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 or FGFR3 gene alterations.

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

11. Erdafitinib for use according to any one of claims 1 to 10, wherein the one or more FGFR gene alterations are detected in a urine sample of the patient prior to 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, wherein FGFR3-TACC3 is FGFR3-TACC3 variant 1 (FGFR3-TACC3 V1) or FGFR3-TACC3 variant 3 (FGFR3-TACC3V3), FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof.

13. Erdafitinib for use according to claim 12, wherein the FGFR2 gene alteration and / or the FGFR3 gene alteration is selected from FGFR3-TACC3 variant 1 (FGFR3-TACC3V1), FGFR3 G370C, FGFR3 S249C, FGFR3 Y373C and FGFR3 R248C.

14. Erdafitinib for use according to any one of claims 1 to 13, wherein Erdafitinib is delivered locally in the form of a solid pharmaceutical composition comprising: (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of at least 45% by weight of the solid pharmaceutical composition; and (b) 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 glidant, a lubricant, a formaldehyde scavenger, or any combination thereof.

16. Erdafitinib for use according to claim 14 or 15, wherein the 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 / or wherein the solid pharmaceutical composition comprises an intragranular solid composition comprising at least one intragranular pharmaceutical excipient and an extragranular solid composition comprising at least one extragranular pharmaceutical excipient, and 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, pyrrolysine, asparagine, glutamine, tris(hydroxymethyl)aminomethane, their conjugates, their pharmaceutically acceptable salts, or any combination thereof.

19. 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 wt% to 5 wt%, 0.05 wt% to 3 wt%, 0.1 wt% to 2 wt%, 0.5 wt% to 1.5 wt%, or about 1 wt%.

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-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sulfobutyl ether-β-cyclodextrin sodium salt, hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose E5 (HPMC-E5) or any combination thereof.

22. Erdafitinib for use according to claim 21, wherein the solubilizing agent is hydroxypropyl-β-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 wt% to 20 wt%, 5 wt% to 15 wt%, 7 wt% to 12 wt%, or about 10 wt%.

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 polyvinyl pyrrolidone (PVP), poly(vinyl acetate) (PVA), vinyl pyrrolidone-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 wt% to 30 wt%, 10 wt% to 25 wt%, 12 wt% to 22 wt%, or 14 wt% to 19 wt%.

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, docusate sodium, 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 wt% to 2.5 wt%, 0.05 wt% to 1.0 wt%, or 0.1 wt% to 0.5 wt%.

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 hydroxypropyl cellulose, crospovidone (cross-linked polyvinyl pyrrolidone), croscarmellose sodium (cross-linked sodium carboxymethyl cellulose), 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 wt% to 3 wt%, 0.5 wt% to 2.5 wt%, 1 wt% to 2 wt%, or about 1.5 wt%.

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, dibasic calcium phosphate, anhydrous dibasic calcium 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 wt% to 30 wt%, 15 wt% to 25 wt%, or 18 wt% to 22 wt%.

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 glidant.

36. Erdafitinib for use according to claim 35, wherein the glidant 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 glidant in the solid pharmaceutical composition is 0.01 wt% to 5 wt%, 0.05 wt% to 3 wt%, 0.1 wt% to 1 wt%, or about 0.5 wt%.

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. Erdafitinib for use according to claim 38, wherein the lubricant comprises magnesium stearate, stearic acid, magnesium silicate, aluminum silicate, isopropyl myristate, sodium oleate, sodium stearoyl lactylate, 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 wt% to 5 wt%, 0.1 wt% to 3 wt%, 1 wt% to 2 wt%, or about 1.5 wt%.

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 minitablet is in the form of a solid cylinder having a cylindrical axis, a cylindrical side, a circular end face perpendicular to the cylindrical axis, a diameter passing through the circular end face, and a length along the cylindrical side face.

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

1.

44. Erdafitinib for use according to claim 42 or 43, wherein the minitablet has a diameter of 1.0 mm to 3.2 mm, or 1.5 mm to 3.1 mm.

45. Erdafitinib for use according to any one of claims 14 or 41 to 44, wherein the solid pharmaceutical composition comprises: (a) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition; (b) hydroxypropyl-β-cyclodextrin; (c) meglumine; (d) microcrystalline cellulose; (e) silicified microcrystalline cellulose; (f) vinylpyrrolidone-vinyl acetate copolymer; (g) colloidal silicon dioxide; (h) hydroxypropyl methylcellulose; and (i) Magnesium stearate.

46. ​​Erdafitinib for use according to any one of claims 14, 41 to 44, wherein the solid pharmaceutical composition consists essentially of: (a) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition; (b) hydroxypropyl-β-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) vinyl pyrrolidone-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; and (i) magnesium stearate at a concentration of 1.5% by weight of the solid pharmaceutical composition.

47. Erdafitinib for use according to any one of claims 14, 41 to 44, wherein the solid pharmaceutical composition comprises: (a) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition; (b) hydroxypropyl-β-cyclodextrin; (c) microcrystalline cellulose; (d) silicified microcrystalline cellulose; (e) vinylpyrrolidone-vinyl acetate copolymer; (f) colloidal silicon dioxide; (g) hydroxypropyl methylcellulose; and (h) Magnesium stearate.

48. Erdafitinib for use according to any one of claims 14, 41 to 44, wherein the solid pharmaceutical composition comprises: (a) Erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the solid pharmaceutical composition; (b) hydroxypropyl-β-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) vinyl pyrrolidone-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; and (h) magnesium stearate at a concentration of 1.5% by weight of the solid pharmaceutical composition.

49. Erdafitinib for use according to any one of claims 1 to 13, wherein Erdafitinib is delivered locally in the form of a drug delivery system comprising: a housing defining an enclosed drug reservoir lumen bounded by a first wall structure formed from a first material and a second wall structure formed from a second material, the first wall structure and the second wall structure being adjacent to each other at two interfacial edges and together forming a tube defining the enclosed drug reservoir lumen, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, such that erdafitinib can be released in vivo by diffusion through the second material forming the second wall structure.

50. Erdafitinib for use according to any one of claims 1 to 13, wherein Erdafitinib is delivered locally in the form of a drug delivery system comprising: a housing defining a closed drug reservoir lumen bounded by a first wall structure formed from a first material and a second wall structure formed from a second material, the first wall structure and the second wall structure being adjacent to each other at two interfacial edges and together forming a tube defining the closed drug reservoir lumen, wherein the first material comprises an aromatic polyester hydrocarbon-based thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, such that erdafitinib can be released in vivo by diffusion through the second wall structure.

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

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. Erdafitinib for use according to any one of claims 49 to 52, wherein the two interface edges are arranged at an arc angle of 15 to 270 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube.

54. 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. Erdafitinib for use according to claim 54, wherein the two interface edges are arranged at an arc angle of 45 to 90 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube.

56. Erdafitinib for use according to claim 54, wherein the two interface edges are arranged at an arc angle of 150 to 270 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube.

57. Erdafitinib for use according to claim 54, wherein the two interface edges are arranged at an arc angle of 90 to 180 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube.

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

59. 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. Erdafitinib for use according to claim 59, wherein the two interface edges are arranged at an arc angle of about 90 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube.

61. 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. Erdafitinib for use according to claim 61, wherein the two interface edges are arranged at an arc angle of about 180 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube.

63. Erdafitinib for use according to any one of claims 49 to 62, wherein the system comprises 500 mg of Erdafitinib.

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

65. Erdafitinib for use according to any one of claims 49 to 64, wherein the second wall structure occupies less than 50% of the cross-sectional area of ​​the tube in a cross section perpendicular to the longitudinal axis of the tube; or wherein the second wall structure occupies less than 25% of the cross-sectional area of ​​the tube in a cross section perpendicular to the longitudinal axis of the tube.

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

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

68. Erdafitinib for use according to any one of claims 49 to 67, wherein the system is elastically deformable and comprises overlapping coils formed by the tubes, and the tubes have two opposing free ends that are directed away from each other when the system is in a low-profile deployed shape and directed towards each other when the system is in a relatively expanded retention shape.

69. Erdafitinib for use according to any one of claims 49 to 68, wherein the system is elastically deformable and has a biovoid retention shape, and the tube has two opposing free ends located within the outer boundaries of the biovoid retention shape.

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

71. Erdafitinib 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 pharmaceutical formulation comprises a solid pharmaceutical composition as defined in 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 mini-tablets arranged serially in the drug lumen.

74. Erdafitinib for use according to claim 73, wherein the plurality of minitablets comprises a minitablet as defined in any one of claims 42 to 44.

75. Erdafitinib for use according to any one of claims 1 to 13, wherein Erdafitinib is delivered locally in the form of a drug delivery system comprising: 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; and a drug formulation disposed in the lumen of the drug reservoir, the drug formulation comprising erdafitinib, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib can 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 interfacial 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 interfacial edges are arranged at an arc angle of about 90 degrees from the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube, (ii) the drug delivery system is configured to release the erdafitinib at an average rate of 4 mg / day, and the two interfacial edges are arranged at an arc angle of about 180 degrees from 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 interfacial edges are arranged at an arc angle of 240 degrees.

77. Erdafitinib for use according to claim 75 or 76, wherein the system is elastically deformable and comprises overlapping coils formed by the tubes, and the tubes have two opposing free ends that are directed away from each other when the system is in a low-profile deployed shape and directed towards each other when the system is in a relatively expanded retention shape.

78. Erdafitinib for use according to any one of claims 1 to 13, wherein Erdafitinib is delivered locally in the form of a drug delivery system comprising: a housing defining an enclosed drug reservoir lumen bounded by a first wall structure formed from a first material and a second wall structure formed from a second material, the first and second wall structures being adjacent to one another at two interfacial edges and together forming a tube defining the enclosed drug reservoir lumen, the second wall structure forming a longitudinal strip extending along the length of the tube, wherein the first material comprises a polycarbonate-based aromatic thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising a solid pharmaceutical composition according to any one of claims 14 to 48, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib can be released in vivo by diffusion through the second material forming the second wall structure, wherein the drug delivery system is configured to release a therapeutically effective amount of erdafitinib at a substantially zero-order release rate over at least 3 days, and wherein (i) the drug delivery system is configured to release the erdafitinib at an average rate of 2 mg / day, and the two interface edges are disposed at an arc angle of approximately 90 degrees from the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube, (ii) the drug delivery system is configured to release the erdafitinib at an average rate of 4 mg / day, and the two interface edges are disposed at an arc angle of approximately 180 degrees from the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube, or (iii) the drug delivery system is configured to release the erdafitinib at an average rate of 6 mg / day, and the two interface edges are disposed at an arc angle of 240 degrees.

79. Erdafitinib for use according to any one of claims 1 to 13, wherein Erdafitinib is delivered locally in the form of a drug delivery system comprising: a housing defining an enclosed drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being adjacent to one another at two interfacial edges and together forming a tube defining the enclosed drug reservoir lumen, the second wall structure forming a longitudinal strip extending along the length of the tube, wherein the first material comprises an aromatic polyester hydrocarbon-based thermoplastic polyurethane and the second material comprises an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the closed drug reservoir lumen, the drug formulation comprising a solid pharmaceutical composition according to any one of claims 14 to 48, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to the erdafitinib and the second wall structure is permeable to the erdafitinib, such that the erdafitinib can be released in vivo by diffusion through the second wall structure, wherein the drug delivery system is configured to release a therapeutically effective amount of erdafitinib at a substantially zero-order release rate over at least 3 days, and wherein (i) the drug delivery system is configured to release the erdafitinib at an average rate of 2 mg / day, and the two interfacial edges are disposed at an arc angle of approximately 90 degrees from 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 interfacial edges are disposed at an arc angle of approximately 180 degrees from 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 pharmaceutical formulation comprises a solid pharmaceutical formulation according to any one of claims 45-46.

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

83. Erdafitinib 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. Erdafitinib 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; an ultimate tensile (psi) of about 8300; an ultimate elongation (%) (D412) of about 400; 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 mold shrinkage (in / in) (1" x 0.25" x 6" bar) of about 0.

011.

85. Erdafitinib for use according to any one of claims 49 to 84, wherein the second material has a Shore durometer of about 72A; a specific gravity of about 1.04; a flexural modulus (psi) of 1,000; an ultimate tensile (psi) of about 5,800; an ultimate elongation (%) (D412) of about 660; 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 mold shrinkage (in / in) of about 0.008-0.0012.

86. Erdafitinib for use according to any one of claims 49 to 83, wherein the first material has a Shore durometer of about 79A; a specific gravity of about 1.03; an ultimate tensile (psi) of about 2000; an ultimate 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; Flexural modulus (psi) of about 2500 (ASTM 790); Vicat softening point (°C) of about 75; and a mold shrinkage of approximately 0.08 (in / in) (1"x0.25"x6" bar).

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