Treatment method for bladder cancer using intravesical administration of erdafitinib

Abstract

A treatment method comprising the step of administering erdafitinib for use in the treatment of bladder cancer and a drug delivery system comprising erdafitinib are provided herein.

Description

Technology Field

[0001] Cross-reference regarding related applications

[0002] This application is U.S. Provisional Application No. 63 / 582,833 filed September 14, 2023; No. 63 / 582,835 filed September 14, 2023; No. 63 / 583,820 filed September 19, 2023; No. 63 / 590,367 filed October 13, 2023; No. 63 / 590,368 filed October 13, 2023; No. 63 / 590,370 filed October 13, 2023; No. 63 / 590,376 filed October 13, 2023; No. 63 / 623,192 filed January 19, 2024; Claiming priority and benefit of No. 63 / 561,725 ​​filed on March 5, 2024; No. 63 / 566,181 filed on March 15, 2024; No. 63 / 640,816 filed on April 30, 2024; and No. 63 / 691,878 filed on September 6, 2024, the contents of each of which are incorporated herein by reference in their entirety.

[0003] Mention of electronic sequence list

[0004] The contents of the electronic sequence list (761662002540seqlist.xml; size: 53,246 bytes; date of creation: August 28, 2024) are incorporated herein by reference in their entirety.

[0005] Technology field

[0006] The present disclosure generally falls within the field of bladder cancer treatment methods. Background Technology

[0007] The present disclosure generally falls within the field of pharmaceutical formulations and drug-device combination products, and more specifically relates to erdafitinib-based formulations and systems for intravesical administration of such formulations.

[0008] Erdafitinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazole-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 International Publication WO 2011 / 135376. Erdafitinib has been shown to inhibit FGFR phosphorylation and signaling, and to reduce cell viability in cell lines expressing FGFR gene variants, including point mutations, amplification, and fusion. Erdafitinib has demonstrated antitumor activity in FGFR-expressing cell lines and in xenograft models derived from tumor types, including bladder cancer.

[0009] Currently, erdafitinib (BALVERSA®) 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 that has a susceptible fibroblast growth factor receptor (FGFR)3 or FGFR2 gene mutation and has progressed during or after at least one line of previous platinum-containing chemotherapy (including neoadjuvant or adjuvant platinum-containing chemotherapy within 12 months).

[0010] Individuals with high-risk NMIBC are often treated with BCG initially, but up to 50% of patients experience recurrence. A subset of patients may undergo radical cystectomy, but the utility of radical cystectomy is limited due to high morbidity and reduced quality of life.

[0011] A method for treating high-risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient with recurrent Bacillus Calmette-Guerin (BCG)-experience, comprising the step of locally administering erdafitinib to the patient's bladder, is provided herein. Additionally, a method for treating intermediate-risk non-muscle invasive bladder cancer (IR-NMIBC) in a patient is provided herein, comprising the step of locally administering erdafitinib to the patient's bladder.

[0012] In some embodiments, a drug delivery system is provided herein, the system comprising: a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and a second wall structure formed of a second material comprising an aliphatic polyether-based thermoplastic polyurethane; A drug formulation comprising erdafitinib, which is disposed in a drug reservoir lumen and comprises (i) a second wall structure, or both the first wall structure and the second wall structure are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through a second material forming the second wall structure, and the first wall structure and the second wall structure are adjacent to each other at two interfacial edges and together form a tube, and the drug delivery system is configured to release erdafitinib at an average rate of about 2.5 mg / day to about 3.5 mg / day, and the two interfacial edges are arranged at an arc angle of about 125 to about 145 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, and the arc angle corresponds to the second wall structure.

[0013] In some embodiments, a drug delivery system is provided herein, the system comprising: a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and a second wall structure formed of a second material comprising an aliphatic polyether-based thermoplastic polyurethane; A drug formulation comprising erdafitinib is placed in a drug reservoir lumen and comprises (i) a second wall structure, or both the first wall structure and the second wall structure are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through a second material forming the second wall structure, and the first wall structure and the second wall structure are adjacent to each other at two interfacial edges and together form a tube, and the drug delivery system is configured to release erdafitinib at an average rate of about 3 mg / day, and the two interfacial edges are arranged at an arc angle of about 135 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, and the arc angle corresponds to the second wall structure. Brief explanation of the drawing

[0014] Detailed descriptions are provided with reference to the attached 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 illustrated 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 a fixed scale. Fig. 1 is a cross-sectional view of one embodiment of a drug delivery system having a coiled retention shape according to the present disclosure. Fig. 2 is a cross-sectional view of one embodiment of a drug delivery system according to the present disclosure. Fig. 3is a cross-sectional view of one embodiment of a drug delivery system according to the present disclosure. Fig. 4 This is a photograph of one embodiment of a drug delivery system loaded with an erdafitinib drug tablet according to the present disclosure. Fig. 5 This is a cross-sectional view of one embodiment of a drug delivery system having an elastic retention frame having a coil-shaped structure before loading a drug tablet, according to the present disclosure. Fig. 6a This is a cross-sectional view of one embodiment of an elastic retaining frame having a coil retaining shape according to the present disclosure. Fig. 6b Is Fig. 6a This is a partial enlarged view of one end of the retaining frame. Fig. 7a This is a perspective view of one embodiment of a drug delivery system having a relatively straightened shape, elastic retaining frame, or a state without a drug placed inside, according to the present disclosure. Fig. 7b is line 7B-7B Taken according to, Fig. 7a This is a cross-sectional view of the drug delivery system illustrated in [figure]. Fig. 7c is line 7C-7C Taken according to, Fig. 7a This is a cross-sectional view of the drug delivery system illustrated in [figure]. Fig. 8 This is a photograph showing a cross-section of a drug reservoir lumen of a drug delivery system in a state without a drug placed inside, according to the present disclosure. Fig. 9a represents two doses for erdafitinib treatment (TAR-210-B, approx. 2 mg / day; TAR-210-D, approx. 4 mg / day) and participants from two cohorts treated in the clinical study described in Example 1 of the present invention. Fig. 9b represents a clinical protocol for the administration of erdafitinib. TURBT, transurethral bladder tumor resection as described in Example 1 of the present invention. Fig. 10This represents a summary of the demographics of 43 patients (16 patients in Cohort 1 and 27 patients in Cohort 3) treated in the clinical study described in Example 1, Part A of the present invention. FIGS. 11a and FIGS. 11b This represents a summary of baseline disease characteristics for 43 patients treated in the clinical study described in Example 1, Part A of the present invention. Fig. 12a This is a pool lane plot of the treatment duration and response of patients in Cohort 1 of the clinical study described in Example 1, Part A of the present invention, who were treated with TAR-210-B (approx. 2 mg / day erdafitinib; diagonal line) or TAR-210-D (approx. 4 mg / day erdafitinib; dot). It includes a legend describing the patients' treatment status and key time points. Non-CR, non-complete response; non-PD, non-progressive disease. Fig. 12b This is a pool lane plot of the treatment duration and response of patients in Cohort 3 of the clinical study described in Example 1, Part A of the present invention, who were treated with TAR-210-B (approx. 2 mg / day erdafitinib; diagonal line) or TAR-210-D (approx. 4 mg / day erdafitinib; dot). It includes a legend describing the patients' treatment status and key time points. Non-CR, non-complete response; non-PD, non-progressive disease. Fig. 13 This shows a summary of recurrence-free survival for 16 patients treated in Cohort 1 of the clinical study of Example 1, Part A. Fig. 14 This represents a summary of complete responses for 15 patients treated and showing therapeutic efficacy in Cohort 3 of the clinical study of Example 1, Part A. Fig. 15 This shows a summary of the duration of response for 13 patients who achieved a complete response in Cohort 3 of the clinical study of Example 1, Part A. Fig. 16It represents a summary of the treatment status for 43 patients treated in Cohort 1 and Cohort 3 of the clinical study described in Example 1, Part A, including ongoing study treatment, completed study treatment, and discontinued study treatment. Fig. 17 This shows a summary of adverse effects that occurred after administration in 43 patients treated in Cohort 1 and Cohort 3 of the clinical study described in Example 1, Part A. Fig. 18 This shows the quantified urine concentration (left) and quantified plasma concentration (right) of erdafitinib from patient samples after administration of TAR-210-B (dotted line) or TAR-210-D (solid line) in Example 1, Part A. Fig. 19a This is a schematic summary of the clinical study regarding the safety and efficacy of the intravesical drug delivery system (TAR-210) in the treatment of patients with intermediate-risk (IR) non-muscle-invasive bladder cancer (NMIBC) as described in Example 2. SOC, standard treatment; LG, low grade; MMC, mitomycin C; Gem, gemcitabine. Fig. 19b This is a schematic overview of the treatment phases of the clinical study described in Example 2. Patients are randomized in a 1:1 ratio and are treated with an intravesical drug delivery system (TAR-210) as described in Group A, or with gemcitabine or MMC for up to 1 year as described in Group B. TURBT, transurethral bladder tumor resection; CT, computed tomography; IV, intravenous; MRI, magnetic resonance imaging; EOT, termination of treatment. Fig. 20 This is a schematic overview of the histopathological and urinalysis agreement study using paired samples from bladder cancer patients in the Bladder BRIDGister clinical trial in Germany. Fig. 21 This is a heat map of gene mutations identified from matched urine NGS and FFPE tissue RT-PCR samples (bladder cancer patients from the Bladder BRIDGister clinical trial in Germany). Fig. 22aThis is a scatter plot of variant allele frequencies (VAF) between urine NGS (X-axis) and tissue ("FFPE") RT-PCR (Y-axis) variants matched for all identified gene variants, including somatic and germline variants. Fig. 22b is somatic cells FGFR3 This is a scatter plot of variant allele frequencies (VAF) between urine NGS (X-axis) and tissue ("FFPE") RT-PCR (Y-axis) variants matched for the variant. Fig. 23 This shows a flowchart comparing the urinalysis performance and tissue biopsy performance of all NMIBC patients (N=178) screened on the cut-off date. The patient is a patient from the first human subject study as described in Example 1. Fig. 24a This is a pool lane-shaped plot showing clinical efficacy data (treatment duration and response) for disease-evaluable HR-NMIBC patients in Cohort 1 who were screened by urine sample testing and / or tumor tissue sample testing and treated with the intravesical drug delivery system TAR-210-B (approx. 2 mg / day erdafitinib) or TAR-210-D (approx. 4 mg / day erdafitinib). The patients are from the initial human study as described in Example 1. A legend ("Registered"; left side of the figure) indicating patient enrollment by tumor tissue sample testing (left side of the legend) or urine sample testing (right side of the legend) is included with associated check marks. Another legend describing the patients' treatment status and key time points is included (right side of the figure). Fig. 24bThis is a pool lane-shaped plot showing clinical efficacy data (treatment duration and response) for disease-evaluable IR-NMIBC patients in Cohort 3 who were screened by urine sample testing and / or tumor tissue sample testing and treated with the intravesical drug delivery system TAR-210-B (approx. 2 mg / day erdafitinib) or TAR-210-D (approx. 4 mg / day erdafitinib). The patients are from the initial human study as described in Example 1. A legend ("Registered"; left side of the figure) indicating patient enrollment by tumor tissue testing (left side of the legend) or urine sample testing (right side of the legend) is included with associated check marks. Another legend describing the patients' treatment status and key time points is included (right side of the figure). Fig. 25 represents the distribution of pathogenic somatic variants for the 15 most frequent genes detected in urine from all evaluable samples. Del = deletion; UTR = untranslated region; Ins = insertion; CNV = copy number variant. FIGS. 26a to 26d This represents the updated protocol for the Phase 1 clinical trial of intravesical administration of erdafitinib of Example 1. Fig. 27a is a schematic plan view of one embodiment of a drug delivery system according to the present disclosure, illustrated in a coil holding shape. Fig. 27a In this, the part of the housing demarcating the drug reservoir lumen is shown to be translucent and shows the erdafitinib mini-tablet contained therein. Fig. 27b is illustrated in a coil holding shape, Fig. 27a This is a schematic lower plan view of the drug delivery system. Fig. 27b In this, the part of the housing demarcating the drug reservoir lumen is shown to be translucent and shows the erdafitinib mini-tablet contained therein. Fig. 28 silver Fig. 27a Taken along line AA, Fig. 27a This is a cross-sectional view of the drug delivery system. Fig. 29ais illustrated as a relatively linear insertion shape, Fig. 27a This is a schematic side view of the drug delivery system. Fig. 29a In this, the part of the housing demarcating the drug reservoir lumen is shown to be translucent and shows the erdafitinib mini-tablet contained therein. Fig. 29b is illustrated as a relatively linear insertion shape, Fig. 27a This is a side cross-sectional view of a part of the drug delivery system. Fig. 29b In this, the housing is shown in cross-section to indicate the erdafitinib mini-tablet located in the drug reservoir lumen and the retention frame located in the retention frame lumen, and the end of the drug delivery system is cut off. Fig. 30a This represents a summary of the demographics of 64 patients (21 patients in Cohort 1 and 43 patients in Cohort 3) treated in the clinical study described in Example 1, Part C of the present invention. Fig. 30b This represents a summary of baseline disease characteristics for 64 patients (21 patients in Cohort 1 and 43 patients in Cohort 3) treated in the clinical study described in Example 1, Part C of the present invention. Fig. 31a This is a pool lane plot of the treatment duration and response of patients in Cohort 1 of the clinical study described in Example 1, Part C of the present invention, who were treated with TAR-210-B (approx. 2 mg / day erdafitinib; circular pattern) or TAR-210-D (approx. 4 mg / day erdafitinib; dashed pattern). It includes a legend describing the patients' treatment status and key time points. RFS, relapse-free survival. Fig. 31bThis is a pool lane plot of the duration of treatment and response of patients in Cohort 3 of the clinical study described in Example 1, Part C of the present invention, who were treated with TAR-210-B (approx. 2 mg / day erdafitinib; circular pattern) or TAR-210-D (approx. 4 mg / day erdafitinib; dotted pattern). It includes a legend describing the patients' treatment status and key time points. DOR, duration of response; CR, complete response; nonCR, non-complete response; nonPD, non-progressive disease. Fig. 32a represents the urinary concentration of erdafitinib from patient samples after administration of TAR-210-B or TAR-210-D in Example 1, Part C. Fig. 32b represents the plasma concentration of erdafitinib from patient samples after administration of TAR-210-B or TAR-210-D in Example 1, Part C. Fig. 33 Example 4, Part B shows a pie chart demonstrating the proportion of patients eligible for efficacy evaluation registered by urine and tissue samples for patients in Cohort 1 (HR-NMIBC) and Cohort 3 (IR-NMIBC). Fig. 34a This shows a diagram illustrating the proportion of Cohort 1 patients with recurrence-free HR-NMIBC by the sample type registered in Example 4, Part B. Fig. 34b This shows a diagram illustrating the proportion of patients in Cohort 3 with IR-NMIBC showing a complete response in a 3-month evaluation by the sample type registered in Example 4, Part B. Fig. 35 This shows a summary of demographic and baseline disease characteristics for 21 HR-NMIBC (Cohort 1) patients and 49 IR-NMIBC (Cohort 3) patients treated in the clinical study described in Example 1, Part D of the present invention. Fig. 36aThis is a pool lane plot of the treatment duration and response of HR-NMIBC (Cohort 1) patients in the clinical study described in Example 1, Part D of the present invention who were treated with TAR-210-B (approx. 2 mg / day erdafitinib; diagonal line) or TAR-210-D (approx. 4 mg / day erdafitinib; dot). It includes a legend describing the patients' treatment status and key time points. Fig. 36b This is a pool lane plot of the treatment duration and response of patients in the IR-NMIBC (Cohort 3) clinical study described in Example 1, Part D of the present invention who were treated with TAR-210-B (approx. 2 mg / day erdafitinib; diagonal line) or TAR-210-D (approx. 4 mg / day erdafitinib; dot). It includes a legend describing the patients' treatment status and key time points. Fig. 37a This represents the quantified urinary concentration of erdafitinib from patient samples after administration of TAR-210-B (dotted line) or TAR-210-D (solid line) in Example 1, Part D. Fig. 37b This represents the quantified plasma concentration of erdafitinib from patient samples after administration of TAR-210-B (dotted line) or TAR-210-D (solid line) in Example 1, Part D. Specific details for implementing the invention

[0015] Under limited available therapies and poor outcomes, a treatment method for non-muscle-invasive bladder cancer (NMIBC) in a large patient cohort is provided herein, specifically for high-risk (HR) NMIBC, such as recurrent HR-NMIBC, and intermediate-risk (IR) NMIBC, such as recurrent IR-NMIBC. Intravesical delivery of erdafitinib provides a much-needed treatment option for NMIBC by delivering treatment for local bladder cancer while avoiding systemic toxicity. As demonstrated herein, a treatment method for HR-NMIBC, particularly for relapsed Calmette-Gueren (BCG)-experienced high-risk NMIBC, comprising the step of locally administering about 2 mg / day erdafitinib to about 4 mg / day erdafitinib to the patient's bladder for about 90 days, results in at least 85% relapse-free (RF) rate in the patient group receiving 2 mg / day erdafitinib and at least 80% RF rate in the patient group receiving 4 mg / day erdafitinib. In addition, a treatment method for IR-NMIBC, particularly for relapsed intermediate-risk NMIBC, is presented, which includes the step of locally administering about 2 mg / day to about 4 mg / day of erdafitinib to the patient's bladder for about 90 days, resulting in at least a 75% complete response (CR) rate in the patient group receiving 2 mg / day of erdafitinib and at least a 90% CR rate in the patient group receiving 4 mg / day of erdafitinib. The method of the present application demonstrates excellent RF and CR rates for each cohort of patients treated. Furthermore, the method provided herein shows limited end-onset adverse events (TEAEs) and very few serious TEAEs, suggesting that it is a safe and well-tolerated treatment.

[0016] In additional embodiments, local and sequential administration of erdafitinib to the bladder according to the method presented herein demonstrated improved event-free survival rates and duration of response (DOR). Patients who received this treatment and achieved an effective response had the potential to experience 6 months of event-free survival or DOR.

[0017] The unexpected improvement in RF and CR rates of the method disclosed herein provides the additional benefit of delaying invasive replacement therapies, such as surgical removal of the bladder (radical cystectomy), which has a significant impact on the quality of life of the individual. These impacts on quality of life include urinary incontinence, sexual dysfunction, infertility, and bowel function complications. Furthermore, local administration of erdafitinib to the bladder according to the method presented herein results in reduced side effects compared to systemic chemotherapy. In addition, these clinical improvements provide a safe and effective treatment method for individuals with NMIBC, such as relapsed high-risk and intermediate-risk NMIBC.

[0018] Additionally, to treat NMIBC in patients using this route of administration, erdafitinib formulations and release systems adapted for intravesical drug delivery are described herein. A system capable of delivering erdafitinib at a release rate effective for the local treatment of bladder cancer is further provided.

[0019] Erdafitinib exhibits pH-dependent solubility over the normal urine pH range of 5.5 to 7. In some embodiments, the formulation and release system are adjusted to minimize the effect of urine pH and composition on the system release rate.

[0020] specific terms

[0021] Disease-free survival (DFS) is defined as the time from the date of randomization to the date of the earliest event (i.e., up to 5 years) in which non-muscle-invasive bladder cancer (NMIBC) of any grade is first documented, the date of disease progression, or the date of death from any cause.

[0022] Recurrence is defined as a recurrence of NMIBC regardless of grade based on pathological evaluation.

[0023] Recurrence-free survival (RFS) is defined as the time from randomization to the first detection of high-grade Ta or T1 bladder cancer or positive urine cytology.

[0024] Recurrence-free survival (RFS) is defined as the proportion of patients with RFS from the start of study treatment until the detection of high-grade Ta or T1 bladder cancer or a positive urine cytology result, where the proportion is evaluated initially after about 3 months or about 90 days of erdafitinib treatment, and then every 3 months during the study period (year 1), and during the follow-up period (every 3 months until the end of year 2, and every 6 months during year 3).

[0025] The recurrence-free rate is defined as the proportion of patients without recurrence at least one disease assessment, where the rate is initially assessed after about 3 months or about 90 days of erdafitinib treatment, followed by assessments every 3 months during the study period (year 1), and during the follow-up period (every 3 months until the end of year 2, and every 6 months during year 3).

[0026] The high-grade recurrence rate is defined as the proportion of patients who have high-grade Ta or T1 bladder cancer detected or positive urine cytology results for HG urothelial carcinoma (HGUC or repeat samples showing suspected HGUC), where the proportion is evaluated initially during about 3 months or about 90 days of erdafitinib treatment, and then every 3 months during the study period (year 1), and during the follow-up period (every 3 months until the end of year 2, and every 6 months during year 3).

[0027] The low-grade recurrence rate is defined as the proportion of patients who have low-grade Ta or T1 bladder cancer detected or positive urine cytology results for LG urothelial carcinoma, where the proportion is evaluated initially after about 3 months or about 90 days of erdafitinib treatment, and then every 3 months during the study period (year 1), and during the follow-up period (every 3 months until the end of year 2, and every 6 months in year 3).

[0028] The progressive disease rate is defined as the proportion of patients who progress to muscle-invasive bladder cancer (MIBC) (stage T2 or higher), where the rate is evaluated initially after about 3 months or about 90 days of erdafitinib treatment, and then every 3 months during the study period (year 1), and during the follow-up period (every 3 months until the end of year 2, and every 6 months in year 3).

[0029] Non-complete response (non-CR) or non-progressive disease (non-PD) is defined as the absence of new or larger tumors identified during cystoscopy.

[0030] Disease progression is defined as ≥ T2 disease or evaluation after baseline of positive lymph nodes or metastasis.

[0031] A complete response (CR) is defined as the absence of urothelial carcinoma by pathologically confirmed cystoscopy and a negative urine cytology result in the first evaluation.

[0032] The complete response (CR) rate is defined as the proportion of patients who have the absence of pathologically confirmed urothelial carcinoma by cystoscopy and negative urine cytology results at the first evaluation.

[0033] The duration of CR is defined as the time from the first documented record of CR to the date of documented relapse or progression, or death, whichever occurs earlier.

[0034] The pathological complete response (pCR) rate is defined as the percentage of participants with no pathological evidence of intravesical disease (pT0) and no pathological evidence of lymph node infiltration (pN0).

[0035] The rate of no pathological evidence of bladder disease (pT0) is defined as the percentage of participants without pathological evidence of bladder disease.

[0036] BCG-recovered individuals are defined as individuals who experience relapsed high-grade Ta / T1 disease within 18 months of completing previous BCG therapy. The minimum therapeutic requirement for previous BCG therapy is at least 5 of the 6 full doses of BCG during the initial induction course (with or without maintenance therapy). Full dose BCG is at least 1 x 10⁶ 8 It is defined as one full vial containing colony-forming units.

[0037] The downstaging rate below pT2 is defined as the percentage of participants with a pT stage of less than 2.

[0038] As used herein, weight % with respect to a drug or excipient refers to weight % based on the total weight of the relevant formulation, unless otherwise indicated.

[0039] This application considers any combination of any of the embodiments disclosed herein.

[0040] The embodiments described herein regarding the treatment method are also applicable to use in treatment, or to use in a treatment method, or to the manufacture of a medicine for treatment. For example, the disclosure of a method for treating recurrent Calmette-Gueren (BCG)-experienced high-risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient by administering erdafitinib as described herein also includes erdafitinib for use in treating recurrent Calmette-Gueren (BCG)-experienced high-risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient as described herein, or erdafitinib for use in a method for treating recurrent Calmette-Gueren (BCG)-experienced high-risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient as described herein, or erdafitinib for manufacturing a medicine for treating recurrent Calmette-Gueren (BCG)-experienced high-risk non-muscle invasive bladder cancer (HR-NMIBC) in a patient as described herein, or recurrent Calmette-Gueren (BCG)-experienced high-risk non-muscle invasive in a patient as described herein It can also be said that erdafitinib is used for the manufacture of drugs for the treatment of bladder cancer (HR-NMIBC).

[0041] References to "about" values ​​or parameters in this document include (and describe) variations of the values ​​or parameters themselves. For example, a description of "about X" includes a description of "X".

[0042] Erdafitinib Formulations and Tablets

[0043] In one embodiment, the present disclosure provides an erdafitinib formulation, in particular an erdafitinib tablet, suitable for use in the disclosed intravesical drug delivery system. In particular, erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1 H A drug tablet comprising [pyrazol-4-yl]quinoxaline-6-yl]ethane-1,2-diamine is provided. As another example, a drug tablet comprising erdafitinib HCl salt is provided. After the drug delivery system is inserted into the bladder, the drug is released from the system into the bladder. For example, in one embodiment, the drug delivery system may be operated by diffusion, which causes a continuous release of the drug into the bladder over an extended period as the drug is released from the tablet within the system.

[0044] To increase or maximize the amount of drug that can be stored within and released from the disclosed drug delivery system, the drug tablet may have a relatively high weight content of erdafitinib. This relatively high weight fraction of erdafitinib in the drug tablet entails a reduced fraction or low weight fraction of excipients that may be necessary for tablet manufacturing, system assembly, and drug use considerations. For the purposes of this disclosure, terms such as “weight fraction,” “weight percentage,” and “weight percentage” with respect to any drug or API (active pharmaceutical ingredient) refer to the form of the drug or API used, whether in the free base form, free acid form, salt form, or hydrate form. For example, a drug tablet containing 90 weight% (90 wt%) of the drug or excipient in the salt form may contain less than 90 weight% of that drug in the free base form. Unless otherwise specified, weight percentages are expressed relative to the total solid pharmaceutical composition.

[0045] The erdafitinib drug tablets of the present disclosure comprise an erdafitinib content and an excipient content. The drug content may comprise one or more forms of erdafitinib, such as a free base or salt form, and the excipient content may comprise one or more excipients. Certain embodiments comprise an erdafitinib free base API, and exemplary formulations presented herein comprise an erdafitinib free base API. The term “excipient” is known in the art, and representative examples of excipients useful for the disclosed drug tablets may include, but are not limited to, components such as binders, lubricants, lubricants, disintegrants, solubilizers, coloring agents, fillers or diluents, wetting agents, stabilizers, formaldehyde capture agents, coatings, and preservatives, or any combination thereof, as well as other components to facilitate the manufacture, storage, or administration of the drug tablet.

[0046] Another aspect of the present disclosure provides a process for manufacturing a solid pharmaceutical composition, the process may comprise: (a) preparing a solid composition within granules comprising or substantially composed of (i) an erdafitinib free base and (ii) at least one pharmaceutical excipient within granules; (b) combining the solid composition within granules with at least one pharmaceutical excipient outside granules to form a blend; and (c) compressing the blend to form a solid pharmaceutical composition. In an embodiment, the erdafitinib free base may be present at a concentration of at least 45% by weight of the solid pharmaceutical composition. The at least one pharmaceutical excipient within granules and the at least one pharmaceutical excipient outside granules may include or be selected from at least one common (mutually present) pharmaceutical excipient between the pharmaceutical excipient within granules and the pharmaceutical excipient outside granules, or there may be no common (mutually present) pharmaceutical excipient. A solid pharmaceutical composition may be prepared by a process comprising a solid composition in granules prepared by a roller compression process or by a fluid bed granulation process. In some embodiments, step (a) of preparing a solid composition in granules comprises: (1) preparing a pre-blend comprising erdafitinib free base and one or more excipients; (2) preparing a binder solution; and (3) preparing a solid composition in granules by combining the pre-blend and the binder solution. In some embodiments, step (a) of preparing a solid composition in granules comprises: (1) preparing a pre-blend comprising erdafitinib free base and one or more excipients; (2) preparing a binder solution; and (3) preparing a solid composition in granules by combining the pre-blend and the binder solution by a fluid bed granulation process.In some embodiments, the step (a) of preparing a solid composition in granules comprises: (1) preparing a pre-blend comprising erdafitinib free base, a stabilizer, a solubilizer, and a filler; (2) preparing a binder solution comprising a binder and a solvent; and (3) preparing a solid composition in granules by mixing the pre-blend and the binder solution by a fluid bed granulation process. In some embodiments, the step (a) of preparing a solid composition in granules comprises: (1) preparing a pre-blend comprising erdafitinib free base, meglumine, hydroxypropyl-beta-cyclodextrin, and microcrystalline cellulose; (2) preparing a binder solution comprising hydroxypropyl methylcellulose and purified water; and (3) preparing a solid composition in granules by mixing the pre-blend and the binder solution by a fluid bed granulation process. In some embodiments, the step (a) of preparing a solid composition in granules comprises: (1) preparing a pre-blend comprising erdafitinib free base, a solubilizer, and a filler; (2) preparing a binder solution comprising a binder and a solvent; and (3) preparing a solid composition in granules by mixing the pre-blend and the binder solution by a fluid bed granulation process. In some embodiments, the step (a) of preparing a solid composition in granules comprises: (1) preparing a pre-blend of erdafitinib free base, hydroxypropyl-beta-cyclodextrin, and microcrystalline cellulose; (2) preparing a binder solution comprising hydroxypropyl methylcellulose and purified water; and (3) preparing a solid composition in granules by mixing the pre-blend and the binder solution by a fluid bed granulation process.

[0047] Another aspect of the present disclosure provides a process for manufacturing a solid pharmaceutical composition, the process may comprise: (a) preparing a solid composition within granules comprising or substantially composed of (i) an erdafitinib HCl salt form and (ii) at least one pharmaceutical excipient within granules; (b) combining the solid composition within granules with at least one pharmaceutical excipient outside granules to form a blend; and (c) compressing the blend to form a solid pharmaceutical composition. In an embodiment, the erdafitinib HCl salt form may be present at a concentration of at least 45% by weight of the solid pharmaceutical composition. The at least one pharmaceutical excipient within granules and the at least one pharmaceutical excipient outside granules may include or be selected from at least one common (mutually present) pharmaceutical excipient between the pharmaceutical excipient within granules and the pharmaceutical excipient outside granules, or there may be no common (mutually present) pharmaceutical excipient. A solid pharmaceutical composition can be manufactured by a process comprising a solid composition in granules produced by a roller compression process or a fluid bed granulation process.

[0048] In an embodiment, the erdafitinib drug tablet comprises erdafitinib in the form of a free base. Another embodiment of the erdafitinib drug tablet may comprise erdafitinib in the form of a salt. In one embodiment, the erdafitinib drug tablet may comprise 40 weight% or more of erdafitinib free base, and the remainder may comprise excipients, such as lubricants, binders, and stabilizers, that facilitate the manufacture and use of the drug tablet. Alternatively, the erdafitinib drug tablet may comprise 45 weight% or more, 50 weight% or more, 55 weight% or more, or 60 weight% or more of erdafitinib free base. In each of these weight percentage embodiments, the actual upper limit of erdafitinib free base in the tablet formulation is about 65 weight% or 70 weight%. Accordingly, in one embodiment, the drug tablet may contain 40% to 60% by weight of erdafitinib in the form of a free base, or 45% to 55% by weight of erdafitinib in the form of a free base. In some of the embodiments described above, the drug tablet may contain about 5% to about 15% by weight of hydroxypropyl-β-cyclodextrin (HP-β-CD). In some of the embodiments described above, the drug tablet may contain about 10% by weight of hydroxypropyl-β-cyclodextrin (HP-β-CD). In an embodiment, the drug tablet may contain 50% by weight of erdafitinib in the form of a free base based on the total weight of the tablet. In an embodiment, the drug tablet may comprise 50 weight% of erdafitinib in the form of a free base and about 5 weight% to about 15 weight% of hydroxypropyl-β-cyclodextrin (HP-β-CD) based on the total weight of the tablet. In an embodiment, the drug tablet may comprise 50 weight% of erdafitinib in the form of a free base and 10 weight% of hydroxypropyl-β-cyclodextrin (HP-β-CD) based on the total weight of the tablet.

[0049] In an embodiment, the erdafitinib drug tablet comprises erdafitinib in the form of an HCl salt. In one embodiment, the erdafitinib drug tablet may comprise 40 weight% or more of the erdafitinib HCl salt form, and the remainder may comprise excipients, such as lubricants, binders, and stabilizers, to facilitate the manufacture and use of the drug tablet. Alternatively, the erdafitinib drug tablet may comprise 45 weight% or more, 50 weight% or more, 55 weight% or more, or 60 weight% or more of the erdafitinib HCl salt form. In each of these weight percentage embodiments, the actual upper limit of the erdafitinib salt form in the tablet formulation is about 65 weight% or 70 weight%. Accordingly, in one embodiment, the drug tablet may contain 40% to 60% by weight of erdafitinib in the form of an HCl salt, or 45% to 55% by weight of erdafitinib in the form of an HCl salt. In an embodiment, the drug tablet may contain 50% by weight of erdafitinib in the form of an HCl salt based on the total weight of the tablet.

[0050] In one embodiment, the erdafitinib drug and excipients are selected, and the tablet is formulated to enable the release of the drug from the tablet. In some embodiments, the erdafitinib drug and excipients are selected, and the tablet is formulated to enable the solubilization of the drug from the tablet. In an embodiment, erdafitinib is formulated into a pharmaceutical composition that can be stabilized inside or outside a drug delivery system without causing substantial or harmful changes to the chemical or physical composition of the drug tablet that would render it unsuitable for delivering 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 in its entirety. In particular, the drug delivery system comprising the drug tablet is sterilized by gamma irradiation.

[0051] In one embodiment, the erdafitinib drug tablet may be sized and shaped for use with an implantable drug delivery system, including the intravesical drug delivery system disclosed herein. For example, the erdafitinib drug tablet may be a "mini-tablet" which is generally smaller in size than a conventional tablet, allowing the system-received drug tablet to be inserted into a body cavity, such as a bladder, through a lumen, such as a urethra. The erdafitinib tablet may be coated or uncoated. In particular, uncoated tablets formulated according to the present disclosure have been found to work well in combination with the system. As disclosed herein, "mini-tablet" and "tablet" are used interchangeably to refer to a tablet capable of allowing the system-received drug tablet to be inserted into a body cavity, such as a bladder, through a lumen, such as a urethra.

[0052] In an embodiment, the drug tablet for intravesical insertion or other in vivo implantation may be in the form of a solid cylinder having a cylindrical axis, a cylindrical side, a circular end plane perpendicular to the cylindrical axis, a diameter across the circular end plane, and a length along the cylindrical side. In the cylindrical form, each mini-tablet may have a length (L) exceeding its diameter (D), so 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 may be 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, or a range of values ​​between these aspect ratios. An embodiment of the mini-tablet may 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 embodiments, the mini-tablet 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.

[0053] The API used in solid tablet formulations is N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1 H It may be erdafitinib, which is [pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, and its chemical structure is exemplified below. The disclosed erdafitinib tablets for use in an intravesical system may be formulated using erdafitinib free base or a salt thereof. In one embodiment, the disclosed erdafitinib tablets for use in an intravesical system may comprise erdafitinib free base. In one embodiment, the disclosed erdafitinib tablets for use in an intravesical system may comprise erdafitinib HCl salt, particularly erdafitinib HCl salt in a crystalline form. In some of the aforementioned embodiments, the disclosed erdafitinib tablets for use in an intravesical system may comprise erdafitinib free base in a crystalline form. As described herein, by including specific stabilizers, solubilizers, and excipients within the erdafitinib free base formulation, stabilization and solubility properties advantageous for the effective use of the disclosed free base formulation in the intravesical system can be provided.

[0054]

[0055] In embodiments, the erdafitinib drug tablet may incorporate various excipients, which include, but are not limited to, at least one solubilizing agent, at least one binder, at least one wetting agent, at least one disintegrating agent, at least one stabilizer, at least one diluent, at least one lubricating agent, at least one lubricant, etc. Any excipient or any combination of excipients may be present in the solid composition within the granule, the solid composition outside the granule, or both the solid composition within the granule and the solid composition outside the granule. In one embodiment, at least one pharmaceutical excipient within the granule and at least one pharmaceutical excipient outside the granule may be identical, that is, selected from at least one common (mutually present) pharmaceutical excipient. In a further embodiment, the pharmaceutical excipient within the granule and the pharmaceutical excipient outside the granule do not include a common (mutually present) pharmaceutical excipient, thereby making the pharmaceutical excipient within the granule and the pharmaceutical excipient outside the granule mutually exclusive. In an embodiment, an erdafitinib drug tablet, particularly comprising 40% to 70% by weight, or 40% to 60% by weight, or 45% to 55% by weight, for example 50% by weight of erdafitinib, comprises at least one solubilizing agent, at least one binder, at least one stabilizer, at least one diluent, at least one lubricant, at least one lubricant, etc., or any combination thereof. In an embodiment, an erdafitinib drug tablet, particularly comprising 40% to 70% by weight, or 40% to 60% by weight, or 45% to 55% by weight, for example 50% by weight of erdafitinib, comprises at least one solubilizing agent, at least one binder, at least one diluent, at least one lubricant, at least one lubricant, etc., or any combination thereof.

[0056] It will be understood that these functional descriptions for various excipients are generally used as follows. Solubilizers can improve or enhance the solubility of the API, e.g., erdafitinib free base, within the drug lumen of the initiated system or in a body cavity, e.g., the bladder, once the API is released from the system. Binders can hold the solid particles of the composition together for physical stability. Wetting agents can help maintain the solubility of the drug by lowering the surface tension between the drug and the medium in which it exists. Disintegrators can aid in the disintegration of minitablets when releasing the drug substance upon contact with water. Stabilizers improve the chemical stability of formulations containing the API, e.g., thermal stability, or protect the API against degradation. Diluents can function as bulking agents to increase the volume or weight of the composition, which can help provide tablets of the desired size or aid in the tabletability of API-excipient blends. Lubricants can improve the flow characteristics of the (granular) particles of the tablet components or the powder blend to be tableted. Lubricants can prevent particles of the composition from adhering to components of the manufacturing apparatus, such as the die and punch of a tablet press. In one embodiment, the excipient may be water-soluble. In another embodiment, the excipient may be colloidal in water. According to another embodiment, the excipient may be soluble under conditions of its dissolution in a patient, such as in the bladder. These and other excipients are described in more detail below.

[0057] Stabilizers, such as formaldehyde scavengers

[0058] In one embodiment, the erdafitinib API may be sensitive to degradation under certain conditions when introduced into a solid formulation. For example, erdafitinib degrades or is modified in the presence of formaldehyde to form the cyclization product 6,8-dimethoxy-4-(l-methylethyl)-1-[3-(1-methyl-1H -pyrazol-4-yl)quinoxalin-6-yl]-2,3,4,5-tetrahydro-1 H -1,4-benzodiazepines may be formed. Formaldehyde may come into contact with erdafitinib from various sources in the environment, such as packaging materials, or as a contaminant in excipients or other ingredients of the formulation.

[0059] Accordingly, in one embodiment, the erdafitinib pharmaceutical formulation may include a formaldehyde scavenger to improve the stability or shelf life of the formulation. Various formaldehyde scavengers may be used that can prevent, slow down, reduce, or delay the formation of degradation products when erdafitinib comes into contact with formaldehyde. Accordingly, the stability of the erdafitinib pharmaceutical formulation, e.g., its chemical stability, may be increased in the presence of a formaldehyde scavenger compared to an erdafitinib pharmaceutical formulation without a formaldehyde scavenger. In one embodiment, the formaldehyde scavenger may be present in the solid pharmaceutical composition as a component of the solid composition within granules, the solid composition outside granules, or both the solid composition within granules and the solid composition outside granules. In one embodiment, a formaldehyde scavenger, particularly meglumine, is present in the solid pharmaceutical composition as a component of the solid composition within granules.

[0060] Formaldehyde scavengers may comprise or be selected from compounds containing a reactive nitrogen center, such as compounds containing amine or amide groups. Without being limited by theory, these compounds react with formaldehyde to form Schiff base imines (R 1 R 2 C=NR 3 , here R 3It is believed to be capable of forming (which is not hydrogen), which itself can bind to formaldehyde. Examples of such formaldehyde scavengers include, but are not limited to, amino acids, amino sugars, alpha-(α-)amine compounds, conjugates and derivatives thereof, and mixtures thereof. Such formaldehyde scavenger compounds may comprise two or more amine and / or amide moietys capable of scavenging formaldehyde.

[0061] In one embodiment, the formaldehyde scavenger may comprise, 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, conjugates thereof, pharmaceutically acceptable salts thereof, or any combination thereof, or may be selected from. According to one embodiment, the formaldehyde scavenger may comprise or be selected from meglumine or pharmaceutically acceptable salts thereof, in particular meglumine bases.

[0062] Accordingly, one aspect of the present disclosure is the use of a formaldehyde scavenger, in particular meglumine, to increase the stability of any type of erdafitinib, including erdafitinib free base, salt thereof, or solvate thereof, in erdafitinib pharmaceutical formulations, e.g., drug tablet formulations. The chemical stability of the erdafitinib pharmaceutical formulation is increased compared to an erdafitinib pharmaceutical formulation or composition that does not contain a formaldehyde scavenger. One aspect of the present disclosure is a method for preventing, slowing, reducing, or delaying the formation of degradation products, e.g., the following compounds, that may be formed from erdafitinib in the presence of formaldehyde:

[0063] .

[0064] In one embodiment, a decomposition product, such as a compound, may occur in a solid tablet composition, such as a mini-tablet formulation, particularly a mini-tablet as disclosed herein.

[0065] When present in the erdafitinib solid pharmaceutical composition, the formaldehyde scavenger may be 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%. In some embodiments, when present in the erdafitinib solid pharmaceutical composition, the formaldehyde scavenger may be present at a concentration of about 1 wt%. When present in the erdafitinib solid pharmaceutical composition, the formaldehyde scavenger may be present in the solid pharmaceutical composition at a concentration of, for example, 5 wt% to 10 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, or about 10 wt%. In some embodiments, the erdafitinib solid pharmaceutical composition contains erdafitinib free base and a formaldehyde scavenger is present. In some embodiments, the erdafitinib solid pharmaceutical composition contains erdafitinib free base and a 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%. In some embodiments, the erdafitinib solid pharmaceutical composition contains erdafitinib free base and a formaldehyde scavenger is present in the solid pharmaceutical composition at a concentration of about 1 wt%. In any of the aforementioned embodiments, the formaldehyde scavenger is meglumine.

[0066] In some embodiments, pharmaceutical compositions as described herein, particularly erdafitinib drug tablets, do not contain stabilizers or formaldehyde scavengers.

[0067] Solubilizer

[0068] In one embodiment, the erdafitinib formulation may comprise a solubilizing agent. The solubilizing agent may be present in the granular component, the extragranular component, or both the granular component and the extragranular component of the formulation. In an embodiment, the solubilizing agent may comprise, for example, (a) cyclic oligosaccharides, (b) cellulose functionalized with a methoxy-, 2-hydroxypropoxy-, acetyl-, or succinoyl- moiety or a combination thereof, or (c) salts thereof, or may be selected from these. In one embodiment, the solubilizing agent is present in the granular component.

[0069] In an embodiment, the solubilizing agent for the erdafitinib tablet formulation may include or be selected from oligosaccharides. In an embodiment, the solubilizing agent may include or be selected from cyclic oligosaccharides, such as cyclodextrin. Cyclodextrin solubilizing agents suitable for the erdafitinib tablet formulation include, but are not limited to, hydroxypropyl-beta-cyclodextrin, hydroxypropyl-gamma-cyclodextrin, sulfobutyl ether-beta-cyclodextrin sodium salt, or any combination thereof. In another embodiment, the solubilizing agent may include or be hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose E5 (HPMC-E5), or a combination thereof.

[0070] An oligosaccharide solubilizer may be present in an erdafitinib tablet formulation, e.g., an 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. A cyclodextrin solubilizer may be present in an erdafitinib tablet formulation, e.g., an erdafitinib free base formulation, at a concentration of 1 wt%, 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt%, or 20 wt%, or any range between these weight percentages.

[0071] In one embodiment, the solubilizer for the erdafitinib tablet formulation disclosed herein may comprise hydroxypropyl-beta-cyclodextrin (HP-β-CD) or may be hydroxypropyl-beta-cyclodextrin. One embodiment of the erdafitinib free base formulation comprises a hydroxypropyl-beta-cyclodextrin solubilizer, and in particular, the erdafitinib free base formulation comprises hydroxypropyl-beta-cyclodextrin at a concentration of 8 wt% to 12 wt%, or alternatively, 10 wt% or about 10 wt%. In some embodiments, the formulation comprises hydroxypropyl-beta-cyclodextrin at a concentration of about 10 wt%. In this formulation, the erdafitinib free base API may be present at a concentration of 40 wt% to 70 wt%, or 40 wt% to 60 wt%, or 45 wt% to 55 wt%, for example, 50 wt%. In one embodiment, hydroxypropyl-beta-cyclodextrin is present in the solid composition within the granules. In an embodiment, the drug tablet may comprise 50 wt% of erdafitinib in free base form, 1 wt% of meglumine, and 8 wt% to 12 wt%, or alternatively 10 wt% or about 10 wt% of hydroxypropyl-beta-cyclodextrin. In an embodiment, the drug tablet may comprise 50 wt% of erdafitinib in free base form, 10 wt% of hydroxypropyl-beta-cyclodextrin (HP-β-CD), and 1 wt% of meglumine based on the total weight of the tablet. In an embodiment, the drug tablet may comprise at least about 45 weight% of erdafitinib in the form of a free base, 10 weight% of hydroxypropyl-β-cyclodextrin (HP-β-CD), and 0 weight% of meglumine based on the total weight of the tablet. In an embodiment, the drug tablet may comprise 50 weight% of erdafitinib in the form of a free base, 10 weight% of hydroxypropyl-β-cyclodextrin (HP-β-CD), and 0 weight% of meglumine based on the total weight of the tablet.

[0072] binder

[0073] Pharmaceutical excipients for an erdafitinib solid pharmaceutical composition may comprise one or more binders. One or more binders may be present in the solid pharmaceutical composition as components of the solid composition within granules, the solid composition outside granules, or both the solid composition within granules and the solid composition outside granules. Suitable binders may be water-soluble, water-insoluble, slightly water-soluble, or a combination thereof. In one embodiment, the binder may comprise a polymer binder, such as a water-soluble polymer binder, a slightly water-soluble polymer binder, a water-insoluble polymer binder, or any combination thereof. The polymer binder may comprise a nonionic polymer.

[0074] It will be understood by those skilled in the art that binders can also function as diluents (also referred to as fillers) in pharmaceutical compositions. Accordingly, the binders provided in this disclosure may also be used for their diluent functions as needed and unless otherwise indicated.

[0075] In one embodiment, a suitable binder may comprise or be selected from polyvinylpyrrolidone (PVP, which is also referred to as polyvidon, povidone, or poly(1-vinyl-2-pyrrolidinone)), poly(vinyl acetate) (PVA), vinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide (PEO, which is also referred to as poly(ethylene glycol) or PEG), polypropylene oxide (PPO, which is also referred to as poly(propylene glycol) or PPG), ethylene glycol-propylene glycol copolymer, poloxamer, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, silicified microcrystalline cellulose, or a combination thereof. In one embodiment, a suitable binder may comprise or be selected from polyvinylpyrrolidone (PVP, which is also referred to as polyvidon, povidone, or poly(1-vinyl-2-pyrrolidinone)), poly(vinyl acetate) (PVA), vinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide (PEO, which is also referred to as poly(ethylene glycol) or PEG), polypropylene oxide (PPO, which is also referred to as poly(propylene glycol) or PPG), ethylene glycol-propylene glycol copolymer, poloxamer, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, or a combination thereof. In one embodiment, a suitable binder may comprise or be selected from hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, vinylpyrrolidone-vinyl acetate copolymer, or a combination thereof. In one embodiment, a suitable binder may comprise or be selected from hydroxypropyl methylcellulose (HPMC), vinylpyrrolidone-vinyl acetate copolymer (copovidone), or a combination thereof. In some embodiments, the binder may be hydroxypropyl methylcellulose (HPMC). In some embodiments, the binder is about 1 of the solid composition.It may be hydroxypropyl methylcellulose (HPMC) present at a concentration of 5 weight%. In some embodiments, the binder may be hydroxypropyl methylcellulose (HPMC) present at 1.5 weight% of the solid composition and is present in the solid composition within the granules.

[0076] In additional embodiments, a suitable binder may comprise or be selected from a polymer or copolymer of vinylpyrrolidone (VP, also 1-vinyl-2-pyrrolidinone) and vinyl acetate (VA). Such a copolymer of VP and VA may also be referred to as "copovidone". A suitable binder may also comprise or be selected from a polymer or copolymer of ethylene oxide (EO) and propylene oxide (PO). Likewise, these binders may be used in combination with other binders, for example, in combination with microcrystalline cellulose, hydroxypropyl cellulose (HPC), or hydroxypropyl methylcellulose (HPMC).

[0077] In one embodiment, the total concentration of at least one binder in the solid pharmaceutical composition may 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%.

[0078] According to another embodiment, a suitable polymer binder may comprise or be selected from a copolymer of vinylpyrrolidone and vinyl acetate—which may be referred to as poly(vinylpyrrolidone-co-vinyl acetate) or poly(VP-co-VA). Examples of suitable poly(vinylpyrrolidone-co-vinyl acetate) binders include Kollidon® VA64 and Kollidon® VA64 Fine (BASF, Ludwigshafen am Rhein, Germany), which have a molecular weight (Mw) range of 45,000 g / mol to 70,000 g / mol based on light scattering measurements of the solution. Another suitable binder is Kollidon® K30.

[0079] In an embodiment, a polymer binder, such as a vinylpyrrolidone-vinyl acetate copolymer, may be present in the disclosed erdafitinib tablet formulation at a concentration of 2 wt% to 15 wt%, alternatively 4 wt% to 12 wt%, alternatively 6 wt% to 10 wt%, or alternatively 8 wt% or about 8 wt%. For example, the vinylpyrrolidone-vinyl acetate copolymer binder may be present in the erdafitinib tablet formulation, for example, an erdafitinib free base formulation, at a concentration of 2 wt%, 3 wt%, 4 wt%, 5 wt%, 6 wt%, 7 wt%, 8 wt%, 9 wt%, 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, or any range between these weight percentages, for example, 7.5 wt%. In one embodiment, the vinylpyrrolidone-vinyl acetate copolymer is present at a concentration of 8 weight percent of the solid composition. In one embodiment, the vinylpyrrolidone-vinyl acetate copolymer is present in the solid composition within the granules. In one embodiment, the vinylpyrrolidone-vinyl acetate copolymer is present in the solid composition within the granules, and the solid composition within the granules is prepared by roller compression. In one embodiment, the vinylpyrrolidone-vinyl acetate copolymer is present in the solid composition within the granules, and the solid composition within the granules is prepared by fluid bed granulation. In one embodiment, the vinylpyrrolidone-vinyl acetate copolymer is present in the solid composition outside the granules. In one embodiment, the vinylpyrrolidone-vinyl acetate copolymer is present at a concentration of about 7.5 weight percent of the solid composition. In one embodiment, the vinylpyrrolidone-vinyl acetate copolymer is present at a concentration of about 7.5 weight% of the solid composition and is present in the solid composition other than granules.

[0080] In one embodiment, the binder may comprise or be microcrystalline cellulose. For example, microcrystalline cellulose may be present in the solid pharmaceutical composition at a concentration of 5 wt% to 30 wt%, 10 wt% to 20 wt%, 5 wt% to 20 wt%, 6 wt% to 15 wt%, or 7 wt% to 12 wt%. For example, microcrystalline cellulose may be present in the solid pharmaceutical composition as a filler and / or binder at a concentration of about 17.5 wt%. For example, microcrystalline cellulose may be present in the solid pharmaceutical composition at a concentration of about 17.5 wt% of the solid composition and is present in the solid composition within granules and in the solid composition outside granules. For example, microcrystalline cellulose may be present in the solid pharmaceutical composition as a filler in the granule composition at a concentration of about 10 weight% of the solid composition, and may be present in the solid pharmaceutical composition as a binder in the granule composition at a concentration of about 7.5 weight% of the solid composition.

[0081] According to another embodiment, the binder may comprise silicified microcrystalline cellulose or may be silicified microcrystalline cellulose. For example, silicified microcrystalline cellulose may be present in the solid pharmaceutical composition at a concentration of 3% to 18% by weight, 4% to 15% by weight, or 5% to 12% by weight.

[0082] In additional embodiments, the binder may comprise hydroxypropyl methylcellulose (HPMC) or may be hydroxypropyl methylcellulose. For example, hydroxypropyl methylcellulose (HPMC) may be present in the solid pharmaceutical composition at a concentration of 0.25 wt% to 5 wt%, 0.5 wt% to 4 wt%, or 0.75 wt% to 3 wt%. In one embodiment, the HPMC binder may be present in the solid composition within the granules of the solid pharmaceutical composition.

[0083] humectant

[0084] Pharmaceutical excipients for the erdafitinib solid pharmaceutical composition may include one or more wetting agents. One or more wetting agents may be present in the solid pharmaceutical composition within the granules, the solid composition outside the granules, or both the solid composition within the granules and the solid composition outside the granules. In exemplary embodiments, the wetting agent may include an anionic surfactant or a nonionic surfactant, particularly an anionic surfactant, or may be selected independently thereof. For example, the wetting agent may include sodium lauryl sulfate, sodium stearyl fumarate, polysorbate, e.g., polysorbate 80, sodium docusate, or any combination thereof, or may be selected independently thereof. In an embodiment, the total concentration of the wetting agent in the solid pharmaceutical composition may be 0.01 wt% to 2.5 wt%, 0.05 wt% to 1.0 wt%, or 0.1 wt% to 0.5 wt%. In one embodiment, the wetting agent is present in the solid composition within the granules. In one embodiment, the wetting agent is sodium lauryl sulfate.

[0085] In one embodiment, the erdafitinib solid pharmaceutical composition does not contain one or more wetting agents.

[0086] disintegrant

[0087] Pharmaceutical excipients for an erdafitinib solid pharmaceutical composition may include one or more disintegrants. One or more disintegrants may be present in the solid pharmaceutical composition within granules, in the solid composition outside granules, or in both the solid composition within granules and the solid composition outside granules. In one embodiment, the disintegrant is present in the solid composition within granules. In one embodiment, the disintegrant is present in the solid composition within granules, and the solid composition within granules is prepared by roller compression.

[0088] In exemplary embodiments, the disintegrant may comprise a functionalized polysaccharide or a cross-linked polymer, or may be independently selected from these. For example, in one embodiment, the disintegrant may comprise, for example, (a) cellulose functionalized to a methoxy-, 2-hydroxypropoxy-, or carboxymethoxy- moiety, a salt thereof, or a combination thereof, (b) carboxymethylated starch, or (c) a cross-linked polymer, or may be selected from these.

[0089] In the embodiments, the disintegrant may comprise hydroxypropyl methylcellulose, low-substituted hydroxypropylcellulose, crospovidone (cross-linked polyvinylpyrrolidone), croscarmellose sodium (cross-linked sodium carboxymethylcellulose), sodium starch glycolate, or any combination thereof, or may be selected independently from therein.

[0090] If present, the disintegrant may be present at a concentration within a certain range. In an embodiment, the total concentration of the disintegrant in the solid pharmaceutical composition may be 0.1% to 3% by weight, 0.5% to 2.5% by weight, 1% to 2% by weight, or about 1.5% by weight.

[0091] In one embodiment, the erdafitinib solid pharmaceutical composition does not contain one or more disintegrants.

[0092] Diluent or filler

[0093] Pharmaceutical excipients for an erdafitinib solid pharmaceutical composition may include one or more diluents. One or more diluents may be present in the solid pharmaceutical composition as components of the solid composition within granules, the solid composition outside granules, or both the solid composition within granules and the solid composition outside granules.

[0094] In exemplary embodiments, the diluent may comprise or be selected from sugar, starch, microcrystalline cellulose, sugar alcohol, hydrogen phosphate, dihydrogen phosphate, carbonate salt, or a combination thereof. In one embodiment, the diluent may comprise or be selected from lactose, dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, silicified microcrystalline cellulose, dibasic calcium phosphate, anhydrous dibasic calcium phosphate, calcium carbonate, sucrose, or any combination thereof.

[0095] In an embodiment, the total concentration of the diluent in the solid pharmaceutical composition may be 10 wt% to 60 wt%, 10 wt% to 50 wt%, 10 wt% to 40 wt%, 12 wt% to 30 wt%, 15 wt% to 25 wt%, or 18 wt% to 22 wt%, or 20 wt% to 40 wt%, or 20 wt% to 30 wt%, or 25 wt% to 30 wt%. For example, in some embodiments, the diluent may comprise or be selected from microcrystalline cellulose present at a concentration of 15 wt% to 25 wt%, or 20 wt% to 22 wt%, or 15 wt% to 20 wt%. In further embodiments, the diluent may comprise or be selected from anhydrous dibasic calcium phosphate present at a concentration of 18 wt% to 20 wt%. In a further embodiment, the diluent may comprise anhydrous dibasic calcium phosphate present at a concentration of about 19 wt% or may be such anhydrous dibasic calcium phosphate. In a further embodiment, the diluent may comprise anhydrous dibasic calcium phosphate present at a concentration of about 19 wt% or may be such anhydrous dibasic calcium phosphate, which is present in the solid composition other than granules. In a further embodiment, the diluent may comprise silicified microcrystalline cellulose present at a concentration of 10 wt% to 20 wt%, or 10 wt% to 15 wt%, or 10 wt% to 12 wt%, or may be selected from these. For example, the diluent may comprise silicified microcrystalline cellulose present at a concentration of about 10.75 wt% or 11.75 wt% of the solid composition. For example, the diluent may include silicified microcrystalline cellulose present at a concentration of about 10.75 wt% or 11.75 wt% of the solid composition and is present in the composition other than the granules. For example, the diluent may include silicified microcrystalline cellulose present at a concentration of about 10.75 wt% of the solid composition and is present in the composition other than the granules.For example, the diluent may comprise silicified microcrystalline cellulose present at a concentration of about 11.75 wt% of the solid composition and is present in the composition outside the granules. In a further embodiment, the diluent does not comprise silicified microcrystalline cellulose. In a further embodiment, the diluent may comprise microcrystalline cellulose and silicified microcrystalline cellulose. In a further embodiment, the diluent may comprise microcrystalline cellulose or silicified microcrystalline cellulose. In a further embodiment, the diluent may comprise microcrystalline cellulose present at a concentration of about 10 wt%. In a further embodiment, the diluent may comprise microcrystalline cellulose present at a concentration of about 10 wt%, which is present in the composition inside the granules. For example, microcrystalline cellulose may be present in the solid pharmaceutical composition as a filler and / or binder at a concentration of about 17.5 wt%. For example, microcrystalline cellulose may be present in the solid pharmaceutical composition at a concentration of about 17.5% by weight of the solid composition, and may be present in the solid composition within the granules and the solid composition outside the granules. For example, microcrystalline cellulose may be present in the solid pharmaceutical composition as a filler in the composition within the granules at a concentration of about 10% by weight of the solid composition, and may be present in the solid pharmaceutical composition as a binder in the composition outside the granules at a concentration of about 7.5% by weight of the solid composition.

[0096] 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. Accordingly, some compounds or substances may be described herein as providing binder functions and providing diluent / filler functions.

[0097] Hwaltaekje

[0098] Pharmaceutical excipients for erdafitinib solid pharmaceutical compositions may include one or more lubricants. One or more lubricants may be present in the solid pharmaceutical composition as components of the solid composition within granules, the solid composition outside granules, or both the solid composition within granules and the solid composition outside granules. In one embodiment, the lubricant is present in the solid composition outside granules. As used herein, a lubricant refers to a pharmaceutical excipient that improves or optimizes the particle flow characteristics of granular or powdered tablet components in particulate form by reducing interactions, attractive forces, cohesive forces, or friction between particles. A pharmaceutically acceptable lubricant is a non-toxic and pharmacologically inert substance. Additionally, the lubricant may be water-soluble or water-insoluble.

[0099] In one embodiment, the lubricant may comprise or be selected from colloidal silicon dioxide, colloidal anhydrous silicon dioxide, talc, or any combination thereof. In an embodiment, the total concentration of the lubricant in the solid pharmaceutical composition may be 0.01 wt% to 5 wt%, 0.05 wt% to 3 wt%, 0.1 wt% to 1 wt%, or about 0.2 wt%, or about 0.25 wt%, or about 0.3 wt%, about 0.35 wt%, or about 0.4 wt%, or about 0.45 wt%, or about 0.5 wt%. In one embodiment, the lubricant is colloidal silicon dioxide. In some embodiments, the lubricant is colloidal silicon dioxide present at about 0.5 wt% of the solid composition. In some embodiments, the lubricant is colloidal silicon dioxide present at about 0.5 wt% of the solid composition and is present in the composition other than granules. In some embodiments, the lubricant is colloidal silicon dioxide present at about 0.25 weight% of the solid composition. In some embodiments, the lubricant is colloidal silicon dioxide present at about 0.25 weight% of the solid composition and is present in the composition other than the granules.

[0100] slush

[0101] Pharmaceutical excipients for the erdafitinib solid pharmaceutical composition may include one or more lubricants. One or more lubricants may be present in the solid pharmaceutical composition as components of the solid composition within granules, the solid composition outside granules, or both the solid composition within granules and the solid composition outside granules. In one embodiment, the lubricant is present in the solid composition outside granules. In one embodiment, the lubricant is present in the solid composition within granules, and the solid composition within granules is produced by roller compression. As used herein, the lubricant refers to a pharmaceutical excipient added to a tablet formulation that reduces friction on the surface of the tablet. In an embodiment, the lubricant may reduce friction between the surface of the tablet and the processing equipment, for example, between the surface of the tablet and the wall of the die cavity where the tablet is formed. Thus, the lubricant may reduce friction between the die wall and the granules of the formulation as the tablet is formed and discharged. Pharmaceutically acceptable lubricants are non-toxic and pharmacologically inert substances. In addition, the lubricant may be water-soluble or water-insoluble.

[0102] In one embodiment, the lubricant may comprise, for example, fatty acids, fatty acid salts, fatty acid esters, talc, glyceride esters, metal silicates, or any combination thereof, or may be selected therefrom. In an embodiment, the lubricant may comprise or be selected therefrom magnesium stearate, stearic acid, magnesium silicate, aluminum silicate, isopropyl myristate, sodium oleate, sodium stearoyl lactate, sodium stearoyl fumarate, titanium dioxide, or a combination thereof. Examples of the lubricant 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 embodiment, the total concentration of the lubricant in the solid pharmaceutical composition may be 0.05 wt% to 5 wt%, 0.1 wt% to 3 wt%, 1 wt% to 2 wt%, or about 1.5 wt%. In one embodiment, the lubricant is magnesium stearate. In some embodiments, the lubricant is magnesium stearate and is present in the composition within the granules or in the composition outside the granules. In some embodiments, the lubricant is magnesium stearate and is present in the composition within the granules and in the composition outside the granules. In some embodiments, the lubricant is magnesium stearate present at about 1.5 wt% of the solid composition. In some embodiments, the lubricant is magnesium stearate present at about 1.5 wt% of the solid composition and is present in the composition within the granules. In some embodiments, the lubricant is magnesium stearate present at about 1.5 wt% of the solid composition and is present in the composition outside the granules. In some embodiments, the lubricant is magnesium stearate present at about 1.5 weight percent of the solid composition and is present in the composition inside the granules and the composition outside the granules.

[0103] Formulation development

[0104] Erdafitinib formulations, particularly erdafitinib tablets, are provided herein, which comprise (a) a high erdafitinib drug loading rate, e.g., 40 wt% to 70 wt%, or 40 wt% to 60 wt%, or 45 wt% to 55 wt%, or about 50 wt%, or 45 wt% to 55 wt%, or about 50 wt%, and / or; (b) provide acceptable chemical stability of erdafitinib and / or; or (c) support high production rates, e.g., for tablet production on an industrial scale, and in particular tablets in which the length (L) exceeds the diameter (D) so that the aspect ratio (L:D) exceeds 1:1, particularly tablets with 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, particularly of mini-tablets, particularly Supports industrial-scale production and / or, (d) provides a tablet having sufficient physical rigidity, particularly suitable for inclusion in the drug delivery systems described herein, particularly permeation systems, and / or, (e) exhibits desired disintegration and / or solubility characteristics.

[0105] Erdafitinib formulations having a range of combinations of both intragranular and extragranular excipients presented as formulations 4A, 4B, 4C, and 4D Table 1 Additional erdafitinib formulations having various excipient combinations presenting formulations 3.2, 3.3, 3.4, and 4.1 are provided. Table 2 It is provided in.

[0106] [Table 1]

[0107]

[0108] [Table 2]

[0109]

[0110] Solid formulations of erdafitinib, in particular erdafitinib minitablets, in particular those having a high erdafitinib drug loading rate (e.g., 40 wt% to 70 wt%, or 40 wt% to 60 wt%, or 45 wt% to 55 wt%, or about 50 wt%, or 45 wt% to 55 wt%, or about 50 wt%) are provided herein. In one embodiment, the tablet may be obtained by a process comprising fluid bed granulation. In one embodiment, the tablet may be obtained by a process comprising roller compression. In one embodiment, the solid composition within the granule comprises cyclodextrin, in particular hydroxypropyl-beta-cyclodextrin. In one embodiment, the formulation does not contain mannitol in the solid composition within the granule. In one embodiment, the solid composition within the granule does not contain a water-soluble filler. In one embodiment, the formulation comprises a water-insoluble filler, such as microcrystalline cellulose.

[0111] In one embodiment, a fluid bed granulation process for producing granules comprising erdafitinib and hydroxypropyl-beta-cyclodextrin is provided. In one embodiment, the process does not include the use of a water-soluble filler, such as mannitol.

[0112] Solid formulations of erdafitinib, particularly erdafitinib minitablets, particularly those having a high erdafitinib drug loading rate (e.g., in the range of 45% by weight to 55% by weight, or about 50% by weight), comprising a vinylpyrrolidinone-vinyl acetate copolymer and microcrystalline cellulose, particularly in a weight ratio of 1:99 to 99:1, or 5:95 to 95:5, or 10:90 to 90:10, or 20:80 to 80:20, or 30:70 to 70:30, or 40:60 to 60:40, or 50:50. Unexpectedly, it was found that the ejection force during tableting, particularly of minitablets, such as those described herein, was reduced in the presence of this mixture. Powder formulations containing such a mixture were found to have excellent flow characteristics. In one embodiment, the formulation further comprises hydroxypropyl-beta-cyclodextrin. In one embodiment, the formulation does not comprise mannitol.

[0113] In one embodiment, a process for manufacturing tablets, particularly mini-tablets as described herein, is provided, and the powder blend to be compressed comprises a vinylpyrrolidinone-vinyl acetate copolymer and microcrystalline cellulose, particularly in a weight ratio of 1:99 to 99:1, or 5:95 to 95:5, or 10:90 to 90:10, or 20:80 to 80:20, or 30:70 to 70:30, or 40:60 to 60:40, or 50:50. In one embodiment, a process for manufacturing tablets, particularly mini-tablets as described herein, is provided, wherein the powder blend to be tableted comprises erdafitinib, vinylpyrrolidinone-vinyl acetate copolymer, and microcrystalline cellulose, in particular, the weight ratio of vinylpyrrolidinone-vinyl acetate copolymer and microcrystalline cellulose is in the range of 1:99 to 99:1, or 5:95 to 95:5, or 10:90 to 90:10, or 20:80 to 80:20, or 30:70 to 70:30, or 40:60 to 60:40, or 50:50. In one embodiment, the powder blend to be tableted further comprises hydroxypropyl-beta-cyclodextrin. In one embodiment, the powder blend to be tableted does not comprise mannitol.

[0114] The present invention provides erdafitinib solid formulations, particularly erdafitinib powder formulations or erdafitinib minitablets, having a low fine particle content, e.g., less than 20%, or less than 10%, or less than 5%, or about 3% or less, or about 2% or less, particularly erdafitinib drug loading rates (e.g., 40% to 70% by weight, or 40% to 60% by weight, or 45% to 55% by weight, or about 50% by weight, or 45% to 55% by weight, or about 50% by weight). The fine particles can increase ejection force during tableting, particularly during tableting of minitablets as described herein, especially at high speed, e.g., 2500 tablets / minute.

[0115] In one embodiment, formulations comprising erdafitinib, hydroxypropyl-beta-cyclodextrin, vinylpyrrolidinone-vinyl acetate copolymer, and microcrystalline cellulose, particularly tablets or mini-tablets, particularly those having a high erdafitinib drug loading rate (e.g., 40 wt% to 70 wt%, or 40 wt% to 60 wt%, or 45 wt% to 55 wt%, or about 50 wt%, or 45 wt% to 55 wt%, or about 50 wt%). In one embodiment, the formulation further comprises meglumine. In one embodiment, the formulation does not comprise mannitol. In one embodiment, the formulation further comprises at least one or all of a lubricant, such as colloidal silica; a lubricant, such as magnesium stearate; a binder, such as a cellulose derivative, such as hydroxypropyl methylcellulose; and a filler, such as silicified microcrystalline cellulose.

[0116] In one embodiment, formulations comprising erdafitinib, hydroxypropyl-beta-cyclodextrin, vinylpyrrolidinone-vinyl acetate copolymer, and microcrystalline cellulose, particularly tablets or mini-tablets, particularly having a high erdafitinib drug loading rate (e.g., 40 wt% to 70 wt%, or 40 wt% to 60 wt%, or 45 wt% to 55 wt%, or about 50 wt%, or 45 wt% to 55 wt%, or about 50 wt%). In one embodiment, the formulation further comprises at least one or all of a lubricant, such as colloidal silica; a lubricant, such as magnesium stearate; a binder, such as a cellulose derivative, such as hydroxypropyl methylcellulose; and a filler, such as silicified microcrystalline cellulose. In one embodiment, the formulation does not comprise a stabilizer, such as meglumine. In one embodiment, the formulation does not contain mannitol.

[0117] In one embodiment, the formulation is formulation 4A. In one embodiment, the formulation is formulation 4B. In one embodiment, the formulation is formulation 4C. In one embodiment, the formulation is formulation 4D.

[0118] Accordingly, formulation 4D formulation is incorporated into the present disclosure, wherein the solid pharmaceutical composition comprises (a) 50 wt% of erdafitinib free base; (b) 10 wt% of hydroxypropyl-beta-cyclodextrin; (c) 1 wt% of meglumine; (d) 17.5 wt% of microcrystalline cellulose; (e) 10.75 wt% of silicified microcrystalline cellulose; (f) 7.5 wt% of vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25 wt% of colloidal silicon dioxide; (h) 1.5 wt% of hydroxypropyl methylcellulose; and (i) 1.5 wt% of magnesium stearate, wherein these weight percentages are relative to the total solid pharmaceutical composition. In one embodiment, the formulation comprises: (a) a step of preparing a solid composition within granules by a fluid bed granulation process, wherein the solid composition within granules is substantially composed of (i) erdafitinib free base present at a concentration of 50 wt% of the solid pharmaceutical composition; (ii) hydroxypropyl-beta-cyclodextrin present at a concentration of 10 wt% of the solid pharmaceutical composition; (iii) meglumine present at a concentration of 1 wt% of the solid pharmaceutical composition; (iv) microcrystalline cellulose present at a concentration of 10 wt% of the solid pharmaceutical composition; and (v) hydroxypropyl methylcellulose present at a concentration of 1.5 wt% of the solid pharmaceutical composition; and (b) a step of combining the solid composition within granules with extragranular components to form a blend, wherein the extragranular components are (i) microcrystalline cellulose present at a concentration of 7.5 wt% of the solid pharmaceutical composition; and (ii) vinylpyrrolidone-vinyl acetate copolymer present at a concentration of 7.5 wt% of the solid pharmaceutical composition; (iii) silicified microcrystalline cellulose present at a concentration of 10.75 wt% of the solid pharmaceutical composition; (iv) colloidal silicon dioxide present at a concentration of 0.25 wt% of the solid pharmaceutical composition; and (iv) 1 of the solid pharmaceutical composition.It can be manufactured by a process comprising: (c) a step substantially composed of magnesium stearate present at a concentration of 5 weight%; and (c) a step of compressing the blend into a solid pharmaceutical composition in the form of a mini-tablet. In one embodiment, the tablet contains 11.5 mg of erdafitinib. In one embodiment, the tablet is a 23 mg tablet.

[0119] Accordingly, formulation 4C is incorporated into the present disclosure, wherein the solid pharmaceutical composition comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 1.5 wt% hydroxypropyl methylcellulose; (e) 21.0 wt% mannitol; (f) 0.25 wt% sodium lauryl sulfate; (g) 7.25 wt% microcrystalline cellulose; (h) 7.25 wt% vinylpyrrolidone-vinyl acetate copolymer; (i) 0.25 wt% colloidal silicon dioxide; and (j) 1.50 wt% magnesium stearate, wherein these weight percentages are relative to the total solid pharmaceutical composition. In one embodiment, this formulation may be prepared by a process comprising: (a) preparing a granular solid composition by a fluid bed granulation process; (b) combining the granular solid composition with non-granular components to form a blend; and (c) compressing the blend into a solid pharmaceutical composition in the form of a mini-tablet, wherein the granular components and non-granular components are as follows: in the example Table 1 It is presented in [it]. In one embodiment, the tablet contains 11.5 mg of erdafitinib. In one embodiment, the tablet is a 23 mg tablet.

[0120] Accordingly, formulation 4B is incorporated into the present disclosure, wherein the solid pharmaceutical composition comprises (a) 50 wt% of erdafitinib free base; (b) 10 wt% of hydroxypropyl-beta-cyclodextrin; (c) 1 wt% of meglumine; (d) 24.5 wt% of microcrystalline cellulose; (e) 6.0 wt% of silicified microcrystalline cellulose; (f) 6.0 wt% of vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5 wt% of colloidal silicon dioxide; and (h) 2.0 wt% of magnesium stearate, wherein these weight percentages are relative to the total solid pharmaceutical composition. In one embodiment, this formulation comprises the step of (a) preparing a solid composition in granules by a fluid bed granulation process; It can be manufactured by a process comprising: (b) a step of mixing a solid composition within granules with components outside granules to form a blend; and (c) a step of compressing the blend into a solid pharmaceutical composition in the form of a mini-tablet, wherein the components within granules and the components outside granules are as follows: in the example Table 1 As presented in [it]. In one embodiment, this formulation may be prepared by a process comprising: (a) preparing a granular solid composition by a roller compression process; (b) combining the granular solid composition with extragranular components to form a blend; and (c) compressing the blend into a solid pharmaceutical composition in the form of a mini-tablet, wherein the granular components and extragranular components are [in the example]. Table 1 It is presented in [it]. In one embodiment, the tablet contains 11.5 mg of erdafitinib. In one embodiment, the tablet is a 23 mg tablet.

[0121] Accordingly, formulation 4A is incorporated into the present disclosure, wherein the solid pharmaceutical composition comprises (a) 50 wt% of erdafitinib free base; (b) 10 wt% of hydroxypropyl-beta-cyclodextrin; (c) 1 wt% of meglumine; (d) 10 wt% of microcrystalline cellulose; (e) 19 wt% of anhydrous dibasic calcium phosphate; (f) 8 wt% of vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5 wt% of colloidal silicon dioxide; and (h) 1.50 wt% of magnesium stearate, wherein these weight percentages are relative to the total solid pharmaceutical composition. In one embodiment, this formulation comprises the step of (a) preparing a solid composition in granules by a fluid bed granulation process; It can be manufactured by a process comprising: (b) a step of mixing a solid composition within granules with components outside granules to form a blend; and (c) a step of compressing the blend into a solid pharmaceutical composition in the form of a mini-tablet, wherein the components within granules and the components outside granules are as follows: in the example Table 1 As presented in [it]. In one embodiment, this formulation may be prepared by a process comprising: (a) preparing a granular solid composition by a roller compression process; (b) combining the granular solid composition with extragranular components to form a blend; and (c) compressing the blend into a solid pharmaceutical composition in the form of a mini-tablet, wherein the granular components and extragranular components are [in the example]. Table 1 It is presented in [it]. In one embodiment, the tablet contains 11.5 mg of erdafitinib. In one embodiment, the tablet is a 23 mg tablet.

[0122] Accordingly, Formulation 4.1 is incorporated into the present disclosure, wherein the solid pharmaceutical composition comprises (a) 50 wt% of erdafitinib free base; (b) 10 wt% of hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% of microcrystalline cellulose; (d) 11.75 wt% of silicified microcrystalline cellulose; (e) 7.5 wt% of vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% of colloidal silicon dioxide; (g) 1.5 wt% of hydroxypropyl methylcellulose; and (h) 1.5 wt% of magnesium stearate, wherein these weight percentages are relative to the total solid pharmaceutical composition. In one embodiment, the formulation comprises: (a) a step of preparing a solid composition within granules by a fluid bed granulation process, wherein the solid composition within granules is substantially composed of (i) an erdafitinib free base present at a concentration of 50 wt% of the solid pharmaceutical composition; (ii) a hydroxypropyl-beta-cyclodextrin present at a concentration of 10 wt% of the solid pharmaceutical composition; (iii) a microcrystalline cellulose present at a concentration of 10 wt% of the solid pharmaceutical composition; and (iv) a hydroxypropyl methylcellulose present at a concentration of 1.5 wt% of the solid pharmaceutical composition; and (b) a step of combining the solid composition within granules with extragranular components to form a blend, wherein the extragranular components are (i) a microcrystalline cellulose present at a concentration of 7.5 wt% of the solid pharmaceutical composition; and (ii) vinylpyrrolidone-vinyl acetate copolymer present at a concentration of 7.5 wt% of the solid pharmaceutical composition; (iii) silicified microcrystalline cellulose present at a concentration of 11.75 wt% of the solid pharmaceutical composition; (iv) colloidal silicon dioxide present at a concentration of 0.25 wt% of the solid pharmaceutical composition; and (iv) 1 of the solid pharmaceutical composition.It can be manufactured by a process comprising: (c) a step substantially composed of magnesium stearate present at a concentration of 5 weight%; and (c) a step of compressing the blend into a solid pharmaceutical composition in the form of a mini-tablet. In one embodiment, the tablet contains 11.5 mg of erdafitinib. In one embodiment, the tablet is a 23 mg tablet.

[0123] Accordingly, Formulation 3.4 is incorporated into the present disclosure, wherein the solid pharmaceutical composition comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 17.5 wt% microcrystalline cellulose; (e) 10.75 wt% silicified microcrystalline cellulose; (f) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25 wt% colloidal silicon dioxide; (h) 1.5 wt% hydroxypropyl methylcellulose; and (i) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the total solid pharmaceutical composition.

[0124] In one embodiment, the formulation comprises: (a) a step of preparing a solid composition within granules by a fluid bed granulation process, wherein the solid composition within granules is substantially composed of (i) erdafitinib free base present at a concentration of 50 wt% of the solid pharmaceutical composition; (ii) hydroxypropyl-beta-cyclodextrin present at a concentration of 10 wt% of the solid pharmaceutical composition; (iii) meglumine present at a concentration of 1 wt% of the solid pharmaceutical composition; (iv) microcrystalline cellulose present at a concentration of 10 wt% of the solid pharmaceutical composition; and (v) hydroxypropyl methylcellulose present at a concentration of 1.5 wt% of the solid pharmaceutical composition; and (b) a step of combining the solid composition within granules with extragranular components to form a blend, wherein the extragranular components are (i) microcrystalline cellulose present at a concentration of 7.5 wt% of the solid pharmaceutical composition; and (ii) a vinylpyrrolidone-vinyl acetate copolymer present at a concentration of 7.5 wt% of the solid pharmaceutical composition; (iii) silicified microcrystalline cellulose present at a concentration of 10.75 wt% of the solid pharmaceutical composition; (iv) colloidal silicon dioxide present at a concentration of 0.25 wt% of the solid pharmaceutical composition; and (iv) magnesium stearate present at a concentration of 1.5 wt% of the solid pharmaceutical composition, substantially comprising; and (c) compressing the blend into the form of a solid pharmaceutical composition in the form of a mini-tablet. In one embodiment, the tablet contains 11.5 mg of erdafitinib. In one embodiment, the tablet is a 23 mg tablet.

[0125] Diffusion-based drug delivery system

[0126] A drug delivery system particularly suitable for the effective release of drug formulations containing erdafitinib, such as those described in detail above or below, is described herein. Instead of an osmotic drug release mechanism, these specific systems have been developed in which drug release is controlled by drug diffusion through a drug-permeable polymer component forming part of the system housing.

[0127] In certain embodiments, the system comprises a drug-permeable polymer component or portion forming a part of the housing. For example, the drug-permeable component or portion of the system may be a part of the housing formed of a material distinct from the rest of the housing (e.g., a strip or multiple strips of material extending along at least a portion of the length of the housing), thereby allowing the size, shape (e.g., arc angle), thickness, and material properties of the drug-permeable wall structure to 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 portion and the drug-impermeable portion are formed of a thermoplastic polyurethane composition to provide (i) controlled diffusion of a drug from the system, (ii) desired mechanical properties (e.g., can be made straight for insertion / removal, is sufficiently ductile to exhibit excellent tolerance during retention, the tube remains intact for minimal compression / extension, elastic deformability (compliance) with detrusor muscle contraction), (iii) a system in which the shape can be thermally fixed to have a desired retention shape, and / or (iv) a system that can be manufactured by a co-extrusion process.

[0128] 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 using HP-β-CD. In some embodiments, the drug-permeable portion is permeable to erdafitinib free base, erdafitinib HCl salt, and erdafitinib free base formulated using HP-β-CD. In any of the aforementioned embodiments, the material of the drug-permeable portion is an aliphatic polyether-based TPU. In some of the aforementioned embodiments, the material of the drug-permeable portion is an aliphatic polyether-based TPU, which is Lubrizol Tecophilic HP-60D-35 or HP-93A-100.

[0129] In some embodiments, the drug-permeable portion is permeable to erdafitinib free bases formulated using HP-β-CD. In some embodiments, the drug-permeable portion is permeable to erdafitinib free bases formulated using HP-β-CD and is impermeable or substantially impermeable to erdafitinib free bases formulated without HP-β-CD. In any of the aforementioned embodiments, the material of the drug-permeable portion is an aliphatic polyether-based TPU. In some of the aforementioned embodiments, the material of the drug-permeable portion is Lubrizol Tecoflex EG-80A.

[0130] Exemplary materials for the drug-permeable portion (e.g., the "stripe" material of the permeation system) include, but are not limited to, aliphatic polyether-based thermoplastic polyurethanes (TPU), 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 using 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 using 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.

[0131] Exemplary materials for the drug-impermeable portion (e.g., "base" material of the permeation system) include, but are not limited to, silicone elastomer materials such as NuSil MED-4750; TPUs such as Lubrizol Carbothane Aliphatic PC-3575A, Tecothane Soft AR-62A, AR-75A-B20, AC-4075A-B20, Carbothane Aromatic AC-4075A, Tecothane TT-1074A, Tecoflex EG-80A; and ethylene vinyl acetates such as 3M CoTran 9712. In some embodiments, the material of the drug-impermeable portion is selected from MED-4750, PC-3575A, PC-3575A, AR-62A, AR-75A-B20, AC-4075A-B20, AC-4075A, TT-1074A, EG-80A, and CoTran 9712. In some embodiments, the material of the drug-impermeable portion is selected from MED-4750, PC-3575A, PC-3575A, AR-62A, AR-75A-B20, AC-4075A-B20, AC-4075A, TT-1074A, and CoTran 9712. In some embodiments, the material of the drug-impermeable portion is AR-75A-B20. In some embodiments, the material of the drug-impermeable portion is AC-4075A-B20.

[0132] 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.

[0133] It should be understood that Lubrizol Tecophilic HP series materials are aliphatic polyether-based TPUs designed for extrusion but also processable by injection molding, formulated to absorb an equilibrium water content of up to 100% of the weight of the dry resin. HP-60D-35 has Shore hardness = approx. 42D (ASTM D2240), specific gravity = approx. 1.12 (ASTM D792), flexural modulus (psi) = 4000 (ASTM D790), maximum tensile strength (psi) = approx. 7800 (dry) and 4900 (wet) (ASTM D412), maximum elongation (%) = approx. 450 (dry) and 390 (wet) (D412); and water absorption (%) by the Lubrizol method = approx. 35. HP-93A-100 has Shore hardness = approx. 83A (ASTM D2240), specific gravity = approx. 1.13 (ASTM D792), flexural modulus (psi) = 2900 (ASTM D790), maximum tensile strength (psi) = approx. 2200 (dry) and 1400 (wet) (ASTM D412), maximum elongation (%) = approx. 1040 (dry) and 620 (wet) (D412); and water absorption (%) by Lubrizol method = approx. 100.

[0134] 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 Shore hardness = approx. 72A (ASTM D2240), specific gravity = approx. 1.04 (ASTM D792), flexural modulus (psi) = 1,000 (ASTM D790), maximum tensile strength (psi) = approx. 5,800 (ASTM D412), maximum elongation (%) = approx. 660 (D412); tensile modulus (psi) = approx. 300 at 100% elongation, approx. 500 at 200% elongation, and approx. 800 at 300% elongation (ASTM D412); and mold shrinkage (in / in) = approx. 0.008 to 0.012 (ASTM D955).

[0135] 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 Shore hardness = approx. 78A (ASTM D2240), specific gravity = approx. 1.38 (ASTM D792), maximum tensile strength (psi) = approx. 8300 (ASTM D412), maximum elongation (%) = approx. 400 (D412); tensile modulus (psi) = approx. 560 at 100% elongation, approx. 1300 at 200% elongation, and approx. 3400 at 300% elongation (ASTM D412); Flexural modulus (psi) = approximately 1800, Vicat temperature (°C) = approximately 55, and mold shrinkage rate (in / in) (1"x0.25"x6" bar) = approximately 0.011 (ASTM D955).

[0136] It should be understood that Lubrizol Tecothane Soft material is an aromatic polyester hydrocarbon-based TPU that can be processed by extrusion or injection molding. AR-75A has Shore hardness = approx. 79A (ASTM D785), specific gravity = approx. 1.03 (ASTM D792), maximum tensile strength (psi) = approx. 2000 (ASTM D412), maximum elongation (%) = approx. 530 (ASTM D412), tensile modulus (psi) = approx. 730 at 100% elongation, approx. 1000 at 200% elongation, and approx. 1300 at 300% elongation (ASTM D412); flexural modulus (psi) = approx. 2500 (ASTM 790); Vicat softening point (°C) = approx. 75; and mold shrinkage rate (in / in) (1"x0.25"x6" bar) = approximately 0.08 (ASTM D955). AR-75A-B20 is AR-75A filled with 20% BaSO4 and can be prepared, for example, by a compounding solution.

[0137] The test results mentioned for Lubrizol Tecophilic HP, Tecoflex, Aromatic Carbothane AC, and Tecothane Soft materials are approximated based on small samples of TPU; accordingly, it should be further understood that the properties of these materials may show slight variations from the properties listed herein.

[0138] In one mode, Fig. 1 As illustrated in [figure], the wall structure ( 104 The drug reservoir lumen that forms the boundary ( 106 A drug delivery system comprising a tubular housing having ) 100 ) is provided, where (i) wall structure( 104 At least a portion of ) is water-permeable, and (ii) at least a portion of the wall structure is (drug unit( 108 It is permeable to drugs contained in ), and thereby the drugs are permeable to the wall structure ( 104 Release is possible in vivo by diffusion through the drug-permeable portion of the wall structure. In certain embodiments, as discussed in more detail below, the wall structure comprises a first wall structure and a second wall structure, together forming a housing. As used herein, the phrase “diffusion through the drug-permeable portion” (e.g., “diffusion through the second wall structure”) refers to the release of a drug by passing through the wall-forming material by molecular diffusion, and does not refer to release by passing through an opening or open structure extending through such a wall.

[0139] In one mode, Fig. 2 As shown in [figure], the drug delivery system ( 200 ) is provided, and the drug delivery system is a first wall structure formed from a first material ( 206 A second wall structure formed from ) and a second material ( 205 Includes a housing having ), and wall structures adjacent to each other, drug storage lumen ( 208A tube that limits ) is formed together, where (i) a second wall structure ( 205 ), or the first wall structure ( 206 ) and the second wall structure ( 205 Both are permeable to water, and (ii) the first wall structure ( 206 ) is impermeable to drugs, and the second wall structure ( 205 ) is permeable to drugs, and thus the drugs are permeable to the second wall structure ( 205 It can be released in vivo through diffusion via ). As used herein, the term “impermeable to drugs” refers to a wall being substantially impermeable to a solubilized drug, thereby preventing a substantial amount of the solubilized drug from diffusing through it over the duration of treatment in which the system is located in vivo.

[0140] In certain embodiments, the tube is cylindrical or has other suitable shapes or designs. As used herein, the term “cylindrical” refers to a housing having an outer wall that is substantially cylindrical when used in relation to a tubular housing. In some embodiments, the system is “closed” and thus does not include an opening; drug release occurs only by diffusion through a second wall structure.

[0141] In some embodiments, Fig. 2 and Fig. 3 As illustrated in [figure], the first wall structure ( 206 / 306 ) and the second wall structure ( 205 / 305 ) are adjacent to each other to form a cylindrical tube together. For example, such a system can be formed in a co-extrusion or 3D-printing process, thereby forming the first wall structure and the second wall structure integrally. In one embodiment, the co-extruded first wall structure and the second wall structure are thermoplastic polymers having desired properties.

[0142] Fig. 3As illustrated in [figure], the first wall structure ( 306 ) and the second wall structure ( 305 ) is a lumen containing a drug formulation ( 308 A cylindrical tube having ) is formed together. A second wall structure ( 305 ) is the first wall structure ( 306 It is in the form of a longitudinal strip extending along at least a portion of the length of ) and is permeable to drugs, whereas the first wall structure ( 306 ) is not permeable to drugs. In certain embodiments, multiple drug-permeable strips may be used in a single system. In certain embodiments, a single drug-permeable strip may be used in a single system. Accordingly, the size, shape, thickness, and material properties of the second wall structure may be selected to achieve a desired drug release rate.

[0143] In a preferred embodiment, as discussed in more detail below, the system can be elastically deformed between a low-profile unfolded shape (e.g., a relatively straight shape) suitable for insertion into the patient's bladder through the patient's urethra and a relatively extended retention shape (e.g., a pretzel shape, a bi-oval coil shape, an S-shape, etc.) suitable for retention within the bladder.

[0144] In some embodiments, FIGS. 7a to 7c As illustrated in [figure], the system maintains the frame lumen ( 734 It further includes ). In certain embodiments, the retaining frame lumen includes an elastic wire, such as a nitinol wire. In certain other embodiments, the retaining frame lumen is filled with a shape-set elastomer.

[0145] In another embodiment, FIGS. 1 to 3 and Fig. 8As illustrated in [Image], the system does not include a retaining frame lumen or a retaining frame or wire. Instead, the material of the housing is configured to be elastically deformable between a straight shape and a retaining shape in the absence of a retaining frame or wire. In certain embodiments, the tubular housing is thermally fixed in shape to have a coil or other retaining shape. Accordingly, in such embodiments, the design and manufacture of the system are simplified, and the overall size of the system is minimized (or, if the size of the system is kept constant, the drug payload may be increased). In embodiments without a retaining frame, the tubular housing material provides the functions of (i) forming a drug reservoir lumen, (ii) controlling drug release, and (iii) retaining the system within the bladder upon deployment.

[0146] In one embodiment, FIGS. 7a to 7c As illustrated in [figure], the first end ( 706 ) and the second end ( 708 The drug reservoir lumen extending between ) 704 ) slender elastic housing ( 702 A drug delivery system including ) 700 ) is provided. Elastic housing( 702 ) is the first wall structure ( 716 ) and second wall structure ( 724 Tubular wall structure including ) 710 It is formed by ), and the wall structures are adjacent to each other, forming a drug reservoir lumen ( 704 A tube that limits ) is formed together, where (i) a second wall structure ( 724 ), or the first wall structure ( 716 ) and the second wall structure ( 724 Both are permeable to water, and (ii) the first wall structure ( 716 ) is impermeable to drugs, and the second wall structure ( 724 ) is permeable to drugs, and thus the drugs are permeable to the second wall structure (724 It can be released within the body through diffusion via ).

[0147] In an embodiment where the first wall structure and the second wall structure together form a cylindrical tube, any suitable end plug or stopper or thermally formed seal may be used to seal the end of the tube after the drug is loaded. These end plugs / stoppers ensure that the drug-permeable polymer portion forming a part of the outer tube is the only route for drug release.

[0148] In some embodiments, Fig. 2 and Fig. 3 As illustrated in, the wall ( 206 , 205 / 306 , 305 ) has a substantially constant thickness along its circumference. For example, a first wall structure (forming a cylindrical tube together) and a second wall structure ( 206 , 205 / 306 , 305 The inner diameter of ) 210 / 310 ) and outer diameter( 212 / 312 ) is identical. In another embodiment, the wall may have varying thicknesses along the circumference of the wall.

[0149] Accordingly, in the system described herein, drug release is controlled by the diffusion of a drug through a drug-permeable component that defines a portion of the system housing. The drug-permeable wall structure can be positioned and dimensioned and may have material properties to provide a desired rate of controlled drug diffusion from the system.

[0150] Specific materials and arc angles of the drug-permeable portion or wall structure may be selected to achieve a specific drug release profile, namely, water and drug permeation rates. As used herein, the term "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.

[0151] For example, in a specific embodiment, Fig. 2 and Fig. 3 As illustrated in [figure], the second wall structure ( 205 / 305 ) comprises 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 comprises 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 comprises less than 25% of the cross-sectional area of ​​the tube in a cross section perpendicular to the longitudinal axis of the tube.

[0152] In certain embodiments, FIGS. 2, FIGS. 3, FIGS. 7a to 7c, and Fig. 8 As illustrated in [Figure], the first wall structure and the second wall structure forming the tube bordering the drug reservoir lumen are adjacent to each other at two interface edges, thereby the wall structures collectively form the tube defining the drug reservoir lumen. In these embodiments, the two interface edges are arranged at an arc angle of about 15 to about 270 degrees on 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 + or - 3 degrees.

[0153] In one embodiment, Fig. 2 As illustrated in [figure], the second wall structure ( 205 ) is a cylindrical tube ( in cross-section 200 An arc of approximately 60 degrees on the circumference of ) 214 It has ). In one embodiment, Fig. 3 As illustrated in [figure], the second wall structure ( 305) is a cylindrical tube ( in cross-section 300 An arc of approximately 30 degrees on the circumference of ) 314 ...has ) In one embodiment, the second wall structure has an arc angle of about 15 degrees to about 270 degrees. As further described below, in certain embodiments, the second wall structure has an arc angle of about 45 degrees to about 90 degrees, about 120 degrees to about 150 degrees, about 150 degrees to about 270 degrees, or about 210 degrees to about 270 degrees, e.g., about 45 degrees, about 90 degrees, about 135 degrees, about 180 degrees, and about 240 degrees. In certain embodiments, the second wall structure has an arc angle of about 125 degrees to about 145 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.

[0154] Fig. 1 As illustrated in the figure, when the system is formed to have a retaining shape, the second wall structure may be located at an internal curvature (0 degrees), an external curvature (180 degrees), an upper position (90 degrees), or an intermediate position. An upper position (90 degrees) may be preferred when the second wall structure is formed of a material that expands significantly when it absorbs water.

[0155] In some embodiments, the intravesical drug delivery system comprises base AC-4075A-B20 and stripe EG-80-A as described herein, wherein the stripe angle (e.g., Fig. 8(Reference) is 45 to 270 degrees of the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube. In some embodiments, the stripe angle is 45 to 90 degrees, particularly 90 degrees. In some embodiments, an intravesical drug delivery system having a stripe angle of 90 degrees releases about 2 mg / day of erdafitinib. In some embodiments, the stripe angle is 125 to 145 degrees. In some embodiments, the stripe angle is 135 degrees plus / - 10 degrees. In some embodiments, an intravesical drug delivery system having a stripe angle of 125 to 145 degrees releases about 2.5 mg / day to about 3.5 mg / day of erdafitinib. In some embodiments, an intravesical drug delivery system having a stripe angle of 135 degrees plus / - 10 degrees releases about 2.5 mg / day to about 3.5 mg / day of erdafitinib. In some embodiments, the stripe angle is 150 to 270 degrees, particularly 180 degrees. In some embodiments, an intravesical drug delivery system having a stripe angle of 180 degrees releases about 4 mg / day of erdafitinib. In some embodiments, the stripe angle is about 135 degrees. In some embodiments, an intravesical drug delivery system having a stripe angle of 135 degrees releases about 3 mg / day of erdafitinib. In some embodiments, the intravesical drug delivery system is closed at both ends. In some embodiments, the intravesical drug delivery system is sealed at both ends of the drug lumen (e.g., Fig. 7 reference mark 704 ), therefore, does not include an opening for drug release. In some embodiments, the intravesical drug delivery system drug release is a stripe ( Fig. 7 , second wall structure, reference numeral 724 It is accomplished only by diffusion through ).

[0156] Accordingly, a tubular system designed to reduce or control the drug release rate without negatively altering the dimensional and mechanical properties suitable for system deployment and tolerability has been developed. In some embodiments, the design reduces the drug release rate by reducing the length of the drug-permeable region so that it extends along only a portion of the total length of the system. Thus, a larger arc angle of the drug-permeable region may be used to adjust the drug release rate from the system. Additionally, by reducing the length of the drug-permeable region, a smaller amount of drug-permeable material may be used to achieve the reduced drug release rate compared to a conventional system.

[0157] Once the drug is loaded into the drug reservoir lumen, any suitable end plug or stopper or thermally formed seal may be used to seal / close the first and second ends of the drug reservoir lumen. These end plugs / stoppers ensure that the second material forming part of the elastic housing is the only path for drug release. In certain embodiments, the end plug is formed of a first material that is impermeable to the drug (i.e., the material forming the first wall structure).

[0158] In the embodiments described above, 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 in relation to the erdafitinib solid formulation, the drug is in a solid form (e.g., a tablet or a plurality of tablets), and at least a portion of the tubular body is water-permeable to enable the in vivo solubilization of the drug while it is within the drug reservoir lumen. In some embodiments, the first material or the first wall structure may be the only permeable portion. In other embodiments, both the first material / wall structure and the second material / wall structure may be water-permeable.

[0159] The material for the wall structure of the system can be selected from various suitable thermoplastic polyurethane (TPU)-based materials. In particular, the first material forming the first wall structure (i.e., a material impermeable to drugs contained within the drug reservoir) is a polycarbonate-based aromatic thermoplastic polyurethane (e.g., CARBOTHANE TM TPU, e.g., AC-4075A, available from Lubrizol) or aromatic polyester hydrocarbon-based thermoplastic polyurethane (e.g., TECOTHANE TM It may be TPU (e.g., AR-75A, 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 O-[(CH2)6-CO3] n It is represented as -(CH2)-O--. AC-4075A has a durometer-Shore hardness = 77A, specific gravity = 1.19, flexural modulus = 1500 psi, and maximum elongation = 400%. AR-75A has a durometer-Shore hardness = 79A, specific gravity = 1.03, flexural modulus = 2500 psi, and maximum elongation = 530%. In particular, the second material forming the second wall structure (i.e., the material permeable to the drug contained within the drug reservoir) is an aliphatic polyether-based thermoplastic polyurethane (e.g., TECOFLEX TM It may be TPU (e.g., EG-80A, 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 the polyol segment is O-(CH2-CH2-CH2-CH 2)xIt is represented as -O--. EG-80A has a durometer Shore hardness = 72A, specific gravity = 1.04, flexural modulus = 1000 psi, and maximum elongation = 660%. TPU may further contain a radiopaque agent, e.g., barium sulfate, e.g., AC-4075A-B20, which is a polycarbonate-based aromatic thermoplastic polyurethane with a barium sulfate loading rate of 20%.

[0160] In one embodiment, the inner diameter of the cylindrical tube may be about 1.0 mm to about 2.5 mm. In one embodiment, the outer diameter of the cylindrical tube is about 2.0 mm to about 4.1 mm. In one embodiment, the thickness of the first wall structure, the second wall structure, or both is about 0.2 mm to about 1.0 mm. In some embodiments, the thickness of the second wall structure is about 0.16 mm to about 0.24 mm. In one embodiment, the thickness of the second wall structure is about 0.16 mm to about 0.24 mm, wherein the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib.

[0161] Therefore, in contrast to drug delivery systems that form drug-permeable tubes using homogeneous materials (e.g., a blend of permeable and impermeable thermoplastic materials), the mechanical properties of a tube utilizing a double-walled structure (e.g., a drug-permeable strip embodiment) can be separated from the drug release (e.g., diffusion) properties of the tube. For example, in a single-material tube, changing the material of the tube affects both the mechanical and diffusion properties of the system. Controlling the release rate by the stripe angle can have the additional advantage of not requiring a change in the outer diameter of the system; in contrast, if the release rate is controlled by changing the wall thickness, the system may become too large to pass through the urethra or too thin to provide the mechanical strength required for the system. Furthermore, the drug release properties of the blended polymer may not be easily predictable. Additionally, achieving a truly homogeneous blend when mixing two thermoplastic materials is often difficult. Therefore, experiments are required to control the drug release rate using such tubular drug delivery systems. In contrast, the double-walled structure described herein can provide enhanced flexibility in adjusting the specific drug release rate from the delivery system.

[0162] For use in the bladder, it is important that the system be compliant (e.g., easily bendable and soft-feeling) during bladder muscle contraction to avoid or alleviate discomfort and irritation to the patient. Therefore, it should be noted that the durometer of the first and second constituent materials is important, and the proportion of high-durometer material may be limited in constructing the system housing of a given size to maintain a suitably compliant state in the bladder. For example, a suitable first wall material, such as TECOTHANE or CARBOTHANE, may have a Shore hardness greater than 70A, e.g., 77A to 65D, while a suitable second wall material, such as TECOFLEX, may have a Shore hardness less than 90A or less than 80A, e.g., 72A. In some embodiments, the first material has a Shore hardness value of 70A to 80A, while the second material has a Shore hardness value of 70A to 75A. Accordingly, in certain embodiments, the second wall material has a Shore hardness less than that of the first wall material, and both wall materials have a Shore hardness of less than 80A. Accordingly, to achieve the desired mechanical properties of the tube, it may be advantageous to use a combination of two different polymer materials rather than manufacturing the system housing entirely from a water-swellable and hydrophilic drug-permeable second material.

[0163] In an embodiment, the system described herein is configured to release a therapeutically effective amount of drug, wherein the release rate of the drug from the drug delivery system is zero over at least 36 hours. In one embodiment, the release rate of the drug from the drug delivery system is substantially zero over at least 7 days. In an embodiment, the system is configured to release a therapeutically effective amount of drug over a period of 2 to 6 months, e.g., 2 to 90 days, 7 to 30 days, or 7 to 14 days. Preferably, the release rate of the drug from the drug delivery system is zero over at least 7 days, e.g., 7 to 14 days, or longer, e.g., up to 3 months or 90 days. In a specific embodiment, the system is configured to begin releasing the drug after a lag time. In a specific embodiment, the lag time may be at least about 30 minutes, about 12 hours to about 24 hours, or up to about 2 days. These systems may be effective in releasing a therapeutically effective amount of drug for a period of up to 6 months or up to 3 months (90 days).

[0164] As discussed in more detail below, drug formulations, such as those described throughout this disclosure, are disposed within a drug reservoir lumen defined by a first wall structure and a second wall structure. In a particularly preferred embodiment, the drug is an erdafitinib-based pharmaceutical formulation as described herein. In certain embodiments, the system is configured to release erdafitinib at an average rate of about 2 mg / day to about 4 mg / day, for example, about 2.5 mg / day to about 3.5 mg / day, depending on the desired therapeutic regimen. In some embodiments, the system is configured to release erdafitinib at an average rate of about 2 mg / day to about 4 mg / day. In such embodiments, the two interfacial edges may be positioned at an arc angle of 45 to 270 degrees, for example, an arc angle of 90 to 180 degrees, more particularly an arc angle of 125 to 145 degrees.

[0165] In one embodiment, the system is configured to release erdafitinib at an average rate of 2 mg / day, and the two interfacial edges are positioned at an arc angle of about 90 degrees. In another embodiment, the system is configured to release erdafitinib at an average rate of 4 mg / day, and the two interfacial edges are positioned at an arc angle of about 180 degrees. In certain embodiments, the release profile of the drug is substantially independent of pH over a range of pH 5 to 7. In certain embodiments, the release profile of the drug is substantially independent of pH over a range of pH 5.5 to 7. In certain embodiments, the release profile of the drug is substantially independent of pH over a range of pH 5.5 to 8. In certain embodiments, the release rate is maintained for a period of up to 6 months, specifically up to 3 months or 90 days.

[0166] In one embodiment, a drug delivery system is provided, which comprises (i) a housing defining a drug reservoir lumen and a retention frame lumen, (ii) a plurality of tablets containing erdafitinib disposed within the drug reservoir lumen, and (iii) a nitinol wire form (retention frame) disposed within the retention frame lumen. The drug reservoir lumen is defined / bounded by a first wall structure (base) formed of a first material which is an aromatic polyester hydrocarbon-based thermoplastic polyurethane, in particular AC-4075A-B20, and a second wall structure (stripe) formed of a second material which is an aliphatic polyether-based thermoplastic polyurethane, in particular EG-80A, wherein the first wall structure and the second wall structure are adjacent to each other at two interface edges to together form a tube defining a closed drug reservoir lumen. In one embodiment, the closed drug reservoir lumen accommodates a plurality of tablets as described herein, in particular a plurality of mini-tablets, in particular erdafitinib mini-tablets. 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 and has a total of about 500 mg of erdafitinib. In one embodiment, the stripe angle is 90 degrees, and the average release rate of erdafitinib from the system is about 2 mg / day. In one embodiment, the stripe angle is 180 degrees, and the average release rate of erdafitinib from the system is about 4 mg / day. In one embodiment, the stripe angle is 90 degrees, and the average release rate of erdafitinib from the system is approximately 2 mg / day. In one embodiment, the stripe angle is 90 degrees, and the average release rate of erdafitinib from the system is approximately 2 mg / day at a pH of about 5 to about 6.8.In one embodiment, the stripe angle is 180 degrees, and the average release rate of erdafitinib from the system is approximately 4 mg / day. In one embodiment, the stripe angle is 180 degrees, and the average release rate of erdafitinib from the system is approximately 4 mg / day at a pH of about 5 to about 6.8, and approximately 2 mg / day at a pH of about 8. In one embodiment, the tablet has formulation 4D as described herein. In one embodiment, the tablet has formulation 4C as described herein. In one embodiment, the tablet has formulation 4B as described herein. In one embodiment, the tablet has formulation 4A as described herein. In one embodiment, the tablet has formulation 4.1 as described herein. In one embodiment, the tablet has formulation 3.4 as described herein. In one embodiment, the tablet has formulation 3.3 as described herein. In one embodiment, the tablet has formulation 3.2 as described herein.

[0167] Other aspects of drug delivery systems

[0168] In certain embodiments, the system is configured for insertion and maintenance into the bladder of a patient. For example, the system is, for instance, Fig. 7a and Fig. 7b As illustrated, a relatively low profile (e.g., straight) shape suitable for insertion into the patient's body cavity through the lumen, and Fig. 1, Fig. 4, Fig. 5, and Fig. 6a As illustrated in [Figure], the system may be elastically deformable between a relatively extended retention shape suitable for maintaining the system within a body cavity, e.g., a bladder. The relatively extended shape may include a pair of overlapping coils and is sometimes referred to as a "pretzel" shape. In certain embodiments, both ends of the elongated system are generally located within the boundaries of a double elliptical-like shape.

[0169] For example, when in an extended retention position after deployment into the bladder, the system may resist excretion in response to the force of urination or other forces. After drug release, the system may be removed, for example, by a cystoscope and forceps, or at least partially bioerodible to avoid a recovery procedure.

[0170] The system may be loaded with one or more drug unit forms, such as at least one drug of the tablets described throughout this disclosure. Solid drug composition forms, such as tablets, may provide a relatively large drug payload volume relative to the total system volume and may potentially improve the stability of the drug during transport, storage, before use, or before drug release. However, the solid drug may need to be solubilized in vivo to diffuse into the patient's surrounding tissues or body cavities in a therapeutically effective amount through the drug-permeable component. The drug reservoir lumen may accommodate multiple disclosed drug tablets in an elongated form in an end-to-end serial arrangement. In some embodiments, the system accommodates about 10 to 100 cylindrical drug tablets, about 30 to 60 cylindrical drug tablets, about 40 to 50 cylindrical drug tablets, about 42 to 46 cylindrical drug tablets (e.g., 44 tablets), e.g., mini-tablets, which can be loaded continuously into the drug reservoir lumen. In one embodiment, the tablets are those described herein. In one embodiment, the tablet is a tablet of formulation 4A. In one embodiment, the tablet is a tablet of formulation 4B. In one embodiment, the tablet is a tablet of formulation 4C. In one embodiment, the tablet is a tablet of formulation 4D. In one embodiment, the tablet is a tablet of 4.1. In one embodiment, the tablet is a tablet of formulation 3.4. In one embodiment, the tablet is a tablet of formulation 3.3. In one embodiment, the tablet is a tablet of formulation 3.2.

[0171] The system may be inserted into the patient using a cystoscope, a catheter, or any other suitable or custom-made insertion device. Typically, a cystoscope for adults has a working channel with an outer diameter of about 5 mm and an inner diameter of about 2.4 mm to about 2.6 mm. In an embodiment, the cystoscope may have a working channel with a larger inner diameter, such as an inner diameter of 4 mm or more. Thus, the system may be relatively small in size. For example, when the system is elastically deformed into a relatively straight shape, the system for adult patients may have a total outer diameter of less than about 2.6 mm, e.g., about 2.0 mm to about 2.4 mm. In addition to allowing insertion, the relatively small size of the system may also reduce patient discomfort and trauma to the bladder. In one embodiment, the overall configuration of the system promotes in vivo tolerability for most patients. In a specific embodiment, the system is configured to be tolerable based on the bladder characteristics and design considerations described in U.S. Patent No. 11,065,426.

[0172] In the three-dimensional space occupied by the system in the retaining shape, the maximum dimension of the system in any direction is preferably smaller than 10 cm, which is the approximate diameter of the bladder when filled. In some embodiments, the maximum dimension of the system may be less than about 9 cm in any direction, e.g., about 8 cm, 7 cm, 6 cm, 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 cm, or less. In certain embodiments, the maximum dimension of the system is less than about 7 cm in any direction, e.g., 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 is less than about 6 cm in any direction, e.g., about 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 cm, or less. More specifically, the three-dimensional space occupied by the system is defined in three vertical directions. Along one of these directions, the system has its maximum dimension, and along the other two directions, the system may have smaller dimensions. For example, the smaller dimensions in the other two directions may be less than about 4 cm, e.g., about 3.5 cm, 3 cm, 2.5 cm, or less. In a preferred embodiment, the system has dimensions of less than 3 cm in at least one of these directions.

[0173] In some embodiments, the system may have different dimensions in at least two of three directions, and accordingly, in some cases, the system is non-uniform in shape in each of the three directions. Due to the non-uniform shape, the system can achieve an orientation of reduced compression in the empty bladder, which is also non-uniform in shape. In other words, a specific orientation of the system within the empty bladder allows the system to apply less contact pressure to the bladder wall, thereby making the system more tolerable to the patient.

[0174] The overall shape of the system may allow it to self-reorient within the bladder, thereby reducing its engagement or contact with the bladder wall. For example, the overall external shape of the system may be curved, and all or most of the system's external or exposed surfaces may be substantially rounded. The system may also be substantially free of sharp edges, and its external surface may be formed from a material that exhibits reduced frictional engagement with the bladder wall. Such a configuration allows the system to reposition itself within the empty bladder, thereby enabling it to apply lower contact pressure to the bladder wall. In other words, the system may slide or roll against the bladder wall to enter a lower energy position, which refers to a position where the system experiences less compression.

[0175] In one embodiment, the system has a shape that is largely planar, even though the system occupies three-dimensional space. Such a system may define a minor axis—about which the system is substantially symmetric—and a major axis substantially perpendicular to the minor axis. The maximum dimension of the system in the direction of the major axis cannot exceed about 6 cm, and in certain embodiments is less than 5 cm, e.g., about 4.5 cm, about 4 cm, about 3.5 cm, about 3 cm, or less. The maximum dimension of the system in the direction of the minor axis cannot exceed about 4.5 cm, and in certain embodiments is less than 4 cm, e.g., about 3.5 cm, about 3 cm, or less. The system is curved substantially around its entire outer periphery in both the major and minor cross-sectional planes. In other words, the entire outer shape of the system is curved, and the cross-sectional shape of the system is rounded. Thus, except for the edges at the two flat ends, the system has substantially no edges, and these edges are completely protected within the system when the system is placed on a plane. These characteristics allow the system to reorient itself to a position of reduced compression when in an empty bladder.

[0176] The system may also have a sufficiently small retention shape to enable intravesical mobility. In particular, when deployed, the system is small enough to move within the bladder—for example, freely or unhinderedly through the entire bladder under most conditions of bladder fullness—thereby facilitating patient tolerability of the system. The free movement of the system also facilitates uniform drug delivery throughout the entire bladder.

[0177] The system may also be configured to facilitate buoyancy, for example, by using a low-density constituent material for the housing component and / or by introducing a gas or gas-generating material into the housing, as described, for example, in U.S. Patent No. 9,457,176. Generally, the system in the dry state and the drug-loaded state may have a density in the range of about 0.5 g / mL to about 1.5 g / mL, e.g., about 0.7 g / mL to about 1.3 g / mL. In some embodiments, the system in the dry state and the drug-loaded state has a density of less than 1 g / mL.

[0178] In one embodiment, the intravesical drug delivery system is non-biodegradable. In another embodiment, the intravesical drug delivery system may be made fully or partially biodegradable, so that explantation or recovery of the system is not required after release of the drug formulation. In some embodiments, the system is partially biodegradable, so that upon partial erosion, the system breaks down into non-biodegradable fragments small enough to be excreted from the bladder. For example, the system described herein may be designed to conform to the characteristics of those described in U.S. Patent No. 8,690,840.

[0179] The drug delivery system is sterilized before being inserted into a patient. In one embodiment, the system is sterilized using a suitable process such as gamma irradiation or ethylene oxide sterilization, but other sterilization processes may be used.

[0180] The system described herein may include radiopaque parts or structures to facilitate detection or observation of the system (e.g., by X-ray imaging or fluoroscopy) by a medical professional as part of an implantation or retrieval procedure. In one embodiment, the housing is composed of a radiopaque filler material, such as a material containing barium sulfate or other radiopaque materials known in the art. Some housings may be made radiopaque by blending a radiopaque filler, such as barium sulfate or other suitable materials, during the processing of the material forming the housing. The radiopaque material may be associated with the retaining frame in embodiments comprising a retaining frame. Ultrasound imaging or fluoroscopy may be used to image the system in vivo.

[0181] In some embodiments, the device components of the system comprise a drug-impermeable base material and a drug-permeable stripe material, and the base material is a TPU having a 20% BaSO4 filler, such as Lubrizol's Carbothane. TM AC-4075A-B20 or Tecothane TM It is AR-75A-B20 (Lubrizol Life Science (Beslehem, Pennsylvania, USA)).

[0182] The drug delivery system may further include retrieval features, such as a string, a loop, or other structures that facilitate the removal of the system from the patient. In one case, the system may be removed from the bladder by pulling the system through the urethra using a string. The system may be configured to exhibit a relatively narrow or linear shape when the system is pulled into the lumen of a catheter or cystoscope or into the urethra by the retrieval features.

[0183] Maintenance of the system in the body cavity

[0184] The system described herein is elastically deformable between a relatively low profile (e.g., straight or uncoiled) shape suitable for insertion into a patient's bladder (or other body cavity) through a lumen and a relatively extended retention shape suitable for maintaining the system within the bladder (or other body cavity). In certain embodiments, the drug delivery system may naturally exhibit a retention shape and may be deformed into a relatively straight shape for insertion into the body, either manually or with the assistance of an external device. Once deployed, the system may spontaneously or naturally return to its initial retention shape for maintenance within the body.

[0185] For the purposes of this disclosure, terms such as “retaining shape,” “relatively extended shape,” etc. generally refer to any shape suitable for retaining the system in an intended implantation position, including coiled or “pretzel” shapes, for example Fig. 1 and Fig. 4 Includes, but not limited to, those illustrated in [the document], which are suitable for maintaining the system within the bladder. Similarly, terms such as "deployment shape," "relatively low profile shape," "relatively linear shape," etc., generally refer to any shape suitable for deploying the drug delivery system into the body, including linear or elongated shapes, e.g. Fig. 7a and Fig. 7b The devices described herein include, but are not limited to, the system is suitable for deploying through the working channel of a catheter, cystoscope, or other deployment device positioned within the lumen of the body, e.g., the urethra. For example, the housing or tube of the system may have two free ends opposite each other, which are oriented away from each other when the system is in a low-profile deployment shape and oriented toward each other when the system is in a relatively extended retention shape.

[0186] In some embodiments, FIGS. 7a to 7cAs illustrated in [figure], the system maintains the frame lumen ( 734 It further includes a retaining frame (not shown) positioned within the retaining frame lumen. For example, the retaining frame lumen and the retaining 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 retaining frame lumen may be sealed with a suitable plug or adhesive material, such as a silicone adhesive material.

[0187] Fig. 4 This exemplifies a system (300) in which a drug tablet (108) is loaded into the drug storage lumen of the system housing (304). Fig. 5 As can be seen from, before loading the tablet, the retaining frame (303) forces the system housing (304) to have a separate, extended shape compared to the retaining shape when the drug tablet (108) is loaded.

[0188] In certain embodiments where an increased payload is required, additional length of the drug reservoir lumen / tube may be provided. In one embodiment, Fig. 6a and Fig. 6b As illustrated in [Figure], the retaining frame has an outer periphery defined by two overlapping portions (coils) of the nitinol wire. Each end portion of the wire extends inward from the outer periphery and includes (i) a curved transition region having a smaller radius of curvature than the outer portion of the wire, and (ii) a straight portion terminating at a rounded end cap. In contrast, Fig. 5 In the system illustrated in [Image], the retaining frame has an outer circumference defined by a single coil. Fig. 6a and Fig. 6b A system having a maintenance frame Fig. 5It enables a relatively longer drug storage (e.g., to accommodate more tablets) in a system having the same "footprint" (outer shape and dimensions) as the system exemplified in.

[0189] In another embodiment, FIGS. 1 to 3 As illustrated in [Image], the system does not include a retaining frame lumen or a retaining frame or wire. Instead, the housing material is configured to be elastically deformable between a straight shape and a retaining shape in the absence of a retaining frame or wire. In such an embodiment, the design and manufacture of the system are simplified, and the overall size of the system is minimized (or, if the size of the system is kept constant, the drug payload may be increased). In an embodiment without a retaining frame, the tubular housing material provides the function of (i) forming a drug reservoir lumen, (ii) controlling drug release, and (iii) retaining the system within the bladder upon deployment.

[0190] For example, the tubular housing may be thermally fixed in shape to have a retaining shape. Thus, the housing may comprise one or more thermoplastic materials suitable for thermally forming into a retaining shape. In a specific embodiment, the drug delivery system comprises a tubular housing having a closed drug reservoir lumen bounded by a wall structure comprising at least one thermoplastic material, wherein (i) at least a portion of the wall structure is water permeable and at least a portion of the wall structure is drug permeable; (ii) the tubular housing is elastically deformable from a retaining shape suitable for retaining the system within the bladder to a relatively straight shape suitable for insertion through the lumen into the bladder; and (iii) the tubular wall is thermally shaped to have a retaining shape. A photograph showing a cross-section of the drug reservoir lumen of the drug delivery system without a drug placed inside. Fig. 8 It is depicted in. Fig. 8As shown in [figure], the second wall structure has an arc angle of about 30 degrees of the circumference of the cylindrical tube in cross-section ( 802 has ).

[0191] In a specific embodiment, the first and second wall structures are each thermoplastic polyurethane, and the tubular housing is thermally shaped to have a retaining shape. In one embodiment, the tubular wall has a spring constant effective in preventing the system from exhibiting a relatively straight shape once it is implanted in the bladder. Thus, the properties of the tubular wall allow the system to function as a spring, deforming in response to a compression rod, but allowing it to spontaneously return to its initial shape once the rod is removed.

[0192] In certain embodiments, the system may naturally exhibit a retaining shape, deform into a relatively straight shape, and spontaneously return to the retaining shape upon insertion into the body. The tubular wall structure in the retaining shape may be shaped for retention within the body cavity, and the relatively straight shape may be shaped for insertion into the body through the working channel of an unfolding device, such as a catheter or cystoscope. To achieve such results, the tubular wall structure may have an elastic limit, modulus, and / or spring constant selected to prevent the system from exhibiting a relatively low profile shape once implanted. Such a configuration may limit or prevent accidental escape of the system from the body under expected forces. For example, the system may be retained within the bladder during urination or contraction of the detrusor muscle.

[0193] In a preferred embodiment, the system can be elastically deformed between a relatively straight shape suitable for insertion through a catheter or cystoscope extending through the patient's urethra and a curved or coiled shape suitable for retaining the system within the bladder after release from the end of the catheter or cystoscope (i.e., preventing its escape from the bladder during urination).

[0194] Fig. 1 As illustrated in [Figure], the retaining shape may include a coiled or "pretzel" shape. The pretzel shape substantially comprises at least two sub-circles, each having a smaller arc within itself and sharing a common larger arc. When the pretzel shape is initially compressed, the larger arc absorbs most of the compressive force and begins to deform, but as compression continues, the smaller arc overlaps, and subsequently, all three arcs come to resist the compressive force. The resistance of the system as a whole to compression increases once the two sub-circles overlap, hindering the collapse and voiding of the system as the bladder contracts during urination.

[0195] The wall structure of the retaining shape may have a two-dimensional structure confined to a plane, a three-dimensional structure, such as a structure occupying the interior of a spheroid, or any combination thereof. The retaining shape may include one or more linearly or radially connected loops, curls, or subcircles that change in the same direction or alternately and may or may not overlap. The retaining shape may include one or more circles or ovals arranged in a two-dimensional or three-dimensional configuration, the circles or ovals may be closed or open, have the same or different sizes, may or may not overlap, and may be joined together at one or more connection points. The retaining shape may also be a three-dimensional structure shaped to occupy or wrap around an ellipsoid-shaped space, such as a spherical space, a space having an elongated sphere shape, or a space having a supernate sphere shape. The wall structure of the retaining shape may be shaped to occupy or wrap around a spherical space. The retaining wall structure can generally take the shape of two intersecting circles in different planes, two intersecting circles in different planes with inwardly curled ends, three intersecting circles in different planes, or a spherical spiral. In each of these examples, the wall structure can be extended into a linear shape to be unfolded through a unfolding device. The wall structure can be wound through or around a spherical space or other ellipsoidal-shaped space in various other ways.

[0196] A drug delivery system utilizing a thermally formed co-extruded tube having a drug-permeable portion and a drug-impermeable portion can integrate three functional components (drug reservoir / housing, drug permeation pathway, and retention feature) into a single thermally formed co-extruded tube component, which can simplify system design and the ability to control the drug release rate. As discussed herein, in such a system, the drug release rate can be modified relatively easily by controlling the angle and thickness of the drug-permeable portion (e.g., strip) without changing the entire tube housing material.

[0197] A thermally shaped co-extruded tubular housing can be loaded with drug tablets, and both ends can be thermally sealed or sealed with an adhesive (e.g., a first wall material). If localized deformation of the tube cross-section or tube kinking occurs, tablet loading will be difficult. Therefore, tube dimensions must be selected to prevent twisting when the tube is thermally shaped. The critical bending radius of the elastic tube under pure bending conditions (R * ) can be approximated using the following equation:

[0198]

[0199] Here, v is Poisson's rhyme, and r is the average radius (i.e., (ID+OD) / 4), and w ε is the tube wall thickness, ID is the tube inner diameter, and OD is the tube outer diameter. Poisson's ratio for polyurethane v For = 0.49, the estimated critical radius is 0.5 cm. Therefore, in some embodiments, when thermally shaping the polyurethane tube, the radius of curvature should preferably be greater than 0.5 cm along the entire length of the tube to prevent twisting. Accordingly, in one embodiment, the retaining shape includes at least one loop having a radius of curvature of at least 0.5 cm.

[0200] Drug delivery system

[0201] In some embodiments, as a drug delivery system, a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and a second wall structure formed of a second material comprising an aliphatic polyether-based thermoplastic polyurethane; and comprises a drug formulation comprising erdafitinib, disposed in a drug reservoir lumen, wherein (i) a second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through a second material forming the second wall structure, and the first wall structure and the second wall structure are adjacent to each other at two interfacial edges and together form a tube, and the drug delivery system is configured to release erdafitinib at an average rate of about 2 mg / day to about 4 mg / day, optionally the system is configured to release erdafitinib at an average rate of about 2.5 mg / day to about 3.5 mg / day, and the two interfacial edges are about 90 degrees to about 3.5 degrees of the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube. A drug delivery system is provided herein, which is arranged at an arc angle of 180 degrees, preferably from about 125 degrees to about 145 degrees. In some embodiments, the drug delivery system comprises about 40 to about 50, about 42 to about 48, or about 44 to about 46 erdafitinib mini-tablets. In some embodiments, the drug delivery system comprises 42 to 46 erdafitinib mini-tablets. In some embodiments, the drug delivery system comprises 43 erdafitinib mini-tablets. In some embodiments, the drug delivery system is configured to release erdafitinib at an average rate of 3 mg / day, and two interfacial edges are arranged at an arc angle of 135 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube.In some embodiments, the drug delivery system comprises AC-4075A-B20 and EG-80-A. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 17.5 wt% microcrystalline cellulose; (e) 10.75 wt% silicified microcrystalline cellulose; (f) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25 wt% colloidal silicon dioxide; (h) 1.5 wt% hydroxypropyl methylcellulose; and (i) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the total solid pharmaceutical composition. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the total solid pharmaceutical composition. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 24.5 wt% microcrystalline cellulose; (e) 6.0 wt% silicified microcrystalline cellulose; (f) 6.0 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5 wt% colloidal silicon dioxide; and (h) 2.0 wt% magnesium stearate, wherein these weight percentages are relative to the total solid pharmaceutical composition.

[0202] In some embodiments, as a drug delivery system, a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and a second wall structure formed of a second material comprising an aliphatic polyether-based thermoplastic polyurethane; A drug delivery system is provided herein, comprising a drug formulation containing erdafitinib disposed in a drug reservoir lumen, wherein (i) a second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through a second material forming the second wall structure, and the first wall structure and the second wall structure are adjacent to each other at two interfacial edges and together form a tube, and the drug delivery system is configured to release erdafitinib at an average rate of about 3 mg / day, and the two interfacial edges are arranged at an arc angle of about 135 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. In some embodiments, the drug delivery system comprises about 40 to about 50, about 42 to about 48, or about 44 to about 46 erdafitinib mini-tablets. In some embodiments, the drug delivery system comprises 42 to 46 erdafitinib mini-tablets. In some embodiments, the drug delivery system comprises 43 erdafitinib mini-tablets. In some embodiments, the drug delivery system is configured to release erdafitinib at an average rate of 3 mg / day, and two interfacial edges are positioned at an arc angle of 135 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. In some embodiments, the drug delivery system comprises AC-4075A-B20 and EG-80-A.In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 17.5 wt% microcrystalline cellulose; (e) 10.75 wt% silicified microcrystalline cellulose; (f) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25 wt% colloidal silicon dioxide; (h) 1.5 wt% hydroxypropyl methylcellulose; and (i) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the total solid pharmaceutical composition. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the total solid pharmaceutical composition. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 24.5 wt% microcrystalline cellulose; (e) 6.0 wt% silicified microcrystalline cellulose; (f) 6.0 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5 wt% colloidal silicon dioxide; and (h) 2.0 wt% magnesium stearate, wherein these weight percentages are relative to the total solid pharmaceutical composition.

[0203] FIGS. 27a to 29 This illustrates an embodiment of a drug delivery system according to the present disclosure. FIGS. 27a to 29drug delivery system ( 2700 ) is referred to herein as "TAR-210-C" and is designed to release approximately 3 mg of erdafitinib per day. Fig. 27a is a drug delivery system illustrated in a coil-holding shape ( 2700 This is a schematic plan of ). Fig. 27b is a drug delivery system illustrated in a coil-holding shape ( 2700 This is a schematic lower plan of ). Fig. 28 silver Fig. 27a A drug delivery system taken along line AA ( 2700 This is a cross-sectional view of ). Fig. 29a A drug delivery system illustrated with a relatively linear insertion shape ( 2700 This is a schematic side view of ). Fig. 29b A drug delivery system illustrated with a relatively linear insertion shape ( 2700 This is a side cross-sectional view of a part of ).

[0204] Fig. 27a and Fig. 27b Referring to, in some embodiments, a drug delivery system ( 2700 ) is housing( 2704 Includes ). Housing( 2704 ) is the drug storage lumen( 2732 ) and retaining frame lumens( 2734 )( Fig. 27b Limits to (visible only in). Fig. 27a and Fig. 27b In, drug storage lumen ( 2732 The portion of the housing (2704) demarcating the ) is shown to be translucent, and the erdafitinib mini-tablet ( 2708 Shows ).

[0205] As in other embodiments disclosed herein, the drug reservoir lumen ( 2732 ) and retaining frame lumens( 2734 ) can be monolithic with each other, for example, can be co-molded in an extrusion process. As previously mentioned, the drug reservoir lumen ( 2732) is a plurality of erdafitinib mini-tablets (which will be explained in more detail below) 2708 Contains ) retention frame lumen( 2734 ) is a retaining frame such as elastic or superelastic nitinol wire ( 2903 )( Fig. 28 and Fig. 29b It accommodates (as can be seen in ). As described together with other embodiments of the drug delivery system disclosed herein, the drug delivery system ( 2700 ) has a low-profile unfolding shape suitable for insertion into the patient's bladder through the patient's urethra (e.g., a relatively straight shape; Fig. 29a and Fig. 29b (Reference) and drug delivery system within the bladder ( 2700 A relatively extended retention shape suitable for retaining ) (e.g., a double elliptical coil shape; Fig. 27a and Fig. 27b It is elastically deformable between ). According to an embodiment, when in the unfolded shape, the drug delivery system (2700) can be inserted through the patient's urethra using a urinary placement catheter. Retaining frame ( 2903 Due to the elastic properties of ), the drug delivery system ( 2700 ) naturally returns to its retained shape when there are no external constraints, for example, when exiting a urinary placement catheter.

[0206] Fig. 27a Referring to, in some embodiments, when the coil holding shape is arbitrary direction ( X, Y ) as a drug delivery system( 2700 ) is the maximum dimension of approximately 6 cm or less (e.g., Fig. 27a of L It has ). In some embodiments, when in a coil-holding shape, the drug delivery system ( 2700 ) is an arbitrary direction( X, Y The maximum dimension of approximately 5.5 cm or less (e.g., Fig. 27a of L It has ). In some embodiments, when in a coil-holding shape, the drug delivery system (2700 ) is a circumscribed rectangle of 5.5 cm x 4.5 cm ( X, Y It fits inside.

[0207] Fig. 28 Referring to the cross-sectional view, the housing ( 2704 ) drug storage lumen( 2732 ) and retaining frame lumens( 2734 ) is illustrated. According to an embodiment, the drug storage lumen ( 2732 ) is the first material ( 2906 A first wall structure formed of ) and a second material ( 2905 It is bordered by a second wall structure formed of ). According to an embodiment, the second material of the second wall structure ( 2905 ), or the first material of the first wall structure ( 2906 ) and the second material of the second wall structure ( 2905 Both are permeable to water. According to some embodiments, the first material of the first wall structure ( 2906 ) and the second material of the second wall structure ( 2905 Both are permeable to water. According to some embodiments, the first material of the first wall structure ( 2906 ) is impermeable to erdafitinib, and the second material of the second wall structure ( 2905 ) is permeable to erdafitinib, so erdafitinib is a second material forming a second wall structure ( 2905 It can be released in vivo by diffusion through ). According to an embodiment, the first material ( 2906 ) comprises a polycarbonate-based aromatic thermoplastic polyurethane, and a second material ( 2905 ) comprises an aliphatic polyether-based thermoplastic polyurethane. In some embodiments, the first material ( 2906 ) is AC-4075A, and the second material( 2905 ) is EG-80-A. In some embodiments, the first material ( 2906 ) is AC-4075A-B20, and the second material( 2905) is EG-80-A.

[0208] Continue Fig. 28 Referring to, in some embodiments, the first wall structure and the second wall structure have two interface edges ( 2905A, 2905B They are adjacent to each other at ) and form a tube together. For example, the first and second wall structures are at the interface edge ( 2905A, 2905B They can be joined together or co-extruded at ). Two interface edges ( 2905A , 2905B ) is the longitudinal axis of the tube( Z An arc angle of about 125 to about 145 degrees, particularly about 135 degrees, of the circumference of the tube in a cross-section perpendicular to ) 2914 It can be arranged as ). In some embodiments, Fig. 28 As shown in [figure], the arc angle ( 2914 ) is approximately 135 degrees. In some embodiments, the arc angle ( 2914 ) is approximately 135 degrees, and the second material forming the second wall structure ( 2905 Including ), the arc of the second wall structure is an arc angle ( 2914 Corresponds to ). According to an embodiment, the second wall structure is permeable to erdafitinib, so erdafitinib is a second material forming the second wall structure ( 2905 It can be released in vivo by diffusion through ).

[0209] As mentioned herein, the term "arc angle" refers to the angular dimension of the arc of the circumference of a tube in a cross section perpendicular to the longitudinal axis of the tube. For example, in some embodiments, the arc angle ( 2914 ) is the second wall structure drug reservoir lumen ( 2704 Occupying approximately 135 degrees of the circumference of ) and the first wall structure is the drug storage lumen ( 2704 It is approximately 135 degrees to occupy approximately 225 degrees of the circumference of the circle. Unless otherwise indicated, the terms “arc angle” and “stripe angle” are used interchangeably throughout this disclosure.

[0210] Continue Fig. 28Referring to, in some embodiments, a drug delivery system ( 2700 The second material of ) 2905 ) is the drug storage lumen( 2732 A wall thickness of 0.2 ± 0.04 mm extending along the diameter of ) T ) limits. In some embodiments, the drug reservoir lumen ( 2732 ) has an inner diameter of 2.64 ± 0.05 mm ( D Limits )

[0211] As discussed above, in some embodiments, a drug delivery system ( 2700 ) housing( 2704 ) is the retained frame lumen( 2734 Includes ). According to an embodiment, wire form ( 2903 ) is the retained frame lumen( 2734 It is placed within ) and has a diameter of approximately 0.305 mm ( d Limits )

[0212] Fig. 29a and Fig. 29b Referring to, drug delivery system ( 2700 ) is depicted as a relatively straight insertion shape. Fig. 29a In, drug storage lumen ( 2732 The part of the housing demarcating ) appears to be translucent, and the erdafitinib mini-tablet contained therein ( 2708 Shows ). Fig. 29b In this case, the housing is an erdafitinib mini-tablet located in the drug storage lumen (2732). 2708 ) and retaining frame lumens( 2734 It is shown in cross-section to indicate the retaining frame (2903) located in ). Fig. 29b In, drug delivery system ( 2700 The end of ) 2808 , 2810 ) is cut off.

[0213] Fig. 29a As illustrated in and as mentioned above, the drug delivery system ( 2700Some embodiments of ) are, for example, a housing ( 2704 The first and second opposing ends (limited by ) 2808, 2810 Includes ). Continuously Fig. 29a Referring to, according to some embodiments, a drug delivery system ( 2700 ) are the first and second opposing ends ( 2808, 2810 A length of about 17 cm between ( 2812 ) is limited. According to some embodiments, the drug storage lumen ( 2732 ) are the first and second opposing ends ( 2808 , 2810 In ), for example, plug( 2820 )( Fig. 29b (See reference), is sealed with a thermoplastic material, and / or a sealant. Sealing at the opposing end (2808, 2810) ensures that the drug-permeable second wall structure of the drug reservoir lumen (2732) is the only route for drug release.

[0214] In some embodiments, the drug formulation comprises (a) 50 wt% of erdafitinib free base; (b) 10 wt% of hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% of microcrystalline cellulose; (d) 11.75 wt% of silicified microcrystalline cellulose; (e) 7.5 wt% of vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% of colloidal silicon dioxide; (g) 1.5 wt% of hydroxypropyl methylcellulose; and (h) 1.5 wt% of magnesium stearate, wherein these weight percentages are relative to the total drug formulation.

[0215] Fig. 29a and Fig. 29b Referring to, in some embodiments, the drug formulation is a mini-tablet ( 2708 ...includes ). In some embodiments, the drug formulation is a mini-tablet ( 2708 It consists of ). In some embodiments, a drug delivery system ( 2700 ) is about 42 to 44 erdafitinib mini-tablets ( 2708Includes ). In some embodiments, a drug delivery system ( 2700 ) contains 43 erdafitinib mini-tablets ( 2708 ...includes ). In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib.

[0216] In some embodiments, each mini-tablet ( 2708 ) has a weight of about 22 mg to about 24 mg. In some embodiments, each mini-tablet ( 2708 ) has a weight of about 23 mg.

[0217] Fig. 29a Referring to, in some embodiments, each mini-tablet ( 2708 ) has a thickness of about 3.0 mm to about 3.4 mm ( 2802 ) limits. In some embodiments, each mini-tablet ( 2708 ) has a thickness of approximately 3.2 mm ( 2802 Limits )

[0218] Continue Fig. 29a Referring to, in some embodiments, each mini-tablet ( 2708 ) has a diameter of about 2.60 mm to about 2.66 mm ( 2806 ) limits. In some embodiments, each mini-tablet ( 2708 ) has a diameter of approximately 2.63 mm ( 2806 Limits )

[0219] Fig. 29b Referring to, in some embodiments, a plurality of mini-tablets ( 2708 ) are arranged in series and drug core( 2822 Limits ). For example, drug core( 2822 ) contains 43 erdafitinib mini-tablets ( 2708 It may include ). Drug core( 2822 ) is the drug core( 2822 )'s 1st mini-tablet( 2708a The outer surface of ) and the drug core (2822 The last mini-refinery of ) 2708b Drug core length between opposing outer surfaces of ) 2824 ) can be limited. According to an embodiment, the drug core length ( 2824 ) can be about 15 cm.

[0220] In some embodiments, as a drug delivery system, a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and a second wall structure formed of a second material comprising an aliphatic polyether-based thermoplastic polyurethane; A drug delivery system is provided herein, comprising a drug formulation comprising erdafitinib disposed in a drug reservoir lumen and comprising (i) a second wall structure, or both the first wall structure and the second wall structure are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through a second material forming the second wall structure, 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 the two interfacial edges are arranged at an arc angle of about 125 to about 145 degrees, particularly about 135 degrees, of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, and the arc angle comprises a second material forming the second wall structure such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees, and the arc of the second wall structure corresponds to the arc angle, comprising a second material forming the second wall structure. In some embodiments, the drug formulation comprises (a) 50 wt% of erdafitinib free base; (b) 10 wt% of hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% of microcrystalline cellulose; (d) 11.75 wt% of silicified microcrystalline cellulose; (e) 7.5 wt% of vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% of colloidal silicon dioxide; (g) 1.5 wt% of hydroxypropyl methylcellulose; and (h) 1.5 wt% of magnesium stearate, wherein these weight percentages are relative to the total drug formulation.

[0221] In some embodiments, as a drug delivery system, a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and a second wall structure formed of a second material comprising an aliphatic polyether-based thermoplastic polyurethane; A drug delivery system is provided herein, comprising a drug formulation comprising erdafitinib disposed in a drug reservoir lumen and comprising (i) both the first wall structure and the second wall structure are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through a second material forming the second wall structure, 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 the two interfacial edges are arranged at an arc angle of about 125 to about 145 degrees, particularly about 135 degrees, of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, and the arc angle comprises a second material forming the second wall structure such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees, and the arc of the second wall structure corresponds to the arc angle, comprising a second material forming the second wall structure. In some embodiments, the drug formulation comprises (a) 50 wt% of erdafitinib free base; (b) 10 wt% of hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% of microcrystalline cellulose; (d) 11.75 wt% of silicified microcrystalline cellulose; 7.5 wt% of vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% of colloidal silicon dioxide; (g) 1.5 wt% of hydroxypropyl methylcellulose; and (h) 1.5 wt% of magnesium stearate, wherein these weight percentages are relative to the total drug formulation.

[0222] In some embodiments, as a drug delivery system, a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and a second wall structure formed of a second material comprising an aliphatic polyether-based thermoplastic polyurethane; A drug delivery system is provided herein, comprising a drug formulation comprising erdafitinib disposed in a drug reservoir lumen and comprising (i) a second wall structure, or both the first wall structure and the second wall structure are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through a second material forming the second wall structure, 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 the two interfacial edges are arranged at an arc angle of about 125 to about 145 degrees, particularly about 135 degrees, of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, and the arc angle comprises a second material forming the second wall structure such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees, and the arc of the second wall structure corresponds to the arc angle, including a second material forming the second wall structure. In some embodiments, both the first wall structure and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.It contains 5 weight percent of magnesium stearate, wherein these weight percentages are relative to the total drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib.

[0223] In some embodiments, as a drug delivery system, a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and a second wall structure formed of a second material comprising an aliphatic polyether-based thermoplastic polyurethane; A drug delivery system is provided herein, comprising a drug formulation comprising erdafitinib disposed in a drug reservoir lumen and comprising (i) a second wall structure, or both the first wall structure and the second wall structure are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through a second material forming the second wall structure, 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 the two interfacial edges are arranged at an arc angle of about 125 to about 145 degrees, particularly about 135 degrees, of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, and the arc angle comprises a second material forming the second wall structure such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees, and the arc of the second wall structure corresponds to the arc angle, including a second material forming the second wall structure. In some embodiments, both the first wall structure and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.It contains 5 weight percent of magnesium stearate, wherein these weight percentages are relative to the total drug formulation. In some embodiments, the drug formulation comprises a mini-tablet. In some embodiments, the drug formulation consists of a mini-tablet. In some embodiments, the drug formulation consists of a mini-tablet. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib mini-tablets. In some embodiments, the drug delivery system comprises 43 erdafitinib mini-tablets. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A.

[0224] In some embodiments, as a drug delivery system, a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and a second wall structure formed of a second material comprising an aliphatic polyether-based thermoplastic polyurethane; A drug delivery system is provided herein, comprising a drug formulation comprising erdafitinib disposed in a drug reservoir lumen and comprising (i) a second wall structure, or both the first wall structure and the second wall structure are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through a second material forming the second wall structure, 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 the two interfacial edges are arranged at an arc angle of about 125 to about 145 degrees, particularly about 135 degrees, of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, and the arc angle comprises a second material forming the second wall structure such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees, and the arc of the second wall structure corresponds to the arc angle, including a second material forming the second wall structure. In some embodiments, both the first wall structure and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.It contains 5 weight percent of magnesium stearate, wherein these weight percentages are relative to the total drug formulation. In some embodiments, the drug formulation comprises a minitablet. In some embodiments, the drug formulation consists of a minitablet. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each mini-tablet has a weight of about 22 mg to about 24 mg. In some embodiments, each mini-tablet has a weight of about 23 mg.

[0225] In some embodiments, as a drug delivery system, a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and a second wall structure formed of a second material comprising an aliphatic polyether-based thermoplastic polyurethane; A drug delivery system is provided herein, comprising a drug formulation comprising erdafitinib disposed in a drug reservoir lumen and comprising (i) a second wall structure, or both the first wall structure and the second wall structure are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through a second material forming the second wall structure, wherein the first and second wall structures are adjacent to each other at two interfacial edges and together form a tube, and the two interfacial edges are arranged at an arc angle of about 125 to about 145 degrees, particularly about 135 degrees, of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, and the arc angle comprises a second material forming the second wall structure such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees, and the arc of the second wall structure corresponds to the arc angle, including a second material forming the second wall structure. In some embodiments, both the first wall structure and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.It contains 5 weight percent of magnesium stearate, wherein these weight percentages are relative to the total drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight of about 22 mg to about 24 mg. In some embodiments, each minitablet has a weight of about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, each minitablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, each minitablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, each minitablet has a thickness of about 3.2 mm.

[0226] In some embodiments, as a drug delivery system, a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and a second wall structure formed of a second material comprising an aliphatic polyether-based thermoplastic polyurethane; A drug delivery system is provided herein, comprising a drug formulation comprising erdafitinib disposed in a drug reservoir lumen and comprising (i) a second wall structure, or both the first wall structure and the second wall structure are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through a second material forming the second wall structure, and the first and second wall structures are adjacent to each other at two interfacial edges and together form a tube, and the two interfacial edges are arranged at an arc angle of about 125 to about 145 degrees, particularly about 135 degrees, of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, and the arc angle comprises a second material forming the second wall structure such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees, and the arc of the second wall structure corresponds to the arc angle, including a second material forming the second wall structure. In some embodiments, both the first wall structure and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.It contains 5 weight percent of magnesium stearate, wherein these weight percentages are relative to the total drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight of about 22 mg to about 24 mg. In some embodiments, each minitablet has a weight of about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, each minitablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, each minitablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, each minitablet has a thickness of about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, each minitablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, each minitablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter of about 2.63 mm.

[0227] In some embodiments, as a drug delivery system, a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and a second wall structure formed of a second material comprising an aliphatic polyether-based thermoplastic polyurethane; A drug delivery system is provided herein, comprising a drug formulation comprising erdafitinib disposed in a drug reservoir lumen and comprising (i) a second wall structure, or both the first wall structure and the second wall structure are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through a second material forming the second wall structure, and the first and second wall structures are adjacent to each other at two interfacial edges and together form a tube, and the two interfacial edges are arranged at an arc angle of about 125 to about 145 degrees, particularly about 135 degrees, of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, and the arc angle comprises a second material forming the second wall structure such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees, and the arc of the second wall structure corresponds to the arc angle, including a second material forming the second wall structure. In some embodiments, both the first wall structure and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.It contains 5 weight percent of magnesium stearate, wherein these weight percentages are relative to the total drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight of about 22 mg to about 24 mg. In some embodiments, each minitablet has a weight of about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, each minitablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, each minitablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, each minitablet has a thickness of about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, each minitablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, each minitablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter of about 2.63 mm. In some embodiments, the housing has a first end and a second end, and limits the length between the first end and the second end, and the length is about 17 cm.In some embodiments, the drug reservoir lumen is sealed at the first and second opposing ends, for example, with a plug, a thermoplastic material, and / or a sealant.

[0228] In some embodiments, as a drug delivery system, a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and a second wall structure formed of a second material comprising an aliphatic polyether-based thermoplastic polyurethane; A drug delivery system is provided herein, comprising a drug formulation comprising erdafitinib disposed in a drug reservoir lumen and comprising (i) a second wall structure, or both the first wall structure and the second wall structure are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through a second material forming the second wall structure, and the first and second wall structures are adjacent to each other at two interfacial edges and together form a tube, and the two interfacial edges are arranged at an arc angle of about 125 to about 145 degrees, particularly about 135 degrees, of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, and the arc angle comprises a second material forming the second wall structure such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees, and the arc of the second wall structure corresponds to the arc angle, including a second material forming the second wall structure. In some embodiments, both the first wall structure and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.It contains 5 weight percent of magnesium stearate, wherein these weight percentages are relative to the total drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight of about 22 mg to about 24 mg. In some embodiments, each minitablet has a weight of about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, each minitablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, each minitablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, each minitablet has a thickness of about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, each minitablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, each minitablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter of about 2.63 mm. In some embodiments, the housing has a first end and a second end, and limits the length between the first end and the second end, and the length is about 17 cm.In some embodiments, the drug reservoir lumen is sealed at the first and second opposing ends, for example, with a plug, a thermoplastic material, and / or a sealant. In some embodiments, the housing of the drug delivery system comprises a retaining frame lumen and a wire form disposed within the retaining frame lumen. In some embodiments, the wire form has a diameter of about 0.305 mm and a length of about 156 mm. In some embodiments, the wire form is a nitinol wire.

[0229] In some embodiments, as a drug delivery system, a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and a second wall structure formed of a second material comprising an aliphatic polyether-based thermoplastic polyurethane; A drug delivery system is provided herein, comprising a drug formulation comprising erdafitinib disposed in a drug reservoir lumen and comprising (i) a second wall structure, or both the first wall structure and the second wall structure are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through a second material forming the second wall structure, and the first and second wall structures are adjacent to each other at two interfacial edges and together form a tube, and the two interfacial edges are arranged at an arc angle of about 125 to about 145 degrees, particularly about 135 degrees, of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, and the arc angle comprises a second material forming the second wall structure such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees, and the arc of the second wall structure corresponds to the arc angle, including a second material forming the second wall structure. In some embodiments, both the first wall structure and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.It contains 5 weight percent of magnesium stearate, wherein these weight percentages are relative to the total drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight of about 22 mg to about 24 mg. In some embodiments, each minitablet has a weight of about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, each minitablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, each minitablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, each minitablet has a thickness of about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, each minitablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, each minitablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter of about 2.63 mm. In some embodiments, the housing has a first end and a second end, and limits the length between the first end and the second end, and the length is about 17 cm.In some embodiments, the drug reservoir lumen is sealed at the first and second opposing ends, for example, with a plug, a thermoplastic material, and / or a sealant. In some embodiments, the housing of the drug delivery system comprises a retention frame lumen and a wire form disposed within the retention frame lumen. In some embodiments, the wire form has a diameter of about 0.305 mm and a length of about 156 mm. In some embodiments, the wire form is a nitinol wire. In some embodiments, a plurality of mini-tablets are arranged in series and define the drug core length between the first face of the first mini-tablet and the opposing second face of the last mini-tablet in the drug core, and the drug core length is about 15 cm.

[0230] In some embodiments, as a drug delivery system, a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and a second wall structure formed of a second material comprising an aliphatic polyether-based thermoplastic polyurethane; A drug delivery system is provided herein, comprising a drug formulation comprising erdafitinib disposed in a drug reservoir lumen and comprising (i) a second wall structure, or both the first wall structure and the second wall structure are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through a second material forming the second wall structure, and the first and second wall structures are adjacent to each other at two interfacial edges and together form a tube, and the two interfacial edges are arranged at an arc angle of about 125 to about 145 degrees, particularly about 135 degrees, of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, and the arc angle comprises a second material forming the second wall structure such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees, and the arc of the second wall structure corresponds to the arc angle, including a second material forming the second wall structure. In some embodiments, both the first wall structure and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.It contains 5 weight percent of magnesium stearate, wherein these weight percentages are relative to the total drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight of about 22 mg to about 24 mg. In some embodiments, each minitablet has a weight of about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, each minitablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, each minitablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, each minitablet has a thickness of about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, each minitablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, each minitablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter of about 2.63 mm. In some embodiments, the housing has a first end and a second end, and limits the length between the first end and the second end, and the length is about 17 cm.In some embodiments, the drug reservoir lumen is sealed at the first and second opposing ends, for example, with a plug, a thermoplastic material, and / or a sealant. In some embodiments, the housing of the drug delivery system comprises a retaining frame lumen and a wire form disposed within the retaining frame lumen. In some embodiments, the wire form has a diameter of about 0.305 mm and a length of about 156 mm. In some embodiments, the wire form is a nitinol wire. In some embodiments, a plurality of mini-tablets are arranged in series and define the drug core length between the first face of the first mini-tablet and the opposing second face of the last mini-tablet in the drug core, and the drug core length is about 15 cm. In some embodiments, the second material of the drug delivery system defines a wall thickness of 0.2 ± 0.04 mm extending along the diameter of the drug reservoir lumen.

[0231] In some embodiments, as a drug delivery system, a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and a second wall structure formed of a second material comprising an aliphatic polyether-based thermoplastic polyurethane; A drug delivery system is provided herein, comprising a drug formulation comprising erdafitinib disposed in a drug reservoir lumen and comprising (i) a second wall structure, or both the first wall structure and the second wall structure are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through a second material forming the second wall structure, and the first and second wall structures are adjacent to each other at two interfacial edges and together form a tube, and the two interfacial edges are arranged at an arc angle of about 125 to about 145 degrees, particularly about 135 degrees, of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, and the arc angle comprises a second material forming the second wall structure such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees, and the arc of the second wall structure corresponds to the arc angle, including a second material forming the second wall structure. In some embodiments, both the first wall structure and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.It contains 5 weight percent of magnesium stearate, wherein these weight percentages are relative to the total drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight of about 22 mg to about 24 mg. In some embodiments, each minitablet has a weight of about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, each minitablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, each minitablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, each minitablet has a thickness of about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, each minitablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, each minitablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter of about 2.63 mm. In some embodiments, the housing has a first end and a second end, and limits the length between the first end and the second end, and the length is about 17 cm.In some embodiments, the drug reservoir lumen is sealed at the first and second opposing ends, for example, with a plug, a thermoplastic material, and / or a sealant. In some embodiments, the housing of the drug delivery system comprises a retaining frame lumen and a wire form disposed within the retaining frame lumen. In some embodiments, the wire form has a diameter of about 0.305 mm and a length of about 156 mm. In some embodiments, the wire form is a nitinol wire. In some embodiments, a plurality of mini-tablets are arranged in series and define the drug core length between the first face of the first mini-tablet and the opposing second face of the last mini-tablet in the drug core, and the drug core length is about 15 cm. In some embodiments, the second material of the drug delivery system defines a wall thickness of 0.2 ± 0.04 mm extending along the diameter of the drug reservoir lumen. In some embodiments, the drug reservoir lumen defines an inner diameter of 2.64 ± 0.05 mm.

[0232] In some embodiments, as a drug delivery system, a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and a second wall structure formed of a second material comprising an aliphatic polyether-based thermoplastic polyurethane; A drug delivery system is provided herein, comprising a drug formulation comprising erdafitinib disposed in a drug reservoir lumen and comprising (i) a second wall structure, or both the first wall structure and the second wall structure are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through a second material forming the second wall structure, and the first and second wall structures are adjacent to each other at two interfacial edges and together form a tube, and the two interfacial edges are arranged at an arc angle of about 125 to about 145 degrees, particularly about 135 degrees, of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, and the arc angle comprises a second material forming the second wall structure such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees, and the arc of the second wall structure corresponds to the arc angle, including a second material forming the second wall structure. In some embodiments, both the first wall structure and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.It contains 5 weight percent of magnesium stearate, wherein these weight percentages are relative to the total drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight of about 22 mg to about 24 mg. In some embodiments, each minitablet has a weight of about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, each minitablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, each minitablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, each minitablet has a thickness of about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, each minitablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, each minitablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter of about 2.63 mm. In some embodiments, the housing has a first end and a second end, and limits the length between the first end and the second end, and the length is about 17 cm.In some embodiments, the drug reservoir lumen is sealed at the first and second opposing ends, for example, with a plug, a thermoplastic material, and / or a sealant. In some embodiments, the housing of the drug delivery system comprises a retaining frame lumen and a wire form disposed within the retaining frame lumen. In some embodiments, the wire form has a diameter of about 0.305 mm and a length of about 156 mm. In some embodiments, the wire form is a nitinol wire. In some embodiments, a plurality of mini-tablets are arranged in series and define the drug core length between the first face of the first mini-tablet and the opposing second face of the last mini-tablet in the drug core, and the drug core length is about 15 cm. In some embodiments, the second material of the drug delivery system defines a wall thickness of 0.2 ± 0.04 mm extending along the diameter of the drug reservoir lumen. In some embodiments, the drug reservoir lumen defines an inner diameter of 2.64 ± 0.05 mm. In some embodiments, the drug delivery system is elastically deformable between a coil retaining shape and a relatively straight inserting shape. In some embodiments, the coil retaining shape includes a double elliptical shape.

[0233] In some embodiments, as a drug delivery system, a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and a second wall structure formed of a second material comprising an aliphatic polyether-based thermoplastic polyurethane; A drug delivery system is provided herein, comprising a drug formulation comprising erdafitinib disposed in a drug reservoir lumen and comprising (i) a second wall structure, or both the first wall structure and the second wall structure are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through a second material forming the second wall structure, and the first and second wall structures are adjacent to each other at two interfacial edges and together form a tube, and the two interfacial edges are arranged at an arc angle of about 125 to about 145 degrees, particularly about 135 degrees, of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, and the arc angle comprises a second material forming the second wall structure such that the arc of the second wall structure corresponds to the arc angle. In some embodiments, the arc angle is about 135 degrees, and the arc of the second wall structure corresponds to the arc angle, including a second material forming the second wall structure. In some embodiments, both the first wall structure and the second wall structure are permeable to water. In some embodiments, the drug formulation comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.It contains 5 weight percent of magnesium stearate, wherein these weight percentages are relative to the total drug formulation. In some embodiments, the drug formulation comprises minitablets. In some embodiments, the drug formulation consists of minitablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdafitinib minitablets. In some embodiments, the drug delivery system comprises 43 erdafitinib minitablets. In some embodiments, the first material comprises AC-4075A and the second material comprises EG-80-A. In some embodiments, the first material comprises AC-4075A-B20 and the second material comprises EG-80-A. In some embodiments, each minitablet has a weight of about 22 mg to about 24 mg. In some embodiments, each minitablet has a weight of about 23 mg. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdafitinib. In some embodiments, the drug formulation comprises about 500 mg of erdafitinib. In some embodiments, the drug formulation comprises minitablets, each minitablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, the drug formulation consists of minitablets, each minitablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, each minitablet has a thickness of about 3.2 mm. In some embodiments, the drug formulation comprises minitablets, each minitablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, the drug formulation consists of minitablets, each minitablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, each minitablet has a diameter of about 2.63 mm. In some embodiments, the housing has a first end and a second end, and limits the length between the first end and the second end, and the length is about 17 cm.In some embodiments, the drug reservoir lumen is sealed at the first and second opposing ends, for example, with a plug, a thermoplastic material, and / or a sealant. In some embodiments, the housing of the drug delivery system comprises a retaining frame lumen and a wire form disposed within the retaining frame lumen. In some embodiments, the wire form has a diameter of about 0.305 mm and a length of about 156 mm. In some embodiments, the wire form is a nitinol wire. In some embodiments, a plurality of mini-tablets are arranged in series and define the drug core length between the first face of the first mini-tablet and the opposing second face of the last mini-tablet in the drug core, and the drug core length is about 15 cm. In some embodiments, the second material of the drug delivery system defines a wall thickness of 0.2 ± 0.04 mm extending along the diameter of the drug reservoir lumen. In some embodiments, the drug reservoir lumen defines an inner diameter of 2.64 ± 0.05 mm. In some embodiments, the drug delivery system is elastically deformable between a coil-holding shape and a relatively straight insertion shape. In some embodiments, the coil-holding shape includes a double elliptical shape. In some embodiments, when in the coil-holding shape, the drug delivery system has a maximum dimension of about 6 cm or less in any direction. In some embodiments, when in the coil-holding shape, the drug delivery system has a maximum dimension of about 5.5 cm or less in any direction. In some embodiments, when in the coil-holding shape, the drug delivery system fits within a circumscribed rectangle of 5.5 cm x 4.5 cm.

[0234] In some embodiments, the first wall structure and the second wall structure are permeable to water. In some embodiments, the first wall structure is impermeable to erdafitinib, and the second wall structure is permeable to erdafitinib. In some embodiments, erdafitinib can be released in vivo by diffusion through a second material forming the second wall structure, and the first and second wall structures are adjacent to each other at two interface edges and together form a tube.

[0235] In some embodiments, as a drug delivery system, a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and a second wall structure formed of a second material comprising an aliphatic polyether-based thermoplastic polyurethane; and a drug formulation disposed in the drug reservoir lumen comprising erdafitinib, wherein (i) the first wall structure and the second wall structure are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through the second material forming the second wall structure, and the first and second wall structures are adjacent to each other at two interface edges and together form a tube, the drug delivery system is provided herein.

[0236] In some embodiments, the drug delivery system described herein is configured to release erdafitinib at an average rate of about 2 mg / day, and two interfacial 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, the thickness of the first wall structure, the second wall structure, or both is about 0.2 mm to about 1.0 mm, the thickness of the second wall structure is about 0.16 mm to about 0.24 mm, the first wall structure is impermeable to erdafitinib, and the second wall structure is permeable to erdafitinib.

[0237] In some embodiments, the drug delivery system described herein is configured to release erdafitinib at an average rate of about 2.5 mg / day to about 3.5 mg / day, and two interfacial edges are arranged at an arc angle of about 125 to about 145 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, the thickness of the first wall structure, the second wall structure, or both is about 0.2 mm to about 1.0 mm, the thickness of the second wall structure is about 0.16 mm to about 0.24 mm, the first wall structure is impermeable to erdafitinib, and the second wall structure is permeable to erdafitinib.

[0238] In some embodiments, the drug delivery system described herein is configured to release erdafitinib at an average rate of about 3 mg / day, and two interfacial edges are arranged at an arc angle of about 135 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, the thickness of the first wall structure, the second wall structure, or both is about 0.2 mm to about 1.0 mm, the thickness of the second wall structure is about 0.16 mm to about 0.24 mm, the first wall structure is impermeable to erdafitinib, and the second wall structure is permeable to erdafitinib.

[0239] In some embodiments, the drug delivery system described herein is configured to release erdafitinib at an average rate of about 4 mg / day, and two interfacial 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, the thickness of the first wall structure, the second wall structure, or both is about 0.2 mm to about 1.0 mm, the thickness of the second wall structure is about 0.16 mm to about 0.24 mm, the first wall structure is impermeable to erdafitinib, and the second wall structure is permeable to erdafitinib.

[0240] Drug tablets

[0241] As discussed herein with regard to pharmaceutical formulations of erdafitinib, the drug may be provided in a solid form (e.g., solid mini-tablet) suitable for loading into the drug reservoir lumen of the system. In a preferred embodiment, Fig. 1 As illustrated in [figure], the drug formulation is a system ( 100 Drug units loaded into the drug reservoir lumen of ) 108 It is formed by ). Each drug unit is a solid individual object that substantially maintains a selectively imparted shape (drug unit (e.g., tablet) and delivery system assembly (e.g., loading into system drug reservoir), storage, and handling prior to in vivo insertion under temperature and pressure conditions to which it would typically be exposed).

[0242] Individual drug units may have any selected shape and dimensions that substantially fit within the system described herein. In one embodiment, the drug unit may be sized and shaped so that the drug reservoir lumen within the housing is substantially filled with a selected number of drug units. Each drug unit may have a cross-sectional shape substantially corresponding to the cross-sectional shape of the drug reservoir lumen of the specific housing. For example, the drug unit may be substantially cylindrical for positioning within a substantially cylindrical drug reservoir lumen. Once loaded, the drug unit, in some embodiments, substantially fills the drug reservoir lumen to form a portion of the drug housing.

[0243] In one embodiment, the drug units are shaped so that they align in a row when the system is in its unfolded configuration. For example, each drug unit may have a cross-sectional shape corresponding to the cross-sectional shape of the drug reservoir lumen within the housing, and each drug unit may have an end-face shape corresponding to the end-face of an adjacent drug unit. The gaps or interruptions between the drug units may allow the individual drug units to maintain their solid form while accommodating deformation or movement of the system, for example, during unfolding. Thus, the drug delivery system may be relatively flexible or deformable, even though a solid drug composition, such as a tablet, is loaded, because each drug unit may be able to move relative to an adjacent drug unit.

[0244] In an embodiment in which the drug unit is designed for insertion or implantation into the body, e.g., the lumen of the bladder or a body cavity via a drug delivery system, the drug unit may be a “mini-tablet” sized and shaped to be suitable for insertion through the body’s natural lumen, e.g., the urethra. For the purposes of this disclosure, the term “mini-tablet” generally refers to a solid drug unit having a substantially cylindrical shape, having substantially cylindrical side and end faces. The mini-tablet has a diameter extending along the end face ranging from about 1.0 to about 3.2 mm, e.g., about 1.5 to about 3.1 mm. The mini-tablet has a length extending along the side ranging from about 1.7 mm to about 4.8 mm, e.g., about 2.0 mm to about 4.5 mm. The wear of the tablet may be less than about 2%. In one embodiment, the tablet is as described herein. In one embodiment, the tablet is a tablet of formulation 4A. In one embodiment, the tablet is a tablet of formulation 4B. In one embodiment, the tablet is a tablet of formulation 4C. In one embodiment, the tablet is a tablet of formulation 4D.

[0245] Treatment methods

[0246] In some embodiments, a method for treating HR-NMIBC in a patient, e.g., recurrent Calmette-Gueren (BCG)-experienced high-risk non-muscle-invasive bladder cancer (HR-NMIBC), comprises the step of administering erdafitinib locally to the patient's bladder for at least 90 days at a dose of about 2 mg / day to about 4 mg / day, e.g., about 2.5 mg / day to about 3.5 mg / day, wherein, in particular, such treatment results in a recurrence-free rate of at least 50% in the patient population receiving such treatment. In some embodiments, the patient population comprises, consists of, or substantially consists of the patients of Cohort 1 as described herein.

[0247] In another embodiment, a method for treating HR-NMIBC in a patient, e.g., relapsed BCG-experienced HR-NMIBC, comprises the step of deploying an intravesical drug delivery system into the patient's bladder, wherein the intravesical drug delivery system comprises a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed within the closed drug reservoir lumen, wherein the drug reservoir lumen is formed by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first and second wall structures are joined together at two interfacial edges and together form a tube defining the closed drug reservoir lumen, wherein the tube defines the longitudinal axis and the two interfacial edges are arranged at an arc angle of 45 to 270 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. In some embodiments, the treatment method comprises the step of releasing erdafitinib by diffusion through a second material forming a second wall structure rather than a first material forming a first wall structure. In some embodiments, the treatment method includes the step of removing the drug delivery system after at least about 90 days. In some embodiments, the treatment method results in at least a 50% relapse-free rate in the patient population receiving this treatment. In some embodiments, the patient population includes, consists of, or substantially consists of Cohort 1 patients with relapsed BCG-experienced HR-NMIBC. In some embodiments, the second wall structure, or both the first wall structure and the second wall structure, are permeable to water. In some embodiments, the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, so that erdafitinib can be released in vivo by diffusion through the second material forming the second wall structure. In some embodiments, the arc angle is 45 to 90 degrees of the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube.In some embodiments, the arc angle is 150 to 270 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. In some embodiments, the arc angle is 125 to 145 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube.

[0248] In some embodiments, the method comprises the step of administering about 2 mg / day to about 4 mg / day of erdafitinib locally to the bladder of a patient with HR-NMIBC, e.g., recurrent Calmette-Gueren (BCG)-experienced high-risk non-muscle invasive bladder cancer (HR-NMIBC), for at least about 90 days. In some embodiments, the method comprises the step of administering about 2 mg / day of erdafitinib to a patient with recurrent Calmette-Gueren (BCG)-experienced high-risk non-muscle invasive bladder cancer (HR-NMIBC). In some embodiments, the method comprises the step of administering about 4 mg / day of erdafitinib to a patient with recurrent Calmette-Gueren (BCG)-experienced high-risk non-muscle invasive bladder cancer (HR-NMIBC).

[0249] In some embodiments, the treatment method results in at least 50% relapse-free rate in a patient population receiving treatment, and the patient population includes, consists of, or substantially consists of Cohort 1 patients with relapsed BCG-experienced HR-NMIBC. In some embodiments, the relapse-free rate in the patient population is at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85%. In some embodiments, the relapse-free rate in the patient population is at least 50%. In some embodiments, the relapse-free rate in the patient population is at least 55%. In some embodiments, the relapse-free rate in the patient population is at least 60%. In some embodiments, the relapse-free rate in the patient population is at least 65%. In some embodiments, the relapse-free rate in the patient population is at least 70%. In some embodiments, the relapse-free rate in the patient population is at least 75%. In some embodiments, the relapse-free rate in the patient population is at least 80%. In some embodiments, the relapse-free rate in the patient population is at least 85%. In some embodiments, the relapse-free rate in the patient population is about 80% for patients treated with about 2 mg / day of erdafitinib. In some embodiments, the relapse-free rate in the patient population is about 80% for patients treated with about 2 mg / day of erdafitinib, and the patient population includes, consists of, or substantially consists of patients in Cohort 1 as described herein. In some embodiments, the relapse-free rate in the patient population is at least 88.9% for patients treated with about 2 mg / day of erdafitinib, and the patient population includes, consists of, or substantially consists of patients in Cohort 1 as described herein. In some embodiments, the relapse-free rate in the patient population is about 83%, e.g., about 83.3%, for patients treated with about 4 mg / day of erdafitinib. In some embodiments, the recurrence-free rate in the patient population is about 83% for patients treated with about 4 mg / day of erdafitinib, e.g., about 83.It is 3%, and the patient population includes, consists of, or substantially consists of the Cohort 1 patients as described herein. In some embodiments, the relapse-free rate in the patient population is at least 85.7% for patients treated with about 4 mg / day, and the patient population includes, consists of, or substantially consists of the Cohort 1 patients as described herein. In some embodiments, the relapse-free rate in the patient population is about 82%, e.g., about 81.8%, for patients treated with about 2 mg / day to about 4 mg / day of erdafitinib. In some embodiments, the relapse-free rate in the patient population is about 82%, e.g., about 81.8%, for patients treated with about 2 mg / day to about 4 mg / day of erdafitinib, and the patient population includes, consists of, or substantially consists of the Cohort 1 patients as described herein. In some embodiments, the recurrence-free rate is evaluated after 3 months or 90 days of erdafitinib treatment.

[0250] In some embodiments, the method further includes the step of performing transurethral bladder tumor resection (TURBT) before the step of administering erdafitinib.

[0251] In some embodiments, the method comprises the step of administering about 2 mg / day to about 4 mg / day of erdafitinib locally to the patient's bladder for at least about 90 days, and the patient has high-grade Ta or T1 bladder cancer. In some embodiments, the patient population has high-grade Ta or T1 bladder cancer. In some embodiments, the patient population includes, consists of, or substantially consists of Cohort 1 patients with recurrent BCG-experienced HR-NMIBC. In some embodiments, the patient has a histologically confirmed high-grade Ta or T1 lesion. In some embodiments, the patient population has a histologically confirmed high-grade Ta or T1 lesion. In some embodiments, the patient does not have carcinoma in situ (CIS). In some embodiments, the patient population does not have carcinoma in situ (CIS). In some embodiments, the patient has recurrent high-grade Ta or T1 bladder cancer within 18 months of completion of previous BCG therapy. In some embodiments, the patient population has recurrent high-grade Ta or T1 bladder cancer within 18 months of completion of previous BCG therapy. In some embodiments, the patient has previously received at least 5 of the 6 full doses of the BCG induction course. In some embodiments, the patient population has previously received at least 5 of the 6 full doses of the BCG induction course. In some embodiments, the patient has high-risk papillary solitary NMIBC. In some embodiments, the patient population has high-risk papillary solitary NMIBC. In some embodiments, the patient population includes, consists of, or substantially consists of the Cohort 1 patients as described herein.

[0252] In another embodiment, a method for treating IR-NMIBC in a patient, e.g., recurrent intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC), comprises the step of administering erdafitinib locally to the patient's bladder for at least 90 days at a dose of about 2 mg / day to about 4 mg / day, e.g., about 2.5 mg / day to about 3.5 mg / day, wherein, in particular, such treatment yields a complete response rate of at least 50% in a patient population receiving such treatment. In some embodiments, the patient population comprises, consists of, or substantially consists of Cohort 3 patients with recurrent IR-NMIBC.

[0253] In another embodiment, a method for treating IR-NMIBC in a patient, e.g., recurrent IR-NMIBC, comprises the step of deploying an intravesical drug delivery system into the patient's bladder, wherein the intravesical drug delivery system comprises a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed within the closed drug reservoir lumen, wherein the drug reservoir lumen is formed by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first and second wall structures are joined together at two interfacial edges and together form a tube defining the closed drug reservoir lumen, wherein the tube defines the longitudinal axis and the two interfacial edges are arranged at an arc angle of 45 to 270 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. In some embodiments, the treatment method comprises the step of releasing erdafitinib by diffusion through a second material forming a second wall structure rather than a first material forming a first wall structure. In some embodiments, the treatment method includes the step of removing the drug delivery system after at least about 90 days. In some embodiments, the treatment method yields a complete response rate of at least 50% in the patient population receiving this treatment. In some embodiments, the patient population includes, consists of, or substantially consists of Cohort 3 patients with relapsed IR-NMIBC. In some embodiments, the second wall structure, or both the first wall structure and the second wall structure, are permeable to water. In some embodiments, the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, so that erdafitinib can be released in vivo by diffusion through the second material forming the second wall structure. In some embodiments, the two interfacial edges are positioned at an arc angle of 45 to 90 degrees, particularly an arc angle of 90 degrees, in a cross section perpendicular to the longitudinal axis of the tube.In some embodiments, the two interface edges are arranged at an arc angle of 150 to 270 degrees, particularly an arc angle of 180 degrees, in a cross section perpendicular to the longitudinal axis of the tube. In some embodiments, the two interface edges are arranged at an arc angle of 125 to 145 degrees, particularly an arc angle of 135 degrees, in a cross section perpendicular to the longitudinal axis of the tube.

[0254] In some embodiments, the method comprises the step of administering about 2 mg / day to about 4 mg / day of erdafitinib topically to the bladder of a patient with IR-NMIBC, e.g., relapsed IR-NMIBC, for at least about 90 days. In some embodiments, the method comprises the step of administering about 2 mg / day of erdafitinib to a patient with relapsed IR-NMIBC. In some embodiments, the method comprises the step of administering about 4 mg / day of erdafitinib to a patient with relapsed IR-NMIBC.

[0255] In some embodiments, the treatment method yields a complete response rate of at least 50% in a population of patients with relapsed IR-NMIBC receiving treatment. In some embodiments, the complete response rate in the patient population is at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, or 85%. In some embodiments, the complete response rate in the patient population is at least 50%. In some embodiments, the complete response rate in the patient population is at least 55%. In some embodiments, the complete response rate in the patient population is at least 60%. In some embodiments, the complete response rate in the patient population is at least 65%. In some embodiments, the complete response rate in the patient population is at least 70%. In some embodiments, the complete response rate in the patient population is at least 75%. In some embodiments, the complete response rate in the patient population is at least 80%. In some embodiments, the complete response rate in the patient population is at least 85%. In some embodiments, the complete response rate in the patient population is about 75% for patients treated with about 2 mg / day of erdafitinib. In some embodiments, the complete response rate in the patient population is 75% for patients treated with about 2 mg / day, and the patient population includes, consists of, or substantially consists of Cohort 3 patients as described herein. In some embodiments, the complete response rate in the patient population is about 100% for patients treated with about 4 mg / day of erdafitinib. In some embodiments, the complete response rate in the patient population is 100% for patients treated with about 4 mg / day, and the patient population includes, consists of, or substantially consists of Cohort 3 patients as described herein. In some embodiments, the complete response rate in the patient population is about 87%, e.g., about 86.7%, for patients treated with about 2 mg / day to about 4 mg / day of erdafitinib.In some embodiments, the complete response rate in the patient population is about 87%, e.g., about 86.7%, for patients treated with about 2 mg / day to about 4 mg / day of erdafitinib, and the patient population includes, consists of, or substantially consists of the patients of Cohort 3 as described herein. In some embodiments, the complete response rate is evaluated at 3 months or 90 days of erdafitinib treatment.

[0256] In some embodiments, the method comprises the step of administering about 2 mg / day to about 4 mg / day of erdafitinib topically to the patient's bladder for at least about 90 days, and the patient has only a history of low-grade disease. In some embodiments, the patient population has only a history of low-grade disease. In some embodiments, the patient has recurrent intermediate-risk papillary disease. In some embodiments, the patient population has recurrent intermediate-risk papillary disease. In some embodiments, the patient has not previously had carcinoma in situ. In some embodiments, the patient population has not previously had carcinoma in situ. In some embodiments, the patient has visible disease at the time erdafitinib is administered. In some embodiments, the patient population has visible disease at the time erdafitinib is administered. In some embodiments, the patient has Ta or T1 bladder cancer. In some embodiments, the patient population has Ta or T1 bladder cancer. In some embodiments, the patient has not received TURBT prior to the step of administering erdafitinib. In some embodiments, the patient population did not receive TURBT prior to the step of administering erdafitinib. In some embodiments, the patient population includes, consists of, or substantially consists of Cohort 3 patients with relapsed IR-NMIBC as described herein.

[0257] In some embodiments, the method comprises the step of administering about 2 mg / day of erdafitinib to a patient. In some embodiments, the method comprises the step of administering about 4 mg / day of erdafitinib to a patient.

[0258] In some embodiments, a method for treating HR-NMIBC in a patient, e.g., recurrent Calmette-Gueren (BCG)-experienced high-risk non-muscle-invasive bladder cancer (HR-NMIBC), comprises the step of administering erdafitinib locally to the patient's bladder for at least about 90 days at a dose of about 2 mg / day to about 4 mg / day, more particularly about 3 mg / day, wherein the erdafitinib formulation is Formulation 4B as described herein. In some embodiments, the solid pharmaceutical composition comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 24.5 wt% microcrystalline cellulose; (e) 6.0 wt% silicified microcrystalline cellulose; (f) 6.0 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5 wt% colloidal silicon dioxide; and (h) 2.0 wt% magnesium stearate, wherein these weight percentages are relative to the total solid pharmaceutical composition. In some embodiments, the formulation is contained within an intravesical drug delivery system, in particular, the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, both ends of the intravesical drug delivery system are closed.

[0259] In another aspect, a method is provided herein as a method for treating IR-NMIBC in a patient, e.g., recurrent intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC), comprising the step of administering erdafitinib locally to the patient's bladder for at least about 90 days at a dose of about 2 mg / day to about 4 mg / day, more particularly about 3 mg / day, wherein the erdafitinib formulation is the formulation 4B as described herein. In some embodiments, the solid pharmaceutical composition comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 24.5 wt% microcrystalline cellulose; (e) 6.0 wt% silicified microcrystalline cellulose; (f) 6.0 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5 wt% colloidal silicon dioxide; and (h) 2.0 wt% magnesium stearate, wherein these weight percentages are relative to the total solid pharmaceutical composition. In some embodiments, the formulation is contained within an intravesical drug delivery system, in particular, the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, both ends of the intravesical drug delivery system are closed.

[0260] In some embodiments, a method for treating HR-NMIBC in a patient, e.g., recurrent Calmette-Gueren (BCG)-experienced high-risk non-muscle-invasive bladder cancer (HR-NMIBC), comprises the step of administering erdafitinib locally to the patient's bladder for at least about 90 days at a dose of about 2 mg / day to about 4 mg / day, more particularly about 3 mg / day, wherein the erdafitinib formulation is Formulation 3.4 as described herein. In some embodiments, the solid pharmaceutical composition comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 17.5 wt% microcrystalline cellulose; (e) 10.75 wt% silicified microcrystalline cellulose; (f) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25 wt% colloidal silicon dioxide; (h) 1.5 wt% hydroxypropyl methylcellulose; and (i) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the total solid pharmaceutical composition. In some embodiments, the formulation is contained within an intravesical drug delivery system, in particular, the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, both ends of the intravesical drug delivery system are closed.

[0261] In another embodiment, a method is provided herein as a method for treating IR-NMIBC in a patient, e.g., recurrent intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC), comprising the step of administering about 2 mg / day to about 4 mg / day of erdafitinib, more particularly about 3 mg / day, topically to the patient's bladder for at least about 90 days, wherein the erdafitinib formulation is Formulation 3.4 as described herein. Accordingly, Formulation 3.4 is incorporated herein by reference, wherein the solid pharmaceutical composition comprises (a) 50 wt% of erdafitinib free base; (b) 10 wt% of hydroxypropyl-beta-cyclodextrin; (c) 1 wt% of meglumine; (d) 17.5 wt% of microcrystalline cellulose; (e) 10.75 wt% of silicified microcrystalline cellulose; (f) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25 wt% colloidal silicon dioxide; (h) 1.5 wt% hydroxypropyl methylcellulose; and (i) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the total solid pharmaceutical composition. In some embodiments, the formulation is contained within an intravesical drug delivery system, in particular, the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, both ends of the intravesical drug delivery system are closed.

[0262] In some embodiments, a method for treating HR-NMIBC in a patient, e.g., recurrent Calmette-Gueren (BCG)-experienced high-risk non-muscle-invasive bladder cancer (HR-NMIBC), comprises the step of administering erdafitinib locally to the patient's bladder for at least about 90 days at a dose of about 2 mg / day to about 4 mg / day, more particularly about 3 mg / day, wherein the erdafitinib formulation is Formulation 4.1 as described herein. In some embodiments, the solid pharmaceutical composition comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the total solid pharmaceutical composition. In some embodiments, the formulation is contained within an intravesical drug delivery system, in particular, the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, both ends of the intravesical drug delivery system are closed.

[0263] In another embodiment, a method is provided herein for the treatment of IR-NMIBC in a patient, e.g., recurrent intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC), comprising the step of administering erdafitinib locally to the patient's bladder for at least about 90 days at a dose of about 2 mg / day to about 4 mg / day, more particularly about 3 mg / day, wherein the erdafitinib formulation is Formulation 4.1 as described herein. Accordingly, Formulation 4.1 is incorporated herein by reference, wherein the solid pharmaceutical composition comprises: (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; and (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the total solid pharmaceutical composition. In some embodiments, the formulation is contained within an intravesical drug delivery system, in particular, the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, both ends of the intravesical drug delivery system are closed.

[0264] In some embodiments, a method for treating HR-NMIBC in a patient, e.g., recurrent Calmette-Gueren (BCG)-experienced high-risk non-muscle-invasive bladder cancer (HR-NMIBC), comprises the step of deploying an intravesical drug delivery system as described herein. In some embodiments, the drug delivery system comprises a housing that defines a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first and second wall structures exist at two interfacial edges and together form a tube defining a closed drug reservoir; A drug formulation comprising erdafitinib is placed in a drug reservoir lumen and comprises (i) a second wall structure, or both the first wall structure and the second wall structure are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through a second material forming the second wall structure.

[0265] In some embodiments, a method for treating IR-NMIBC in a patient, e.g., recurrent intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC), comprises the step of deploying an intravesical drug delivery system as described herein. In some embodiments, the drug delivery system comprises a housing that defines a drug reservoir lumen bounded by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first and second wall structures exist at two interface edges and together form a tube defining a closed drug reservoir; A drug formulation comprising erdafitinib is placed in a drug reservoir lumen and comprises (i) a second wall structure, or both the first wall structure and the second wall structure are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through a second material forming the second wall structure.

[0266] In some embodiments, a method for treating HR-NMIBC in a patient, e.g., recurrent Calmette-Gueren (BCG)-experienced high-risk non-muscle-invasive bladder cancer (HR-NMIBC), comprises the step of deploying an intravesical drug delivery system as described herein, wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, both ends of the intravesical drug delivery system are closed.

[0267] In some embodiments, a method for treating IR-NMIBC in a patient, e.g., recurrent intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC), comprises the step of deploying an intravesical drug delivery system as described herein, wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, both ends of the device are closed.

[0268] In some embodiments, the method comprises the step of administering about 2 mg / day to about 4 mg / day of erdafitinib topically to the patient's bladder for at least about 90 days, wherein the patient had not received prior treatment with an FGFR inhibitor. In some embodiments, the patient population had not received prior treatment with an FGFR inhibitor.

[0269] In some embodiments, the patient has at least one FGFR2 gene variant. In some embodiments, the patient has at least one FGFR3 gene variant. In some embodiments, the patient has at least one FGFR2 and at least one FGFR3 gene variant. In some embodiments, the patient population has at least one FGFR2 gene variant. In some embodiments, the patient population has at least one FGFR3 gene variant. In some embodiments, the patient population has at least one FGFR2 and at least one FGFR3 gene variant.

[0270] In some embodiments, the FGFR2 gene variant includes an activated tumor FGFR2 mutation or fusion. In some embodiments, the FGFR2 gene variant includes an activated tumor FGFR2 fusion. In some embodiments, the FGFR3 gene variant includes an activated tumor FGFR3 mutation or fusion. In some embodiments, the FGFR3 gene variant includes an activated tumor FGFR3 mutation. In some embodiments, the FGFR3 gene variant includes an activated tumor FGFR3 fusion. In some embodiments, the FGFR2 gene variant and the FGFR3 gene variant include an activated tumor FGFR2 or three mutations or fusions. In some embodiments, the FGFR3 gene variant is FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, and FGFR3It is an FGFR3 mutation selected from the group consisting of G370C. In some embodiments, the FGFR3 gene mutation is FGFR3:TACC3_V1 It is a gene fusion comprising. In some embodiments, the FGFR gene variant is detected using PCR or NGS assay of a urine sample obtained from a patient. In some embodiments, the FGFR gene variant is detected using PCR or NGS assay of a tumor tissue sample obtained from a patient. In some embodiments, the FGFR gene variant is detected using histopathological images of tumor tissue through digital histopathology analysis.

[0271] In some embodiments, FGFR gene variants 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 agreement between the FGFR variants detected by the urine sample assay and the tumor tissue sample assay. In some embodiments, the urine sample assay identifies bladder cancer patients not identified by the tumor tissue sample assay. In some embodiments, patients are identified by the urine sample assay alone. In some embodiments, patients are identified by the urine sample assay alone due to the lack of available samples or insufficient tumor tissue. In some embodiments, the urine sample assay identifies at least about 5%, 10%, 15%, 20%, 25%, or 27% more bladder cancer patients than the tumor tissue sample assay. In some embodiments, urine sample testing identifies 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 testing. In some embodiments, urine sample testing identifies about 29% more bladder cancer patients than tumor tissue sample testing. In one embodiment, urine sample testing is a Next-Generation Sequencing (NGS) test, particularly PredicineCare TM(NGS) assay. In one embodiment, the tumor tissue sample assay is a PCR (polymerase chain reaction) assay, specifically the QIAGEN therascreen® FGFR RGQ RT-PCR kit.

[0272] In some embodiments, at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of treated patients identified by urine sample testing alone achieved relapse-free or complete response. In some embodiments, about 50% to 100%, 55% to 95%, 60% to 90%, 65% to 85%, or 70% to 80% of treated patients identified by urine sample testing alone achieved relapse-free or complete response. In some embodiments, at least about 80%, 90%, 95%, or 100% of treated patients identified by urine sample testing alone achieved relapse-free or complete response. In some embodiments, at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of treated patients identified by urine sample testing alone achieved relapse-free or complete response. In some embodiments, about 80%, 90%, 95%, or 100% of all treated patients identified by urine sample testing alone achieved relapse-free or complete response. In one embodiment, the urine sample testing is a Next-Generation Sequencing (NGS) test, in particular PredicineCare TM (NGS) test.

[0273] In some embodiments, a method comprising the step of administering erdafitinib comprises the step of deploying an intravesical drug delivery system comprising erdafitinib into the patient's bladder. In some embodiments, the method comprises the step of administering about 2 mg / day to about 4 mg / day of erdafitinib, and the step of administering erdafitinib comprises the step of deploying an intravesical drug delivery system as described herein. In some embodiments, the method comprises the step of removing the drug delivery system after about 90 days. In some embodiments, the drug delivery system comprises about 400, about 450, about 500, about 550, or about 600 mg of erdafitinib. In some embodiments, the drug delivery system comprises about 480, about 485, about 490, about 495, about 500, about 505, about 510, about 515, or about 520 mg of erdafitinib. In some embodiments, the drug delivery system contains about 500 mg of erdafitinib.

[0274] In some embodiments, the method comprises the step of administering about 2 mg / day to about 4 mg / day of erdafitinib, and the step of administering erdafitinib comprises the step of deploying an intravesical drug delivery system as described herein. In some embodiments, the method comprises the step of administering about 2.5 mg / day to about 3.5 mg / day of erdafitinib, and the step of administering erdafitinib comprises the step of deploying an intravesical drug delivery system as described herein. In some embodiments, the method comprises the step of administering about 2 mg / day, about 3 mg / day, or about 4 mg / day of erdafitinib, and the step of administering erdafitinib comprises the step of deploying an intravesical drug delivery system as described herein.

[0275] In some embodiments, the drug delivery system comprises a double-lumen tube comprising a drug reservoir lumen containing erdafitinib and a small lumen containing an elastic nitinol wire. In some embodiments, the drug reservoir lumen is bordered by a first wall structure formed of a first material and a second wall structure formed of a second material. In some embodiments, the first wall structure and the second wall structure form a tube that defines a drug reservoir lumen that is adjacent to each other at two interface edges and closed together, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling release of erdafitinib by diffusion through the second wall structure. In some embodiments, the second wall structure forms a longitudinal strip extending along the length of the tube. In some embodiments, two interface edges are positioned at an arc angle of 45 to 270 degrees on the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. In some embodiments, two interface edges are positioned at an arc angle of 45 to 90 degrees, particularly 90 degrees, on the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. In some embodiments, two interface edges are positioned at an arc angle of 150 to 270 degrees, particularly 180 degrees, on the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. In some embodiments, two interface edges are positioned at an arc angle of 125 to 145 degrees on the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. In some embodiments, two interface edges are positioned at an arc angle of 135 degrees on the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube.

[0276] In some embodiments, the drug delivery system is elastically deformable. In some embodiments, the drug delivery system has a double elliptical retention shape. In some embodiments, the drug delivery system is elastically deformable and has a double elliptical retention shape.

[0277] In some embodiments, erdafitinib is in the form of a plurality of mini-tablets arranged in a continuous sequence within a drug lumen. In some embodiments, the drug lumen comprises about 40 to 43 erdafitinibs containing mini-tablets. In some embodiments, the drug lumen comprises 40 erdafitinibs containing mini-tablets. In some embodiments, the drug lumen comprises 41 erdafitinibs containing mini-tablets. In some embodiments, the drug lumen comprises 42 erdafitinibs containing mini-tablets. In some embodiments, the drug lumen comprises 43 erdafitinibs containing mini-tablets. In some embodiments, a plurality of mini-tablets are arranged within a drug lumen of an intravesical drug delivery system, and the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, both ends of the intravesical drug delivery system are closed. In some embodiments, the erdafitinib-containing minitablet comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 17.5 wt% microcrystalline cellulose; (e) 10.75 wt% silicified microcrystalline cellulose; (f) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25 wt% colloidal silicon dioxide; (h) 1.5 wt% hydroxypropyl methylcellulose; and (i) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the total minitablet. In some embodiments, the erdafitinib-containing minitablet comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silicon dioxide; (g) 1.It comprises 5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the total mini tablet. In some embodiments, the erdafitinib-containing mini tablet comprises (a) 50 wt% erdafitinib free base; (b) 10 wt% hydroxypropyl-beta-cyclodextrin; (c) 1 wt% meglumine; (d) 24.5 wt% microcrystalline cellulose; (e) 6.0 wt% silicified microcrystalline cellulose; (f) 6.0 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5 wt% colloidal silicon dioxide; and (h) 2.0 wt% magnesium stearate, wherein these weight percentages are relative to the total mini tablet.

[0278] In a specific embodiment, a method for treating bladder cancer having one or more FGFR gene mutations is provided, comprising the step of locally delivering erdafitinib into the bladder of a patient requiring bladder cancer treatment in an amount effective for treating bladder cancer, wherein one or more FGFR gene mutations are detected in a urine sample from the patient, in particular, one or more FGFR gene mutations are detected in a urine sample from the patient using a urine-based PCR or NGS assay. In a specific embodiment, a method for treating bladder cancer having one or more FGFR gene mutations is provided, comprising the step of (a) evaluating a urine sample from a bladder cancer patient for the presence of one or more FGFR gene mutations, in particular, evaluating a urine sample from a bladder cancer patient for the presence of one or more FGFR gene mutations using a urine-based PCR or NGS assay; and (b) locally delivering erdafitinib if one or more FGFR gene mutations are present in the sample, comprising, or substantially comprising, the step of In a specific embodiment, a method for treating bladder cancer having one or more FGFR gene mutations is provided, comprising the step of locally delivering erdafitinib in a therapeutically effective amount into the bladder of a patient requiring bladder cancer treatment, wherein the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a urine sample from the patient, in particular, the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a urine sample from the patient using a urine-based PCR or NGS assay.In a specific embodiment, a method for treating bladder cancer having one or more FGFR gene mutations is provided, comprising the step of locally delivering erdafitinib in a therapeutically effective amount into the bladder of a patient requiring treatment for bladder cancer, wherein the patient’s suitability for treatment is determined by detecting one or more FGFR gene mutations in a urine sample from the patient, in particular, by detecting one or more FGFR gene mutations in a urine sample from the patient using a urine-based PCR or NGS assay. In a specific embodiment, erdafitinib is provided for use in treating bladder cancer having one or more FGFR gene mutations in a patient, wherein erdafitinib is locally delivered into the bladder of the patient, and one or more FGFR gene mutations are detected in a urine sample from the patient, in particular, one or more FGFR gene mutations are detected in a urine sample from the patient using a urine-based PCR or NGS assay. In a specific embodiment, erdafitinib is provided for use in the treatment of bladder cancer in which a patient has one or more FGFR gene mutations, the treatment comprises (a) evaluating a urine sample from a bladder cancer patient for the presence of one or more FGFR gene mutations, particularly using a urine-based PCR or NGS assay to evaluate a urine sample from a bladder cancer patient for the presence of one or more FGFR gene mutations; and (b) locally delivering erdafitinib to the patient if one or more FGFR gene mutations are present in the sample, or is composed of, or substantially composed of.In a specific embodiment, erdafitinib is provided for use in the treatment of bladder cancer having one or more FGFR gene mutations in a patient, erdafitinib is to be delivered locally into the patient's bladder, and the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a urine sample from the patient, in particular, the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a urine sample from the patient using a urine-based PCR or NGS assay. In a specific embodiment, erdafitinib is provided for use in the treatment of bladder cancer having one or more FGFR gene mutations in a patient, erdafitinib is to be delivered locally into the patient's bladder, and the patient's suitability for treatment is determined by the detection of one or more FGFR gene mutations in a urine sample from the patient, in particular, the patient's suitability for treatment is determined by the detection of one or more FGFR gene mutations in a urine sample from the patient using a urine-based PCR or NGS assay. In a specific embodiment, the use of erdafitinib is provided for the manufacture of a medicine for the treatment of bladder cancer in which a patient has one or more FGFR gene mutations, wherein erdafitinib is to be delivered locally into the patient's bladder, and one or more FGFR gene mutations are detected in a urine sample from the patient, in particular, one or more FGFR gene mutations are detected in a urine sample from the patient using urine-based PCR or NGS assay.In a specific embodiment, the use of erdafitinib is provided for the manufacture of a medicine for treating bladder cancer in which a patient has one or more FGFR gene mutations, wherein the treatment comprises (a) evaluating a urine sample from a bladder cancer patient for the presence of one or more FGFR gene mutations, particularly using a urine-based PCR or NGS assay to evaluate a urine sample from a bladder cancer patient for the presence of one or more FGFR gene mutations; and (b) locally delivering erdafitinib if one or more FGFR gene mutations are present in the sample, or is composed of, or substantially composed of. In a specific embodiment, the use of erdafitinib is provided for the manufacture of a medicine for the treatment of bladder cancer having one or more FGFR gene mutations in a patient, erdafitinib is to be delivered locally into the patient's bladder, and the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a urine sample from the patient, in particular, the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a urine sample from the patient using a urine-based PCR or NGS assay. In a specific embodiment, the use of erdafitinib is provided for the manufacture of a medicine for the treatment of bladder cancer having one or more FGFR gene mutations in a patient, erdafitinib is to be delivered locally into the patient's bladder, and the patient's suitability for treatment is determined by the detection of one or more FGFR gene mutations in a urine sample from the patient, in particular, the patient's suitability for treatment is determined by the detection of one or more FGFR gene mutations in a urine sample from the patient using a urine-based PCR or NGS assay. The method or use may include the step of locally delivering or locally administering erdafitinib into the bladder of a patient requiring treatment, particularly a cancer patient, in an amount effective for treating bladder cancer (e.g., about 2 mg / day to about 4 mg / day as described herein) (e.g., in any formulation described herein).In one embodiment, the patient, specifically a human, is a patient with relapsed BCG-experienced HR-NMIBC. In one embodiment, the patient, specifically a human, is a patient with relapsed Calmette-Gueren (BCG)-experienced high-risk papillary monolithic NMIBC (high-grade Ta / T1) cancer who refuses or is unsuitable for radical cystectomy (Rcy). In one embodiment, the patient, specifically a human, is a patient with relapsed BCG-experienced high-risk papillary monolithic NMIBC (high-grade Ta / T1) cancer who has scheduled an Rcy. In one embodiment, the patient, specifically a human, is a patient with relapsed intermediate-risk NMIBC (Ta and T1) cancer who has only a prior history of low-grade disease.

[0279] In a specific embodiment, a method for treating bladder cancer having one or more FGFR gene mutations is provided, comprising the step of locally delivering erdafitinib into the bladder of a patient requiring bladder cancer treatment in an amount effective for treating bladder cancer, wherein one or more FGFR gene mutations are detected in a tumor tissue sample from the patient, in particular, one or more FGFR gene mutations are detected in a tumor tissue sample from the patient using tissue-based PCR or NGS assay, or one or more FGFR gene mutations are detected in a histopathological image of the tumor tissue through digital histopathological analysis. In a specific embodiment, a method for treating bladder cancer having one or more FGFR gene mutations is provided, comprising: (a) evaluating a tumor tissue sample from a bladder cancer patient for the presence of one or more FGFR gene mutations, particularly evaluating a tumor tissue sample from a bladder cancer patient for the presence of one or more FGFR gene mutations using tissue-based PCR or NGS assay, or evaluating a histopathological image of a tumor tissue from a bladder cancer patient for the presence of one or more FGFR gene mutations through digital histopathological analysis; and (b) locally delivering erdafitinib if one or more FGFR gene mutations are present in the sample, comprising, or substantially comprising, the step of delivering erdafitinib locally.In a specific embodiment, a method for treating bladder cancer having one or more FGFR gene mutations is provided, comprising the step of locally delivering erdafitinib in a therapeutically effective amount into the bladder of a patient requiring bladder cancer treatment, wherein the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a tumor tissue sample from the patient, in particular, the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a tumor tissue sample from the patient using tissue-based PCR or NGS assay, or the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a histopathological image of the tumor tissue through digital histopathological analysis. In a specific embodiment, a method for treating bladder cancer having one or more FGFR gene mutations is provided, comprising the step of locally delivering erdafitinib into the bladder of a patient requiring bladder cancer treatment in a therapeutically effective amount, wherein the patient’s suitability for treatment is determined by detecting one or more FGFR gene mutations in a tumor tissue sample from the patient, in particular, by detecting one or more FGFR gene mutations in a tumor tissue sample from the patient using tissue-based PCR or NGS assay, or by detecting one or more FGFR gene mutations in a histopathological image of the tumor tissue through digital histopathological analysis.In a specific embodiment, erdafitinib is provided for use in the treatment of bladder cancer in which a patient has one or more FGFR gene mutations, erdafitinib is locally delivered into the patient's bladder, and one or more FGFR gene mutations are detected in a tumor tissue sample from the patient, in particular, one or more FGFR gene mutations are detected in a tumor tissue sample from the patient using tissue-based PCR or NGS assay, or one or more FGFR gene mutations are detected in a histopathological image of the tumor tissue through digital histopathological analysis. In a specific embodiment, erdafitinib is provided for use in treating bladder cancer in a patient having one or more FGFR gene mutations, and the treatment comprises (a) evaluating a tumor tissue sample from a bladder cancer patient for the presence of one or more FGFR gene mutations, particularly using tissue-based PCR or NGS assays to evaluate a tumor tissue sample from a bladder cancer patient for the presence of one or more FGFR gene mutations, or evaluating histopathological images of tumor tissue from a bladder cancer patient for the presence of one or more FGFR gene mutations through digital histopathological analysis; and (b) locally delivering erdafitinib to the patient if one or more FGFR gene mutations are present in the sample, or is composed of, or substantially composed of.In a specific embodiment, erdafitinib is provided for use in treating bladder cancer in which a patient has one or more FGFR gene mutations, erdafitinib is to be delivered locally into the patient's bladder, and the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a tumor tissue sample from the patient, in particular, the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a tumor tissue sample from the patient using tissue-based PCR or NGS assay, or the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a histopathological image of the tumor tissue through digital histopathological analysis. In a specific embodiment, erdafitinib is provided for use in treating bladder cancer in a patient having one or more FGFR gene mutations, erdafitinib is to be delivered locally into the patient's bladder, and the patient's treatment suitability is determined by detecting one or more FGFR gene mutations in a tumor tissue sample from the patient, in particular by detecting one or more FGFR gene mutations in a tumor tissue sample from the patient using tissue-based PCR or NGS assay, or the patient's treatment suitability is determined by detecting one or more FGFR gene mutations in a histopathological image of the tumor tissue through digital histopathological analysis. In a specific embodiment, the use of erdafitinib is provided for the manufacture of a medicine for treating bladder cancer in which a patient has one or more FGFR gene mutations, wherein erdafitinib is to be delivered locally into the patient's bladder, and one or more FGFR gene mutations are detected in a tumor tissue sample from the patient, in particular, one or more FGFR gene mutations are detected in a tumor tissue sample from the patient using tissue-based PCR or NGS assay, or one or more FGFR gene mutations are detected in a histopathological image of the tumor tissue through digital histopathological analysis.In a specific embodiment, the use of erdafitinib is provided for the manufacture of a medicine for treating bladder cancer in which a patient has one or more FGFR gene mutations, wherein the treatment comprises (a) evaluating a tumor tissue sample from a bladder cancer patient for the presence of one or more FGFR gene mutations, particularly using tissue-based PCR or NGS assays to evaluate the tumor tissue sample from the bladder cancer patient for the presence of one or more FGFR gene mutations, or evaluating histopathological images of the tumor tissue from the bladder cancer patient for the presence of one or more FGFR gene mutations through digital histopathological analysis; and (b) locally delivering erdafitinib if one or more FGFR gene mutations are present in the sample, or is composed of, or is substantially composed of. In a specific embodiment, the use of erdafitinib is provided for the manufacture of a medicine for the treatment of bladder cancer having one or more FGFR gene mutations in a patient, wherein erdafitinib is to be delivered locally into the patient's bladder, and the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a tumor tissue sample from the patient, in particular, the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a tumor tissue sample from the patient using tissue-based PCR or NGS assay, or the patient is selected for treatment based on the detection of one or more FGFR gene mutations in a histopathological image of the tumor tissue through digital histopathological analysis.In a specific embodiment, the use of erdafitinib is provided for the manufacture of a medicine for the treatment of bladder cancer having one or more FGFR gene mutations in a patient, wherein erdafitinib is to be delivered locally into the patient's bladder, and the patient's therapeutic suitability is determined by detecting one or more FGFR gene mutations in a tumor tissue sample from the patient, in particular by detecting one or more FGFR gene mutations in a tumor tissue sample from the patient using tissue-based PCR or NGS assay, or by detecting one or more FGFR gene mutations in a histopathological image of the tumor tissue through digital histopathological analysis. The method or use may include the step of locally delivering or locally administering erdafitinib (e.g., in any formulation described herein) in an amount effective for treating bladder cancer (e.g., about 2 mg / day to about 4 mg / day as described herein) into the bladder of a patient requiring treatment, particularly a cancer patient. In one embodiment, the patient, specifically a human, is a patient with relapsed BCG-experienced HR-NMIBC. In one embodiment, the patient, specifically a human, is a patient with relapsed Calmette-Gueren (BCG)-experienced high-risk papillary monolithic NMIBC (high-grade Ta / T1) cancer who refuses or is unsuitable for radical cystectomy (Rcy). In one embodiment, the patient, specifically a human, is a patient with relapsed BCG-experienced high-risk papillary monolithic NMIBC (high-grade Ta / T1) cancer who has scheduled an Rcy. In one embodiment, the patient, specifically a human, is a patient with relapsed intermediate-risk NMIBC (Ta and T1) cancer who has only a prior history of low-grade disease.

[0280] In some embodiments, a method for treating relapsed BCG-experienced HR-NMIBC in a patient comprises the step of deploying an intravesical drug delivery system into the patient's bladder, wherein the intravesical drug delivery system comprises a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed within the closed drug reservoir lumen, wherein the drug reservoir lumen is formed by a first wall structure formed of a first material and a second wall structure formed of a second material, and the first and second wall structures are joined together at two interfacial edges and together form a tube defining the closed drug reservoir lumen, and (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through the second material forming the second wall structure, and the tube is longitudinally A method is provided herein in which two interfacial edges are arranged at an arc angle of 45 to 270 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. In some embodiments, the treatment method comprises the step of releasing erdafitinib by diffusion through a second material forming a second wall structure rather than a first material forming a first wall structure. In some embodiments, the treatment method comprises the step of removing the drug delivery system after at least about 90 days, and such treatment results in a relapse-free rate of at least 50% in a population of patients receiving such treatment. In some embodiments, the drug delivery system comprises a formulation 4B, formulation 4B is incorporated herein by reference, and the solid pharmaceutical composition comprises (a) 50 wt% of erdafitinib free base; (b) 10 wt% of hydroxypropyl-beta-cyclodextrin; (c) 1 wt% of meglumine; (d) 24.5 wt% of microcrystalline cellulose; (e) 6.0 wt% silicified microcrystalline cellulose; (f) 6.It comprises 0 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5 wt% colloidal silicon dioxide; and (h) 2.0 wt% magnesium stearate, wherein these weight percentages are relative to the total solid pharmaceutical composition. In some embodiments, the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, both ends of the intravesical drug delivery system are closed.

[0281] In some embodiments, a method for treating relapsed BCG-experienced HR-NMIBC in a patient comprises the step of deploying an intravesical drug delivery system into the patient's bladder, wherein the intravesical drug delivery system comprises a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed within the closed drug reservoir lumen, wherein the drug reservoir lumen is formed by a first wall structure formed of a first material and a second wall structure formed of a second material, and the first and second wall structures are joined together at two interfacial edges and together form a tube defining the closed drug reservoir lumen, and (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through the second material forming the second wall structure, and the tube is longitudinally A method is provided herein in which two interfacial edges are arranged at an arc angle of 45 to 270 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. In some embodiments, the treatment method comprises the step of releasing erdafitinib by diffusion through a second material forming a second wall structure rather than a first material forming a first wall structure. In some embodiments, the treatment method comprises the step of removing the drug delivery system after at least about 90 days, and such treatment results in a relapse-free rate of at least 50% in a population of patients receiving such treatment. In some embodiments, the drug delivery system comprises Formulation 4.1, which is incorporated herein by reference, and the solid pharmaceutical composition comprises (a) 50 wt% of erdafitinib free base; (b) 10 wt% of hydroxypropyl-beta-cyclodextrin; (c) 17.5 wt% of microcrystalline cellulose; (d) 11.75 wt% silicified microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.It comprises 25 wt% colloidal silicon dioxide; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the total solid pharmaceutical composition.

[0282] In some embodiments, a method for treating relapsed BCG-experienced HR-NMIBC in a patient comprises the step of deploying an intravesical drug delivery system into the patient's bladder, wherein the intravesical drug delivery system comprises a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed within the closed drug reservoir lumen, wherein the drug reservoir lumen is formed by a first wall structure formed of a first material and a second wall structure formed of a second material, and the first and second wall structures are joined together at two interfacial edges and together form a tube defining the closed drug reservoir lumen, and (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through the second material forming the second wall structure, and the tube is longitudinally A method is provided herein in which two interfacial edges are arranged at an arc angle of 45 to 270 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. In some embodiments, the treatment method comprises the step of releasing erdafitinib by diffusion through a second material forming a second wall structure rather than a first material forming a first wall structure. In some embodiments, the treatment method comprises the step of removing the drug delivery system after at least about 90 days, and such treatment results in a relapse-free rate of at least 50% in a population of patients receiving such treatment. In some embodiments, the drug delivery system comprises formulation 3.4, formulation 3.4 is incorporated herein by reference, and the solid pharmaceutical composition comprises (a) 50 wt% of erdafitinib free base; (b) 10 wt% of hydroxypropyl-beta-cyclodextrin; (c) 1 wt% of meglumine; (d) 17.5 wt% of microcrystalline cellulose; (e) 10.75 wt% silicified microcrystalline cellulose; (f) 7.It comprises 5 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25 wt% colloidal silicon dioxide; (h) 1.5 wt% hydroxypropyl methylcellulose; and (i) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the total solid pharmaceutical composition.

[0283] In some embodiments, a method for treating recurrent IR-NMIBC in a patient comprises the step of deploying an intravesical drug delivery system into the patient's bladder, wherein the intravesical drug delivery system comprises a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed within the closed drug reservoir lumen, wherein the drug reservoir lumen is formed by a first wall structure formed of a first material and a second wall structure formed of a second material, and the first and second wall structures are joined together at two interfacial edges and together form a tube defining the closed drug reservoir lumen, and (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through the second material forming the second wall structure, and the tube defines the longitudinal axis and two The interfacial edge is positioned at an arc angle of 45 to 270 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. In some embodiments, the treatment method comprises the step of releasing erdafitinib by diffusion through a second material forming a second wall structure rather than a first material forming a first wall structure. In some embodiments, the treatment method comprises the step of removing the drug delivery system after at least about 90 days, and such treatment yields a complete response of at least 50% in a population of patients receiving such treatment. In some embodiments, the drug delivery system comprises a formulation 4B, formulation 4B is incorporated herein by reference, and the solid pharmaceutical composition comprises (a) 50 wt% of erdafitinib free base; (b) 10 wt% of hydroxypropyl-beta-cyclodextrin; (c) 1 wt% of meglumine; (d) 24.5 wt% of microcrystalline cellulose; (e) 6.0 wt% silicified microcrystalline cellulose; (f) 6.0 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.It comprises 5 wt% colloidal silicon dioxide; and (h) 2.0 wt% magnesium stearate, wherein these weight percentages are relative to the total solid pharmaceutical composition. In some embodiments, the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, both ends of the intravesical drug delivery system are closed.

[0284] In some embodiments, a method for treating recurrent IR-NMIBC in a patient comprises the step of deploying an intravesical drug delivery system into the patient's bladder, where...

Claims

Claim 1 As a drug delivery system, a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and a second wall structure formed of a second material comprising an aliphatic polyether-based thermoplastic polyurethane; and comprises a drug formulation comprising erdafitinib disposed in the drug reservoir lumen, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through a second material forming the second wall structure, and the first and second wall structures are adjacent to each other at two interfacial edges and together form a tube, and the drug delivery system is configured to release erdafitinib at an average rate of about 2.5 mg / day to about 3.5 mg / day, and the two interfacial edges are arranged at an arc angle of about 125 to about 145 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, and the arc angle is the second wall A drug delivery system corresponding to a structure. Claim 2 As a drug delivery system, a housing defining a drug reservoir lumen bounded by a first wall structure formed of a first material comprising a polycarbonate-based aromatic thermoplastic polyurethane and a second wall structure formed of a second material comprising an aliphatic polyether-based thermoplastic polyurethane; A drug delivery system comprising a drug formulation containing erdafitinib disposed in the drug reservoir lumen, wherein (i) the second wall structure, or both the first wall structure and the second wall structure, are permeable to water, and (ii) the first wall structure is impermeable to erdafitinib and the second wall structure is permeable to erdafitinib, thereby enabling erdafitinib to be released in vivo by diffusion through a second material forming the second wall structure, and the first and second wall structures are adjacent to each other at two interfacial edges and together form a tube, and the drug delivery system is configured to release erdafitinib at an average rate of about 3 mg / day, and the two interfacial edges are arranged at an arc angle of about 135 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, and the arc angle corresponds to the second wall structure. Claim 3 A drug delivery system comprising 42 to 46 erdafitinib mini-tablets according to claim 1 or 2. Claim 4 In paragraph 3, a drug delivery system comprising 43 erdafitinib mini-tablets. Claim 5 A drug delivery system according to any one of claims 1 to 4, wherein the first material comprises AC-4075A and the second material comprises EG-80-A, and optionally the first material comprises AC-4075A-B20. Claim 6 In any one of claims 1 to 5, the drug formulation comprises (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1) at a concentration of 50 weight% of the drug formulation H -pyrazol-4-yl)quinoxaline-6-yl]ethane-1,2-diamine); (b) hydroxypropyl-beta-cyclodextrin at a concentration of 10 wt% of the above drug formulation; (c) meglumine at a concentration of 1 wt% of the above drug formulation; (d) microcrystalline cellulose at a concentration of 17.5 wt% of the above drug formulation; (e) silicified microcrystalline cellulose at a concentration of 10.75 wt% of the above drug formulation; (f) vinylpyrrolidone-vinyl acetate copolymer at a concentration of 7.5 wt% of the above drug formulation; (g) colloidal silicon dioxide at a concentration of 0.25 wt% of the above drug formulation; (h) hydroxypropyl methylcellulose at a concentration of 1.5 wt% of the above drug formulation; and (i) comprising magnesium stearate at a concentration of 1.5 wt% of the above drug formulation; or (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1) at a concentration of 50 wt% of the above drug formulation H A drug delivery system comprising: (a) hydroxypropyl-beta-cyclodextrin; (b) meglumine; (d) microcrystalline cellulose; (e) silicified microcrystalline cellulose; (f) vinylpyrrolidone-vinyl acetate copolymer; (g) colloidal silicon dioxide; (h) hydroxypropyl methylcellulose; and (i) magnesium stearate. Claim 7 In any one of claims 1 to 5, the drug formulation comprises (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1) at a concentration of 50 weight% of the drug formulation H -pyrazole-4-yl)quinoxaline-6-yl]ethane-1,2-diamine); (b) hydroxypropyl-beta-cyclodextrin at a concentration of 10 wt% of the above drug formulation; (c) microcrystalline cellulose at a concentration of 17.5 wt% of the above drug formulation; (d) silicified microcrystalline cellulose at a concentration of 11.75 wt% of the above drug formulation; (e) vinylpyrrolidone-vinyl acetate copolymer at a concentration of 7.5 wt% of the above drug formulation; (f) colloidal silicon dioxide at a concentration of 0.25 wt% of the above drug formulation; (g) hydroxypropyl methylcellulose at a concentration of 1.5 wt% of the above drug formulation; and (h) magnesium stearate at a concentration of 1.5 wt% of the above drug formulation; or or (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1) at a concentration of 50 weight% of the above drug formulation H A drug delivery system comprising: (a) hydroxypropyl-beta-cyclodextrin; (b) microcrystalline cellulose; (d) silicified microcrystalline cellulose; (e) vinylpyrrolidone-vinyl acetate copolymer; (f) colloidal silicon dioxide; (g) hydroxypropyl methylcellulose; and (h) magnesium stearate. Claim 8 In any one of claims 1 to 5, the drug formulation comprises (a) erdafitinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1) at a concentration of 50 weight% of the drug formulation H -pyrazol-4-yl)quinoxaline-6-yl]ethane-1,2-diamine); (b) hydroxypropyl-beta-cyclodextrin at a concentration of 10 wt% of the above drug formulation; (c) meglumine at a concentration of 1 wt% of the above drug formulation; (d) microcrystalline cellulose at a concentration of 24.5 wt% of the above drug formulation; (e) silicified microcrystalline cellulose at a concentration of 6 wt% of the above drug formulation; (f) vinylpyrrolidone-vinyl acetate copolymer at a concentration of 6 wt% of the above drug formulation; (g) colloidal silicon dioxide at a concentration of 0.5 wt% of the above drug formulation; (h) magnesium stearate at a concentration of 2 wt% of the above drug formulation; or (a) erdafitinib free at a concentration of 50 wt% of the above drug formulation Base(N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1 H A drug delivery system comprising: (a) hydroxypropyl-beta-cyclodextrin; (b) meglumine; (d) microcrystalline cellulose; (e) silicified microcrystalline cellulose; (f) vinylpyrrolidone-vinyl acetate copolymer; (g) colloidal silicon dioxide; and (h) magnesium stearate. Claim 9 A drug delivery system according to any one of claims 1 to 8, wherein the first wall structure and the second wall structure have a thickness of about 0.2 mm to about 1.0 mm. Claim 10 A drug delivery system according to any one of claims 1 to 9, wherein the second wall structure has a thickness, the thickness of the second wall structure is about 0.16 mm to about 0.24 mm, the first wall structure is impermeable to erdafitinib, and the second wall structure is permeable to erdafitinib. Claim 11 A drug delivery system according to any one of claims 1 to 10, wherein the drug formulation comprises a mini-tablet, and each mini-tablet has a weight of about 22 mg to about 24 mg. Claim 12 A drug delivery system according to any one of claims 1 to 11, wherein the drug formulation comprises a mini-tablet, and each mini-tablet has a weight of about 23 mg. Claim 13 A drug delivery system according to any one of claims 1 to 12, wherein the drug formulation comprises a mini-tablet, and each mini-tablet has a thickness of about 3.0 mm to about 3.4 mm. Claim 14 A drug delivery system according to any one of claims 1 to 13, wherein the drug formulation comprises a mini-tablet, and each mini-tablet has a thickness of about 3.2 mm. Claim 15 A drug delivery system according to any one of claims 1 to 14, wherein the drug formulation comprises a mini-tablet, and each mini-tablet has a diameter of about 2.60 mm to about 2.66 mm. Claim 16 A drug delivery system according to any one of claims 1 to 15, wherein the drug formulation comprises a mini-tablet, and each mini-tablet has a diameter of about 2.63 mm. Claim 17 A drug delivery system according to any one of claims 1 to 16, wherein the housing has a first end and a second end, and the length between the first end and the second end is defined, said length being about 17 cm. Claim 18 A drug delivery system according to any one of claims 1 to 17, wherein the housing of the drug delivery system comprises a retaining frame lumen and a wire form disposed within the retaining frame lumen. Claim 19 In claim 18, the above wire form is a drug delivery system having a diameter of about 0.305 mm and a length of about 156 mm. Claim 20 A drug delivery system according to claim 18 or 19, wherein the wire form is a nitinol wire. Claim 21 A drug delivery system according to any one of claims 1 to 20, comprising a plurality of mini-tablets arranged in series, wherein the drug core length between the first surface of the first mini-tablet and the opposing second surface of the last mini-tablet is defined. Claim 22 A drug delivery system according to claim 21, wherein the length of the drug core is approximately 15 cm. Claim 23 A drug delivery system according to any one of claims 1 to 22, wherein the second material of the drug delivery system defines a wall thickness extending along the diameter of the drug reservoir lumen, and the wall thickness is 0.2 ± 0.04 mm. Claim 24 A drug delivery system according to any one of claims 1 to 23, wherein the drug reservoir lumen limits the inner diameter and the inner diameter is 2.64 ± 0.05 mm. Claim 25 A drug delivery system that is elastically deformable between a coil-retaining shape and a relatively straight insertion shape, in any one of claims 1 to 24. Claim 26 A drug delivery system according to claim 25, wherein the coil retaining shape comprises a double elliptical shape. Claim 27 A drug delivery system having a maximum dimension of about 6 cm or less in any direction when in the coil holding shape according to claim 25 or 26. Claim 28 A drug delivery system having a maximum dimension of about 5.5 cm or less in any direction when in the coil holding shape according to any one of claims 25 to 27. Claim 29 A drug delivery system that is accommodated within a circumscribed rectangle of 5.5 cm x 4.5 cm when in the coil retaining shape, in any one of claims 25 to 28. Claim 30 A drug delivery system according to any one of claims 1 to 29, wherein erdafitinib is an erdafitinib free base. Claim 31 A drug delivery system according to any one of claims 1 to 30, wherein both the first wall structure and the second wall structure are permeable to water. Claim 32 A method for treating non-muscle-invasive bladder cancer in a patient, comprising: deploying the drug delivery system according to any one of claims 1 to 31 into the bladder of the patient; releasing erdafitinib by diffusion through the second material forming the second wall structure, rather than the first material forming the first wall structure; and removing the drug delivery system after at least about 90 days. Claim 33 In paragraph 32, the method wherein the cancer is intermediate risk non-muscle invasive bladder cancer (IR-NMIBC). Claim 34 In paragraph 32, the method wherein the cancer is newly diagnosed intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC). Claim 35 In paragraph 32, the method wherein the cancer is recurrent intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC). Claim 36 A method according to any one of paragraphs 32 to 35, wherein the cancer possesses an FGFR mutation. Claim 37 In paragraph 35, the method wherein the FGFR variant is an FGFR2 variant or an FGFR3 variant. Claim 38 In paragraph 36 or 37, the FGFR variant is an FGFR3 variant, in particular an FGFR3 mutation or an FGFR3 fusion. Claim 39 In claim 38, the FGFR3 variant is at least one of FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3, particularly FGFR3-TACC3 variant 1 (FGFR3-TACC3 V1) or FGFR3-TACC3 variant 3 (FGFR3-TACC3 V3), FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof. Claim 40 A method according to any one of paragraphs 32 to 39, wherein the patient has not received recent Calmet-Gueren (BCG) treatment. Claim 41 A method according to any one of claims 32 to 40, wherein the patient has one or more of the risk factors of multiple low-grade (LG) tumors, a solitary LG tumor >3 cm, early recurrence of an LG tumor (<1 year), frequent recurrence (more than once a year), or recurrence after previous intravesical chemotherapy. Claim 42 A method according to any one of paragraphs 32 to 41, wherein such treatment results in a median duration of response of at least 12 months, or about 12 months. Claim 43 A method according to any one of claims 33 to 40, wherein such treatment results in a complete response rate of about 90% in a patient population treated with about 2 mg / day to about 4 mg / day of erdafitinib, said complete response rate evaluated at 12 weeks. Claim 44 A method according to any one of claims 33 to 40, wherein such treatment results in a complete response rate of about 85% in a patient population treated with about 2 mg / day to about 4 mg / day of erdafitinib, said complete response rate evaluated at 12 weeks. Claim 45 In paragraph 32, the method wherein the cancer is high-risk non-muscle-invasive bladder cancer (HR-NMIBC). Claim 46 In paragraph 45, the above cancer possesses an FGFR mutation. Claim 47 In paragraph 46, the method wherein the FGFR variant is an FGFR2 variant or an FGFR3 variant. Claim 48 Method according to claim 46 or 47, wherein the FGFR variant is an FGFR3 variant, in particular an FGFR3 mutation or an FGFR3 fusion. Claim 49 In claim 48, the FGFR3 variant is at least one of FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3, particularly FGFR3-TACC3 variant 1 (FGFR3-TACC3 V1) or FGFR3-TACC3 variant 3 (FGFR3-TACC3 V3), FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof. Claim 50 A method according to any one of claims 45 to 49, wherein the relapse-free survival (RFS) rate, particularly the 12-month RFS rate, is about 90% in a patient population treated with about 2 mg / day to about 4 mg / day of erdafitinib, particularly about 3 mg / day of erdafitinib. Claim 51 A method according to any one of claims 45 to 49, wherein the relapse-free survival (RFS) rate, particularly the 12-month RFS rate, is about 75% or about 79% or about 80% in a patient population treated with about 2 mg / day to about 4 mg / day of erdafitinib, particularly about 3 mg / day of erdafitinib. Claim 52 A method for treating intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC) in a patient, comprising the step of locally administering about 2 mg / day to about 4 mg / day of erdafitinib into the patient's bladder for at least about 90 days, wherein i) the patient is a newly diagnosed or relapsed IR-NMIBC patient; ii) the patient is determined to have an intermediate risk of relapse or progression; iii) the patient has a selected FGFR gene mutation; iv) the patient has no prior experience with Calmette-Gueren (BCG) treatment; and v) the patient has one or more risk factors selected from a list consisting of a) multiple low-grade (LG) tumors, b) a solitary LG tumor >3 cm, c) frequent relapses (more than once per year), and d) relapse after previous intravesical chemotherapy. Claim 53 In claim 52, the patient and / or patient group has a histologically confirmed diagnosis of IR-NMIBC and has at least one of the following disease characteristics: i) Ta LG / G1: recurrent; ii) Ta LG / G1: primary and (multifocal or ≥ 3 cm); and / or iii) Ta G2: primary or recurrent. Claim 54 A method for treating recurrent intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC) in a patient, comprising the step of locally administering about 2 mg / day to about 4 mg / day of erdafitinib into the patient's bladder for at least about 90 days, wherein such treatment results in a complete response rate of at least 50% in the patient population receiving such treatment. Claim 55 A method for treating recurrent intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC) in a patient, comprising the step of deploying an intravesical drug delivery system into the patient's bladder, wherein the intravesical drug delivery system comprises a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed within the closed drug reservoir lumen, wherein the drug reservoir lumen is formed by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first wall structure and the second wall structure are joined together at two interfacial edges and together form a tube defining the closed drug reservoir lumen, wherein the tube defines a longitudinal axis, and the two interfacial edges are arranged at an arc angle of 45 to 270 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, and the arc angle corresponds to the second wall structure; and diffusion through the second material forming the second wall structure rather than the first material forming the first wall structure A method comprising the step of releasing erdafitinib by; and the step of removing the drug delivery system after at least about 90 days, wherein such treatment results in a complete response rate of at least 50% in a population of patients receiving such treatment. Claim 56 A method according to any one of paragraphs 52 to 55, wherein such treatment results in a median duration of response of at least 12 months, or about 12 months. Claim 57 A method according to any one of claims 52 to 56, wherein such treatment results in a complete response rate of about 90% in a patient population treated with about 2 mg / day to about 4 mg / day of erdafitinib, said complete response rate evaluated at 12 weeks. Claim 58 A method according to any one of claims 52 to 57, wherein such treatment results in a complete response rate of about 85% in a patient population treated with about 2 mg / day to about 4 mg / day of erdafitinib, said complete response rate evaluated at 12 weeks. Claim 59 A method comprising the step of administering about 2.5 mg / day to about 3.5 mg / day of erdafitinib to the patient in any one of claims 52 to 58. Claim 60 A method comprising the step of administering about 3 mg / day of erdafitinib to the patient in any one of claims 52 to 59. Claim 61 A method for treating recurrent Calmette-Gueren (BCG)-experienced high-risk non-muscle-invasive bladder cancer (HR-NMIBC) in a patient, comprising the step of locally administering about 2 mg / day to about 4 mg / day of erdafitinib into the patient's bladder for at least about 90 days, wherein such treatment results in at least a 50% recurrence-free rate in the patient population receiving such treatment. Claim 62 A method for treating recurrent Calmette-Gueren (BCG)-experienced high-risk non-muscle-invasive bladder cancer (HR-NMIBC) in a patient, comprising the step of deploying an intravesical drug delivery system into the patient's bladder, wherein the intravesical drug delivery system comprises a housing defining a closed drug reservoir lumen and a drug formulation comprising erdafitinib disposed within the closed drug reservoir lumen, wherein the drug reservoir lumen is formed by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first wall structure and the second wall structure are joined together at two interfacial edges and together form a tube defining the closed drug reservoir lumen, wherein the tube defines a longitudinal axis, and the two interfacial edges are arranged at an arc angle of 45 to 270 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, and the arc angle corresponds to the second wall structure; wherein the second material other than the first material forming the first wall structure A method comprising the step of releasing erdafitinib by diffusion through the second material forming a wall structure; and the step of removing the drug delivery system after at least about 90 days, wherein such treatment results in a recurrence-free rate of at least 50% in a group of patients receiving such treatment. Claim 63 A method according to claim 61 or 62, wherein the relapse-free survival (RFS) rate, particularly the 12-month RFS rate, is about 90% in a patient population treated with about 2 mg / day to about 4 mg / day of erdafitinib, particularly about 3 mg / day of erdafitinib. Claim 64 A method according to claim 61 or 62, wherein the relapse-free survival (RFS) rate, particularly the 12-month RFS rate, is about 75% or about 79% or about 80% in a patient population treated with about 2 mg / day to about 4 mg / day of erdafitinib, particularly about 3 mg / day of erdafitinib. Claim 65 A method comprising the step of administering about 2.5 mg / day to about 3.5 mg / day of erdafitinib to the patient in any one of claims 61 to 64. Claim 66 A method comprising the step of administering about 3 mg / day of erdafitinib to the patient in any one of claims 61 to 65. Claim 67 A method comprising, in any one of claims 52 to 66, further a step of selecting a patient to be treated using a urine sample test. Claim 68 In paragraph 67, the above urine sample test is a urine sample NGS or PCR test, particularly a urine sample NGS test. Claim 69 A method according to claim 67 or 68, wherein the urine sample test detects the presence of at least one FGFR2 gene variant and / or FGFR3 gene variant. Claim 70 In claim 69, the method wherein the FGFR2 gene mutation and / or the FGFR3 gene mutation comprises an activated tumor FGFR2 or FGFR3 mutation or fusion. Claim 71 In paragraph 69 or 70, the FGFR2 gene variant and / or the FGFR3 gene variant FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3, in particular FGFR3-TACC3 V1 or FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7, or any combination thereof are selected, in particular the FGFR2 gene variant and / or the FGFR3 gene variant is FGFR3-TACC3 variant 1 (FGFR3-TACC3 V1), FGFR3 G370C, FGFR3 S249C, FGFR3 Y373C, and FGFR3 A method selected from R248C. Claim 72 A method according to any one of claims 67 to 71, wherein at least 50%, 60%, 70%, 80%, or 90% of the treated patients selected by the urine sample test are recurrence-free or achieve a complete response. Claim 73 A method according to any one of claims 67 to 71, wherein at least 90%, 95%, 96%, 97%, 98%, 99%, or 100% of the treated patients selected by the urine sample test are recurrence-free or achieve a complete response. Claim 74 The method according to claim 55 or 62, wherein the drug formulation comprises about 480 mg to about 510 mg of erdafitinib, optionally erdafitinib being an erdafitinib free base.

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