Methods of treating bladder cancer using intravesical administration of erdafitinib

Abstract

Provided herein are therapeutic methods for use in treating bladder cancer, the therapeutic methods comprising administration of erdafitinib and drug delivery systems comprising erdafitinib.

Description

[0001] Cross-reference to related applications This application claims priority and interest in the following U.S. provisional applications: No. 63 / 582,833, filed September 14, 2023; No. 63 / 582,835, filed September 14, 2023; No. 63 / 583,820, filed September 19, 2024; No. 63 / 590,367, filed October 13, 2023; No. 63 / 590,368, filed October 13, 2023; and No. 63 / 590,370, filed October 13, 2023. The contents of each of the following U.S. Provisional Applications are incorporated herein by reference in their entirety: No. 63 / 590,376, filed October 13, 2023; No. 63 / 623,192, filed January 19, 2023; No. 63 / 561,725, filed March 5, 2024; No. 63 / 566,181, filed March 15, 2024; No. 63 / 640,816, filed April 30, 2024; and No. 63 / 691,878, filed September 6, 2024.

[0002] Reference to the electronic sequence list The electronic sequence list (761662002540seqlist.xml; size: 53,246 bytes; and creation date: August 28, 2024) is incorporated herein by reference in its entirety. Technical Field

[0003] This disclosure pertains to the field of treatment methods for bladder cancer. Background Technology

[0004] This disclosure generally pertains to the field of pharmaceutical formulations and drug-device combination products, and more specifically relates to erdatinib-based formulations and systems for intravesical administration of such formulations.

[0005] Erdatinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) is a potent pan-FGFR kinase inhibitor that binds to and inhibits the enzymatic activities of FGFR1, FGFR2, FGFR3, and FGFR4. The synthetic preparation of erdatinib has been described in WO2011 / 135376. Erdatinib has been found to inhibit FGFR phosphorylation and signaling, and to reduce cell viability in cell lines expressing FGFR gene alterations (including point mutations, amplifications, and fusions). Erdatinib has demonstrated antitumor activity in FGFR-expressing cell lines and xenograft models derived from tumor types, including bladder cancer.

[0006] Currently, erdatinib (BALVERSA) ® It is available as a film-coated tablet for oral administration and is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who have susceptible fibroblast growth factor receptor (FGFR)3 or FGFR2 gene alterations and who have progressed during or after at least one first-line platinum-based chemotherapy (including within 12 months of neoadjuvant or adjuvant platinum-based chemotherapy).

[0007] Individuals with high-risk NMIBC are usually initially treated with BCG; however, up to 50% of patients experience recurrence. A portion of patients are eligible for radical cystectomy; however, its effectiveness is limited due to the high morbidity and reduced quality of life. Summary of the Invention

[0008] This article provides a method for treating recurrent high-risk non-muscle-invasive bladder cancer (HR-NMIBC) that has undergone BCG vaccination, involving local administration of erdatinib to the patient's bladder. This article also provides a method for treating patients with recurrent intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC), involving local administration of erdatinib to the patient's bladder.

[0009] In some aspects, this document provides a drug delivery system comprising: a housing defining a drug reservoir lumen defined by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises an aromatic thermoplastic polyurethane based on polycarbonate and the second material comprises a thermoplastic polyurethane based on aliphatic polyether; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdatinib, wherein: (i) the second wall structure or both the first wall structure and the second wall structure are water-permeable, and (ii) the first wall structure is water-permeable to erdatinib. Erdatinib is impermeable and the second wall structure is permeable to erdatinib, allowing erdatinib to be released in vivo by diffusion through the second material forming the second wall structure. 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 configured to release erdatinib at an average rate of about 2.5 mg / day to about 3.5 mg / day. The two interface edges are set at an arc angle of about 125 degrees to about 145 degrees around the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube, where the arc angle corresponds to the second wall structure.

[0010] In some aspects, this document provides a drug delivery system comprising: a housing defining a drug reservoir lumen defined by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises an aromatic thermoplastic polyurethane based on polycarbonate and the second material comprises a thermoplastic polyurethane based on aliphatic polyether; and a drug formulation disposed in the drug reservoir lumen, the drug formulation comprising erdatinib, wherein: (i) the second wall structure or both the first wall structure and the second wall structure are water-permeable, and (ii) The first wall structure is impermeable to erdatinib and the second wall structure is permeable to erdatinib, allowing erdatinib to be released in vivo by diffusion through the second material forming the second wall structure. 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 configured to release erdatinib at an average rate of about 3 mg / day. The two interface edges are set at an arc angle of about 135 degrees around the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube, where the arc angle corresponds to the second wall structure. Attached Figure Description

[0011] Specific embodiments are illustrated with reference to the accompanying drawings. Similar or identical items may be indicated using the same reference numerals. Various embodiments may utilize elements and / or components other than those shown in the drawings, and some elements and / or components may not be present in various embodiments. Elements and / or components in the drawings are not necessarily drawn to scale.

[0012] Figure 1 This is a longitudinal cross-sectional view of one embodiment of a drug delivery system in a curled-up, shape-retaining configuration according to the present disclosure.

[0013] Figure 2 This is a cross-sectional view of one embodiment of the drug delivery system according to the present disclosure.

[0014] Figure 3 This is a cross-sectional view of one embodiment of the drug delivery system according to the present disclosure.

[0015] Figure 4 This is a photograph of one embodiment of a drug delivery system containing erdatinib tablets according to this disclosure.

[0016] Figure 5 This is a longitudinal cross-sectional view of one embodiment of a drug delivery system according to the present disclosure, which is in a curled-up, shape-retaining state, has an elastic retaining frame, and is prior to loading a drug tablet.

[0017] Figure 6A This is a longitudinal cross-sectional view of one embodiment of an elastic retaining frame in a curled shape according to the present disclosure.

[0018] Figure 6B yes Figure 6A A magnified view of one end of the frame.

[0019] Figure 7A This is a perspective view of one embodiment of a drug delivery system according to the present disclosure, which is in a relatively straight shape and has no drug disposed therein or has no elastic retaining frame.

[0020] Figure 7B yes Figure 7A The drug delivery system shown is a longitudinal cross-sectional view taken along line 7B-7B.

[0021] Figure 7C yes Figure 7A The drug delivery system shown is a cross-sectional view taken along line 7C-7C.

[0022] Figure 8 This is a photograph showing a cross-section of the lumen of a drug reservoir in a drug delivery system according to this disclosure, in which no drug is disposed.

[0023] Figure 9A Two doses of erdatinib treatment (TAR-210-B, approximately 2 mg / day; TAR-210-D, approximately 4 mg / day) and two participant cohorts treated in the clinical study described in Example 1 of this document are shown.

[0024] Figure 9B The clinical protocol for administering erdatinib is described. TURBT, as described in Example 1 of this document, involves transurethral resection of bladder tumors.

[0025] Figure 10 This document presents a demographic summary of 43 patients (16 from cohort 1 and 27 from cohort 3) treated in the clinical studies described in Example 1, Part A of this document.

[0026] Figures 11A to 11B This document presents a summary of the baseline disease characteristics of 43 patients treated in the clinical study described in Example 1, Part A of this document.

[0027] Figure 12A This is a swimlane plot showing the duration of treatment and response in cohort 1 of the clinical study described in Example 1, Part A of this document, for patients treated with TAR-210-B (approximately 2 mg / day of erdatinib; diagonal stripes) or TAR-210-D (approximately 4 mg / day of erdatinib; dotted stripes). Legends are included to describe patient treatment status and milestones. Non-CR (complete response); non-PD (non-progressive disease).

[0028] Figure 12B This is a swimlane plot showing the duration of treatment and response in cohort 3 of the clinical study described in Example 1, Part A of this article, for patients treated with TAR-210-B (approximately 2 mg / day erdatinib; diagonal stripes) or TAR-210-D (approximately 4 mg / day erdatinib; dotted stripes). Legends are included to depict patient treatment status and milestones. Non-CR (complete response); non-PD (non-progressive disease).

[0029] Figure 13 This presents a summary of relapse-free survival in 16 patients treated in cohort 1 of the clinical study in Part A of Example 1.

[0030] Figure 14 The summary of the complete responses of the 15 patients treated in cohort 3 of the clinical study in Part A of Example 1 is shown, and the therapeutic efficacy is demonstrated.

[0031] Figure 15 The summary shows the response duration of 13 patients who achieved a full response in cohort 3 of the clinical study in Part A of Example 1.

[0032] Figure 16 This section presents a summary of the treatment outcomes for 43 patients treated in cohorts 1 and 3 of the clinical studies described in Part A of Example 1, including ongoing study treatments, completed study treatments, and discontinued study treatments.

[0033] Figure 17 This document presents a summary of adverse effects observed in the treatment of 43 patients in cohorts 1 and 3 of the clinical studies described in Part A of Example 1.

[0034] Figure 18 The diagram shows the quantitative urinary concentration (left) and quantitative plasma concentration (right) of erdatinib from patient samples after administration of TAR-210-B (dashed line) or TAR-210-D (solid line) in Part A of Example 1.

[0035] Figure 19A This is a schematic overview of the clinical studies related to the safety and efficacy of the intravesical drug delivery system (TAR-210) described in Example 2 in the treatment of patients with intermediate-risk (IR) non-muscle-invasive bladder cancer (NMIBC). SOC, Standard of Care; LG, Low-grade; MMC, Mitomycin C; Gem, Gemcitabine.

[0036] Figure 19BThis is a schematic overview of the treatment period of the clinical study described in Example 2. Patients were randomized 1:1 and treated for up to 1 year with the intravesical drug delivery system (TAR-210) as described in Group A or with gemcitabine or MMC as described in Group B. TURBT, transurethral resection of bladder tumor; CT, computed tomography scan; IV, intravenous injection; MRI, magnetic resonance imaging; EOT, end of treatment.

[0037] Figure 20 This is a schematic overview of a concordance study of tissue and urine measurements performed using paired samples from bladder cancer patients in the BRIDGister clinical trial in Germany.

[0038] Figure 21 This is a heatmap of identified genetic alterations from matched urine NGS and FFPE tissue RT-PCR samples (from bladder cancer patients in the BRIDGister clinical trial in Germany).

[0039] Figure 22A It is a scatter plot of variant allele frequencies (VAF) between matched urinary NGS (X-axis) and tissue (“FFPE”) RT-PCR (Y-axis) variants for all identified gene alterations, including somatic and germline variants.

[0040] Figure 22B This is a scatter plot of variant allele frequencies (VAFs) between matched urinary NGS (X-axis) and tissue (“FFPE”) RT-PCR (Y-axis) variants targeting somatic FGFR3 alterations.

[0041] Figure 23 A flowchart is shown comparing the performance of urine and tissue tests from all screened NMIBC patients (N=178) at the cutoff date. Patients were from the first human study described in Example 1.

[0042] Figure 24A This is a swimlane plot showing clinical efficacy data (duration of treatment and response) in patients with evaluable HR-NMIBC in Cohort 1, screened by urine sample testing and / or tumor tissue sample testing, and treated with either the intravesical drug delivery system TAR-210-B (approximately 2 mg / day erdatinib; circular pattern) or TAR-210-D (approximately 4 mg / day erdatinib; dashed pattern). Patients are from the first-in-human study described in Example 1. A legend depicting patient recruitment (“recruitment method”; left side of the figure) by tumor tissue sample testing (left side of the figure) or urine sample testing (right side of the figure) is also included. Another legend (right side of the figure) describing patient treatment status and milestones is also included.

[0043] Figure 24BThis is a swimlane plot showing clinical efficacy data (duration of treatment and response) in patients with evaluable IR-NMIBC in cohort 3, screened by urine sample testing and / or tumor tissue sample testing, and treated with either the intravesical drug delivery system TAR-210-B (approximately 2 mg / day erdatinib; circular pattern) or TAR-210-D (approximately 4 mg / day erdatinib; dashed pattern). Patients are from the first-in-human study described in Example 1. A legend depicting patient recruitment (“recruitment method”; left side of the figure) by tumor tissue sample testing (left side of the figure) or urine sample testing (right side of the figure) is also included. Another legend (right side of the figure) describing patient treatment status and milestones is also included.

[0044] Figure 25 A map of pathogenic somatic variants of the 15 most prevalent genes detected in urine from all evaluable samples was constructed. Del = deletion; UTR = untranslated region; Ins = insertion; CNV = copy number variation.

[0045] Figures 26A to 26D An updated protocol for the Phase I clinical trial of erdatinib intravesical administration as described in Example 1 is shown.

[0046] Figure 27A This is a top schematic diagram of an embodiment of the drug delivery system according to the present disclosure, shown in a curled, retaining shape. Figure 27A In the image, the portion of the outer shell that defines the lumen of the drug reservoir is shown as translucent, revealing the erdatinib microtablets contained within.

[0047] Figure 27B It is displayed by maintaining its shape through curling. Figure 27A A bottom diagram of a drug delivery system. Figure 27B In the image, the portion of the outer shell that defines the lumen of the drug reservoir is shown as translucent, revealing the erdatinib microtablets contained within.

[0048] Figure 28 yes Figure 27A Drug delivery system along Figure 27A The cross-sectional view taken by line AA.

[0049] Figure 29A It is displayed in a relatively straight insertion shape. Figure 27A A side view of a drug delivery system. Figure 29A In the image, the portion of the outer shell that defines the lumen of the drug reservoir is shown as translucent, revealing the erdatinib microtablets contained within.

[0050] Figure 29B It is displayed in a relatively straight insertion shape. Figure 27A A side cross-sectional view of a part of a drug delivery system. Figure 29B The outer shell is shown in cross-section to expose the erdatinib microtablets located in the drug reservoir lumen and the retaining frame located in the retaining frame lumen; the ends of the drug delivery system are truncated.

[0051] Figure 30A This document presents a demographic summary of 64 patients (21 from cohort 1 and 43 from cohort 3) treated in the clinical studies described in Example 1, Part C of this document.

[0052] Figure 30B This document presents a summary of the baseline disease characteristics of 64 patients (21 from cohort 1 and 43 from cohort 3) treated in the clinical study described in Example 1, Part C of this document.

[0053] Figure 31A This is a swimlane plot showing the duration of treatment and response in cohort 1 of the clinical study described in Example 1, Part C of this document, for patients treated with TAR-210-B (approximately 2 mg / day erdatinib; round pattern) or TAR-210-D (approximately 4 mg / day erdatinib; dashed pattern). Legends are included to depict patient treatment status and milestones. RFS, relapse-free survival.

[0054] Figure 31B This is a swimlane plot showing the duration of treatment and response in cohort 3 of the clinical study described in Example 1, Part C of this article, for patients treated with TAR-210-B (approximately 2 mg / day erdatinib; circular pattern) or TAR-210-D (approximately 4 mg / day erdatinib; dot pattern). Legends are included to describe patient treatment status and milestones. DOR, Duration of Response; CR, Complete Response; Non-CR, Incomplete Response; Non-PD, Non-Progressive Disease.

[0055] Figure 32A The urinary concentrations of erdatinib from patient samples are shown after administration of TAR-210-B or TAR-210-D in Part C of Example 1.

[0056] Figure 32B The plasma concentrations of erdatinib from patient samples are shown after administration of TAR-210-B or TAR-210-D in Part C of Example 1.

[0057] Figure 33 A pie chart is shown, which illustrates the proportion of patients recruited by efficacy assessment via urine and tissue samples in cohort 1 (HR-NMIBC) and cohort 3 (IR-NMIBC) in Part B of Example 4.

[0058] Figure 34AThe figure illustrates Example 4, showing the proportion of relapse-free patients with HR-NMIBC in cohort 1 of portion B, based on the type of sample recruited.

[0059] Figure 34B The figure shows the proportion of patients with IR-NMIBC in cohort 3 who had a full response at 3 months of assessment, according to the type of sample recruited, illustrating Example 4.

[0060] Figure 35 This document presents a summary of the demographic and baseline disease characteristics of 21 HR-NMIBC (cohort 1) patients and 49 IR-NMIBC (cohort 3) patients treated in the clinical studies described in Example 1, Part D of this document.

[0061] Figure 36A This is a swimlane plot showing the duration of treatment and response in HR-NMIBC (cohort 1) patients from the clinical study described in Example 1 of this article, Part D, treated with either TAR-210-B (approximately 2 mg / day of erdatinib; diagonal stripes) or TAR-210-D (approximately 4 mg / day of erdatinib; dotted stripes). Legends are included to depict patient treatment status and milestones.

[0062] Figure 36B This is a swimlane plot showing the duration of treatment and response in HR-NMIBC (cohort 3) patients from the clinical studies described in Example 1, Part D of this article, treated with either TAR-210-B (approximately 2 mg / day of erdatinib; diagonal stripes) or TAR-210-D (approximately 4 mg / day of erdatinib; dotted stripes). Legends are included to depict patient treatment status and milestones.

[0063] Figure 37A The quantitative urinary concentrations of erdatinib from patient samples are shown after administration of TAR-210-B (dashed line) or TAR-210-D (solid line) in Part D of Example 1.

[0064] Figure 37B The quantitative plasma concentrations of erdatinib from patient samples are shown after administration of TAR-210-B (dashed line) or TAR-210-D (solid line) in Part D of Example 1. Detailed Implementation

[0065] Due to limited available therapies and adverse outcomes, this article presents a method for treating non-muscle-invasive bladder cancer (NMIBC) in multiple patient cohorts, particularly high-risk (HR) NMIBC (e.g., recurrent HR-NMIBC) and intermediate-risk (IR) NMIBC (e.g., recurrent IR-NMIBC). Intravesical delivery of erdatinib provides local bladder cancer treatment while avoiding systemic toxicity, thus offering a much-needed treatment option for NMIBC. As demonstrated in this article, the method of treating HR-NMIBC (particularly recurrent high-risk NMIBC with BCG experience) involving local administration of approximately 2 mg / day to approximately 4 mg / day of erdatinib for approximately 90 days resulted in a recurrence-free (RF) rate of at least 85% in the patient cohort receiving 2 mg / day of erdatinib and at least 80% in the patient cohort receiving 4 mg / day of erdatinib. Furthermore, a method for treating IR-NMIBC (particularly recurrent intermediate-risk NMIBC) is provided, comprising administering erdatinib locally to the bladder for approximately 2 mg / day to approximately 4 mg / day for approximately 90 days, resulting in a complete response (CR) rate of at least 75% in the patient cohort receiving erdatinib at 2 mg / day and at least 90% in the patient cohort receiving erdatinib at 4 mg / day. The method of this application demonstrates excellent response rate (RF) and CR rate for each treatment cohort. Furthermore, the method provided herein shows limited treatment-emergent adverse events (TEAEs) and very few serious TEAEs, thus demonstrating a safe and well-tolerated treatment.

[0066] In another respect, local and continuous administration of erdatinib to the bladder using the methods described in this article has shown improved event-free survival and duration of response (DOR). Patients who receive this type of treatment and achieve an effective response may experience 6 months of event-free survival or DOR.

[0067] The unexpected improvements in RF and CR rates achieved with the methods disclosed in this article provide the added benefit of delaying invasive replacement therapy (such as surgical cystectomy (radical cystectomy)), leading to a significant impact on individual quality of life. This impact includes incontinence, sexual dysfunction, infertility, and bowel complications. Furthermore, local administration of erdatinib to the bladder according to the methods provided in this article results in fewer side effects compared to systemic chemotherapy. In summary, these clinical improvements provide a safe and effective treatment option for individuals with NMIBC, including those with high-risk and intermediate-risk recurrent NMIBC.

[0068] This article also describes erdatinib formulations and a release system tailored for intravesical drug delivery to utilize this administration route for the treatment of patients with non-MIBC. Furthermore, a system capable of delivering erdatinib at an efficient release rate for the local treatment of bladder cancer is provided.

[0069] Erdatinib exhibits pH-dependent solubility within the normal urine pH range of 5.5 to 7. In some embodiments, the formulation and release system are tailored to minimize the influence of urine pH and the composition on the system release rate.

[0070] certain terms Disease-free survival (DFS) is defined as the time from randomization to the date of first recorded recurrence, disease progression, or death from any cause of non-muscle-invasive bladder cancer (NMIBC) of any grade (i.e., up to 5 years).

[0071] Recurrence is defined as the recurrence of NMIBC based on pathological assessment, independent of grading.

[0072] Recurrence-free survival (RFS) is defined as the time from randomization to the first detection of high-grade Ta or T1 bladder cancer or a positive urine cytology test.

[0073] The recurrence-free survival (RFS) rate was defined as the proportion of patients with RFS who were detected with high-grade Ta or T1 bladder cancer or positive urine cytology from the start of study treatment. This proportion was initially assessed at approximately 3 months or approximately 90 days after erdatinib treatment, and then reassessed every 3 months during the study (year 1) and during follow-up (every 3 months until the end of year 2, and every 6 months in year 3).

[0074] The relapse-free rate was defined as the proportion of patients who had been relapse-free with at least one disease assessment, which was initially assessed at approximately 3 months or approximately 90 days after starting erdatinib treatment, and then reassessed every 3 months during the study (Year 1) and during follow-up (every 3 months until the end of Year 2, and every 6 months in Year 3).

[0075] The high-grade recurrence rate was defined as the proportion of patients with a positive urine cytology test for high-grade Ta or T1 bladder cancer or HG urothelial carcinoma (HGUC or repeat samples showing suspicious HGUC), which was initially assessed at approximately 3 months or approximately 90 days of erdatinib treatment, and then reassessed every 3 months during the study (year 1) and during follow-up (every 3 months until the end of year 2, and every 6 months in year 3).

[0076] The low-grade recurrence rate was defined as the proportion of patients with a positive urine cytology test for low-grade Ta or T1 bladder cancer or LG urothelial carcinoma, which was initially assessed at approximately 3 months or approximately 90 days of erdatinib treatment, and then reassessed every 3 months during the study (year 1) and during follow-up (every 3 months until the end of year 2, and every 6 months in year 3).

[0077] Disease progression rate was defined as the proportion of patients who progressed to muscle-invasive bladder cancer (MIBC) (T2 stage or higher), which was initially assessed at approximately 3 months or approximately 90 days after erdatinib treatment, and then reassessed every 3 months during the study (year 1) and during follow-up (every 3 months until the end of year 2, and every 6 months in year 3).

[0078] Incomplete response (non-CR) or non-progressive disease (non-PD) is defined as no new or larger tumors are identified on cystoscopy.

[0079] Disease progression was defined as a post-baseline assessment with ≥T2 disease or positive lymph nodes or metastases.

[0080] A complete response (CR) is defined as the absence of urothelial carcinoma pathologically confirmed at the time of initial evaluation by cystoscopy, and a negative urine cytology test.

[0081] Complete response (CR) is defined as the proportion of patients who are pathologically confirmed to be free of urothelial carcinoma at the time of initial evaluation by cystoscopy and have negative urine cytology.

[0082] The duration of CR is defined as the time from the first recorded CR until the date of recorded recurrence or progression or death (whichever comes first).

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

[0084] The percentage of participants without pathological evidence of intrabladder disease (pT0) was defined as the percentage of participants without pathological evidence of intrabladder disease.

[0085] BCG experience describes an individual who experiences recurrent high-grade Ta / T1 disease within 18 months of completing prior BCG therapy. The minimum requirement for prior BCG therapy is at least five of six full doses of the initial induction BCG regimen (with or without maintenance therapy). A full dose of BCG is defined as containing at least 1 × 10⁻⁶ mmol / L. 8 One complete vial of a settlement-forming unit.

[0086] The percentage of participants whose stage drops to less than (<) pT2 is defined as the percentage of participants whose pT stage is <2.

[0087] Unless otherwise stated, when used herein, weight % relative to the drug or excipient means weight based on the total weight of the formulation of interest.

[0088] This application considers all combinations of any embodiments disclosed herein.

[0089] The implementation methods of the treatment methods described herein are also applicable to treatment, or used in treatment methods or for manufacturing a medicine for treatment. For example, the disclosure of a method of treating a patient with recurrent BCG-acquired high-risk non-muscle-invasive bladder cancer (HR-NMIBC) as described herein may also be expressed as erdatinib for treating a patient with recurrent BCG-acquired high-risk non-muscle-invasive bladder cancer (HR-NMIBC) as described herein, or erdatinib in a method of treating a patient with recurrent BCG-acquired high-risk non-muscle-invasive bladder cancer (HR-NMIBC) as described herein, or erdatinib for manufacturing a medicine for treating a patient with recurrent BCG-acquired high-risk non-muscle-invasive bladder cancer (HR-NMIBC) as described herein, or erdatinib for manufacturing a medicine for treating a patient with recurrent BCG-acquired high-risk non-muscle-invasive bladder cancer (HR-NMIBC) as described herein.

[0090] The use of "about" in this article to refer to a value or parameter includes (and describes) variations relating to that value or parameter itself. For example, a description of "about X" includes a description of "X".

[0091] Erdatinib formulations and tablets In one aspect, this disclosure provides erdatinib formulations, particularly erdatinib tablets suitable for use in the disclosed intravesical drug delivery system. Specifically, a drug tablet comprising the free base of erdatinib (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) is provided. As another example, a drug tablet comprising an erdatinib HCl salt is provided. After insertion of the drug delivery system into the bladder, the drug is released from the system into the bladder. In one aspect, for example, the drug delivery system may operate by diffusion, which, over a prolonged period, produces a continuous release of the drug into the bladder as the drug is released from the tablet in the system.

[0092] To increase or maximize the amount of drug that can be stored in and released from the disclosed drug delivery system, the drug tablet may have a relatively high erdatinib content (by weight). This relatively high part by weight of erdatinib in the drug tablet is accompanied by a reduced or low part by weight of excipients, which may be necessary for tablet manufacturing and system assembly, as well as for drug use considerations. For the purposes of this disclosure, terms such as “parts by weight,” “percentage by weight,” and “percentage by weight” relating to any drug or API (active pharmaceutical ingredient) refer to the form of the drug or API used (whether in free base, free acid, salt, or hydrate form). For example, a drug tablet having 90% (90 wt%) of the drug or excipient in salt form may include less than 90 wt% of the drug in free base form. Unless otherwise stated, weight percentages are relative to the entire solid pharmaceutical composition.

[0093] The erdatinib pharmaceutical tablets disclosed herein comprise erdatinib contents and excipient contents. The pharmaceutical contents may comprise one or more forms of erdatinib, such as a free base or salt form, and the excipient contents may comprise one or more excipients. Specific embodiments include erdatinib free base API, and the exemplary formulations presented herein comprise erdatinib free base API. The term "excipient" is known in the art, and representative examples of excipients that can be used in the disclosed pharmaceutical tablets may include, but are not limited to, components such as binders, lubricants, flow aids, disintegrants, solubilizers, colorants, fillers or diluents, wetting agents, stabilizers, formaldehyde scavengers, coatings and preservatives, or any combination thereof, as well as other components that facilitate the manufacture, storage, or use of the pharmaceutical tablets.

[0094] Another aspect of this disclosure provides a method for preparing a solid pharmaceutical composition, wherein the method may include: (a) preparing an in-particle solid composition comprising or substantially consisting of: (i) erdatinib free base and (ii) at least one in-particle pharmaceutical excipient; (b) combining the in-particle solid composition with at least one out-of-particle pharmaceutical excipient to form a blend; and (c) compressing the blend into a tablet to form a solid pharmaceutical composition. In embodiments, the erdatinib free base may be present at a concentration of at least 45% by weight of the solid pharmaceutical composition. The at least one in-particle pharmaceutical excipient and the at least one out-of-particle pharmaceutical excipient may comprise or be selected from at least one common (mutually present) pharmaceutical excipient, or there may be no common (mutually present) pharmaceutical excipient between the in-particle excipient and the out-of-particle pharmaceutical excipient. The solid pharmaceutical composition may be prepared by a method including an in-particle solid composition prepared by a rolling method or by a fluidized bed granulation method. In some embodiments, the step of (a) preparing the intraparticle solid composition includes: (1) preparing a premix comprising erdatinib free base and one or more excipients; (2) preparing a binder solution; and (3) preparing the intraparticle solid composition by combining the premix with the binder solution. In some embodiments, the step of (a) preparing the intraparticle solid composition includes: (1) preparing a premix comprising erdatinib free base and one or more excipients; (2) preparing a binder solution; and (3) preparing the intraparticle solid composition by combining the premix with the binder solution using a fluidized bed granulation method. In some embodiments, the step of (a) preparing the intraparticle solid composition includes: (1) preparing a premix comprising erdatinib free base and a stabilizer, a solubilizer, and a filler; (2) preparing a binder solution comprising a binder and a solvent; and (3) preparing the intraparticle solid composition by combining the premix with the binder solution using a fluidized bed granulation method. In some embodiments, the step of (a) preparing the in-particle solid composition includes: (1) preparing a preblator comprising erdatinib free base, meglumine, hydroxypropyl-β-cyclodextrin, and microcrystalline cellulose; (2) preparing a binder solution comprising hydroxypropyl methylcellulose and purified water; and (3) combining the preblator with the binder solution by a fluidized bed granulation method to prepare the in-particle solid composition. In some embodiments, the step of (a) preparing the in-particle solid composition includes: (1) preparing a preblator comprising erdatinib free base, a solubilizer, and a filler; (2) preparing a binder solution comprising a binder and a solvent; and (3) combining the preblator with the binder solution by a fluidized bed granulation method to prepare the in-particle solid composition.In some embodiments, (a) the step of preparing the in-particle solid composition includes: (1) preparing a preblister of erdatinib free base, hydroxypropyl-β-cyclodextrin and microcrystalline cellulose; (2) preparing a binder solution comprising hydroxypropyl methylcellulose and purified water; and (3) combining the preblister with the binder solution by a fluidized bed granulation method to prepare the in-particle solid composition.

[0095] Another aspect of this disclosure provides a method for preparing a solid pharmaceutical composition, wherein the method may include: (a) preparing an in-particle solid composition comprising or substantially consisting of: (i) an erdatinib HCl salt form and (ii) at least one in-particle pharmaceutical excipient; (b) combining the in-particle solid composition with at least one out-of-particle pharmaceutical excipient to form a blend; and (c) compressing the blend into a tablet to form a solid pharmaceutical composition. In embodiments, the erdatinib HCl salt form may be present at a concentration of at least 45% by weight of the solid pharmaceutical composition. The at least one in-particle pharmaceutical excipient and the at least one out-of-particle pharmaceutical excipient may comprise or be selected from at least one common (mutually present) pharmaceutical excipient, or there may be no common (mutually present) pharmaceutical excipient between the in-particle excipient and the out-of-particle pharmaceutical excipient. The solid pharmaceutical composition may be prepared by a method including an in-particle solid composition prepared by a rolling method or by a fluidized bed granulation method.

[0096] In one embodiment, the erdatinib tablet comprises erdatinib in its free base form. Other embodiments of the erdatinib tablet may comprise erdatinib in its salt form. In one aspect, the erdatinib tablet may comprise greater than or equal to 40% by weight of erdatinib free base, the remaining weight comprising excipients, such as lubricants, binders, and stabilizers, to facilitate the preparation and use of the tablet. Alternatively, the erdatinib tablet may comprise greater than or equal to 45%, greater than or equal to 50%, greater than or equal to 55%, or greater than or equal to 60% by weight of erdatinib free base. In each of these weight percentage embodiments, the actual upper limit of erdatinib free base in the tablet formulation is about 65% by weight or 70% by weight. Thus, in one aspect, the tablet may comprise 40% to 60% by weight of erdatinib in its free base form, or 45% to 55% by weight of erdatinib in its free base form. In some embodiments of the foregoing, the pharmaceutical tablet may contain between about 5% and about 15% by weight of hydroxypropyl-β-cyclodextrin (HP-β-CD). In some embodiments of the foregoing, the pharmaceutical tablet may contain about 10% by weight of hydroxypropyl-β-cyclodextrin (HP-β-CD). In one embodiment, based on the total weight of the tablet, the pharmaceutical tablet may contain 50% by weight of erdatinib in its free base form. In another embodiment, based on the total weight of the tablet, the pharmaceutical tablet may contain 50% by weight of erdatinib in its free base form and between about 5% and about 15% by weight of hydroxypropyl-β-cyclodextrin (HP-β-CD). In yet another embodiment, based on the total weight of the tablet, the pharmaceutical tablet may contain 50% by weight of erdatinib in its free base form and 10% by weight of hydroxypropyl-β-cyclodextrin (HP-β-CD).

[0097] In one embodiment, the erdatinib drug tablet comprises erdatinib in its HCl salt form. In one aspect, the erdatinib drug tablet may comprise greater than or equal to 40% by weight of the erdatinib HCl salt form, the remaining weight comprising excipients, such as lubricants, binders, and stabilizers, to facilitate the preparation and use of the drug tablet. Alternatively, the erdatinib drug tablet may comprise greater than or equal to 45%, greater than or equal to 50%, greater than or equal to 55%, or greater than or equal to 60% by weight of the erdatinib HCl salt form. In each of these weight percentage embodiments, the actual limit of the erdatinib salt form in the tablet formulation is about 65% by weight or 70% by weight. Thus, in one aspect, the drug tablet may comprise 40% to 60% by weight of the erdatinib HCl salt form, or 45% to 55% by weight of the erdatinib HCl salt form. In another embodiment, based on the total weight of the tablet, the drug tablet may comprise 50% by weight of the erdatinib HCl salt form.

[0098] In one embodiment, erdatinib and excipients are selected and formulated into tablets to allow for drug release from the tablets. In some embodiments, erdatinib and excipients are selected and formulated into tablets to allow for solubilization and dissolution of the drug from the tablets. In embodiments, erdatinib is formulated into the pharmaceutical composition to be sterilized, either within or outside the drug delivery system, without causing substantial or harmful changes to the chemical or physical composition of the pharmaceutical tablets that would otherwise render the tablets unsuitable for delivery of erdatinib as described herein. In one aspect, erdatinib and excipients are selected based on their suitability for the sterilization process. In one embodiment, the drug delivery system containing the pharmaceutical tablets is sterilized as a whole. In particular, the drug delivery system containing the pharmaceutical tablets is sterilized by gamma radiation.

[0099] In one aspect, erdatinib tablets may have the size and shape for use with implantable drug delivery systems, including the intravesical drug delivery systems disclosed herein. For example, erdatinib tablets may be “microtablets” that are generally smaller than conventional tablets, allowing the system-contained drug tablet to be inserted through a lumen (such as the urethra) into a cavity (such as the bladder). Erdatinib tablets may be coated or uncoated. In particular, uncoated tablets formulated according to this disclosure have been found to perform well with the system. As disclosed herein, “microtablet” and “tablet” are used interchangeably to refer to tablets that allow the system-contained drug tablet to be inserted through a lumen (such as the urethra) into a cavity (such as the bladder).

[0100] In embodiments, the drug tablet for intravesical insertion or other implantation may be in the form of a solid cylinder having a cylindrical axis, cylindrical sides, a circular end face perpendicular to the cylindrical axis, a diameter passing through the circular end face, and a length along the cylindrical sides. In the cylindrical form, each microtablet may have a length (L) exceeding its diameter (D), such that the microtablet has an aspect ratio (L:D) greater than 1:1. For example, the aspect ratio (L:D) of each microtablet may be 1.6, 1.5, 1.4, 1.3, 1.2, 1.1, or a range of values ​​between these aspect ratios. Embodiments of the microtablet 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 respects, microtablets 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.

[0101] The API used in solid tablet formulations may be erdatinib, which is N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine, and its chemical structure is shown below. Erdatinib tablets used in the disclosed intravesical system may be formulated using erdatinib free base or a salt thereof. In one aspect, erdatinib tablets used in the disclosed intravesical system may include erdatinib free base. In another aspect, erdatinib tablets used in the disclosed intravesical system may include erdatinib HCl salt, particularly crystalline erdatinib HCl salt. In some embodiments of the foregoing, erdatinib tablets used in the disclosed intravesical system may include crystalline erdatinib free base. As described herein, the inclusion of certain stabilizers, solubilizers, and excipients in erdatinib free base formulations can provide favorable stability and solubility properties for the effective use of free base formulations in the disclosed intravesical system.

[0102] In the embodiments, erdatinib drug tablets may incorporate various excipients, including but not limited to at least one solubilizer, at least one binder, at least one wetting agent, at least one disintegrant, at least one stabilizer, at least one diluent, at least one flow aid, at least one lubricant, or any combination thereof. Any excipient or any combination of excipients may be present in the in-particle solid composition, the out-of-particle solid composition, or both. In one aspect, at least one in-particle drug excipient and at least one out-of-particle drug excipient may be the same, i.e., selected from at least one common (mutually existing) drug excipient. In another aspect, the in-particle drug excipient and the out-of-particle drug excipient do not include a common (mutually existing) drug excipient, such that the in-particle excipient and the out-of-particle excipient are mutually exclusive. In the embodiments, erdatinib drug tablets (particularly erdatinib drug tablets containing 40% to 70% by weight, or 40% to 60% by weight, or 45% to 55% by weight (e.g., 50% by weight) of erdatinib) comprise at least one solubilizer, at least one binder, at least one stabilizer, at least one diluent, at least one flow aid, at least one lubricant, etc., or any combination thereof.

[0103] It should be understood that these functional descriptions of various excipients are generally used as follows. Solubilizers improve or enhance the solubility of APIs (such as erdatinib free base) within the lumen of the disclosed system or within body cavities (such as the bladder) once the API is released from the system. Binders hold solid particles of the composition together to achieve physical stability. Wetting agents reduce the surface tension between the drug and the medium in which it is situated and help maintain the solubility of the drug. Disintegrants assist in the disintegration of microtablets upon contact with water to release the drug substance. Stabilizers improve the chemical stability of the formulation (including the API), such as thermal stability, or protect the API from degradation. Diluents can be used as fillers to increase the volume or weight of the composition, which may assist in providing tablets of the desired size or may assist in the compressibility of API-excipient blends. Flow aids improve the flow properties of (granular) particles of tablet components or powder blends to be compressed. Lubricants prevent particles of the composition from adhering to components of manufacturing equipment, such as the die and punch of a tableting machine. In one aspect, excipients may be water-soluble. In another respect, the excipients can be in a colloidal state in water. According to yet another respect, the excipients can be soluble under the conditions of their deployment in the patient's body (such as in the bladder). These and other excipients are described in more detail below.

[0104] Stabilizers such as formaldehyde removers In one respect, when incorporated into solid dosage forms, erdatinib API may be sensitive to degradation under certain conditions. For example, erdatinib can be degraded or transformed in the presence of formaldehyde to form the cyclized product 6,8-dimethoxy-4-(1-methylethyl)-1-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine. Formaldehyde from various sources in the environment, such as contaminants from packaging materials or as excipients or other components in the formulation, can come into contact with erdatinib.

[0105] Therefore, in one aspect, erdatinib pharmaceutical formulations may include formaldehyde scavengers to improve the stability or shelf life of the formulation. Various formaldehyde scavengers may be used, which, when erdatinib is exposed to formaldehyde, can prevent, slow down, reduce, or delay the formation of degradation products. Therefore, the stability, such as chemical stability, of erdatinib pharmaceutical formulations can be increased in the presence of formaldehyde scavengers compared to erdatinib pharmaceutical formulations without formaldehyde scavengers. In one aspect, the formaldehyde scavenger may be present in a solid pharmaceutical composition as a component of an in-particle solid composition, an out-of-particle solid composition, or both an in-particle solid composition and an out-of-particle solid composition. In one aspect, a formaldehyde scavenger, particularly meglumine, is present in a solid pharmaceutical composition as a component of an in-particle solid composition.

[0106] Formaldehyde scavengers may include or be selected from compounds containing reactive nitrogen centers, such as compounds containing amine or amide groups. Unbound by theory, these compounds are thought to react with formaldehyde to form a Schiff base imine (R... 1 R 2 C=NR 3 , where R 3 (Not hydrogen), which itself can bind to formaldehyde. Examples of such formaldehyde scavengers include, but are not limited to, amino acids, amino sugars, α-(α-)amine compounds, their conjugates and derivatives, and mixtures thereof. Such formaldehyde scavenger compounds may contain two or more amine and / or amide moieties that can scavenge formaldehyde.

[0107] In one aspect, formaldehyde scavengers may include or be selected from, for example, meglumine, glycine, alanine, serine, threonine, cysteine, valine, leucine, isoleucine, methionine, phenylalanine, tyrosine, aspartic acid, glutamic acid, arginine, lysine, ornithine, taurine, histidine, aspartame, proline, tryptophan, citrulline, pyrrolidone, asparagine, glutamine, tris(hydroxymethyl)aminomethane, conjugates thereof, pharmaceutically acceptable salts thereof, or any combination thereof. According to one aspect, formaldehyde scavengers may include or be selected from meglumine or pharmaceutically acceptable salts thereof, particularly meglumine bases.

[0108] Therefore, one aspect of this disclosure is the use of formaldehyde scavengers (particularly meglumine) in erdatinib pharmaceutical formulations (such as pharmaceutical tablet formulations) to increase the stability of erdatinib in any form, including the free base of erdatinib, its salts, or solvates thereof. The chemical stability of erdatinib pharmaceutical formulations is increased compared to erdatinib pharmaceutical formulations or compositions that do not contain formaldehyde scavengers. Another aspect of this disclosure is a method for preventing, slowing down, reducing, or delaying the formation of degradation products (such as compounds that can be formed from erdatinib in the presence of formaldehyde): .

[0109] In one respect, degradation products (such as the substances described above) may be present in solid tablet compositions such as microtablet formulations, particularly microtablets as disclosed herein.

[0110] When present in the erdatinib solid pharmaceutical composition, the formaldehyde scavenger may be present in the solid pharmaceutical composition at a concentration of 0.01% to 5% by weight, 0.05% to 3% by weight, 0.1% to 2% by weight, 0.5% to 1.5% by weight, or about 1% by weight. In some embodiments, when present in the erdatinib solid pharmaceutical composition, the formaldehyde scavenger may be present at a concentration of about 1% by weight. When present in the erdatinib solid pharmaceutical composition, the formaldehyde scavenger may be present in the solid pharmaceutical composition at a concentration of, for example, 5% to 10% by weight, about 5% by weight, about 6% by weight, about 7% by weight, about 8% by weight, about 9% by weight, or about 10% by weight. In some embodiments, the erdatinib solid pharmaceutical composition contains the erdatinib free base and a formaldehyde scavenger is present. In some embodiments, the erdatinib solid pharmaceutical composition contains a free erdatinib base, and a formaldehyde scavenger is present in the solid pharmaceutical composition at a concentration of 0.01% to 5% by weight, 0.05% to 3% by weight, 0.1% to 2% by weight, 0.5% to 1.5% by weight, or about 1% by weight. In some embodiments of the foregoing, the formaldehyde scavenger is meglumine.

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

[0112] Solubilizer In one aspect, the erdatinib formulation may contain a solubilizer. The solubilizer may be an in-particle component, an out-of-particle component, or both. In embodiments, the solubilizer may comprise or may be selected from, for example, (a) cyclic oligosaccharides, (b) cellulose functionalized with methoxy, 2-hydroxypropoxy, acetyl, or succinyl moieties or combinations thereof, or (c) salts thereof. In one embodiment, the solubilizer is present as an in-particle component.

[0113] In embodiments, the solubilizer for erdatinib tablet formulations may comprise or may be derived from oligosaccharides. In embodiments, the solubilizer may comprise or may be derived from cyclic oligosaccharides such as cyclodextrin. Suitable cyclodextrin solubilizers for erdatinib tablet formulations include, but are not limited to, hydroxypropyl-β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, sodium sulfobutyl ether-β-cyclodextrin, or any combination thereof. In other embodiments, the solubilizer may comprise or may be hydroxypropyl methylcellulose acetate succinate, hydroxypropyl methylcellulose E5 (HPMC-E5), or combinations thereof.

[0114] Oligosaccharide solubilizers may be present in erdatinib tablet formulations (e.g., erdatinib free base formulations) at concentrations of 1% to 20% by weight, alternatively 3% to 18% by weight, alternatively 5% to 15% by weight, alternatively 7% to 12% by weight, or alternatively 10% by weight or about 10% by weight. Cyclodextrin solubilizers may be present in erdatinib tablet formulations (e.g., erdatinib free base formulations) at concentrations of 1% by weight, 2% by weight, 3% by weight, 4% by weight, 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, 10% by weight, 11% by weight, 12% by weight, 13% by weight, 14% by weight, 15% by weight, 16% by weight, 17% by weight, 18% by weight, 19% by weight, or 20% by weight, or any range between these weight percentages.

[0115] In one aspect, the solubilizer used in the erdatinib tablet formulation disclosed herein may comprise or may be hydroxypropyl-β-cyclodextrin (HP-β-CD). One embodiment of the erdatinib free base formulation includes a hydroxypropyl-β-cyclodextrin solubilizer, particularly an erdatinib free base formulation comprising 8% to 12% by weight, or alternatively 10% by weight or about 10% by weight, of hydroxypropyl-β-cyclodextrin. In some embodiments, the formulation comprises about 10% by weight of hydroxypropyl-β-cyclodextrin. In this formulation, the erdatinib free base API may be present at a concentration of 40% to 70% by weight, or 40% to 60% by weight, or 45% to 55% by weight (e.g., 50% by weight). In one embodiment, hydroxypropyl-β-cyclodextrin is present in the intragranular solid composition. In one embodiment, the pharmaceutical tablet may contain 50% by weight of erdatinib in its free base form, 1% by weight of meglumine, and 8% to 12% by weight, or alternatively 10% by weight or about 10% by weight of hydroxypropyl-β-cyclodextrin. In another embodiment, based on the total weight of the tablet, the pharmaceutical tablet may contain 50% by weight of erdatinib in its free base form, 10% by weight of hydroxypropyl-β-cyclodextrin (HP-β-CD), and 1% by weight of meglumine. In yet another embodiment, based on the total weight of the tablet, the pharmaceutical tablet may contain at least about 45% by weight of erdatinib in its free base form, 10% by weight of hydroxypropyl-β-cyclodextrin (HP-β-CD), and 0% by weight of meglumine. In yet another embodiment, based on the total weight of the tablet, the pharmaceutical tablet may contain 50% by weight of erdatinib in its free base form, 10% by weight of hydroxypropyl-β-cyclodextrin (HP-β-CD), and 0% by weight of meglumine.

[0116] adhesives Pharmaceutical excipients used in erdatinib solid pharmaceutical compositions may include one or more binders. One or more binders may be present in the solid pharmaceutical composition as a component of the in-particle solid composition, the out-of-particle solid composition, or both the in-particle and out-of-particle solid compositions. Suitable binders may be water-soluble, water-insoluble, or slightly water-soluble, or combinations thereof. In one aspect, the binder may include polymeric binders, such as water-soluble polymeric binders, slightly water-soluble polymeric binders, water-insoluble polymeric binders, or any combination thereof. Polymeric binders may include nonionic polymers.

[0117] Those skilled in the art will understand that adhesives can also function as diluents (also known as fillers) in pharmaceutical compositions. Therefore, depending on the circumstances and unless otherwise stated, the adhesives provided in this disclosure may also be used for their diluting function.

[0118] In one aspect, suitable adhesives may include or be selected from polyvinylpyrrolidone (PVP, also known as polyvidone, povidone, or poly(1-vinyl-2-pyrrolidone)), poly(vinyl acetate) (PVA), vinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide (PEO, also known as poly(ethylene glycol) or PEG), polypropylene oxide (PPO, also known as poly(propylene glycol) or PPG), ethylene glycol-propylene glycol copolymer, poloxamer, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, silicified microcrystalline cellulose, or combinations thereof. In one aspect, suitable adhesives may include or be selected from polyvinylpyrrolidone (PVP, also known as povidone or poly(1-vinyl-2-pyrrolidone)), poly(vinyl acetate) (PVA), vinylpyrrolidone-vinyl acetate copolymer, polyethylene oxide (PEO, also known as poly(ethylene glycol) or PEG), polypropylene oxide (PPO, also known as poly(propylene glycol) or PPG), ethylene glycol-propylene glycol copolymer, poloxamer, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), or combinations thereof. In one aspect, suitable adhesives may include or be selected from hydroxypropyl methylcellulose (HPMC), microcrystalline cellulose, vinylpyrrolidone-vinyl acetate copolymer, or combinations thereof. In one aspect, suitable adhesives may include or be selected from hydroxypropyl methylcellulose (HPMC), vinylpyrrolidone-vinyl acetate copolymer (copovidone), or combinations thereof. In some embodiments, the adhesive may be hydroxypropyl methylcellulose (HPMC). In some embodiments, the binder may be hydroxypropyl methylcellulose (HPMC) at a concentration of about 1.5% by weight of the solid composition. In some embodiments, the binder may be 1.5% by weight of hydroxypropyl methylcellulose (HPMC) of the solid composition and is present in the solid composition within the particles.

[0119] In another aspect, suitable adhesives may include, or may be selected from, polymers or copolymers of vinylpyrrolidone (VP, also known as 1-vinyl-2-pyrrolidone) and vinyl acetate (VA). Such copolymers of VP and VA may also be referred to as "copolyvinylpyrrolidone". Suitable adhesives may also include, or may be selected from, polymers or copolymers of ethylene oxide (EO) and propylene oxide (PO). Furthermore, these adhesives may be used in combination with other adhesives, such as with microcrystalline cellulose, hydroxypropyl cellulose (HPC), or hydroxypropyl methylcellulose (HPMC).

[0120] In one aspect, the total concentration of the at least one binder in the solid pharmaceutical composition may be 1% to 30% by weight, 2% to 30% by weight, 5% to 30% by weight, 5% to 25% by weight, 10% to 25% by weight, 10% to 22% by weight, 12% to 22% by weight, 14% to 19% by weight, or 12% to 19% by weight.

[0121] According to another aspect, suitable polymeric adhesives may include, or may be selected from, copolymers of vinylpyrrolidone and vinyl acetate, which may be referred to as poly(vinylpyrrolidone-co-vinyl acetate) or poly(VP-co-VA). Examples of suitable poly(vinylpyrrolidone-co-vinyl acetate) adhesives include Kollidon. ® VA64 and Kollidon ® VA64 Fine (BASF, Ludwigshafen am Rhein, Germany), based on measurements of light scattering in the solution, have molecular weights (Mw) ranging from 45,000 g / mol to 70,000 g / mol. Another suitable binder is Kollidon. ® K30.

[0122] In embodiments, a polymer binder such as a vinylpyrrolidone-vinyl acetate copolymer may be present in the disclosed erdatinib tablet formulation at a concentration of 2% to 15% by weight, alternatively 4% to 12% by weight, alternatively 6% to 10% by weight, or alternatively 8% by weight or about 8% by weight. For example, the vinylpyrrolidone-vinyl acetate copolymer binder may be present in the erdatinib tablet formulation (e.g., an erdatinib free base formulation) at a concentration of 2% by weight, 3% by weight, 4% by weight, 5% by weight, 6% by weight, 7% by weight, 8% by weight, 9% by weight, 10% by weight, 11% by weight, 12% by weight, 13% by weight, 14% by weight, 15% by weight, or any range between these weight percentages (e.g., 7.5% by weight). In one aspect, the vinylpyrrolidone-vinyl acetate copolymer is present at a concentration of 8% by weight of the solid composition. In one aspect, the vinylpyrrolidone-vinyl acetate copolymer is present in the in-particle solid composition. In one aspect, the vinylpyrrolidone-vinyl acetate copolymer is present in the intragranular solid composition, and the intragranular solid composition is prepared by rolling. In another aspect, the vinylpyrrolidone-vinyl acetate copolymer is present in the intragranular solid composition, and the intragranular solid composition is prepared by fluidized bed granulation. In one aspect, the vinylpyrrolidone-vinyl acetate copolymer is present in the extragranular solid composition. In one aspect, the vinylpyrrolidone-vinyl acetate copolymer is present at a concentration of about 7.5% by weight of the solid composition. In one aspect, the vinylpyrrolidone-vinyl acetate copolymer is present at a concentration of about 7.5% by weight of the solid composition and is also present in the extragranular solid composition.

[0123] In one aspect, the binder may comprise or may be microcrystalline cellulose. For example, microcrystalline cellulose may be present in the solid pharmaceutical composition at concentrations of 5% to 30% by weight, 10% to 20% by weight, 5% to 20% by weight, 6% to 15% by weight, or 7% to 12% by weight. For example, microcrystalline cellulose may be present in the solid pharmaceutical composition as a filler and / or as a binder at a concentration of about 17.5% by weight. For example, microcrystalline cellulose may be present in the solid pharmaceutical composition at a concentration of about 17.5% by weight of the solid composition, and may be present in both the in-particle solid composition and the out-of-particle solid composition. For example, microcrystalline cellulose may be present in the solid pharmaceutical composition as a filler in the in-particle composition at a concentration of about 10% by weight of the solid composition, and may be present in the solid pharmaceutical composition as a binder in the out-of-particle composition at a concentration of about 7.5% by weight of the solid composition.

[0124] According to another aspect, the binder may contain or may be siliconized microcrystalline cellulose. For example, siliconized microcrystalline cellulose may be present in the solid pharmaceutical composition at concentrations of 3% to 18% by weight, 4% to 15% by weight, or 5% to 12% by weight.

[0125] In another aspect, the binder may comprise or may be hydroxypropyl methylcellulose (HPMC). For example, hydroxypropyl methylcellulose (HPMC) may be present in the solid pharmaceutical composition at concentrations of 0.25% to 5% by weight, 0.5% to 4% by weight, or 0.75% to 3% by weight. In one aspect, the HPMC binder may be present in the solid pharmaceutical composition within the granular solid composition.

[0126] wetting agent The pharmaceutical excipients used in erdatinib solid pharmaceutical compositions may include one or more wetting agents. One or more wetting agents may be present in the solid pharmaceutical composition as an in-particle solid composition, an out-of-particle solid composition, or both. In exemplary embodiments, the wetting agent may include or may be independently selected from anionic surfactants or nonionic surfactants, particularly anionic surfactants. For example, the wetting agent may comprise or may be independently selected from sodium lauryl sulfate, sodium stearoyl fumarate, polysorbate (e.g., polysorbate 80), sodium docusate, or any combination thereof. In embodiments, the total concentration of the wetting agent in the solid pharmaceutical composition may be from 0.01% to 2.5% by weight, 0.05% to 1.0% by weight, or 0.1% to 0.5% by weight. In one embodiment, the wetting agent is present in the in-particle solid composition. In one embodiment, the wetting agent is sodium lauryl sulfate.

[0127] In one embodiment, the erdatinib solid pharmaceutical composition does not include one or more wetting agents.

[0128] Disintegrant The pharmaceutical excipients used in erdatinib solid pharmaceutical compositions may include one or more disintegrants. One or more disintegrants may be present in the solid pharmaceutical composition in an in-particle solid composition, an out-of-particle solid composition, or both an in-particle solid composition and an out-of-particle solid composition. In one embodiment, the disintegrant is present in the in-particle solid composition. In another embodiment, the disintegrant is present in the in-particle solid composition, and the in-particle solid composition is prepared by crushing.

[0129] In exemplary embodiments, the disintegrant may comprise or may be independently selected from functionalized polysaccharides or cross-linked polymers. For example, in one aspect, the disintegrant may comprise or may be selected from, for example (a) cellulose partially functionalized with methoxy, 2-hydroxypropoxy, or carboxymethoxy, salts thereof, or combinations thereof, (b) carboxymethylated starch, or (c) cross-linked polymers.

[0130] In the implementation scheme, the disintegrant may comprise or be independently selected from hydroxypropyl methylcellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium starch glycolate, or any combination thereof.

[0131] When present, the disintegrant can be present at a concentration within a certain range. In embodiments, the total concentration of the disintegrant in the solid pharmaceutical composition can be from 0.1% to 3% by weight, from 0.5% to 2.5% by weight, from 1% to 2% by weight, or about 1.5% by weight.

[0132] In one embodiment, the erdatinib solid pharmaceutical composition does not contain one or more disintegrants.

[0133] diluent or filler The pharmaceutical excipients used in erdatinib solid pharmaceutical compositions may include one or more diluents. One or more diluents may be present in the solid pharmaceutical composition as a component of the in-particle solid composition, the out-of-particle solid composition, or both the in-particle and out-of-particle solid compositions.

[0134] In an exemplary embodiment, the diluent may comprise or be selected from sugar, starch, microcrystalline cellulose, sugar alcohol, hydrogen phosphate, dihydrogen phosphate, carbonate, or combinations thereof. In one aspect, the diluent may comprise or be selected from lactose, dextrin, mannitol, sorbitol, starch, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, anhydrous dicalcium phosphate, calcium carbonate, sucrose, or any combination thereof.

[0135] In embodiments, the total concentration of the diluent in the solid pharmaceutical composition may be 10% to 60% by weight, 10% to 50% by weight, 10% to 40% by weight, 12% to 30% by weight, 15% to 25% by weight, or 18% to 22% by weight, or 20% to 40% by weight, or 20% to 30% by weight, or 25% to 30% by weight. For example, in some aspects, the diluent may comprise or may be microcrystalline cellulose at a concentration of 15% to 25% by weight, or 20% to 22% by weight, or 15% to 20% by weight. In another aspect, the diluent may comprise or may be anhydrous dicalcium phosphate at a concentration of 18% to 20% by weight. In another aspect, the diluent may comprise or may be anhydrous dicalcium phosphate at a concentration of about 19% by weight. In yet another aspect, the diluent may comprise or may be anhydrous dicalcium phosphate at a concentration of about 19% by weight, which is present in the extraparticulate solid composition. In another aspect, the diluent may comprise or may be selected from silanized microcrystalline cellulose at a concentration of 10% to 20% by weight, or 10% to 15% by weight, or 10% to 12% by weight. For example, the diluent may comprise about 10.75% by weight or 11.75% by weight of silanized microcrystalline cellulose in the solid composition. For example, the diluent may comprise about 10.75% by weight or 11.75% by weight of silanized microcrystalline cellulose in the solid composition and is present in the non-particle composition. For example, the diluent may comprise about 10.75% by weight of silanized microcrystalline cellulose in the solid composition and is present in the non-particle composition. For example, the diluent may comprise about 11.75% by weight of silanized microcrystalline cellulose in the solid composition and is present in the non-particle composition. In another aspect, the diluent does not comprise silanized microcrystalline cellulose. In another aspect, the diluent may comprise both microcrystalline cellulose and silanized microcrystalline cellulose. In another aspect, the diluent may comprise either microcrystalline cellulose or silanized microcrystalline cellulose. In another aspect, the diluent may contain microcrystalline cellulose at a concentration of about 10% by weight. In yet another aspect, the diluent may contain microcrystalline cellulose at a concentration of about 10% by weight, which is present in the in-particle composition. For example, microcrystalline cellulose may be present in the solid pharmaceutical composition at a concentration of about 17.5% by weight as a filler and / or as a binder. 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 both the in-particle and out-of-particle solid compositions. For example, microcrystalline cellulose may be present in the solid pharmaceutical composition as a filler in the in-particle composition at a concentration of about 10% by weight, and may be present in the solid pharmaceutical composition as a binder in the out-of-particle composition at a concentration of about 7.5% by weight.

[0136] Those skilled in the art will understand that some of the diluents / fillers disclosed herein can also act as binders in pharmaceutical compositions. Therefore, some compounds or materials may be described herein as providing both binder and diluent / filler functions.

[0137] Flow aid Pharmaceutical excipients used in erdatinib solid pharmaceutical compositions may include one or more flow aids. One or more flow aids may be present in the solid pharmaceutical composition as a component of the in-particle solid composition, the out-of-particle solid composition, or both. In one aspect, the flow aid is present in the out-of-particle solid composition. As used in this disclosure, a flow aid refers to a pharmaceutical excipient that improves or optimizes the particle flow properties of a granular or powdered tablet component in granular form by reducing interparticle interactions, attraction, cohesion, or friction. Pharmaceutically acceptable flow aids are non-toxic and pharmacologically inactive substances. Furthermore, flow aids may be water-soluble or water-insoluble.

[0138] In one aspect, the flow aid may include or be selected from colloidal silica, colloidal anhydrous silica, talc, or any combination thereof. In embodiments, the total concentration of the flow aid in the solid pharmaceutical composition may be from 0.01 wt% to 5 wt%, from 0.05 wt% to 3 wt%, from 0.1 wt% to 1 wt%, or about 0.2 wt%, or about 0.25 wt%, or about 0.3 wt%, or about 0.35 wt%, or about 0.4 wt%, or about 0.45 wt%, or about 0.5 wt%. In one embodiment, the flow aid is colloidal silica. In some embodiments, the flow aid is about 0.5 wt% colloidal silica of the solid composition. In some embodiments, the flow aid is about 0.5 wt% colloidal silica of the solid composition and is present in the extraparticle composition. In some embodiments, the flow aid is about 0.25 wt% colloidal silica of the solid composition. In some embodiments, the flow aid is about 0.25% by weight of colloidal silica in the solid composition and is present in the non-particulate composition.

[0139] lubricant Pharmaceutical excipients used in erdatinib solid pharmaceutical compositions may include one or more lubricants. One or more lubricants may be present in the solid pharmaceutical composition as a component of an in-particle solid composition, an out-of-particle solid composition, or both an in-particle solid composition and an out-of-particle solid composition. In one aspect, the lubricant is present in the out-of-particle solid composition. In another aspect, the lubricant is present in the in-particle solid composition, and said in-particle solid composition is prepared by rolling. As used in this disclosure, a lubricant refers to a pharmaceutical excipient added to a tablet formulation that reduces friction on the tablet surface. In embodiments, the lubricant reduces friction between the tablet surface and processing equipment, such as friction between the tablet surface and the wall of a mold cavity in which the tablet is formed. Thus, when the tablet is formed and ejected, the lubricant reduces friction between the mold wall and the formulation particles. Pharmaceutically acceptable lubricants are non-toxic and pharmacologically inactive substances. Furthermore, the lubricant may be water-soluble or water-insoluble.

[0140] In one aspect, the lubricant may comprise or be selected from, for example, fatty acids, fatty acid salts, fatty acid esters, talc, glycerides, metal silicates, or any combination thereof. In embodiments, the lubricant may comprise or be selected from magnesium stearate, stearic acid, magnesium silicate, aluminum silicate, isopropyl myristate, sodium oleate, sodium stearoyl lactylate, sodium stearoyl fumarate, titanium dioxide, or combinations thereof. Examples of lubricants include, but are not limited to, leucine, sodium lauryl sulfate, sucrose stearate, boric acid, sodium acetate, sodium oleate, sodium stearoyl fumarate, and PEG. In another aspect, the total concentration of the lubricant in the solid pharmaceutical composition may be from 0.05% to 5% by weight, 0.1% to 3% by weight, 1% to 2% by weight, or about 1.5% by weight. In one embodiment, the lubricant is magnesium stearate. In some embodiments, the lubricant is magnesium stearate and is present in the in-particle composition or the out-of-particle composition. In some embodiments, the lubricant is magnesium stearate and is present in both the in-particle composition and the out-of-particle composition. In some embodiments, the lubricant is about 1.5% by weight magnesium stearate of the solid composition. In some embodiments, the lubricant is about 1.5% by weight magnesium stearate of the solid composition and is present in the in-particle composition. In some embodiments, the lubricant is about 1.5% by weight magnesium stearate of the solid composition and is present in the out-of-particle composition. In some embodiments, the lubricant is about 1.5% by weight magnesium stearate of the solid composition and is present in both the in-particle and out-of-particle compositions.

[0141] Formulation development This article provides erdatinib formulations (particularly erdatinib tablets) that (a) contain a high erdatinib drug loading, such as ranging from 40% to 70% by weight, or 40% to 60% by weight, or 45% to 55% by weight, or about 50% by weight, or ranging from 45% to 55% by weight, or about 50% by weight, (b) provide acceptable chemical stability of erdatinib, and (c) support high production rates, for example, for tablet production on an industrial scale, particularly where the length (L) exceeds its diameter (D), making the tablets... Tablets having an aspect ratio (L:D) greater than 1:1, particularly those having a cylindrical diameter of 1.0 mm to 3.2 mm, or 1.5 mm to 3.1 mm, or 2.0 mm to 2.7 mm, or 2.5 mm to 2.7 mm, especially on an industrial scale, particularly for microtablets, (d) provide tablets that are physically robust enough (particularly suitable for inclusion in drug delivery systems (particularly permeation systems) as described herein), and / or (e) exhibit desired disintegration and / or dissolution properties.

[0142] Table 1, listing formulations 4A, 4B, 4C, and 4D, provides erdatinib formulations with a range of excipient combinations (both in-particle and out-of-particle). Table 2, listing formulations 3.2, 3.3, 3.4, and 4.1, provides additional erdatinib formulations with a range of excipient combinations.

[0143] Table 1. Exemplary Erdatinib Microtablet Formulations In one embodiment, the above-mentioned erdatinib microtablet formulation contains about 11.5 mg, particularly 11.5 mg of erdatinib. In another embodiment, the above-mentioned erdatinib microtablet formulation is a 23 mg tablet, particularly a 23 mg tablet.

[0144] In one embodiment, the above-mentioned erdatinib microtablet formulation contains about 11.5 mg, particularly 11.5 mg of erdatinib, and is a 23 mg tablet, particularly a 23 mg tablet.

[0145] Table 2. Examples of Erdatinib formulations In one embodiment, the above-mentioned erdatinib microtablet formulation contains about 11.5 mg, particularly 11.5 mg of erdatinib. In another embodiment, the above-mentioned erdatinib microtablet formulation is a 23 mg tablet, particularly a 23 mg tablet.

[0146] In one embodiment, the above-mentioned erdatinib microtablet formulation contains about 11.5 mg, particularly 11.5 mg of erdatinib, and is a 23 mg tablet, particularly a 23 mg tablet.

[0147] This document provides erdatinib solid dosage forms, particularly erdatinib microtablets, especially those having a high erdatinib drug loading, such as ranging from 40% to 70% by weight, or 40% to 60% by weight, or 45% to 55% by weight, or about 50% by weight, or ranging from 45% to 55% by weight, or about 50% by weight. In one embodiment, the tablets can be obtained by a method including fluidized bed granulation. In one embodiment, the tablets can be obtained by a method including milling. In one embodiment, the in-granule solid composition comprises cyclodextrin, particularly hydroxypropyl-β-cyclodextrin. In one embodiment, the formulation does not contain mannitol in the in-granule solid composition. In one embodiment, the in-granule solid composition does not contain water-soluble fillers. In one embodiment, the formulation contains water-insoluble fillers, such as microcrystalline cellulose.

[0148] In one embodiment, a fluidized bed granulation method is provided for preparing particles comprising erdatinib and hydroxypropyl-β-cyclodextrin. In one aspect, the method does not include the use of water-soluble fillers (such as mannitol).

[0149] This article provides erdatinib solid dosage forms, particularly erdatinib microtablets, especially those with high erdatinib drug loadings (e.g., ranging from 45% to 55% by weight, or about 50% by weight), which contain, in particular, vinylpyrrolidone-vinyl acetate copolymer and microcrystalline cellulose in weight ratios ranging from 1:99 to 99:1, or 5:95 to 95:5, or 10:90 to 90:10, or 20:80 to 80:20, or 30:70 to 70:30, or 40:60 to 60:40, or 50:50. Unexpectedly, it was found that the expulsion force during tableting (particularly during tableting of microtablets such as those described herein) was reduced in the presence of this mixture. Powder formulations containing this mixture were found to have good flow properties. In one aspect, the formulation also contains hydroxypropyl-β-cyclodextrin. In another aspect, the formulation does not contain mannitol.

[0150] In one embodiment, a method for preparing tablets (particularly microtablets as described herein) is provided, wherein the powder blend to be tableted comprises, in particular, a vinylpyrrolidone-vinyl acetate copolymer and microcrystalline cellulose in a weight ratio particularly in the range of 1:99 to 99:1, or 5:95 to 95:5, or 10:90 to 90:10, or 20:80 to 80:20, or 30:70 to 70:30, or 40:60 to 60:40 or 50:50. In one aspect, a method for preparing tablets (particularly microtablets as described herein) is provided, wherein the powder blend to be compressed comprises erdatinib, a vinylpyrrolidone-vinyl acetate copolymer, and microcrystalline cellulose, particularly wherein the weight ratio of the vinylpyrrolidone-vinyl acetate copolymer and microcrystalline cellulose ranges from 1:99 to 99:1, or 5:95 to 95:5, or 10:90 to 90:10, or 20:80 to 80:20, or 30:70 to 70:30, or 40:60 to 60:40, or 50:50. In one aspect, the powder blend to be compressed further comprises hydroxypropyl-β-cyclodextrin. In one aspect, the powder blend to be compressed does not contain mannitol.

[0151] This article provides erdatinib solid dosage forms, particularly erdatinib powder or erdatinib microtablets, especially those with high erdatinib drug loadings, such as ranging from 40% to 70% by weight, or 40% to 60% by weight, or 45% to 55% by weight, or about 50% by weight, or ranging from 45% to 55% by weight, or about 50% by weight, and with low fine particle content, such as less than 20%, or less than 10%, or less than 5%, or about or less than 3%, or about or less than 2%. Fine particles can increase expulsion force during tableting, especially during tableting of microtablets as described herein, particularly when tableted at high rates (e.g., 2500 tablets / min).

[0152] In one embodiment, this document provides a formulation (particularly a tablet or microtablet) comprising erdatinib (particularly having a high erdatinib drug loading, such as ranging from 40% to 70% by weight, or 40% to 60% by weight, or 45% to 55% by weight, or about 50% by weight, or ranging from 45% to 55% by weight, or about 50% by weight), hydroxypropyl-β-cyclodextrin, vinylpyrrolidone-vinyl acetate copolymer, and microcrystalline cellulose. In one aspect, the formulation further comprises meglumine. In one aspect, the formulation does not comprise mannitol. In one aspect, the formulation further comprises at least one or all of a flow aid (e.g., colloidal silica), a lubricant (e.g., magnesium stearate), a binder (e.g., a cellulose derivative, such as hydroxypropyl methylcellulose), and a filler (e.g., silanized microcrystalline cellulose).

[0153] In one embodiment, this document provides a formulation (particularly a tablet or microtablet) comprising erdatinib (particularly having a high erdatinib drug loading, such as ranging from 40% to 70% by weight, or 40% to 60% by weight, or 45% to 55% by weight, or about 50% by weight, or ranging from 45% to 55% by weight, or about 50% by weight), hydroxypropyl-β-cyclodextrin, vinylpyrrolidone-vinyl acetate copolymer, and microcrystalline cellulose. In one aspect, the formulation further comprises at least one or all of a flow aid (e.g., colloidal silica), a lubricant (e.g., magnesium stearate), a binder (e.g., a cellulose derivative, such as hydroxypropyl methylcellulose), and a filler (e.g., silicified microcrystalline cellulose). In one aspect, the formulation does not contain a stabilizer, such as meglumine. In one aspect, the formulation does not contain mannitol.

[0154] 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.

[0155] Therefore, this disclosure covers formulations of form 4D, wherein the solid pharmaceutical composition comprises: (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 1% by weight of meglumine; (d) 17.5% by weight of microcrystalline cellulose; (e) 10.75% by weight of silanized microcrystalline cellulose; (f) 7.5% by weight of vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25% by weight of colloidal silica; (h) 1.5% by weight of hydroxypropyl methylcellulose; and (i) 1.5% by weight of magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In one aspect, the formulation can be prepared by a method comprising the following steps: (a) preparing an in-particle solid composition by a fluidized bed granulation method, the in-particle solid composition comprising essentially the following: (i) 50% by weight of erdatinib free base of the solid pharmaceutical composition; (ii) 10% by weight of hydroxypropyl-β-cyclodextrin of the solid pharmaceutical composition; (iii) 1% by weight of meglumine of the solid pharmaceutical composition; (iv) 10% by weight of microcrystalline cellulose of the solid pharmaceutical composition; and (v) 1.5% by weight of hydroxypropyl methylcellulose of the solid pharmaceutical composition; (b) granulating the in-particle solid composition... The mixture is combined with an extraparticulate component to form a blend, wherein the extraparticulate component comprises essentially the following: (i) 7.5% by weight of microcrystalline cellulose in the solid pharmaceutical composition; (ii) 7.5% by weight of vinylpyrrolidone-vinyl acetate copolymer in the solid pharmaceutical composition; (iii) 10.75% by weight of silanized microcrystalline cellulose in the solid pharmaceutical composition; (iv) 0.25% by weight of colloidal silica in the solid pharmaceutical composition; and (iv) 1.5% by weight of magnesium stearate in the solid pharmaceutical composition; and (c) the blend is compressed to form a solid pharmaceutical composition in the form of microtablets. In one embodiment, the tablet contains 11.5 mg of erdatinib. In one embodiment, the tablet is a 23 mg tablet.

[0156] Therefore, this disclosure covers formulation 4C, wherein the solid pharmaceutical composition comprises: (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 1% by weight of meglumine; (d) 1.5% by weight of hydroxypropyl methylcellulose; (e) 21.0% by weight of mannitol; (f) 0.25% by weight of sodium lauryl sulfate; (g) 7.25% by weight of microcrystalline cellulose; (h) 7.25% by weight of vinylpyrrolidone-vinyl acetate copolymer; (i) 0.25% by weight of colloidal silica; and (j) 1.50% by weight of magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In one aspect, the formulation can be prepared by a method comprising the steps of: (a) preparing an in-particle solid composition by fluidized bed granulation; (b) combining the in-particle solid composition with an out-of-particle component to form a blend; and (c) compressing the blend to form a solid pharmaceutical composition in the form of microtablets, wherein the in-particle component and the out-of-particle component are listed in Table 1 in the examples. In one embodiment, the tablet contains 11.5 mg of erdatinib. In one embodiment, the tablet is a 23 mg tablet.

[0157] Therefore, this disclosure covers the formulation of Formulation 4B, wherein the solid pharmaceutical composition comprises: (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 1% by weight of meglumine; (d) 24.5% by weight of microcrystalline cellulose; (e) 6.0% by weight of silanized microcrystalline cellulose; (f) 6.0% by weight of vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5% by weight of colloidal silica; and (h) 2.0% by weight of magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In one aspect, the formulation may be prepared by a method comprising the steps of: (a) preparing an in-particle solid composition by fluidized bed granulation; (b) combining the in-particle solid composition with an out-of-particle component to form a blend; and (c) compressing the blend to form a solid pharmaceutical composition in the form of microtablets, wherein the in-particle component and the out-of-particle component are listed in Table 1 in the examples. In one aspect, the formulation can be prepared by a method comprising the steps of: (a) preparing an in-particle solid composition by a rolling method; (b) combining the in-particle solid composition with an out-of-particle component to form a blend; and (c) compressing the blend to form a solid pharmaceutical composition in the form of microtablets, wherein the in-particle component and the out-of-particle component are listed in Table 1 in the examples. In one embodiment, the tablet contains 11.5 mg of erdatinib. In one embodiment, the tablet is a 23 mg tablet.

[0158] Therefore, this disclosure covers the formulation of Formulation 4A, wherein the solid pharmaceutical composition comprises: (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 1% by weight of meglumine; (d) 10% by weight of microcrystalline cellulose; (e) 19% by weight of anhydrous dicalcium phosphate; (f) 8% by weight of vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5% by weight of colloidal silica; and (h) 1.50% by weight of magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In one aspect, the formulation may be prepared by a method comprising the steps of: (a) preparing an in-particle solid composition by fluidized bed granulation; (b) combining the in-particle solid composition with an out-of-particle component to form a blend; and (c) compressing the blend to form a solid pharmaceutical composition in the form of microtablets, wherein the in-particle and out-of-particle components are listed in Table 1 in the examples. In one aspect, the formulation can be prepared by a method comprising the steps of: (a) preparing an in-particle solid composition by a rolling method; (b) combining the in-particle solid composition with an out-of-particle component to form a blend; and (c) compressing the blend to form a solid pharmaceutical composition in the form of microtablets, wherein the in-particle component and the out-of-particle component are listed in Table 1 in the examples. In one embodiment, the tablet contains 11.5 mg of erdatinib. In one embodiment, the tablet is a 23 mg tablet.

[0159] Therefore, this disclosure covers formulation 4.1, wherein the solid pharmaceutical composition comprises: (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 17.5% by weight of microcrystalline cellulose; (d) 11.75% by weight of silanized microcrystalline cellulose; (e) 7.5% by weight of vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25% by weight of colloidal silica; (g) 1.5% by weight of hydroxypropyl methylcellulose; and (h) 1.5% by weight of magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In one aspect, the formulation can be prepared by a method comprising the following steps: (a) preparing an in-particle solid composition by fluidized bed granulation, the in-particle solid composition comprising essentially the following: (i) 50% by weight of erdatinib free base of the solid pharmaceutical composition; (ii) 10% by weight of hydroxypropyl-β-cyclodextrin of the solid pharmaceutical composition; (iii) 10% by weight of microcrystalline cellulose of the solid pharmaceutical composition; and (iv) 1.5% by weight of hydroxypropyl methylcellulose of the solid pharmaceutical composition; (b) combining the in-particle solid composition with an extra-particle component to form The blend, wherein the extraparticle components consist substantially of: (i) 7.5% by weight of microcrystalline cellulose in the solid pharmaceutical composition; (ii) 7.5% by weight of vinylpyrrolidone-vinyl acetate copolymer in the solid pharmaceutical composition; (iii) 11.75% by weight of silanized microcrystalline cellulose in the solid pharmaceutical composition; (iv) 0.25% by weight of colloidal silica in the solid pharmaceutical composition; and (iv) 1.5% by weight of magnesium stearate in the solid pharmaceutical composition; and (c) compressing the blend to form a solid pharmaceutical composition in the form of microtablets. In one embodiment, the tablet contains 11.5 mg of erdatinib. In one embodiment, the tablet is a 23 mg tablet.

[0160] Therefore, this disclosure covers formulation 3.4, wherein the solid pharmaceutical composition comprises: (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 1% by weight of meglumine; (d) 17.5% by weight of microcrystalline cellulose; (e) 10.75% by weight of silanized microcrystalline cellulose; (f) 7.5% by weight of vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25% by weight of colloidal silica; (h) 1.5% by weight of hydroxypropyl methylcellulose; and (i) 1.5% by weight of magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition.

[0161] In one aspect, the formulation can be prepared by a method comprising the following steps: (a) preparing an in-particle solid composition by a fluidized bed granulation method, the in-particle solid composition comprising essentially the following: (i) 50% by weight of erdatinib free base of the solid pharmaceutical composition; (ii) 10% by weight of hydroxypropyl-β-cyclodextrin of the solid pharmaceutical composition; (iii) 1% by weight of meglumine of the solid pharmaceutical composition; (iv) 10% by weight of microcrystalline cellulose of the solid pharmaceutical composition; and (v) 1.5% by weight of hydroxypropyl methylcellulose of the solid pharmaceutical composition; (b) granulating the in-particle solid composition... The mixture is combined with an extraparticulate component to form a blend, wherein the extraparticulate component comprises essentially the following: (i) 7.5% by weight of microcrystalline cellulose in the solid pharmaceutical composition; (ii) 7.5% by weight of vinylpyrrolidone-vinyl acetate copolymer in the solid pharmaceutical composition; (iii) 10.75% by weight of silanized microcrystalline cellulose in the solid pharmaceutical composition; (iv) 0.25% by weight of colloidal silica in the solid pharmaceutical composition; and (iv) 1.5% by weight of magnesium stearate in the solid pharmaceutical composition; and (c) the blend is compressed to form a solid pharmaceutical composition in the form of microtablets. In one embodiment, the tablet contains 11.5 mg of erdatinib. In one embodiment, the tablet is a 23 mg tablet.

[0162] diffusion-based drug delivery systems This article describes drug delivery systems, such as those detailed above or below, that are particularly suitable for the efficient release of drug formulations containing erdatinib. These specific systems have been developed in which drug release is not via a permeable drug release mechanism, but rather controlled by drug diffusion through a drug-permeable polymer component that defines a portion of the system shell.

[0163] In some embodiments, the system includes a drug-permeable polymer component or portion forming part of the outer shell. For example, the drug-permeable component or portion of the system may be part of the outer shell formed of a material different from the rest of the outer shell (e.g., one or more strips of material extending along at least a portion of the length of the outer shell), such that the size, shape (e.g., arc angle), thickness, and material properties of the drug-permeable wall structure can be selected to achieve a desired drug release rate. In some embodiments, the drug-permeable portion, the drug-impermeable portion, or both the drug-permeable and impermeable portions are formed of a thermoplastic polyurethane composition to provide (i) controlled diffusion of the drug from the system, (ii) desired mechanical properties (e.g., the ability to straighten for insertion / removal, sufficient softness to be well tolerated during indwelling, the tubing remaining intact with small compression / extension, elastic deformability (compliance) in response to detrusor muscle contraction), (iii) a system that can be thermoformed to have a desired shape retention, and / or (iv) a system that can be manufactured in a co-extrusion process.

[0164] In some embodiments, the drug-permeable portion is permeable to erdatinib free base. In some embodiments, the drug-permeable portion is permeable to erdatinib free base and erdatinib free base formulated with HP-β-CD. In some embodiments, the drug-permeable portion is permeable to erdatinib free base, erdatinib HCl salt, and erdatinib free base formulated with HP-β-CD. In any of the foregoing embodiments, the material of the drug-permeable portion is a TPU based on aliphatic polyethers. In some of the foregoing embodiments, the material of the drug-permeable portion is a TPU based on aliphatic polyethers, such as Lubrizol Tecophilic HP-60D-35 or HP-93A-100.

[0165] In some embodiments, the drug-permeable portion is permeable to erdatinib free base formulated with HP-β-CD. In some embodiments, the drug-permeable portion is permeable to erdatinib free base formulated with HP-β-CD and is impermeable or nearly impermeable to erdatinib free base not formulated with HP-β-CD. In any of the foregoing embodiments, the material of the drug-permeable portion is aliphatic polyether-based TPU. In some of the foregoing embodiments, the material of the drug-permeable portion is Lubrizol Tecoflex. EG-80A.

[0166] Exemplary materials used for drug-permeable portions (e.g., the "strip" material of a permeation system) include, but are not limited to, aliphatic polyether-based thermoplastic polyurethanes (TPUs), such as Lubrizol Tecophilic HP-60D-35, Tecophilic HP-93A-100, and Tecoflex EG-80A. In some embodiments, the material for the drug-permeable portion is Lubrizol Tecophilic HP-60D-35, Tecophilic HP-93A-100, or Tecoflex EG-80A. In some embodiments, the material for the drug-permeable portion is Lubrizol Tecoflex. EG-80A. In some embodiments, the drug is a free erdatinib base, and the drug-permeable portion is made of Lubrizol Tecophilic HP-60D-35 or Tecophilic HP-93A-100. In some embodiments, the drug is a free erdatinib base formulated with HP-β-CD, and the drug-permeable portion is made of Lubrizol Tecophilic HP-60D-35, Tecophilic HP-93A-100, or Tecoflex. EG-80A. In some embodiments, the drug is a free base of erdatinib, formulated with HP-β-CD, and the drug-permeable portion is Lubrizol Tecoflex. EG-80A. In some embodiments, the drug is erdatinib HCl salt, and the material of the drug-permeable portion is Lubrizol Tecophilic HP-60D-35 or Tecophilic HP-93A-100.

[0167] Exemplary materials used for drug-impermeable portions (e.g., the "base" material of a 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, and Tecoflex EG-80A; and vinyl acetate such as 3M CoTran 9712. In some embodiments, the material for the drug-impermeable portion is selected from MED-4750, PC-3575A, PC-3575A, AR-62A, AR-75A-B20, AC-4075A-B20, AC-4075A-B20, AC-4075A, TT-1074A, EG-80A, and CoTran 9712. In some embodiments, the material of the drug-permeable 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-permeable portion is AR-75A-B20. In some embodiments, the material of the drug-permeable portion is AC-4075A-B20.

[0168] 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.

[0169] It should be understood that Lubrizol Tecophilic HP series materials are based on aliphatic polyether TPU, formulated to absorb up to 100% of the dry resin weight in equilibrium water content, designed for extrusion but also for injection molding. HP-60D-35 has a Shore hardness of approximately 42D (ASTM D2240), a specific gravity of approximately 1.12 (ASTM D792), a flexural modulus of 4000 psi (ASTM D790), an ultimate tensile strength of approximately 7800 dry and 4900 wet (ASTM D412), an ultimate elongation of approximately 450 dry and 390 wet (%) (D412), and a water absorption rate of approximately 35% (as measured by the Lubrizol method). HP-93A-100 has a Shore hardness of approximately 83A (ASTM D2240), a specific gravity of approximately 1.13 (ASTM D792), a flexural modulus of 2900 psi (ASTM D790), an ultimate tensile strength of approximately 2200 dry and 1400 wet (ASTM D412), an ultimate elongation of approximately 1040 dry and 620 wet (%) (D412), and a water absorption of approximately 100 (% as determined by the Lubrizol method).

[0170] It should be understood that Lubrizol Tecoflex material is a TPU based on aliphatic polyethers that can be processed by extrusion and injection molding. EG-80A has a Shore hardness of approximately 72A (ASTM D2240), a specific gravity of approximately 1.04 (ASTM D792), a flexural modulus of 1,000 psi (ASTM D790), an ultimate tensile strength of approximately 5,800 psi (ASTM D412), an ultimate elongation of approximately 660 % (D412); a tensile modulus of approximately 300 psi at 100% elongation, approximately 500 psi at 200% elongation, and approximately 800 psi at 300% elongation (ASTM D412); and a molding shrinkage of approximately 0.008–0.012 in / in (ASTM D955).

[0171] It should be understood that Lubrizol Aromatic Carbothane AC series materials are radiopaque (20% BaSO4 filled) polycarbonate-based aromatic TPUs that can be extruded or injection molded. AC-4075A-B20 has a Shore hardness of approximately 78A (ASTM D2240), a specific gravity of approximately 1.38 (ASTM D792), an ultimate tensile strength of approximately 8300 psi (ASTM D412), an ultimate elongation of approximately 400 % (D412); a tensile modulus of approximately 560 at 100% elongation, approximately 1300 at 200% elongation, and approximately 3400 at 300% elongation (ASTM D412); a flexural modulus of approximately 1800 psi, a Vicat temperature of approximately 55 °C, and a molding shrinkage of approximately 0.011 in (in / in) (1” x 0.25” x 6” bar) (ASTM D955).

[0172] It should be understood that Lubrizol Tecothane Soft material is a TPU based on aromatic polyester hydrocarbons that can be processed by extrusion or injection molding. AR-75A has a Shore hardness of approximately 79A (ASTM D785), a specific gravity of approximately 1.03 (ASTM D792), an ultimate tensile strength of approximately 2000 psi (ASTM D412), an ultimate elongation of approximately 530 % (ASTM D412), a tensile modulus of approximately 730 psi at 100% elongation, approximately 1000 psi at 200% elongation, and approximately 1300 psi at 300% elongation (ASTM D412); a flexural modulus of approximately 2500 psi (ASTM 790); a Vicat softening point of approximately 75 °C; and a molding shrinkage of approximately 0.08 in (1” x 0.25” x 6” bar) (ASTM D955). AR-75A-B20 is AR-75A filled with 20% BaSO4 and can be manufactured, for example, by Compounding Solutions.

[0173] It should also be understood that small samples based on TPU approximate the test results of the Lubrizol Tecophilic HP, Tecoflex, Aromatic Carbothane AC, and Tecothane Soft materials; therefore, the properties of these materials may exhibit slight differences from those listed herein.

[0174] In one aspect, such as Figure 1As shown, a drug delivery system 100 is provided, comprising a tubular housing having a drug reservoir lumen 106 defined by a wall structure 104, wherein (i) at least a portion of the wall structure 104 is water-permeable, and (ii) at least a portion of the wall structure is permeable to a drug (contained in a drug unit 108), such that the drug can be released in vivo by diffusion through the drug-permeable portion of the wall structure 104. In some embodiments, as discussed in further detail below, the wall structure includes a first wall structure and a second wall structure that together form the housing. As used herein, the phrase “diffusion through the drug-permeable portion” (e.g., through the “second wall structure”) means that the drug is released by molecular diffusion through the material forming the wall, rather than by diffusion through a pore or open structure extending through the wall.

[0175] In one aspect, such as Figure 2 As shown, a drug delivery system 200 is provided, comprising a housing having a first wall structure 206 formed of a first material and a second wall structure 205 formed of a second material, the first wall structure and the second wall structure being adjacent to each other and together forming a tube defining a drug reservoir lumen 208, wherein (i) the second wall structure 205 or both the first wall structure 206 and the second wall structure 205 are permeable to water, and (ii) the first wall structure 206 is impermeable to a drug and the second wall structure 205 is permeable to a drug, such that the drug can be released in vivo by diffusion through the second wall structure 205. As used herein, the term "impermeable to a drug" means that the wall is substantially impermeable to dissolved drug, such that no substantial amount of dissolved drug can diffuse through the wall during treatment while the system is in vivo.

[0176] In some embodiments, the tube is cylindrical or another suitable shape or design. As used herein, the term "cylindrical" when referring to a tubular housing means a housing having a substantially cylindrical outer wall. In some embodiments, the system is "closed" and therefore does not include orifices; drug release occurs solely through diffusion across a second wall structure.

[0177] In some implementation schemes, such as Figure 2 and Figure 3 As shown, the first wall structure 206 / 306 and the second wall structure 205 / 305 are adjacent to each other and together form a cylindrical tube. For example, such a system can be formed in a co-extrusion or 3D printing process, such that the first and second wall structures are integrally formed. In one embodiment, the co-extruded first and second wall structures are thermoplastic polymers with desired properties.

[0178] like Figure 3As shown, the first wall structure 306 and the second wall structure 305 together form a cylindrical tube with a lumen 308 in which the drug formulation is contained. The second wall structure 305 is in the form of a longitudinal strip extending along at least a portion of the length of the first wall structure 306 and is permeable to the drug, while the first wall structure 306 is impermeable to the drug. In some embodiments, multiple drug-permeable strips may be used in a single system. In some embodiments, a single permeable strip may be used in a single system. Therefore, the size, shape, thickness, and material properties of the second wall structure can be selected to achieve a desired drug release rate.

[0179] In a preferred embodiment, as discussed in further detail below, the system is elastically deformable between a low-profile deployment shape (e.g., a relatively straight shape) suitable for insertion through the patient's urethra and into the patient's bladder, and a relatively extended retention shape (e.g., a pretzel shape, a double-oval curled shape, an S-shape, etc.) suitable for retention within the bladder.

[0180] In some implementation schemes, such as Figures 7A to 7C As shown, the system also includes a retaining frame lumen 734. In some embodiments, the retaining frame lumen comprises an elastic wire, such as nitinol wire. In some other embodiments, the retaining frame lumen is filled with a shape-stabilized elastic polymer.

[0181] In other implementations, such as Figures 1 to 3 and Figure 8 As shown, the system does not include a retaining frame lumen or retaining frame or wire. Instead, the shell material is configured to elastically deform between a straight shape and a retaining shape in the absence of a retaining frame or wire. In some embodiments, the tubular shell is heat-formed to have a coiled or other retaining shape. Thus, in such embodiments, the design and manufacture of the system are simplified, and the overall size of the system is minimized (or the drug payload can be increased if the size of the system remains constant). In embodiments without a retaining frame, the tubular shell material functions to: (i) form a drug reservoir lumen, (ii) control drug release, and (iii) retain the system in the bladder upon deployment.

[0182] In one implementation scheme, such as Figures 7A to 7CAs shown, a drug delivery system 700 is provided, comprising an elongated, resilient housing 702 having a drug reservoir lumen 704 extending between a first end 706 and a second end 708. The resilient housing 702 is formed of a tubular wall structure 710 including a first wall structure 716 and a second wall structure 724 adjacent to each other and together forming a tube defining the drug reservoir lumen 704, wherein (i) the second wall structure 724 or both the first wall structure 716 and the second wall structure 724 are permeable to water, and (ii) the first wall structure 716 is impermeable to a drug and the second wall structure 724 is permeable to a drug, such that the drug can be released in the body through diffusion across the second wall structure 724.

[0183] In embodiments where the first and second wall structures together form a cylindrical tube, any suitable end plug or closure, or thermoformed seal, can be used to seal the ends of the tube after the drug is loaded. These end plugs / closures ensure that the drug forming part of the outer tube can be released through the polymer portion, which is the only pathway for drug release.

[0184] In some implementation schemes, such as Figure 2 and Figure 3 As shown, walls 206, 205 / 306, 305 have a substantially constant thickness along their circumference. For example, the inner diameter 210 / 310 and outer diameter 212 / 312 of the first and second wall structures 206, 205 / 306, 305 (which together form a cylindrical tube) are identical. In other embodiments, the walls may have varying thicknesses along their circumference.

[0185] Therefore, for the system described herein, drug release is controlled by the diffusion of the drug through a drug-permeable component that defines a portion of the system housing. The drug-permeable wall structure can be positioned, sized, and material-property-appropriate to provide the desired rate of controlled diffusion of the drug from the system.

[0186] Specific materials and arc angles of the drug permeable portion or wall structure can be selected to achieve specific drug release profiles, i.e., water and drug permeation rates. As used herein, the phrase "arc angle" refers to the angular dimension of the arc of the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube.

[0187] For example, in some implementations, such as Figure 2 and Figure 3As shown, the second wall structure 205 / 305 occupies less than 90% of the cross-sectional area of ​​the pipe in the cross-section perpendicular to the longitudinal axis of the pipe. In one embodiment, the second wall structure occupies less than 50% of the cross-sectional area of ​​the pipe in the cross-section perpendicular to the longitudinal axis of the pipe. In another embodiment, the second wall structure occupies less than 25% of the cross-sectional area of ​​the pipe in the cross-section perpendicular to the longitudinal axis of the pipe.

[0188] In some implementations, such as Figure 2 , Figure 3 , Figures 7A to 7C and Figure 8 As shown, the first and second wall structures forming the tube defining the drug reservoir lumen are adjacent to each other at two interface edges, such that the wall structures together form the tube defining the drug reservoir lumen. In these embodiments, the two interface edges are set at an arc angle of about 15 degrees to about 270 degrees around the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube. As used herein, the phrase “about” with respect to the arc angle of the second wall structure means an arc angle plus or minus 3 degrees.

[0189] In one implementation scheme, such as Figure 2 As shown, the second wall structure 205 has an arc angle 214 of approximately 60 degrees around the circumference of the cylindrical tube 200 in cross-section. In one embodiment, as... Figure 3 As shown, the second wall structure 305 has an arc angle 314 of approximately 30 degrees around the circumference of the cylindrical tube 300 in cross-section. In one embodiment, the second wall structure has an arc angle of approximately 15 degrees to approximately 270 degrees. As will be further described below, in some embodiments, the second wall structure has an arc angle of approximately 45 degrees to approximately 90 degrees, approximately 120 degrees to approximately 150 degrees, approximately 150 degrees to approximately 270 degrees, or approximately 210 degrees to approximately 270 degrees (such as approximately 45 degrees, approximately 90 degrees, approximately 135 degrees, approximately 180 degrees, and approximately 240 degrees). In some embodiments, the second wall structure has an arc angle of approximately 125 degrees to approximately 145 degrees. In some embodiments, the second wall structure has an arc angle of approximately 45 degrees, approximately 90 degrees, approximately 180 degrees, approximately 240 degrees, or approximately 270 degrees.

[0190] When the system is formed to have the following characteristics Figure 1 When maintaining the shape as shown, the second wall structure can be located on the inner bend (0 degrees), the outer bend (180 degrees), the top (90 degrees), or in between. When the second wall structure is formed of a material that expands significantly after absorbing water, the top (90 degrees) position may be preferred.

[0191] In some embodiments, the intravesical drug delivery system comprises a base AC-4075A-B20 and a stripe EG-80-A as described herein, wherein in a cross-section perpendicular to the longitudinal axis of the tube, the stripe angle (see, for example, Figure 8The striation angle is between 45 and 270 degrees around the circumference of the tube. In some embodiments, the striation angle is between 45 and 90 degrees, particularly 90 degrees. In some embodiments, an intravesical drug delivery system with a 90-degree striation angle releases approximately 2 mg / day of erdatinib. In some embodiments, the striation angle is between 125 and 145 degrees. In some embodiments, the striation angle is 135 degrees + / - 10 degrees. In some embodiments, an intravesical drug delivery system with a striation angle between 125 and 145 degrees releases approximately 2.5 mg / day to approximately 3.5 mg / day of erdatinib. In some embodiments, an intravesical drug delivery system with a striation angle of 135 degrees + / - 10 degrees releases approximately 2.5 mg / day to approximately 3.5 mg / day of erdatinib. In some embodiments, the striation angle is between 150 and 270 degrees, particularly 180 degrees. In some embodiments, an intravesical drug delivery system with a 180-degree striation angle releases approximately 4 mg / day of erdatinib. In some embodiments, the stripe angle is approximately 135 degrees. In some embodiments, an intravesical drug delivery system with a 135-degree stripe angle releases approximately 3 mg / day of erdatinib. In some embodiments, the intravesical drug delivery system is closed at the end. In some embodiments, the intravesical drug delivery system is sealed at the end of the drug lumen (e.g., Figure 7, reference 704) and therefore does not include an orifice for drug release. In some embodiments, drug release from the intravesical drug delivery system occurs solely through diffusion across the stripes (Figure 7, second wall structure, reference 724).

[0192] Therefore, tubular systems have been developed to reduce or control drug release rates without negatively altering mechanical properties and suitable size and tolerance for system deployment. In some embodiments, this design reduces the drug release rate by minimizing the length of the drug-permeable region, making that length extend only a portion of the total system length. Thus, a larger arc angle of the drug-permeable region can be used to tailor the drug release rate from the system. Furthermore, by reducing the length of the drug-permeable region, a smaller amount of drug-permeable material can be used to achieve a reduced drug release rate compared to conventional systems.

[0193] Once the drug is loaded into the drug reservoir lumen, any suitable end plug or closure, or thermoformed seal, can be used to seal / close the first and second ends of the drug reservoir lumen. These end plugs / closures ensure that the second material, forming part of the resilient outer shell, is the sole pathway for drug release. In some 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).

[0194] In the foregoing embodiments, the first material or first wall structure, the second material or first wall structure, or both are formed of a water-permeable material. In a preferred embodiment, as described above with respect to erdatinib solid dosage forms, the drug is in solid form (e.g., one or more tablets), and at least a portion of the tubular body is water-permeable to allow the drug to dissolve in vivo while in the lumen of the drug reservoir. In some embodiments, the first material or first wall structure may be only the water-permeable portion. In other embodiments, both the first material / wall structure and the second material / wall structure may be water-permeable.

[0195] The material used for the wall structure of the system of the present invention can be selected from a variety of suitable thermoplastic polyurethane (TPU)-based materials. In particular, the first material forming the first wall structure (i.e., the material impermeable to the drug contained in the drug reservoir) can be an aromatic thermoplastic polyurethane based on polycarbonate (e.g., CARBOTHANE). ™ TPU, such as AC-4075A, is commercially available from Lubrizol, or thermoplastic polyurethanes based on aromatic polyester hydrocarbons (e.g., TECOTHANE). ™ TPUs, such as AR-75A, are commercially available from Lubrizol. For example, CARBOTHANE polyurethane is a cycloaliphatic polymer and belongs to the type derived from polycarbonate-based polyols. The general structure of the polyol segment is represented as O—[(CH2)6—CO3]. n —(CH2)—O--. AC-4075A has a Shore hardness of 77A, a specific gravity of 1.19, a flexural modulus of 1500 psi, and a limiting elongation of 400%. AR-75A has a Shore hardness of 79A, a specific gravity of 1.03, a flexural modulus of 2500 psi, and a limiting elongation of 530%. Specifically, the second material forming the second wall structure (i.e., a material permeable to the drug contained in the drug reservoir) can be a thermoplastic polyurethane based on aliphatic polyethers (e.g., TECOFLEX). ™ TPUs, such as EG-80A, are commercially available from Lubrizol. For example, TECOFLEX polyurethane is a cycloaliphatic polymer and belongs to the type derived from polyether-based polyols. The general structure of the polyol segment is represented as O—(CH2—CH2—CH2—CH2). x —O--. EG-80A has a Shore hardness of 72A, a specific gravity of 1.04, a flexural modulus of 1000 psi, and a limiting elongation of 660%. TPU may also include radiopaque agents such as barium sulfate, for example, AC-4075A-B20, which is a polycarbonate-based aromatic thermoplastic polyurethane with a barium sulfate loading of 20%.

[0196] In one embodiment, the inner diameter of the cylindrical tube may be from about 1.0 mm to about 2.5 mm. In one embodiment, the outer diameter of the cylindrical tube is from about 2.0 mm to about 4.1 mm. In one embodiment, the thickness of the first wall structure, the second wall structure, or both is from about 0.2 mm to about 1.0 mm. In some embodiments, the thickness of the second wall structure is from about 0.16 mm to about 0.24 mm. In one embodiment, the thickness of the second wall structure is from about 0.16 mm to about 0.24 mm, wherein the first wall structure is impermeable to erdatinib, and the second wall structure is permeable to erdatinib.

[0197] Therefore, compared to drug delivery systems that utilize homogeneous materials (e.g., blends of permeable and impermeable thermoplastics) to form drug-permeable tubes, the mechanical properties of tubes utilizing double-walled structures (e.g., drug-permeable stripe embodiments) may be unrelated to the drug release (e.g., diffusion) characteristics of the tube. For example, in a single-material tube, changing the tube material inherently affects both the mechanical and diffusion characteristics of the system. The ability to control the release rate using stripe angles can have the added benefit of not changing the system's outer diameter; in contrast, control by changing the wall thickness may become too large to pass through the urethra, or too thin to provide the required mechanical strength of the system. Furthermore, the drug release characteristics of blended polymers may be difficult to predict. Moreover, obtaining truly homogeneous blends when mixing two thermoplastics is often challenging. Therefore, in the case of such tubular drug delivery systems, experimentation is required to tune the drug release rate. In contrast, the double-walled structures described herein offer enhanced flexibility in customizing the release rate of a specific drug from the delivery system.

[0198] For use in the bladder, it is important that the system is compliant during detrusor muscle contraction (i.e., flexible and soft to the touch) to avoid or reduce discomfort and irritation to the patient. Therefore, it is noteworthy that the stiffness of the first and second building materials is important, and the proportion of high-stiffness materials can be limited in the process of constructing a system shell of a given size while maintaining its proper compliance in the bladder. For example, a suitable first wall material (such as TECOTHANE or CARBOTHANE) may have a Shore hardness greater than 70 A (such as 77 A to 65 D), while a suitable second wall material (such as TECOFLEX) may have a Shore hardness less than 90 A or less than 80 A (such as 72 A). In some embodiments, the first material has a Shore hardness value of 70 A to 80 A, while the second material has a Shore hardness value of 70 A to 75 A. Therefore, in some embodiments, the second wall material has a lower Shore hardness than the first wall material, and both wall materials have a Shore hardness less than 80 A. Therefore, it may be advantageous to use a combination of two different polymer materials, rather than making the system shell entirely of a second material that is water-swellable and permeable to hydrophilic drugs, in order to achieve the desired mechanical properties of the tube.

[0199] In embodiments, the systems described herein are configured to release a therapeutically effective amount of a drug, wherein the release rate of the drug from the drug delivery system is at grade zero for at least 36 hours. In one embodiment, the release rate of the drug from the drug delivery system is substantially grade zero for at least 7 days. In embodiments, the system is configured to release a therapeutically effective amount of a drug over a period of 2 days to 6 months (e.g., 2 days to 90 days, 7 days to 30 days, or 7 days to 14 days). Ideally, the release rate of the drug from the drug delivery system is at grade zero for at least 7 days (e.g., 7 to 14 days) or longer (e.g., up to 3 months or 90 days). In some embodiments, the system is configured to begin releasing the drug after a lag time. In some embodiments, the lag time may be at least about 30 minutes, about 12 hours to about 24 hours, or up to about 2 days. These systems can effectively release a therapeutically effective amount of a drug for a period of up to 6 months or up to 3 months (90 days).

[0200] As will be discussed in more detail below, the drug formulation (such as those described throughout this disclosure) is disposed in a drug reservoir lumen defined by a first wall structure and a second wall structure. In a particularly preferred embodiment, the drug is an erdatinib-based drug formulation as described herein. In some embodiments, the system is configured to release erdatinib 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, according to the desired treatment regimen. In some embodiments, the system is configured to release erdatinib at an average rate of about 2 mg / day or about 4 mg / day. In such embodiments, the two interface edges may be set at an arc angle of 45 degrees to 270 degrees, for example, at an arc angle of 90 degrees to 180 degrees, and more particularly at an arc angle of 125 degrees to 145 degrees.

[0201] In one embodiment, the system is configured to release erdatinib at an average rate of 2 mg / day, with the two interface edges set at an arc angle of approximately 90 degrees. In another embodiment, the system is configured to release erdatinib at an average rate of 4 mg / day, with the two interface edges set at an arc angle of approximately 180 degrees. In some embodiments, the drug release profile is substantially pH-independent in the pH range of 5 to 7. In some embodiments, the drug release profile is substantially pH-independent in the pH range of 5.5 to 7. In some embodiments, the drug release profile is substantially pH-independent in the pH range of 5.5 to 8. In some embodiments, the release rate is maintained for a period of up to 6 months (particularly up to 3 months or 90 days).

[0202] In one embodiment, a drug delivery system is provided having (i) a housing defining a drug reservoir lumen and a retaining frame lumen, (ii) a plurality of tablets containing erdatinib disposed within the drug reservoir lumen, and (iii) a nitinol wire form (retaining frame) disposed within the retaining frame lumen. The drug reservoir lumen is defined / defined by a first wall structure (base) and a second wall structure (strip), the first wall structure being formed of a first material, which is a thermoplastic polyurethane based on aromatic polyester hydrocarbons (particularly AC-4075A-B20), and the second wall structure being formed of a second material, which is made of a thermoplastic polyurethane based on aliphatic polyethers (particularly EG-80A), wherein the first wall structure and the second wall structure are adjacent to each other at two interface edges and together form a tube defining a closed drug reservoir lumen. In one embodiment, the closed drug reservoir lumen contains a plurality of tablets, particularly a plurality of microtablets, particularly erdatinib microtablets as described herein. In one embodiment, the amount of erdatinib in the drug reservoir lumen is about 500 mg. In one embodiment, the drug reservoir lumen contains about 44 erdatinib microtablets, particularly erdatinib tablets as described herein. In one embodiment, the plurality of tablets consists of 44 microtablets having a total of about 500 mg of erdatinib. In one embodiment, the stripe angle is 90 degrees, and the average release rate of erdatinib from the system is about 2 mg / day. In one embodiment, the stripe angle is 180 degrees, and the average release rate of erdatinib from the system is about 4 mg / day. In one embodiment, the stripe angle is 90 degrees, and the average release rate of erdatinib from the system is about 2 mg / day. In one embodiment, the stripe angle is 90 degrees, and the average release rate of erdatinib from the system is about 2 mg / day at a pH between about 5 and about 6.8. In one embodiment, the stripe angle is 180 degrees, and the average release rate of erdatinib from the system is about 4 mg / day. In one embodiment, the stripe angle is 180 degrees, and the average release rate of erdatinib from the system is approximately 4 mg / day at a pH between approximately 5 and approximately 6.8, and approximately 2 mg / day at a pH of approximately 8. In one embodiment, the tablet has formulation 4D as described herein. In one embodiment, the tablet has formulation 4C as described herein. In one embodiment, the tablet has formulation 4B as described herein. In one embodiment, the tablet has formulation 4A as described herein. 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.

[0203] Other aspects of drug delivery systems In some implementations, the system is configured for intravesical insertion and retention within the patient. For example, the system is capable of being in a relatively low-profile (e.g., straight) shape suitable for insertion into the patient's body cavity via a lumen (such as...). Figures 7A to 7B (as shown) and a relatively extended retaining shape (such as) suitable for holding the system in a body cavity (e.g., the bladder). Figure 1 , Figure 4 , Figure 5 and Figure 6A The elastic deformation between the two (as shown in the diagram) can be significant. The relatively extended shape may include a pair of overlapping curls, sometimes referred to as a "German pretzel" shape. In specific embodiments, the ends of the elongated system are typically located within the boundaries of the biovate-like shape.

[0204] For example, when deployed in the bladder and in an expanded, retaining shape, the system resists excretion in response to urinary or other forces. After drug release, the system can be removed, for example by cystoscopy and forceps, or it can be biodissolving (at least partially) to avoid retrieval procedures.

[0205] This system may be loaded with at least one drug in the form of one or more drug units, such as tablets as described herein. Solid drug composition forms (such as tablets) provide a relatively large drug payload volume relative to the total system volume and potentially enhance drug stability during transport, storage, prior to use, or prior to drug release. However, solid drugs may need to be soluble in vivo to diffuse in a therapeutically effective amount through drug-permeable components and into the patient's surrounding tissues or cavities. The drug reservoir lumen may be elongated in an end-to-end tandem arrangement to accommodate several disclosed drug tablets. 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), such as microtablets, which may be continuously loaded into the drug reservoir lumen. In one aspect, the tablets are those described herein. In one aspect, the tablets are those of formulation 4A. In one aspect, the tablets are those of formulation 4B. In one respect, the tablets are those of formulation 4C. In another respect, the tablets are those of formulation 4D. In one respect, the tablets are those of 4.1. In one respect, the tablets are those of formulation 3.4. In one respect, the tablets are those of formulation 3.3. In one respect, the tablets are those of formulation 3.2.

[0206] The system can be inserted into a patient using a cystoscope, catheter, or any other suitable or custom-made insertion device. Typically, a cystoscope for adults has an outer diameter of about 5 mm and a working channel with an inner diameter of about 2.4 mm to about 2.6 mm. In embodiments, the cystoscope may have a working channel with a larger inner diameter, such as 4 mm or more. Therefore, the system size can be relatively small. For example, a system for adult patients may have a total outer diameter of less than about 2.6 mm (such as between about 2.0 mm and about 2.4 mm) when the system elastically deforms into a relatively straight shape. In addition to allowing insertion, the relatively small size of the system reduces patient discomfort and trauma to the bladder. In one embodiment, the overall construction of the system improves in vivo tolerability for most patients. In a particular 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.

[0207] Within the three-dimensional space occupied by the shape-maintaining system, the maximum dimension of the system in any direction is preferably less than 10 cm, which is the approximate diameter of the bladder when filled. In some embodiments, the maximum dimension of the system in any direction may be less than about 9 cm, such as about 8 cm, 7 cm, 6 cm, 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 cm, or smaller. In specific embodiments, the maximum dimension of the system in any direction is less than about 7 cm, such as about 6 cm, 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 cm, or smaller. In preferred embodiments, the maximum dimension of the system in any direction is less than about 6 cm, such as about 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 cm, or smaller. More specifically, the three-dimensional space occupied by the system is defined by three perpendicular directions. Along one of these directions, the system has its maximum dimension, and along the two other directions, the system may have a smaller dimension. For example, the smaller dimensions in the two other directions may be less than about 4 cm, such as about 3.5 cm, 3 cm, 2.5 cm, or smaller. In a preferred embodiment, the system has a dimension of less than 3 cm in at least one of these directions.

[0208] In some implementations, the system may have different dimensions in at least two of the three directions, and in some cases, different dimensions in each of the three directions, making the system non-uniform in shape. Due to this non-uniform shape, the system may be able to achieve a reduced compression orientation within an empty bladder, which is also non-uniform in shape. In other words, the specific orientation of the system within an empty bladder allows the system to exert less contact pressure on the bladder wall, making the system more tolerable for the patient.

[0209] The overall shape of the system allows it to reorient itself within the bladder to reduce its engagement or contact with the bladder wall. For example, the overall external shape of the system can be curved, and all or most of the system's outer or exposed surfaces can be substantially circular. The system can also be substantially without sharp edges, and its outer surfaces can be formed of a material that experiences reduced frictional engagement with the bladder wall. This configuration allows the system to reposition itself within an empty bladder, resulting in less contact pressure exerted on the bladder wall. In other words, the system can slide or roll against the bladder wall to a lower energy location, meaning a location where the system experiences less compression.

[0210] In one implementation, even though the system occupies three-dimensional space, its shape is typically planar. Such a system may define a minor axis and a major axis, with the system being substantially symmetrical about the minor axis and the major axis being substantially perpendicular to the minor axis. The system may have a maximum dimension of no more than about 6 cm in the major axis direction, and less than 5 cm in specific implementations (such as about 4.5 cm, about 4 cm, about 3.5 cm, about 3 cm, or less). The system may have a maximum dimension of no more than about 4.5 cm in the minor axis direction, and less than 4 cm in specific implementations (such as about 3.5 cm, about 3 cm, or less). The system is substantially curved around its entire periphery in both the primary and secondary cross-sectional planes. In other words, the overall external shape of the system is curved, and the cross-sectional shape of the system is circular. Therefore, the system is essentially edgeless, except for the edges at the two flat ends, which are completely protected within the system when the system is in a plane. These characteristics enable the system to redirect itself to a position of reduced compression when the bladder is empty.

[0211] The system is also small enough to allow intrabladder movement while maintaining its shape. In particular, the system is small enough during deployment to move within the bladder, such as freely or unimpeded throughout the bladder in most cases when the bladder is full, thereby promoting patient tolerance to the system. The free movement of the system also promotes uniform drug delivery throughout the bladder.

[0212] The system can also be configured to promote buoyancy, such as by using a low-density construction material for the housing components and / or by incorporating gas or gas-generating materials into the housing, as described, for example, in U.S. Patent No. 9,457,176. Typically, a system in a dry and drug-loaded state may have a density in the range of about 0.5 g / mL to about 1.5 g / mL (e.g., between about 0.7 g / mL and about 1.3 g / mL). In some embodiments, a system in a dry and drug-loaded state has a density of less than 1 g / mL.

[0213] 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, such that the system does not need to be removed or retrieved after the drug formulation is released. In some embodiments, the system is partially biodegradable, such that the system breaks into small, non-biodegradable fragments upon partial dissolution, sufficient to be excreted from the bladder. For example, the systems described herein may be designed to conform to the characteristics of those systems described in U.S. Patent No. 8,690,840.

[0214] The drug delivery system is sterilized before being inserted into the patient. In one embodiment, the system is sterilized using a suitable method, such as gamma ray or ethylene oxide sterilization, but other sterilization methods may also be used.

[0215] The systems described herein may include radiopaque portions or structures to facilitate detection or observation by a physician during part of an implantation or retrieval procedure (e.g., via X-ray imaging or fluoroscopy). In one embodiment, the housing is constructed of a radiopaque filler material, such as barium sulfate or another radiopaque material known in the art. Some housings may be made radiopaque by blending a radiopaque filler (such as barium sulfate or another suitable material) during the processing of the material forming the housing. In those embodiments that include a retaining frame, the radiopaque material may be associated with the retaining frame. Ultrasound imaging or fluoroscopy may be used to image the system in vivo.

[0216] In some embodiments, the system's components include a drug-impermeable base material and a drug-permeable strip material, and the base material is TPU with 20% BaSO4 filler, such as Lubrizol's Carbothane. ™ AC-4075A-B20 or Tecothane ™ AR-75A-B20. (Lubrizol Life Science (Bethlehem, PA)).

[0217] The drug delivery system may also include a retrieval feature, such as a cord, loop, or other structure that facilitates removal of the system from the patient. In one case, the system can be removed from the bladder by engaging the cord to pull the system through the urethra. When the system is pulled into the lumen of a catheter or cystoscope or into the urethra via the retrieval feature, the system may be configured to have a relatively narrow or linear shape.

[0218] System retention in body cavity The system described herein is capable of elastically deforming between a relatively low-profile (e.g., straight or extended) shape suitable for insertion through a lumen into a patient's bladder (or other body cavity) and a relatively extended retaining shape suitable for holding the system within the bladder (or other body cavity). In some embodiments, the drug delivery system naturally assumes the retaining shape and can be manually or by means of an external device deformed into a relatively straight shape for insertion into the body. Once deployed, the system can spontaneously or naturally return to its initial retaining shape for retention in the body.

[0219] For the purposes of this disclosure, the terms “retaining shape,” “relatively extended shape,” etc., generally refer to any shape suitable for holding the system at the intended implantation location, including but not limited to shapes such as Figure 1 and Figure 4 The diagram illustrates a coiled or "pretzel" shape suitable for holding the system in the bladder. Similarly, the terms "deployment shape," "relatively low profile shape," "relatively straight shape," etc., generally refer to any shape suitable for deploying a drug delivery system into the body, including but not limited to shapes such as... Figures 7A to 7B The linear or elongated shape shown is suitable for deploying the system through a working channel of a catheter, cystoscope, or other deployment instrument positioned in a body cavity (such as the urethra). For example, the system housing or tube may have two opposing free ends that are guided away from each other when the system is in a low-profile deployment shape and guided toward each other when the system is in a relatively extended holding shape.

[0220] In some implementation schemes, such as Figures 7A to 7C As shown, the system also includes a retaining frame lumen 734 and a retaining frame (not shown) positioned within the retaining frame lumen. For example, the retaining frame lumen and retaining frame may be as described in U.S. Application Publication Nos. 2010 / 0331770, 2010 / 0060309, 2011 / 0202036, and 2011 / 0152839, which are incorporated herein by reference. For example, the retaining frame lumen may be sealed with a suitable plug or adhesive material, such as a silicone adhesive.

[0221] Figure 4 A system 300 is shown in which a drug tablet 108 is loaded in a drug reservoir lumen of a system housing 304. (As shown in...) Figure 5 As can be seen, before loading the tablet, the retaining frame 303 pushes the system housing 304 into a different extended shape compared to the shape retention achieved when the system is loaded with the drug tablet 108.

[0222] In some embodiments where increased payload is required, an additional length of drug reservoir lumen / tube may be provided. In one embodiment, such as Figures 6A to 6B As shown, the retaining frame has a periphery defined by two overlapping portions (curls) of a nitinol wire. Each end portion of the wire points inward from the outer periphery and includes (i) a curved transition region having a smaller radius of curvature than the outer periphery of the wire, and (ii) a straight portion terminating in a circular end cap. In contrast, in Figure 5 In the system shown, the retaining frame has an outer perimeter defined by a single curl. Figures 6A to 6B The system of maintaining the framework enables the ability to have with Figure 5 The system shown implements a relatively longer drug reservoir (e.g., to hold more tablets) in the same "footprint" (peripheral shape and size) system.

[0223] In other implementations, such as Figures 1 to 3 As shown, the system does not include a retaining frame lumen or retaining frame or wire. Instead, the shell material is configured to elastically deform between an extended shape and a retaining shape in the absence of a retaining frame or wire. Therefore, in such embodiments, the design and manufacture of the system are simplified, and the overall size of the system is minimized (or the drug payload can be increased while keeping the system size constant). In embodiments without a retaining frame, the tubular shell material functions to: (i) form a drug reservoir lumen, (ii) control drug release, and (iii) retain the system in the bladder upon deployment.

[0224] For example, the tubular housing can be heat-formed to have a retaining shape. Therefore, the housing may comprise one or more thermoplastic materials suitable for thermoforming into a retaining shape. In some embodiments, the drug delivery system includes a tubular housing having a closed drug reservoir lumen defined 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 a bladder to a relatively straight shape suitable for insertion into the bladder through the lumen, and (iii) the tubular wall is thermoformed to have the retaining shape. A photograph of a cross-section of the drug reservoir lumen of a drug delivery system without any drug disposed therein is shown. Figure 8 In. Figure 8 In the middle, the second wall structure has an arc angle of about 30 degrees 802 on the circumference of the cylindrical tube in the cross section.

[0225] In some embodiments, the first and second wall structures are each made of thermoplastic polyurethane, and the tubular shell is thermoformed to retain its shape. In one embodiment, the tubular wall has a spring constant that effectively prevents the system from taking on a relatively straight shape once implanted in the bladder. Thus, the properties of the tubular wall allow the system to act as a spring, deforming in response to compressive loads but spontaneously returning to its initial shape once the load is removed.

[0226] In some implementations, the system can naturally assume 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 can be shaped for retention within a body cavity, and the tubular wall structure in the relatively straight shape can be shaped for insertion into the body through a working channel of a deployment instrument, such as a catheter or cystoscope. To achieve this, the tubular wall structure may have an elastic limit, modulus, and / or spring constant selected to prevent the system from assuming a relatively low profile shape once implanted. This configuration limits or prevents the system from being accidentally expelled from the body under intended forces. For example, the system may remain in the bladder during urination or detrusor muscle contraction.

[0227] In a preferred embodiment, the system is elastically deformable between a relatively straight shape suitable for insertion by means of a catheter or cystoscope extending through the patient's urethra and a curved or coiled shape suitable for holding the system within the bladder after it has been released from the end of the catheter or cystoscope (i.e., preventing it from being expelled from the bladder during urination).

[0228] like Figure 1 As shown, the shape retention may include a curled or "pretzel" shape. A pretzel shape essentially comprises at least two sub-circles, each with its own smaller arc and sharing a common larger arc. When the pretzel shape is first compressed, the larger arc absorbs most of the compressive force and begins to deform, but with continued compression, the smaller arcs overlap, and subsequently, all three arcs resist the compressive force. Once the two sub-circles overlap, the system as a whole increases its resistance to compression, thus preventing the system from collapsing and emptying when the bladder contracts during urination.

[0229] The shape-holding wall structure can have a two-dimensional structure limited to a plane; a three-dimensional structure, such as a structure occupying the interior of a sphere; or some combination thereof. The shape-holding structure can include one or more loops, curls, or subcircles connected linearly or radially, rotating in the same or alternating directions, and overlapping or not overlapping. The shape-holding structure can include one or more circles or ellipses arranged in a two-dimensional or three-dimensional configuration, which can be closed or open, have the same or different dimensions, overlap or not overlap, and are connected together at one or more connection points. The shape-holding structure can also be a three-dimensional structure shaped to occupy or curl around a space of spherical shape, such as a spherical space, a space with a prorate spheroid shape, or a space with an oblate spheroid shape. The shape-holding wall structure can be shaped to occupy or curl around a spherical space. The shape-holding wall structure can typically take the form 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 stretched into a linear shape for deployment by a deployment device. The wall structure can also be wound or coiled through a spherical space or other spherical shapes in a variety of other ways.

[0230] Drug delivery systems utilizing thermoformed co-extruded tubing with drug-permeable and drug-impermeable portions integrate three functional components (drug reservoir / shell, drug permeation path, and retaining feature) into a single thermoformed co-extruded tubing component, which simplifies system design and the ability to control drug release rates. As discussed herein, in such systems, the drug release rate can be relatively easily altered by controlling the angle and thickness of the drug-permeable portion (e.g., a strip) without changing the overall tubing shell material.

[0231] Thermoformed co-extruded tubular shells can be loaded with drug tablets, and both ends can be heat-sealed or sealed with an adhesive (such as a first wall material). Tablet loading will be difficult if localized tube cross-sectional deformation or tube kinking occurs. Therefore, when the tube is thermoformed, the tube size should be selected to prevent kinking. The critical radius of curvature (R) of an elastic tube under pure bending conditions. * The following formula can be used to estimate: Where v is Poisson's ratio, r is the average radius (i.e., (ID+OD) / 4), w is the wall thickness, ID is the inner diameter, and OD is the outer diameter. When the Poisson's ratio v for polyurethane is 0.49, the estimated critical radius is 0.5 cm. Therefore, in some embodiments, when thermoforming polyurethane tubing, the radius of curvature should preferably be greater than 0.5 cm along the entire length of the tubing to prevent kinking. Thus, in one embodiment, maintaining the shape includes at least one loop having a radius of curvature of at least 0.5 cm.

[0232] Drug delivery system In some embodiments, this document provides a drug delivery system comprising a housing defining a drug reservoir lumen defined by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises an aromatic thermoplastic polyurethane based on polycarbonate and the second material comprises a thermoplastic polyurethane based on aliphatic polyether; and a drug formulation comprising erdatinib disposed within the drug reservoir lumen, wherein: (i) the second wall structure or both the first and second wall structures are water-permeable, and (ii) the first wall structure is impermeable to erdatinib and the second wall structure is impermeable to erdatinib. Datatinib is permeable, allowing it to be released in vivo via diffusion through a second material forming a second wall structure. The first and second wall structures are adjacent to each other at two interfacial edges and together form a tube. The drug delivery system is configured to release erdatinib at an average rate of about 2 mg / day to about 4 mg / day, optionally at an average rate of about 2.5 mg / day to about 3.5 mg / day. The two interfacial edges are arranged at an arc angle of about 90 degrees to about 180 degrees, preferably about 125 degrees to about 145 degrees, 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 erdatinib microtablets. In some embodiments, the drug delivery system comprises 42 to 46 erdatinib microtablets. In some embodiments, the drug delivery system comprises 43 erdatinib microtablets. In some embodiments, the drug delivery system is configured to release erdatinib at an average rate of 3 mg / day, and the two interface edges are positioned at a 135-degree arc angle to 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 pharmaceutical formulation comprises (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 1% by weight of meglumine; (d) 17.5% by weight of microcrystalline cellulose; (e) 10.75% by weight of silanized microcrystalline cellulose; (f) 7.5% by weight of vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25% by weight of colloidal silica; (h) 1.5% by weight of hydroxypropyl methylcellulose; and (i) 1.5% by weight of magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition.In some embodiments, the pharmaceutical formulation comprises (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 17.5% by weight of microcrystalline cellulose; (d) 11.75% by weight of silanized microcrystalline cellulose; (e) 7.5% by weight of vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25% by weight of colloidal silica; (g) 1.5% by weight of hydroxypropyl methylcellulose; and (h) 1.5% by weight of magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In some embodiments, the pharmaceutical formulation comprises (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 1% by weight of meglumine; (d) 24.5% by weight of microcrystalline cellulose; (e) 6.0% by weight of silanized microcrystalline cellulose; (f) 6.0% by weight of vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5% by weight of colloidal silica; and (h) 2.0% by weight of magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition.

[0233] In some embodiments, this document provides a drug delivery system comprising a housing defining a drug reservoir lumen defined by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises an aromatic thermoplastic polyurethane based on polycarbonate and the second material comprises a thermoplastic polyurethane based on aliphatic polyether; and a drug formulation comprising erdatinib disposed in the drug reservoir lumen, wherein: (i) the second wall structure or both the first and second wall structures are water-permeable, and (ii) the first wall structure is impermeable to erdatinib and the second wall structure is permeable to erdatinib, such that erdatinib can be released in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent to each other at two interface edges and together form a tube, wherein the drug delivery system is configured to release erdatinib at an average rate of about 3 mg / day, and wherein the two interface edges are arranged at an arc angle of about 135 degrees around 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 erdatinib microtablets. In some embodiments, the drug delivery system comprises 42 to 46 erdatinib microtablets. In some embodiments, the drug delivery system comprises 43 erdatinib microtablets. In some embodiments, the drug delivery system is configured to release erdatinib at an average rate of 3 mg / day, and the two interface edges are positioned at a 135-degree arc angle to 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 pharmaceutical formulation comprises (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 1% by weight of meglumine; (d) 17.5% by weight of microcrystalline cellulose; (e) 10.75% by weight of silanized microcrystalline cellulose; (f) 7.5% by weight of vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25% by weight of colloidal silica; (h) 1.5% by weight of hydroxypropyl methylcellulose; and (i) 1.5% by weight of magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition.In some embodiments, the pharmaceutical formulation comprises (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 17.5% by weight of microcrystalline cellulose; (d) 11.75% by weight of silanized microcrystalline cellulose; (e) 7.5% by weight of vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25% by weight of colloidal silica; (g) 1.5% by weight of hydroxypropyl methylcellulose; and (h) 1.5% by weight of magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In some embodiments, the pharmaceutical formulation comprises (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 1% by weight of meglumine; (d) 24.5% by weight of microcrystalline cellulose; (e) 6.0% by weight of silanized microcrystalline cellulose; (f) 6.0% by weight of vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5% by weight of colloidal silica; and (h) 2.0% by weight of magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition.

[0234] Figures 27A to 2 9 describes an implementation scheme of a drug delivery system according to this disclosure. Figures 27A to 2 The drug delivery system 2700 of the 9 is referred to in this paper as “TAR-210-C” and is designed to release approximately 3 mg of erdatinib daily. Figure 27A This is a top schematic diagram of the drug delivery system 2700, shown in a curled, shape-retaining configuration. Figure 27B This is a bottom schematic diagram of the drug delivery system 2700, shown in a curled, shape-retaining configuration. Figure 28 It is a drug delivery system 2700 along Figure 27A The cross-sectional view taken by line AA. Figure 29A This is a side view of the drug delivery system 2700, shown in a relatively straight insertion shape. Figure 29B This is a side cross-sectional view of a portion of the drug delivery system 2700, shown in a relatively straight, inserted shape.

[0235] See Figure 27A and Figure 27B In some embodiments, the drug delivery system 2700 includes a housing 2704. The housing 2704 defines a drug reservoir lumen 2732 and a retaining frame lumen 2734 (only in...). Figure 27B (See in the middle). Figure 27A and Figure 27B In the image, a portion of the outer shell 2704 that defines the drug reservoir lumen 2732 is shown as translucent, thus revealing the erdatinib microtablets 2708 contained therein.

[0236] As with other embodiments disclosed herein, the drug reservoir lumen 2732 and the retaining frame lumen 2734 can be integral with each other, for example, co-molded during extrusion. As mentioned above, the drug reservoir lumen 2732 contains a plurality of erdatinib microtablets 2708, which will be described in more detail below. The retaining frame lumen 2734 accommodates a retaining frame 2903 (in... Figure 28 and Figure 29B (See below), such as elastic or superelastic nitinol wire. As described in other embodiments of the drug delivery system disclosed herein, the drug delivery system 2700 may be in a low-profile deployment shape (e.g., a relatively straight shape; see below) suitable for insertion through the patient's urethra and into the patient's bladder. Figure 29A , Figure 29B ) and a relatively extended retaining shape (e.g., a biovate coiled shape) suitable for retaining the drug delivery system 2700 within the bladder; Figure 27A and Figure 27B The drug delivery system 2700 can elastically deform between the deployment shape and the urethra of a patient when in the deployment shape. According to the embodiment, when in the deployment shape, the drug delivery system 2700 can be inserted through the patient's urethra using a urinary placement catheter. Due to the elastic nature of the retaining frame 2903, the drug delivery system 2700 naturally returns to the retaining shape when there is no external constraint, such as when leaving the urinary placement catheter.

[0237] See Figure 27A In some embodiments, when in a curled-up, shape-retaining state, the drug delivery system 2700 has a maximum dimension equal to or less than about 6 cm in any direction (X, Y) (e.g., Figure 27A (L in the text). In some embodiments, when in a curled-up, retained shape, the drug delivery system 2700 has a maximum dimension equal to or less than about 5.5 cm in any direction (X, Y) (e.g., Figure 27A (L in the text). In some embodiments, when in a curled-up shape, the drug delivery system 2700 fits within a 5.5cm × 4.5cm envelope (X, Y).

[0238] See Figure 28A cross-sectional view of the housing 2704 shows the drug reservoir lumen 2732 and the retaining frame lumen 2734. According to an embodiment, the drug reservoir lumen 2732 is defined by a first wall structure formed of a first material 2906 and a second wall structure formed of a second material 2905. According to an embodiment, the second material 2905 of the second wall structure, or both the first material 2906 of the first wall structure and the second material 2905 of the second wall structure, are water-permeable. According to some embodiments, both the first material 2906 of the first wall structure and the second material 2905 of the second wall structure are water-permeable. According to some embodiments, the first material 2906 of the first wall structure is impermeable to erdatinib, and the second material 2905 of the second wall structure is permeable to erdatinib, such that erdatinib can be released in vivo by diffusion through the second material 2905 forming the second wall structure. According to an embodiment, the first material 2906 comprises an aromatic thermoplastic polyurethane based on polycarbonate, and the second material 2905 comprises a thermoplastic polyurethane based on aliphatic polyether. 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.

[0239] Still refer to Figure 28 In some embodiments, the first wall structure and the second wall structure are adjacent to each other at two interface edges 2905A, 2905B and together form a tube. For example, the first wall structure and the second wall structure may be bonded together or co-extruded at interface edges 2905A, 2905B. The two interface edges 2905A, 2905B may be set at an arc angle 2914 of about 125 degrees to about 145 degrees, particularly about 135 degrees, of the circumference of the tube in a cross-section perpendicular to the longitudinal axis Z of the tube. In some embodiments, such as Figure 28 As shown, the arc angle 2914 is approximately 135 degrees. In some embodiments, the arc angle 2914 is approximately 135 degrees and contains a second material 2905 forming the second wall structure, such that the arc of the second wall structure corresponds to the arc angle 2914. According to an embodiment, the second wall structure is permeable to erdatinib, allowing erdatinib to be released in vivo via diffusion through the second material 2905 forming the second wall structure.

[0240] As stated herein, the phrase "arc angle" refers to the angular dimension of the arc of the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube. For example, in some embodiments, the arc angle 2914 is about 135 degrees, such that the second wall structure occupies about 135 degrees of the circumference of the drug reservoir lumen 2704, and the first wall structure occupies about 225 degrees of the circumference of the drug reservoir lumen 2704. Unless otherwise stated, the terms "arc angle" and "stripe angle" are used interchangeably throughout this disclosure.

[0241] Still refer to Figure 28 In some embodiments, the second material 2905 of the drug delivery system 2700 defines a wall thickness T of 0.2 ± 0.04 mm extending along the diameter of the drug reservoir lumen 2732. In some embodiments, the drug reservoir lumen 2732 defines an inner diameter D of 2.64 ± 0.05 mm.

[0242] As discussed above, in some embodiments, the housing 2704 of the drug delivery system 2700 includes a retaining frame lumen 2734. According to one embodiment, a linear element 2903 is disposed within the retaining frame lumen 2734 and defines a diameter d of approximately 0.305 mm.

[0243] See Figures 29A to 29B The drug delivery system 2700 is shown in a relatively straight, inserted shape. Figure 29A In the image, the portion of the outer shell defining the drug reservoir lumen 2732 is shown as translucent, revealing the erdatinib microtablets 2708 contained therein. Figure 29B In the image, the outer casing is shown in cross-section to expose the erdatinib microtablet 2708 located in the drug reservoir lumen 2732 and the retaining frame 2903 located in the retaining frame lumen 2734. Figure 29B In this process, the ends 2808 and 2810 of the drug delivery system 2700 are truncated.

[0244] like Figure 29A As shown, and as mentioned above, some embodiments of the drug delivery system 2700 include, for example, a first opposing end 2808 and a second opposing end 2810 defined by a housing 2704. Still refer to Figure 29A According to some embodiments, the drug delivery system 2700 defines a length 2812 of approximately 17 cm between the first and second opposing ends 2808, 2810. According to some embodiments, the drug reservoir lumen 2732 is, for example, fitted with a stopper 2820 at the first and second opposing ends 2808, 2810 (see [link to embodiment]). Figure 29B Thermoplastic plastics and / or sealants are used for sealing. Sealing at opposite ends 2808, 2810 ensures that the drug-permeable second wall structure of the drug reservoir lumen 2732 is the only pathway for drug release.

[0245] In some embodiments, the pharmaceutical formulation comprises (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 17.5% by weight of microcrystalline cellulose; (d) 11.75% by weight of silanized microcrystalline cellulose; (e) 7.5% by weight of vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25% by weight of colloidal silica; (g) 1.5% by weight of hydroxypropyl methylcellulose; and (h) 1.5% by weight of magnesium stearate, wherein these weight percentages are relative to the entire pharmaceutical formulation.

[0246] See Figure 29A and Figure 29B In some embodiments, the drug formulation comprises microtablets 2708. In some embodiments, the drug formulation consists of microtablets 2708. In some embodiments, the drug delivery system 2700 comprises about 42 to 44 erdatinib microtablets 2708. In some embodiments, the drug delivery system 2700 comprises 43 erdatinib microtablets 2708. In some embodiments, the drug formulation comprises about 480 mg to about 510 mg of erdatinib. In some embodiments, the drug formulation comprises about 500 mg of erdatinib.

[0247] In some embodiments, each microtablet 2708 has a weight between about 22 mg and about 24 mg. In some embodiments, each microtablet 2708 has a weight of about 23 mg.

[0248] See Figure 29A In some embodiments, each microtablet 2708 has a thickness 2802 between about 3.0 mm and about 3.4 mm. In some embodiments, each microtablet 2708 has a thickness 2802 of about 3.2 mm.

[0249] Still refer to Figure 29A In some embodiments, each microtablet 2708 defines a diameter 2806 between about 2.60 mm and about 2.66 mm. In some embodiments, each microtablet 2708 defines a diameter 2806 of about 2.63 mm.

[0250] See Figure 29BIn some embodiments, multiple microtablets 2708 are arranged in series and define a core 2822. For example, the core 2822 may contain 43 erdatinib microtablets 2708. The core 2822 may define a core length 2824 between the outer surface of the first microtablet 2708a and the opposing outer surface of the last microtablet 2708b in the core 2822. According to an embodiment, the core length 2824 may be approximately 15 cm.

[0251] In some embodiments, this document provides a drug delivery system comprising a housing defining a drug reservoir lumen defined by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises an aromatic thermoplastic polyurethane based on polycarbonate and the second material comprises a thermoplastic polyurethane based on aliphatic polyether; and a drug formulation comprising erdatinib disposed within the drug reservoir lumen, wherein: (i) the second wall structure or both the first and second wall structures are water-permeable, and (ii) The first wall structure is impermeable to erdatinib, while the second wall structure is permeable to erdatinib, allowing erdatinib to be released in vivo via diffusion through the second material forming the second wall structure. The first and second wall structures are adjacent to each other at two interface edges and together form a tube. These two interface edges are set at an arc angle of approximately 125 to approximately 145 degrees, particularly approximately 135 degrees, of the tube's circumference in a cross-section perpendicular to the tube's longitudinal axis. This arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, the arc angle is approximately 135 degrees and contains the 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 pharmaceutical formulation comprises (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 17.5% by weight of microcrystalline cellulose; (d) 11.75% by weight of silanized microcrystalline cellulose; (e) 7.5% by weight of vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25% by weight of colloidal silica; (g) 1.5% by weight of hydroxypropyl methylcellulose; and (h) 1.5% by weight of magnesium stearate, wherein these weight percentages are relative to the entire pharmaceutical formulation.

[0252] In some embodiments, this document provides a drug delivery system comprising a housing defining a drug reservoir lumen defined by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises an aromatic thermoplastic polyurethane based on polycarbonate and the second material comprises a thermoplastic polyurethane based on aliphatic polyether; and a drug formulation comprising erdatinib disposed in the drug reservoir lumen, wherein: (i) both the first and second wall structures are permeable to water, and (ii) the first wall structure is impermeable to erdatinib and the second wall structure is permeable to erdatinib, such that erdatinib can be released in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent to each other at two interface edges and together form a tube, wherein the two interface edges are set at an arc angle of about 125 degrees 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, wherein the arc angle contains the 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 approximately 135 degrees and contains 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 pharmaceutical formulation comprises (a) 50 wt% erdatinib free base; (b) 10 wt% hydroxypropyl-β-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silanized microcrystalline cellulose; (f) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25 wt% colloidal silica; (h) 1.5 wt% hydroxypropyl methylcellulose; and (f) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire pharmaceutical formulation.

[0253] In some embodiments, this document provides a drug delivery system comprising a housing defining a drug reservoir lumen defined by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises an aromatic thermoplastic polyurethane based on polycarbonate and the second material comprises a thermoplastic polyurethane based on aliphatic polyether; and a drug formulation comprising erdatinib disposed within the drug reservoir lumen, wherein: (i) the second wall structure or both the first and second wall structures are water-permeable, and (ii) The first wall structure is impermeable to erdatinib, and the second wall structure is permeable to erdatinib, allowing erdatinib to be released in vivo by diffusion through the second material forming the second wall structure. The first and second wall structures are adjacent to each other at two interface edges and together form a tube. These two interface edges are set at an arc angle of approximately 125 to approximately 145 degrees, particularly approximately 135 degrees, of the tube's circumference in a cross-section perpendicular to the tube's longitudinal axis. This arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, the arc angle is approximately 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, both the first and second wall structures are permeable to water. In some embodiments, the pharmaceutical formulation comprises (a) 50 wt% erdatinib free base; (b) 10 wt% hydroxypropyl-β-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silanized microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silica; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises microtablets. In some embodiments, the pharmaceutical formulation consists of microtablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdatinib microtablets. In some embodiments, the drug delivery system comprises 43 erdatinib microtablets. In some embodiments, the pharmaceutical formulation comprises about 480 mg to about 510 mg of erdatinib. In some implementations, the drug formulation contains approximately 500 mg of erdatinib.

[0254] In some embodiments, this document provides a drug delivery system comprising a housing defining a drug reservoir lumen defined by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises an aromatic thermoplastic polyurethane based on polycarbonate and the second material comprises a thermoplastic polyurethane based on aliphatic polyether; and a drug formulation comprising erdatinib disposed within the drug reservoir lumen, wherein: (i) the second wall structure or both the first and second wall structures are water-permeable, and (ii) The first wall structure is impermeable to erdatinib, and the second wall structure is permeable to erdatinib, allowing erdatinib to be released in vivo by diffusion through the second material forming the second wall structure. The first and second wall structures are adjacent to each other at two interface edges and together form a tube. These two interface edges are set at an arc angle of approximately 125 to approximately 145 degrees, particularly approximately 135 degrees, of the tube's circumference in a cross-section perpendicular to the tube's longitudinal axis. This arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, the arc angle is approximately 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, both the first and second wall structures are permeable to water. In some embodiments, the pharmaceutical formulation comprises (a) 50 wt% erdatinib free base; (b) 10 wt% hydroxypropyl-β-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silanized microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silica; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises microtablets. In some embodiments, the pharmaceutical formulation consists of microtablets. In some embodiments, the pharmaceutical formulation consists of microtablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdatinib microtablets. In some embodiments, the drug delivery system comprises 43 erdatinib microtablets. In some embodiments, the pharmaceutical formulation comprises about 480 mg to about 510 mg of erdatinib. In some embodiments, the pharmaceutical formulation comprises about 500 mg of erdatinib. 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.

[0255] In some embodiments, this document provides a drug delivery system comprising a housing defining a drug reservoir lumen defined by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises an aromatic thermoplastic polyurethane based on polycarbonate and the second material comprises a thermoplastic polyurethane based on aliphatic polyether; and a drug formulation comprising erdatinib disposed within the drug reservoir lumen, wherein: (i) the second wall structure or both the first and second wall structures are water-permeable, and (ii) The first wall structure is impermeable to erdatinib, and the second wall structure is permeable to erdatinib, allowing erdatinib to be released in vivo by diffusion through the second material forming the second wall structure. The first and second wall structures are adjacent to each other at two interface edges and together form a tube. These two interface edges are set at an arc angle of approximately 125 to approximately 145 degrees, particularly approximately 135 degrees, of the tube's circumference in a cross-section perpendicular to the tube's longitudinal axis. This arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, the arc angle is approximately 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, both the first and second wall structures are permeable to water. In some embodiments, the pharmaceutical formulation comprises (a) 50 wt% erdatinib free base; (b) 10 wt% hydroxypropyl-β-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silanized microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silica; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises microtablets. In some embodiments, the pharmaceutical formulation consists of microtablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdatinib microtablets. In some embodiments, the drug delivery system comprises 43 erdatinib microtablets. In some embodiments, the pharmaceutical formulation comprises about 480 mg to about 510 mg of erdatinib. In some embodiments, the pharmaceutical formulation comprises approximately 500 mg of erdatinib. 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 microtablet has a weight between approximately 22 mg and approximately 24 mg. In some embodiments, each microtablet has a weight of approximately 23 mg.

[0256] In some embodiments, this document provides a drug delivery system comprising a housing defining a drug reservoir lumen defined by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises an aromatic thermoplastic polyurethane based on polycarbonate and the second material comprises a thermoplastic polyurethane based on aliphatic polyether; and a drug formulation comprising erdatinib disposed within the drug reservoir lumen, wherein: (i) the second wall structure or both the first and second wall structures are water-permeable, and (ii) The first wall structure is impermeable to erdatinib, and the second wall structure is permeable to erdatinib, allowing erdatinib to be released in vivo by diffusion through the second material forming the second wall structure. The first and second wall structures are adjacent to each other at two interface edges and together form a tube. These two interface edges are set at an arc angle of approximately 125 to approximately 145 degrees, particularly approximately 135 degrees, of the tube's circumference in a cross-section perpendicular to the tube's longitudinal axis. This arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, the arc angle is approximately 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, both the first and second wall structures are permeable to water. In some embodiments, the pharmaceutical formulation comprises (a) 50 wt% erdatinib free base; (b) 10 wt% hydroxypropyl-β-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silanized microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silica; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises microtablets. In some embodiments, the pharmaceutical formulation consists of microtablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdatinib microtablets. In some embodiments, the drug delivery system comprises 43 erdatinib microtablets. 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 microtablet has a weight between about 22 mg and about 24 mg. In some embodiments, each microtablet has a weight of about 23 mg. In some embodiments, the pharmaceutical formulation comprises about 480 mg to about 510 mg of erdatinib. In some embodiments, the pharmaceutical formulation comprises about 500 mg of erdatinib.In some embodiments, the pharmaceutical formulation comprises microtablets, each microtablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, the pharmaceutical formulation consists of microtablets, each microtablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, each microtablet has a thickness of about 3.2 mm.

[0257] In some embodiments, this document provides a drug delivery system comprising a housing defining a drug reservoir lumen defined by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises an aromatic thermoplastic polyurethane based on polycarbonate and the second material comprises a thermoplastic polyurethane based on aliphatic polyether; and a drug formulation comprising erdatinib disposed within the drug reservoir lumen, wherein: (i) the second wall structure or both the first and second wall structures are water-permeable, and (ii) The first wall structure is impermeable to erdatinib, and the second wall structure is permeable to erdatinib, allowing erdatinib to be released in vivo by diffusion through the second material forming the second wall structure. The first and second wall structures are adjacent to each other at two interface edges and together form a tube. These two interface edges are set at an arc angle of approximately 125 to approximately 145 degrees, particularly approximately 135 degrees, of the tube's circumference in a cross-section perpendicular to the tube's longitudinal axis. This arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, the arc angle is approximately 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, both the first and second wall structures are permeable to water. In some embodiments, the pharmaceutical formulation comprises (a) 50 wt% erdatinib free base; (b) 10 wt% hydroxypropyl-β-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silanized microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silica; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises microtablets. In some embodiments, the pharmaceutical formulation consists of microtablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdatinib microtablets. In some embodiments, the drug delivery system comprises 43 erdatinib microtablets. 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 microtablet has a weight between about 22 mg and about 24 mg. In some embodiments, each microtablet has a weight of about 23 mg. In some embodiments, the pharmaceutical formulation comprises about 480 mg to about 510 mg of erdatinib. In some embodiments, the pharmaceutical formulation comprises about 500 mg of erdatinib.In some embodiments, the pharmaceutical formulation comprises microtablets, each microtablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, the pharmaceutical formulation consists of microtablets, each microtablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, each microtablet has a thickness of about 3.2 mm. In some embodiments, the pharmaceutical formulation comprises microtablets, each microtablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, the pharmaceutical formulation consists of microtablets, each microtablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, each microtablet has a diameter of about 2.63 mm.

[0258] In some embodiments, this document provides a drug delivery system comprising a housing defining a drug reservoir lumen defined by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises an aromatic thermoplastic polyurethane based on polycarbonate and the second material comprises a thermoplastic polyurethane based on aliphatic polyether; and a drug formulation comprising erdatinib disposed within the drug reservoir lumen, wherein: (i) the second wall structure or both the first and second wall structures are water-permeable, and (ii) The first wall structure is impermeable to erdatinib, and the second wall structure is permeable to erdatinib, allowing erdatinib to be released in vivo by diffusion through the second material forming the second wall structure. The first and second wall structures are adjacent to each other at two interface edges and together form a tube. These two interface edges are set at an arc angle of approximately 125 to approximately 145 degrees, particularly approximately 135 degrees, of the tube's circumference in a cross-section perpendicular to the tube's longitudinal axis. This arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, the arc angle is approximately 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, both the first and second wall structures are permeable to water. In some embodiments, the pharmaceutical formulation comprises (a) 50 wt% erdatinib free base; (b) 10 wt% hydroxypropyl-β-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silanized microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silica; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises microtablets. In some embodiments, the pharmaceutical formulation consists of microtablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdatinib microtablets. In some embodiments, the drug delivery system comprises 43 erdatinib microtablets. 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 microtablet has a weight between about 22 mg and about 24 mg. In some embodiments, each microtablet has a weight of about 23 mg. In some embodiments, the pharmaceutical formulation comprises about 480 mg to about 510 mg of erdatinib. In some embodiments, the pharmaceutical formulation comprises about 500 mg of erdatinib.In some embodiments, the pharmaceutical formulation comprises microtablets, each microtablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, the pharmaceutical formulation consists of microtablets, each microtablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, each microtablet has a thickness of about 3.2 mm. In some embodiments, the pharmaceutical formulation comprises microtablets, each microtablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, the pharmaceutical formulation consists of microtablets, each microtablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, each microtablet has a diameter of about 2.63 mm. In some embodiments, the outer casing has a first end and a second end, defining a length between the first end and the second end, wherein the length is about 17 cm. In some embodiments, the drug reservoir lumen is sealed at the first and second opposite ends, for example, with a stopper, thermoplastic material, and / or sealant.

[0259] In some embodiments, this document provides a drug delivery system comprising a housing defining a drug reservoir lumen defined by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises an aromatic thermoplastic polyurethane based on polycarbonate and the second material comprises a thermoplastic polyurethane based on aliphatic polyether; and a drug formulation comprising erdatinib disposed within the drug reservoir lumen, wherein: (i) the second wall structure or both the first and second wall structures are water-permeable, and (ii) The first wall structure is impermeable to erdatinib, and the second wall structure is permeable to erdatinib, allowing erdatinib to be released in vivo by diffusion through the second material forming the second wall structure. The first and second wall structures are adjacent to each other at two interface edges and together form a tube. These two interface edges are set at an arc angle of approximately 125 to approximately 145 degrees, particularly approximately 135 degrees, of the tube's circumference in a cross-section perpendicular to the tube's longitudinal axis. This arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, the arc angle is approximately 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, both the first and second wall structures are permeable to water. In some embodiments, the pharmaceutical formulation comprises (a) 50 wt% erdatinib free base; (b) 10 wt% hydroxypropyl-β-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silanized microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silica; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises microtablets. In some embodiments, the pharmaceutical formulation consists of microtablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdatinib microtablets. In some embodiments, the drug delivery system comprises 43 erdatinib microtablets. 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 microtablet has a weight between about 22 mg and about 24 mg. In some embodiments, each microtablet has a weight of about 23 mg. In some embodiments, the pharmaceutical formulation comprises about 480 mg to about 510 mg of erdatinib. In some embodiments, the pharmaceutical formulation comprises about 500 mg of erdatinib.In some embodiments, the pharmaceutical formulation comprises microtablets, each microtablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, the pharmaceutical formulation consists of microtablets, each microtablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, each microtablet has a thickness of about 3.2 mm. In some embodiments, the pharmaceutical formulation comprises microtablets, each microtablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, the pharmaceutical formulation consists of microtablets, each microtablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, each microtablet has a diameter of about 2.63 mm. In some embodiments, the outer shell has a first end and a second end, defining a length between the first end and the second end, wherein the length is about 17 cm. In some embodiments, the drug reservoir lumen is sealed at the first and second opposite ends, for example, with a stopper, thermoplastic material, and / or sealant. In some embodiments, the outer shell of the drug delivery system includes a retaining frame lumen and a linear element disposed within the retaining frame lumen. In some embodiments, the wire has a diameter of about 0.305 mm and a length of about 156 mm. In some embodiments, the wire is a nitinol wire.

[0260] In some embodiments, this document provides a drug delivery system comprising a housing defining a drug reservoir lumen defined by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises an aromatic thermoplastic polyurethane based on polycarbonate and the second material comprises a thermoplastic polyurethane based on aliphatic polyether; and a drug formulation comprising erdatinib disposed within the drug reservoir lumen, wherein: (i) the second wall structure or both the first and second wall structures are water-permeable, and (ii) The first wall structure is impermeable to erdatinib, and the second wall structure is permeable to erdatinib, allowing erdatinib to be released in vivo by diffusion through the second material forming the second wall structure. The first and second wall structures are adjacent to each other at two interface edges and together form a tube. These two interface edges are set at an arc angle of approximately 125 to approximately 145 degrees, particularly approximately 135 degrees, of the tube's circumference in a cross-section perpendicular to the tube's longitudinal axis. This arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, the arc angle is approximately 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, both the first and second wall structures are permeable to water. In some embodiments, the pharmaceutical formulation comprises (a) 50 wt% erdatinib free base; (b) 10 wt% hydroxypropyl-β-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silanized microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silica; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises microtablets. In some embodiments, the pharmaceutical formulation consists of microtablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdatinib microtablets. In some embodiments, the drug delivery system comprises 43 erdatinib microtablets. 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 microtablet has a weight between about 22 mg and about 24 mg. In some embodiments, each microtablet has a weight of about 23 mg. In some embodiments, the pharmaceutical formulation comprises about 480 mg to about 510 mg of erdatinib. In some embodiments, the pharmaceutical formulation comprises about 500 mg of erdatinib.In some embodiments, the pharmaceutical formulation comprises microtablets, each microtablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, the pharmaceutical formulation consists of microtablets, each microtablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, each microtablet has a thickness of about 3.2 mm. In some embodiments, the pharmaceutical formulation comprises microtablets, each microtablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, the pharmaceutical formulation consists of microtablets, each microtablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, each microtablet has a diameter of about 2.63 mm. In some embodiments, the outer shell has a first end and a second end, defining a length between the first end and the second end, wherein the length is about 17 cm. In some embodiments, the drug reservoir lumen is sealed at the first and second opposite ends, for example, with a stopper, thermoplastic material, and / or sealant. In some embodiments, the outer shell of the drug delivery system includes a retaining frame lumen and a linear element disposed within the retaining frame lumen. In some embodiments, the linear element has a diameter of about 0.305 mm and a length of about 156 mm. In some embodiments, the linear element is a nitinol wire. In some embodiments, multiple microtablets are connected in series, and a core length is defined between the first face of the first microtablet and the opposing second face of the last microtablet, wherein the core length is about 15 cm.

[0261] In some embodiments, this document provides a drug delivery system comprising a housing defining a drug reservoir lumen defined by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises an aromatic thermoplastic polyurethane based on polycarbonate and the second material comprises a thermoplastic polyurethane based on aliphatic polyether; and a drug formulation comprising erdatinib disposed within the drug reservoir lumen, wherein: (i) the second wall structure or both the first and second wall structures are water-permeable, and (ii) The first wall structure is impermeable to erdatinib, and the second wall structure is permeable to erdatinib, allowing erdatinib to be released in vivo by diffusion through the second material forming the second wall structure. The first and second wall structures are adjacent to each other at two interface edges and together form a tube. These two interface edges are set at an arc angle of approximately 125 to approximately 145 degrees, particularly approximately 135 degrees, of the tube's circumference in a cross-section perpendicular to the tube's longitudinal axis. This arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, the arc angle is approximately 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, both the first and second wall structures are permeable to water. In some embodiments, the pharmaceutical formulation comprises (a) 50 wt% erdatinib free base; (b) 10 wt% hydroxypropyl-β-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silanized microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silica; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises microtablets. In some embodiments, the pharmaceutical formulation consists of microtablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdatinib microtablets. In some embodiments, the drug delivery system comprises 43 erdatinib microtablets. 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 microtablet has a weight between about 22 mg and about 24 mg. In some embodiments, each microtablet has a weight of about 23 mg. In some embodiments, the pharmaceutical formulation comprises about 480 mg to about 510 mg of erdatinib. In some embodiments, the pharmaceutical formulation comprises about 500 mg of erdatinib.In some embodiments, the pharmaceutical formulation comprises microtablets, each microtablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, the pharmaceutical formulation consists of microtablets, each microtablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, each microtablet has a thickness of about 3.2 mm. In some embodiments, the pharmaceutical formulation comprises microtablets, each microtablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, the pharmaceutical formulation consists of microtablets, each microtablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, each microtablet has a diameter of about 2.63 mm. In some embodiments, the outer shell has a first end and a second end, defining a length between the first end and the second end, wherein the length is about 17 cm. In some embodiments, the drug reservoir lumen is sealed at the first and second opposite ends, for example, with a stopper, thermoplastic material, and / or sealant. In some embodiments, the outer shell of the drug delivery system includes a retaining frame lumen and a linear element disposed within the retaining frame lumen. In some embodiments, the linear element has a diameter of about 0.305 mm and a length of about 156 mm. In some embodiments, the linear element is a nitinol wire. In some embodiments, multiple microtablets are connected in series, and a core length is defined between the first face of the first microtablet and the opposing second face of the last microtablet, wherein the core length is about 15 cm. In some embodiments, a 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.

[0262] In some embodiments, this document provides a drug delivery system comprising a housing defining a drug reservoir lumen defined by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises an aromatic thermoplastic polyurethane based on polycarbonate and the second material comprises a thermoplastic polyurethane based on aliphatic polyether; and a drug formulation comprising erdatinib disposed within the drug reservoir lumen, wherein: (i) the second wall structure or both the first and second wall structures are water-permeable, and (ii) The first wall structure is impermeable to erdatinib, and the second wall structure is permeable to erdatinib, allowing erdatinib to be released in vivo by diffusion through the second material forming the second wall structure. The first and second wall structures are adjacent to each other at two interface edges and together form a tube. These two interface edges are set at an arc angle of approximately 125 to approximately 145 degrees, particularly approximately 135 degrees, of the tube's circumference in a cross-section perpendicular to the tube's longitudinal axis. This arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, the arc angle is approximately 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, both the first and second wall structures are permeable to water. In some embodiments, the pharmaceutical formulation comprises (a) 50 wt% erdatinib free base; (b) 10 wt% hydroxypropyl-β-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silanized microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silica; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises microtablets. In some embodiments, the pharmaceutical formulation consists of microtablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdatinib microtablets. In some embodiments, the drug delivery system comprises 43 erdatinib microtablets. 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 microtablet has a weight between about 22 mg and about 24 mg. In some embodiments, each microtablet has a weight of about 23 mg. In some embodiments, the pharmaceutical formulation comprises about 480 mg to about 510 mg of erdatinib. In some embodiments, the pharmaceutical formulation comprises about 500 mg of erdatinib.In some embodiments, the pharmaceutical formulation comprises microtablets, each microtablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, the pharmaceutical formulation consists of microtablets, each microtablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, each microtablet has a thickness of about 3.2 mm. In some embodiments, the pharmaceutical formulation comprises microtablets, each microtablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, the pharmaceutical formulation consists of microtablets, each microtablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, each microtablet has a diameter of about 2.63 mm. In some embodiments, the outer shell has a first end and a second end, defining a length between the first end and the second end, wherein the length is about 17 cm. In some embodiments, the drug reservoir lumen is sealed at the first and second opposite ends, for example, with a stopper, thermoplastic material, and / or sealant. In some embodiments, the outer shell of the drug delivery system includes a retaining frame lumen and a linear element disposed within the retaining frame lumen. In some embodiments, the linear element has a diameter of about 0.305 mm and a length of about 156 mm. In some embodiments, the linear element is a nitinol wire. In some embodiments, multiple microtablets are connected in series, and a core length is defined between the first face of the first microtablet and the opposing second face of the last microtablet, wherein the core length is about 15 cm. In some embodiments, a 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.

[0263] In some embodiments, this document provides a drug delivery system comprising a housing defining a drug reservoir lumen defined by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises an aromatic thermoplastic polyurethane based on polycarbonate and the second material comprises a thermoplastic polyurethane based on aliphatic polyether; and a drug formulation comprising erdatinib disposed within the drug reservoir lumen, wherein: (i) the second wall structure or both the first and second wall structures are water-permeable, and (ii) The first wall structure is impermeable to erdatinib, and the second wall structure is permeable to erdatinib, allowing erdatinib to be released in vivo by diffusion through the second material forming the second wall structure. The first and second wall structures are adjacent to each other at two interface edges and together form a tube. These two interface edges are set at an arc angle of approximately 125 to approximately 145 degrees, particularly approximately 135 degrees, of the tube's circumference in a cross-section perpendicular to the tube's longitudinal axis. This arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, the arc angle is approximately 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, both the first and second wall structures are permeable to water. In some embodiments, the pharmaceutical formulation comprises (a) 50 wt% erdatinib free base; (b) 10 wt% hydroxypropyl-β-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silanized microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silica; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises microtablets. In some embodiments, the pharmaceutical formulation consists of microtablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdatinib microtablets. In some embodiments, the drug delivery system comprises 43 erdatinib microtablets. 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 microtablet has a weight between about 22 mg and about 24 mg. In some embodiments, each microtablet has a weight of about 23 mg. In some embodiments, the pharmaceutical formulation comprises about 480 mg to about 510 mg of erdatinib. In some embodiments, the pharmaceutical formulation comprises about 500 mg of erdatinib.In some embodiments, the pharmaceutical formulation comprises microtablets, each microtablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, the pharmaceutical formulation consists of microtablets, each microtablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, each microtablet has a thickness of about 3.2 mm. In some embodiments, the pharmaceutical formulation comprises microtablets, each microtablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, the pharmaceutical formulation consists of microtablets, each microtablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, each microtablet has a diameter of about 2.63 mm. In some embodiments, the outer shell has a first end and a second end, defining a length between the first end and the second end, wherein the length is about 17 cm. In some embodiments, the drug reservoir lumen is sealed at the first and second opposite ends, for example, with a stopper, thermoplastic material, and / or sealant. In some embodiments, the outer shell of the drug delivery system includes a retaining frame lumen and a linear element disposed within the retaining frame lumen. In some embodiments, the linear element has a diameter of about 0.305 mm and a length of about 156 mm. In some embodiments, the linear element is a nitinol wire. In some embodiments, multiple microtablets are connected in series, and a core length is defined between the first face of the first microtablet and the opposing second face of the last microtablet, wherein the core length is about 15 cm. In some embodiments, a 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 coiled retaining shape and a relatively straight insertion shape. In some embodiments, the coiled retaining shape includes a bi-elliptical shape.

[0264] In some embodiments, this document provides a drug delivery system comprising a housing defining a drug reservoir lumen defined by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises an aromatic thermoplastic polyurethane based on polycarbonate and the second material comprises a thermoplastic polyurethane based on aliphatic polyether; and a drug formulation comprising erdatinib disposed within the drug reservoir lumen, wherein: (i) the second wall structure or both the first and second wall structures are water-permeable, and (ii) The first wall structure is impermeable to erdatinib, and the second wall structure is permeable to erdatinib, allowing erdatinib to be released in vivo by diffusion through the second material forming the second wall structure. The first and second wall structures are adjacent to each other at two interface edges and together form a tube. These two interface edges are set at an arc angle of approximately 125 to approximately 145 degrees, particularly approximately 135 degrees, of the tube's circumference in a cross-section perpendicular to the tube's longitudinal axis. This arc angle contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, the arc angle is approximately 135 degrees and contains the second material forming the second wall structure, such that the arc of the second wall structure corresponds to this arc angle. In some embodiments, both the first and second wall structures are permeable to water. In some embodiments, the pharmaceutical formulation comprises (a) 50 wt% erdatinib free base; (b) 10 wt% hydroxypropyl-β-cyclodextrin; (c) 17.5 wt% microcrystalline cellulose; (d) 11.75 wt% silanized microcrystalline cellulose; (e) 7.5 wt% vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25 wt% colloidal silica; (g) 1.5 wt% hydroxypropyl methylcellulose; and (h) 1.5 wt% magnesium stearate, wherein these weight percentages are relative to the entire pharmaceutical formulation. In some embodiments, the pharmaceutical formulation comprises microtablets. In some embodiments, the pharmaceutical formulation consists of microtablets. In some embodiments, the drug delivery system comprises about 42 to 44 erdatinib microtablets. In some embodiments, the drug delivery system comprises 43 erdatinib microtablets. 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 microtablet has a weight between about 22 mg and about 24 mg. In some embodiments, each microtablet has a weight of about 23 mg. In some embodiments, the pharmaceutical formulation comprises about 480 mg to about 510 mg of erdatinib. In some embodiments, the pharmaceutical formulation comprises about 500 mg of erdatinib.In some embodiments, the pharmaceutical formulation comprises microtablets, each microtablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, the pharmaceutical formulation consists of microtablets, each microtablet having a thickness of about 3.0 mm to about 3.4 mm. In some embodiments, each microtablet has a thickness of about 3.2 mm. In some embodiments, the pharmaceutical formulation comprises microtablets, each microtablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, the pharmaceutical formulation consists of microtablets, each microtablet having a diameter of about 2.60 mm to about 2.66 mm. In some embodiments, each microtablet has a diameter of about 2.63 mm. In some embodiments, the outer shell has a first end and a second end, defining a length between the first end and the second end, wherein the length is about 17 cm. In some embodiments, the drug reservoir lumen is sealed at the first and second opposite ends, for example, with a stopper, thermoplastic material, and / or sealant. In some embodiments, the outer shell of the drug delivery system includes a retaining frame lumen and a linear element disposed within the retaining frame lumen. In some embodiments, the linear element has a diameter of about 0.305 mm and a length of about 156 mm. In some embodiments, the linear element is a nitinol wire. In some embodiments, multiple microtablets are connected in series, and a core length is defined between the first face of the first microtablet and the opposing second face of the last microtablet, wherein the core length is about 15 cm. In some embodiments, a 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 coiled retaining shape and a relatively straight insertion shape. In some embodiments, the coiled retaining shape includes a double elliptical shape. In some embodiments, when in the coiled retaining shape, the drug delivery system has a maximum dimension equal to or less than about 6 cm in any direction. In some embodiments, when in the coiled retaining shape, the drug delivery system has a maximum dimension equal to or less than about 5.5 cm in any direction. In some implementations, the drug delivery system fits into a 5.5cm × 4.5cm envelope when in a curled-up shape.

[0265] In some embodiments, the first and second wall structures are permeable to water. In some embodiments, the first wall structure is impermeable to erdatinib, and the second wall structure is permeable to erdatinib. In some embodiments, erdatinib can 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 interface edges and together form a tube.

[0266] In some embodiments, this document provides a drug delivery system comprising a housing defining a drug reservoir lumen defined by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises an aromatic thermoplastic polyurethane based on polycarbonate and the second material comprises a thermoplastic polyurethane based on aliphatic polyether; and a drug formulation disposed in the drug reservoir lumen comprising erdatinib, wherein: (i) both the first and second wall structures are permeable to water, and (ii) the first wall structure is impermeable to erdatinib and the second wall structure is permeable to erdatinib, such that erdatinib can be released in vivo by diffusion through the second material forming the second wall structure, wherein the first and second wall structures are adjacent to each other at two interface edges and together form a tube.

[0267] In some embodiments, the drug delivery system described herein is configured to release erdatinib at an average rate of about 2 mg / day, and the two interface edges are arranged at an arc angle of about 90 degrees around the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube, wherein the thickness of the first wall structure, the second wall structure, or both is about 0.2 mm to about 1.0 mm, wherein the thickness of the second wall structure is about 0.16 mm to about 0.24 mm, and wherein the first wall structure is impermeable to erdatinib, and the second wall structure is permeable to erdatinib.

[0268] In some embodiments, the drug delivery system described herein is configured to release erdatinib at an average rate of about 2.5 mg / day to about 3.5 mg / day, and the two interface edges are arranged at an arc angle of about 125 degrees to about 145 degrees of the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, wherein the thickness of the first wall structure, the second wall structure, or both is about 0.2 mm to about 1.0 mm, wherein the thickness of the second wall structure is about 0.16 mm to about 0.24 mm, and wherein the first wall structure is impermeable to erdatinib, and the second wall structure is permeable to erdatinib.

[0269] In some embodiments, the drug delivery system described herein is configured to release erdatinib at an average rate of about 3 mg / day, and the two interface edges are arranged at an arc angle of about 135 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, wherein the thickness of the first wall structure, the second wall structure, or both is about 0.2 mm to about 1.0 mm, wherein the thickness of the second wall structure is about 0.16 mm to about 0.24 mm, and wherein the first wall structure is impermeable to erdatinib, and the second wall structure is permeable to erdatinib.

[0270] In some embodiments, the drug delivery system described herein is configured to release erdatinib at an average rate of about 4 mg / day, and the two interface edges are arranged at an arc angle of about 180 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, wherein the thickness of the first wall structure, the second wall structure, or both is about 0.2 mm to about 1.0 mm, wherein the thickness of the second wall structure is about 0.16 mm to about 0.24 mm, and wherein the first wall structure is impermeable to erdatinib, and the second wall structure is permeable to erdatinib.

[0271] Drug tablets As discussed herein with respect to erdatinib pharmaceutical formulations, the drug can be delivered in a solid form (e.g., a solid microtablet) suitable for loading into the lumen of a drug reservoir within a system. In a preferred embodiment, such as Figure 1 As shown, a pharmaceutical formulation is formed into a pharmaceutical unit 108 and loaded into a drug reservoir lumen of system 100. Each pharmaceutical unit is a solid discrete object that substantially retains the shape selectively assigned to it (under the temperature and pressure conditions typically exposed to the pharmaceutical unit (e.g., tablet) and delivery system during processing prior to assembly (e.g., loading into the system drug reservoir), storage, and insertion into the body).

[0272] Each drug unit may have substantially any selected shape and size suitable for the system described herein. In one embodiment, the size and shape of the drug units are configured such that a drug reservoir lumen within the housing is substantially filled with a selected number of drug units. The cross-sectional shape of each drug unit may substantially correspond to the cross-sectional shape of the drug reservoir lumen of a particular housing. For example, the drug units may be substantially cylindrical in shape for positioning within a substantially cylindrical drug reservoir lumen. In some embodiments, once loaded, the drug units may substantially fill the drug reservoir lumen forming the drug housing portion.

[0273] In one embodiment, the drug units are shaped to be arranged in a row when the system is in its deployment configuration. For example, the cross-sectional shape of each drug unit may correspond to the cross-sectional shape of a drug reservoir lumen in the housing, and the end face shape of each drug unit may correspond to the end face of an adjacent drug unit. Gaps or breaks between the drug units can accommodate system deformation or movement, such as during deployment, while allowing each drug unit to retain its solid form. Thus, the drug delivery system, despite being loaded with a solid drug composition (such as a tablet), can still be relatively flexible or deformable because it allows each drug unit to move relative to its adjacent drug units.

[0274] In embodiments in which the drug unit is designed for insertion or implantation into a lumen or cavity (such as the bladder) within the body via a drug delivery system, the drug unit may be a “microtablet” of a size and shape adapted for insertion through a natural lumen of the body (such as the urethra). For the purposes of this disclosure, the term “microtablet” generally refers to a solid drug unit of substantially cylindrical shape having an end face and substantially cylindrical sides. The diameter of the microtablet extending along the end face ranges from about 1.0 mm to about 3.2 mm, such as between about 1.5 mm and about 3.1 mm. The length of the microtablet extending along the sides ranges from about 1.7 mm to about 4.8 mm, such as between about 2.0 mm and about 4.5 mm. The friability of the tablet may be less than about 2%. In one aspect, the tablets are those described herein. In one aspect, the tablets are those of formulation 4A. In one aspect, the tablets are those of formulation 4B. In one aspect, the tablets are those of formulation 4C. In one aspect, the tablets are those of formulation 4D.

[0275] Treatment In some aspects, this article provides a method for treating patients with HR-NMIBC (e.g., recurrent high-risk non-muscle-invasive bladder cancer that has undergone BCG vaccination (HR-NMIBC)) comprising administering erdatinib, for example, about 2.5 mg / day to about 3.5 mg / day, locally to the patient's bladder for at least about 90 days, particularly wherein such treatment results in a recurrence-free rate of at least 50% in the patient population receiving this treatment. In some embodiments, the patient population comprises, consists of, or is substantially composed of patients as described herein in Cohort 1.

[0276] In other respects, this article provides a method for treating a patient with HR-NMIBC (e.g., HR-NMIBC with recurrent BCG), the method comprising deploying an intravesical drug delivery system into the patient's bladder, the intravesical drug delivery system comprising a shell defining a closed drug reservoir lumen and a drug formulation containing erdatinib disposed within the closed drug reservoir lumen, wherein the drug reservoir lumen is formed by a first wall structure and a second wall structure, the first wall structure being formed of a first material and the second wall structure being formed of a second material, the first wall structure and the second wall structure being joined to each other at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are arranged at an arc angle of 45 degrees to 270 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. In some embodiments, the treatment includes releasing erdatinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the treatment includes removing the drug delivery system after at least about 90 days. In some embodiments, the treatment results in a relapse-free rate of at least 50% in the patient population receiving this treatment. In some embodiments, the patient population comprises, consists of, or is substantially comprised of Cohort 1 patients with recurrent BCG-repeated HR-NMIBC. In some embodiments, the second wall structure or both the first and second wall structures are water-permeable. In some embodiments, the first wall structure is impermeable to erdatinib, and the second wall structure is permeable to erdatinib, such that erdatinib can be released in vivo by diffusion through the second material forming the second wall structure. In some embodiments, the arc angle in a cross-section perpendicular to the longitudinal axis of the tube is 45 to 90 degrees of the tube circumference. In some embodiments, the arc angle in a cross-section perpendicular to the longitudinal axis of the tube is 150 to 270 degrees of the tube circumference. In some embodiments, the arc angle in a cross-section perpendicular to the longitudinal axis of the tube is 125 to 145 degrees of the tube circumference.

[0277] In some embodiments, the method includes administering erdatinib topically to the bladder of a patient with HR-NMIBC (e.g., recurrent BCG-relapsed high-risk non-muscle-invasive bladder cancer (HR-NMIBC)) for at least approximately 90 days, at a rate of approximately 2 mg / day to approximately 4 mg / day. In some embodiments, the method includes administering erdatinib topically to a patient with recurrent BCG-relapsed high-risk non-muscle-invasive bladder cancer (HR-NMIBC) at a rate of approximately 2 mg / day. In some embodiments, the method includes administering erdatinib topically to a patient with recurrent BCG-relapsed high-risk non-muscle-invasive bladder cancer (HR-NMIBC) at a rate of approximately 4 mg / day.

[0278] In some embodiments, the treatment results in a relapse-free rate of at least 50% in the treated patient population, wherein the patient population comprises, consists of, or is substantially composed of Cohort 1 patients with recurrent 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% for patients treated with approximately 2 mg / day of erdatinib. In some embodiments, the relapse-free rate in a patient population treated with approximately 2 mg / day of erdatinib is approximately 80%, wherein the patient population includes, comprises, or substantially comprises patients from Cohort 1 as described herein. In some embodiments, the relapse-free rate in a patient population treated with approximately 2 mg / day of erdatinib is at least 88.9%, wherein the patient population includes, comprises, or substantially comprises patients from Cohort 1 as described herein. In some embodiments, the relapse-free rate in a patient population treated with approximately 4 mg / day of erdatinib is approximately 83%, such as approximately 83.3%. In some embodiments, the relapse-free rate in a patient population treated with approximately 4 mg / day of erdatinib is approximately 83%, such as approximately 83.3%, wherein the patient population includes, comprises, or substantially comprises patients from Cohort 1 as described herein. In some embodiments, the relapse-free rate in a patient population treated with approximately 4 mg / day of erdatinib is at least 85.7%, wherein the patient population includes, comprises, or substantially comprises patients from Cohort 1 as described herein. In some implementations, the relapse-free rate in the patient population treated with erdatinib at a dose of approximately 2 mg / day to approximately 4 mg / day is approximately 82%, such as approximately 81.8%. In some implementations, the relapse-free rate in the patient population treated with erdatinib at a dose of approximately 2 mg / day to approximately 4 mg / day is approximately 82%, such as approximately 81.8%, wherein the patient population includes, comprises, or is substantially comprised of patients in Cohort 1 as described herein. In some implementations, the relapse-free rate is assessed at 3 months or 90 days of erdatinib treatment.

[0279] In some implementations, the method also includes transurethral resection of bladder tumor (TURBT) prior to administration of erdatinib.

[0280] In some embodiments, the method includes local administration of erdatinib to a patient with high-grade Ta or T1 bladder cancer for at least about 90 days, at a rate of about 2 mg / day to about 4 mg / day. In some embodiments, the patient population has high-grade Ta or T1 bladder cancer. In some embodiments, the patient population comprises, consists of, or is substantially composed of cohort 1 patients with recurrent HR-NMIBC who have undergone BCG therapy. In some embodiments, the patient has histologically confirmed high-grade Ta or T1 lesions. In some embodiments, the patient population has histologically confirmed high-grade Ta or T1 lesions. In some embodiments, the patient does not have carcinoma in situ (CIS). In some embodiments, the patient population does not have CIS. In some embodiments, the patient has recurrent high-grade Ta or T1 bladder cancer within 18 months of completing prior BCG therapy. In some embodiments, the patient population has recurrent high-grade Ta or T1 bladder cancer within 18 months of completing prior BCG therapy. In some embodiments, the patient has previously received at least 5 of 6 full doses of BCG induction therapy. In some embodiments, the patient population has previously received at least five of six full doses of BCG induction therapy. In some embodiments, the patients have high-risk papillary NMIBC. In some embodiments, the patient population has high-risk papillary NMIBC. In some embodiments, the patient population comprises, consists of, or is substantially composed of patients as described herein in Cohort 1.

[0281] In other respects, this article provides a method for treating patients with IR-NMIBC (e.g., recurrent intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC)) comprising administering erdatinib locally to the patient's bladder at a dose of approximately 2 mg / day to approximately 4 mg / day, for example, approximately 2.5 mg / day to approximately 3.5 mg / day, for at least approximately 90 days, particularly wherein such treatment results in a complete response rate of at least 50% in the patient population receiving such treatment. In some embodiments, the patient population comprises, consists of, or is substantially composed of Cohort 3 patients with recurrent IR-NMIBC.

[0282] In other respects, this document provides a method for treating a patient with IR-NMIBC (e.g., recurrent IR-NMIBC), the method comprising deploying an intravesical drug delivery system into the patient's bladder, the intravesical drug delivery system comprising a shell defining a closed drug reservoir lumen and a drug formulation containing erdatinib disposed within the closed drug reservoir lumen, wherein the drug reservoir lumen is formed by a first wall structure and a second wall structure, the first wall structure being formed of a first material and the second wall structure being formed of a second material, the first wall structure and the second wall structure being joined to each other at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are arranged at an arc angle of 45 degrees to 270 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. In some embodiments, the treatment method comprises releasing erdatinib by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the treatment method comprises removing the drug delivery system after at least about 90 days. In some embodiments, the treatment method results in 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 is substantially comprised of Cohort 3 patients with recurrent IR-NMIBC. In some embodiments, the second wall structure or both the first and second wall structures are water-permeable. In some embodiments, the first wall structure is impermeable to erdatinib, and the second wall structure is permeable to erdatinib, such that erdatinib can be released in vivo by diffusion through the second material forming the second wall structure. In some embodiments, the two interface edges are set at an arc angle of 45 to 90 degrees, particularly 90 degrees, of the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube. In some embodiments, the two interface edges are set at an arc angle of 150 to 270 degrees, particularly 180 degrees, of the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube. In some embodiments, the two interface edges are set at an arc angle of 125 to 145 degrees, particularly 135 degrees, of the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube.

[0283] In some embodiments, the method includes administering erdatinib topically to the bladder of a patient with IR-NMIBC (e.g., recurrent IR-NMIBC) for at least about 90 days, at a rate of about 2 mg / day to about 4 mg / day. In some embodiments, the method includes administering erdatinib to a patient with recurrent IR-NMIBC at a rate of about 2 mg / day. In some embodiments, the method includes administering erdatinib to a patient with recurrent IR-NMIBC at a rate of about 4 mg / day.

[0284] In some embodiments, the treatment results in a complete response rate of at least 50% in the treated population of patients with relapsed IR-NMIBC. 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 approximately 75% for patients treated with approximately 2 mg / day of erdatinib. In some embodiments, the complete response rate in the patient population is 75% for patients treated with approximately 2 mg / day, wherein the patient population comprises, consists of, or is substantially composed of patients in Cohort 3 as described herein. In some embodiments, the complete response rate in a patient population is approximately 100% for patients treated with approximately 4 mg / day of erdatinib. In some embodiments, the complete response rate in a patient population is 100% for patients treated with approximately 4 mg / day, wherein the patient population includes, comprises, or substantially comprises patients from cohort 3 as described herein. In some embodiments, the complete response rate in a patient population is approximately 87%, such as approximately 86.7%, for patients treated with erdatinib from approximately 2 mg / day to approximately 4 mg / day. In some embodiments, the complete response rate in a patient population is approximately 87%, such as approximately 86.7%, for patients treated with erdatinib from approximately 2 mg / day to approximately 4 mg / day, wherein the patient population includes, comprises, or substantially comprises patients from cohort 3 as described herein. In some embodiments, the complete response rate is assessed at 3 months or 90 days of erdatinib treatment.

[0285] In some embodiments, the method includes topical administration of erdatinib to a patient's bladder for at least about 90 days at about 2 mg / day to about 4 mg / day, wherein the patient has only a low-grade medical history. In some embodiments, the patient population has only a low-grade medical history. 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 no prior history of carcinoma in situ. In some embodiments, the patient population has no prior history of carcinoma in situ. In some embodiments, the patient has visible disease at the time of erdatinib administration. In some embodiments, the patient population has visible disease at the time of erdatinib administration. 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 undergone TURBT prior to erdatinib administration. In some embodiments, the patient population has not undergone TURBT prior to erdatinib administration. In some embodiments, the patient population comprises, consists of, or is substantially composed of patients in Cohort 3 with recurrent IR-NMIBC as described herein.

[0286] In some embodiments, the method includes administering approximately 2 mg / day of erdatinib to the patient. In some embodiments, the method includes administering approximately 4 mg / day of erdatinib to the patient.

[0287] In some embodiments, the method of treating a patient with HR-NMIBC (e.g., recurrent high-risk non-muscle invasive bladder cancer (HR-NMIBC) that has undergone BCG vaccination) involves administering erdatinib topically to the patient's bladder at a dose of about 2 mg / day to about 4 mg / day, more particularly about 3 mg / day, for at least about 90 days, wherein the erdatinib formulation is Formulation 4B as described herein. In some embodiments, the solid pharmaceutical composition comprises: (a) 50 wt% of erdatinib free base; (b) 10 wt% of hydroxypropyl-β-cyclodextrin; (c) 1 wt% of meglumine; (d) 24.5 wt% of microcrystalline cellulose; (e) 6.0 wt% of silanized microcrystalline cellulose; (f) 6.0 wt% of vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5 wt% of colloidal silica; and (h) 2.0 wt% of magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In some embodiments, the formulation is contained within an intravesical drug delivery system, particularly wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the end of the intravesical drug delivery system is closed.

[0288] In other respects, this article provides a method for treating patients with IR-NMIBC (e.g., recurrent intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC)) comprising administering erdatinib topically to the patient's bladder at a dose of about 2 mg / day to about 4 mg / day, more particularly about 3 mg / day, for at least about 90 days, wherein the erdatinib formulation is Formulation 4B as described herein. In some embodiments, the solid pharmaceutical composition comprises: (a) 50 wt% of erdatinib free base; (b) 10 wt% of hydroxypropyl-β-cyclodextrin; (c) 1 wt% of meglumine; (d) 24.5 wt% of microcrystalline cellulose; (e) 6.0 wt% of silanized microcrystalline cellulose; (f) 6.0 wt% of vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5 wt% of colloidal silica; and (h) 2.0 wt% of magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In some embodiments, the formulation is contained within an intravesical drug delivery system, particularly wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the end of the intravesical drug delivery system is closed.

[0289] In some implementations, the method of treating a patient with HR-NMIBC (e.g., recurrent high-risk non-muscle invasive bladder cancer that has undergone BCG vaccination (HR-NMIBC)) involves administering erdatinib locally to the patient's bladder at a dose of about 2 mg / day to about 4 mg / day, more particularly about 3 mg / day, for at least about 90 days, wherein the erdatinib formulation is the formulation described herein 3.4. In some embodiments, the solid pharmaceutical composition comprises: (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 1% by weight of meglumine; (d) 17.5% by weight of microcrystalline cellulose; (e) 10.75% by weight of silanized microcrystalline cellulose; (f) 7.5% by weight of vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25% by weight of colloidal silica; (h) 1.5% by weight of hydroxypropyl methylcellulose; and (i) 1.5% by weight of magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In some embodiments, the formulation is contained within an intravesical drug delivery system, particularly wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the end of the intravesical drug delivery system is closed.

[0290] In other respects, this article provides a method for treating patients with IR-NMIBC (e.g., recurrent intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC)) comprising administering erdatinib locally to the patient’s bladder at a dose of about 2 mg / day to about 4 mg / day, more particularly about 3 mg / day, for at least about 90 days, wherein the erdatinib formulation is the formulation as described herein 3.4. Therefore, this disclosure covers formulation 3.4, wherein the solid pharmaceutical composition comprises: (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 1% by weight of meglumine; (d) 17.5% by weight of microcrystalline cellulose; (e) 10.75% by weight of silanized microcrystalline cellulose; (f) 7.5% by weight of vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25% by weight of colloidal silica; (h) 1.5% by weight of hydroxypropyl methylcellulose; and (i) 1.5% by weight of magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In some embodiments, the formulation is contained within an intravesical drug delivery system, particularly wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the end of the intravesical drug delivery system is closed.

[0291] In some implementations, the method of treating a patient with HR-NMIBC (e.g., recurrent high-risk non-muscle invasive bladder cancer that has undergone BCG vaccination (HR-NMIBC)) involves administering erdatinib locally to the patient's bladder at a dose of about 2 mg / day to about 4 mg / day, more particularly about 3 mg / day, for at least about 90 days, wherein the erdatinib formulation is the formulation described herein 4.1. In some embodiments, the solid pharmaceutical composition comprises: (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 17.5% by weight of microcrystalline cellulose; (d) 11.75% by weight of silanized microcrystalline cellulose; (e) 7.5% by weight of vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25% by weight of colloidal silica; (g) 1.5% by weight of hydroxypropyl methylcellulose; and (h) 1.5% by weight of magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In some embodiments, the formulation is contained within an intravesical drug delivery system, particularly wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the end of the intravesical drug delivery system is closed.

[0292] In other respects, this article provides a method for treating patients with IR-NMIBC (e.g., recurrent intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC)) comprising administering erdatinib locally to the patient’s bladder at a dose of about 2 mg / day to about 4 mg / day, more particularly about 3 mg / day, for at least about 90 days, wherein the erdatinib formulation is the formulation described herein 4.1. Therefore, this disclosure covers formulation 4.1, wherein the solid pharmaceutical composition comprises: (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 17.5% by weight of microcrystalline cellulose; (d) 11.75% by weight of silanized microcrystalline cellulose; (e) 7.5% by weight of vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25% by weight of colloidal silica; (g) 1.5% by weight of hydroxypropyl methylcellulose; and (h) 1.5% by weight of magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In some embodiments, the formulation is contained within an intravesical drug delivery system, particularly wherein the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the end of the intravesical drug delivery system is closed.

[0293] In some embodiments, a method of treating a patient with HR-NMIBC (e.g., recurrent high-risk non-muscle-invasive bladder cancer (HR-NMIBC) that has undergone BCG vaccination) includes deploying an intravesical drug delivery system as described herein. In some embodiments, the drug delivery system includes a housing defining a drug reservoir lumen defined by a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being adjacent to each other at two interface edges and together forming a tube defining a closed drug reservoir; and a drug formulation disposed within the drug reservoir lumen, the drug formulation comprising erdatinib, wherein: (i) the second wall structure or both the first and second wall structures are water-permeable, and (ii) the first wall structure is impermeable to erdatinib and the second wall structure is permeable to erdatinib, such that erdatinib can be released in vivo by diffusion through the second material forming the second wall structure.

[0294] In some embodiments, a method of treating a patient with IR-NMIBC (e.g., recurrent intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC)) includes deploying an intravesical drug delivery system as described herein. In some embodiments, the drug delivery system includes a housing defining a drug reservoir lumen defined by a first wall structure formed of a first material and a second wall structure formed of a second material, the first and second wall structures being adjacent to each other at two interface edges and together forming a tube defining a closed drug reservoir; and a drug formulation disposed within the drug reservoir lumen, the drug formulation comprising erdatinib, wherein: (i) the second wall structure or both the first and second wall structures are water-permeable, and (ii) the first wall structure is impermeable to erdatinib and the second wall structure is permeable to erdatinib, such that erdatinib can be released in vivo by diffusion through the second material forming the second wall structure.

[0295] In some embodiments, methods for treating patients with HR-NMIBC (e.g., recurrent high-risk non-muscle-invasive bladder cancer that has undergone BCG vaccination (HR-NMIBC)) include 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, the end of the intravesical drug delivery system is closed.

[0296] In some embodiments, a method of treating a patient with IR-NMIBC (e.g., recurrent intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC)) includes 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, the end of the device is closed.

[0297] In some embodiments, the method includes administering erdatinib topically to a patient's bladder for at least approximately 90 days at a dose of approximately 2 mg / day to approximately 4 mg / day, wherein the patient has not previously been treated with an FGFR inhibitor. In some embodiments, the patient population has not previously been treated with an FGFR inhibitor.

[0298] In some embodiments, the patient carries at least one FGFR2 gene alteration. In some embodiments, the patient carries at least one FGFR3 gene alteration. In some embodiments, the patient carries at least one FGFR2 and at least one FGFR3 gene alteration. In some embodiments, the patient population carries at least one FGFR2 gene alteration. In some embodiments, the patient population carries at least one FGFR3 gene alteration. In some embodiments, the patient population has at least one FGFR2 and at least one FGFR3 gene alteration.

[0299] In some embodiments, the FGFR2 gene alteration includes activation of tumor FGFR2 mutations or fusions. In some embodiments, the FGFR2 gene alteration includes activation of tumor FGFR2 fusions. In some embodiments, the FGFR3 gene alteration includes activation of tumor FGFR3 mutations or fusions. In some embodiments, the FGFR3 gene alteration includes activation of tumor FGFR3 mutations. In some embodiments, the FGFR3 gene alteration includes activation of tumor FGFR3 fusions. In some embodiments, both the FGFR2 and FGFR3 gene alterations include activation of tumor FGFR2 or 3 mutations or fusions. In some embodiments, the FGFR3 gene alteration is an FGFR3 mutation selected from the group consisting of: FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, and FGFR3 G370C. In some embodiments, the FGFR3 gene alteration is a gene fusion containing FGFR3:TACC3_V1. In some embodiments, the FGFR gene alteration is detected using PCR or NGS assays on urine samples obtained from the patient. In some implementations, PCR or NGS assays of tumor tissue samples obtained from patients are used to detect FGFR gene alterations. In other implementations, histopathological images of tumor tissue are used to detect FGFR gene alterations via digital histopathological analysis.

[0300] In some embodiments, FGFR gene alterations are detected using NGS or PCR assays of urine samples and tumor tissue samples obtained from the patient. In some embodiments, there is a high degree of concordance between FGFR alterations detected by urine sample assays and tumor tissue sample assays. In some embodiments, urine sample assays identify bladder cancer patients not identified by tumor tissue sample assays. In some embodiments, patients are identified solely by urine sample assays. In some embodiments, patients are identified solely by urine sample assays due to a lack of available samples or insufficient tumor tissue. In some embodiments, urine sample assays identify at least about 5%, 10%, 15%, 20%, 25%, or 27% more bladder cancer patients than tumor tissue sample assays. In some embodiments, urine sample assays identify about 5% to 50%, 10% to 45%, 15% to 40%, 20% to 35%, or 25% to 30% more bladder cancer patients than tumor tissue sample assays. In some embodiments, urine sample assays identify about 29% more bladder cancer patients than tumor tissue sample assays. In one implementation, urine sample testing is performed using NGS (next-generation sequencing), specifically PredicineCare. ™(NGS) assay. In one implementation, the assay of tumor tissue samples is a PCR (polymerase chain reaction) assay, specifically QIAGEN therascreen. ® FGFR RGQ RT-PCR kit.

[0301] In some embodiments, at least 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of treated patients, identified solely by urine sample testing, are relapse-free or have achieved a complete response. In some embodiments, approximately 50% to 100%, 55% to 95%, 60% to 90%, 65% to 85%, or 70% to 80% of treated patients, identified solely by urine sample testing, are relapse-free or have achieved a complete response. In some embodiments, at least approximately 80%, 90%, 95%, or 100% of treated patients, identified solely by urine sample testing, are relapse-free or have achieved a complete response. In some embodiments, at least approximately 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% of treated patients, identified solely by urine sample testing, are relapse-free or have achieved a complete response. In some embodiments, all treated patients, identified solely by urine sample testing, are relapse-free or have achieved a complete response. In one implementation, urine sample testing is performed using NGS (next-generation sequencing), specifically PredicineCare. ™ (NGS) determination.

[0302] In some embodiments, the method of administering erdatinib includes deploying an intravesical drug delivery system containing erdatinib into a patient's bladder. In some embodiments, the method includes administering erdatinib from about 2 mg / day to about 4 mg / day, wherein administering erdatinib includes deploying an intravesical drug delivery system as described herein. In some embodiments, the method includes removing the drug delivery system after about 90 days. In some embodiments, the drug delivery system contains about 400 mg, about 450 mg, about 500 mg, about 550 mg, or about 600 mg of erdatinib. In some embodiments, the drug delivery system contains about 480 mg, about 485 mg, about 490 mg, about 495 mg, about 500 mg, about 505 mg, about 510 mg, about 515 mg, or about 520 mg of erdatinib. In some embodiments, the drug delivery system contains about 500 mg of erdatinib.

[0303] In some embodiments, the method includes administering erdatinib at a dose of about 2 mg / day to about 4 mg / day, wherein administering erdatinib includes deploying an intravesical drug delivery system as described herein. In some embodiments, the method includes administering erdatinib at a dose of about 2.5 mg / day to about 3.5 mg / day, wherein administering erdatinib includes deploying an intravesical drug delivery system as described herein. In some embodiments, the method includes administering erdatinib at a dose of about 2 mg / day, about 3 mg / day, or about 4 mg / day, wherein administering erdatinib includes deploying an intravesical drug delivery system as described herein.

[0304] In some embodiments, the drug delivery system includes a dual-lumen tube comprising a drug reservoir lumen containing erdatinib and a smaller lumen containing a flexible nitinol wire. In some embodiments, the drug reservoir lumen is defined 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 and second wall structures are adjacent to each other at two interface edges and together form a tube defining a closed drug reservoir lumen, wherein (i) the second wall structure or both the first and second wall structures are permeable to water, and (ii) the first wall structure is impermeable to erdatinib and the second wall structure is permeable to erdatinib, such that erdatinib can be released 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, the two interface edges are set at an arc angle of 45 degrees to 270 degrees around the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube. In some embodiments, the two interface edges are set at an arc angle of 45 to 90 degrees, particularly 90 degrees, of the circumference of the pipe in a cross-section perpendicular to the longitudinal axis of the pipe. In some embodiments, the two interface edges are set at an arc angle of 150 to 270 degrees, particularly 180 degrees, of the circumference of the pipe in a cross-section perpendicular to the longitudinal axis of the pipe. In some embodiments, the two interface edges are set at an arc angle of 125 to 145 degrees of the circumference of the pipe in a cross-section perpendicular to the longitudinal axis of the pipe. In some embodiments, the two interface edges are set at an arc angle of 135 degrees of the circumference of the pipe in a cross-section perpendicular to the longitudinal axis of the pipe.

[0305] In some embodiments, the drug delivery system is elastically deformable. In some embodiments, the drug delivery system has a double oval retaining shape. In some embodiments, the drug delivery system is elastically deformable and has a double oval retaining shape.

[0306] In some embodiments, erdatinib is in the form of multiple microtablets sequentially disposed within a drug delivery lumen. In some embodiments, the drug delivery lumen contains approximately 40 to 43 microtablets containing erdatinib. In some embodiments, the drug delivery lumen contains 40 microtablets containing erdatinib. In some embodiments, the drug delivery lumen contains 41 microtablets containing erdatinib. In some embodiments, the drug delivery lumen contains 42 microtablets containing erdatinib. In some embodiments, the drug delivery lumen contains 43 microtablets containing erdatinib. In some embodiments, multiple microtablets are disposed within the drug delivery lumen of an intravesical drug delivery system, wherein the delivery system includes AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the end of the intravesical drug delivery system is closed. In some embodiments, the microtablet containing erdatinib comprises: (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 1% by weight of meglumine; (d) 17.5% by weight of microcrystalline cellulose; (e) 10.75% by weight of silanized microcrystalline cellulose; (f) 7.5% by weight of vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25% by weight of colloidal silica; (h) 1.5% by weight of hydroxypropyl methylcellulose; and (i) 1.5% by weight of magnesium stearate, wherein these weight percentages are relative to the entire microtablet. In some embodiments, the microtablet containing erdatinib comprises: (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 17.5% by weight of microcrystalline cellulose; (d) 11.75% by weight of silanized microcrystalline cellulose; (e) 7.5% by weight of vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25% by weight of colloidal silica; (g) 1.5% by weight of hydroxypropyl methylcellulose; and (h) 1.5% by weight of magnesium stearate, wherein these weight percentages are relative to the entire microtablet. In some embodiments, the microtablet containing erdatinib comprises: (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 1% by weight of meglumine; (d) 24.5% by weight of microcrystalline cellulose; (e) 6.0% by weight of silanized microcrystalline cellulose; (f) 6.0% by weight of vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5% by weight of colloidal silica; and (h) 2.0% by weight of magnesium stearate, wherein these weight percentages are relative to the entire microtablet.

[0307] In one embodiment, a method for treating bladder cancer with one or more FGFR gene alterations is provided, the method comprising locally delivering an effective therapeutic amount of erdatinib to the bladder of a patient in need, wherein the one or more FGFR gene alterations are detected in a urine sample from the patient, particularly wherein the one or more FGFR gene alterations are detected in a urine sample from the patient using a urine-based PCR or NGS assay. In one embodiment, a method for treating bladder cancer with one or more FGFR gene alterations is provided, comprising, or substantially comprises: (a) assessing the presence of the one or more FGFR gene alterations in a urine sample from a bladder cancer patient, particularly assessing the presence of the one or more FGFR gene alterations in a urine sample from a bladder cancer patient using a urine-based PCR or NGS assay; and (b) locally delivering erdatinib if the one or more FGFR gene alterations are present in the sample. In one embodiment, a method for treating bladder cancer with one or more FGFR gene alterations is provided, the method comprising locally delivering a therapeutically effective amount of erdatinib to the bladder of a patient in need, wherein the patient is selected for treatment based on the detection of the one or more FGFR gene alterations in a urine sample from the patient, particularly wherein the patient is selected for treatment based on the detection of the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR or NGS assay. In another embodiment, a method for treating bladder cancer with one or more FGFR gene alterations is provided, the method comprising locally delivering a therapeutically effective amount of erdatinib to the bladder of a patient in need, wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient, particularly wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR or NGS assay. In one embodiment, the use of erdatinib in treating bladder cancer in a patient with one or more FGFR gene alterations is provided, wherein erdatinib is locally delivered to the patient's bladder, and wherein the one or more FGFR gene alterations are detected in a urine sample from the patient, particularly wherein the one or more FGFR gene alterations are detected in a urine sample from the patient using urine-based PCR or NGS assays.In one embodiment, the use of erdatinib in treating a patient with bladder cancer having one or more FGFR gene alterations is provided, comprising, or substantially comprising: (a) assessing the presence of the one or more FGFR gene alterations in a urine sample from a patient with bladder cancer, particularly by assessing the presence of the one or more FGFR gene alterations in a urine sample from a patient with bladder cancer using urine-based PCR or NGS assays; and (b) locally delivering erdatinib to the patient if the one or more FGFR gene alterations are present in the sample. In another embodiment, the use of erdatinib in treating a patient with bladder cancer having one or more FGFR gene alterations is provided, wherein erdatinib will be locally delivered to the bladder of the patient, and wherein the patient is selected for treatment based on the detection of the one or more FGFR gene alterations in a urine sample from the patient, particularly by detecting the one or more FGFR gene alterations in a urine sample from the patient using urine-based PCR or NGS assays. In one embodiment, the use of erdatinib in treating bladder cancer in a patient with one or more FGFR gene alterations is provided, wherein erdatinib is locally delivered to the patient's bladder, and wherein eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient, particularly by detecting the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR or NGS assay. In another embodiment, the use of erdatinib in the preparation of a medicament for treating bladder cancer in a patient with one or more FGFR gene alterations is provided, wherein erdatinib is locally delivered to the patient's bladder, and wherein the one or more FGFR gene alterations are detected in a urine sample from the patient, particularly by detecting the one or more FGFR gene alterations in a urine sample from the patient using a urine-based PCR or NGS assay. In one embodiment, the use of erdatinib in the preparation of a medicament for treating bladder cancer in patients with one or more FGFR gene alterations is provided, comprising, or substantially comprising: (a) assessing the presence of the one or more FGFR gene alterations in a urine sample from a patient with bladder cancer, particularly by urine-based PCR or NGS assay; and (b) locally delivering erdatinib in the presence of the one or more FGFR gene alterations in the sample.In one embodiment, the use of erdatinib in the preparation of a medicament for treating bladder cancer in a patient with one or more FGFR gene alterations is provided, wherein erdatinib will be locally delivered to the patient's bladder, and wherein the patient is selected for treatment based on the detection of the one or more FGFR gene alterations in a urine sample from the patient, particularly wherein the patient is selected for treatment based on the detection of the one or more FGFR gene alterations in a urine sample from the patient using urine-based PCR or NGS assay. In another embodiment, the use of erdatinib in the preparation of a medicament for treating bladder cancer in a patient with one or more FGFR gene alterations is provided, wherein erdatinib will be locally delivered to the patient's bladder, and wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient, particularly wherein the patient's eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a urine sample from the patient using urine-based PCR or NGS assay. This method or use may include the local delivery or administration of erdatinib (such as in any formulation described herein) to the bladder of a patient requiring treatment (particularly a cancer patient) at an amount effective for treating bladder cancer (e.g., about 2 mg / day to about 4 mg / day, as described herein). In one aspect, the patient (particularly a human) is a patient with recurrent HR-NMIBC who has undergone BCG. In another aspect, the patient (particularly a human) is a patient with recurrent BCG-treated, high-risk papillary NMIBC (high-grade Ta / T1) cancer who refuses or is ineligible for radical cystectomy (Rcy). In another aspect, the patient (particularly a human) is a patient with recurrent BCG-treated, high-risk papillary NMIBC (high-grade Ta / T1) cancer who is scheduled for Rcy. In another aspect, the patient (particularly a human) is a patient with recurrent, intermediate-risk NMIBC (Ta and T1) cancer who has only a prior history of low-grade disease.

[0308] In one embodiment, a method for treating bladder cancer with one or more FGFR gene alterations is provided, the method comprising locally delivering an effective therapeutic amount of erdatinib to the bladder of a patient in need, wherein the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient, particularly wherein the one or more FGFR gene alterations are detected in the tumor tissue sample from the patient using tissue-based PCR or NGS assays, or wherein the one or more FGFR gene alterations are detected in a histopathological image of the tumor tissue by digital histopathological analysis. In one embodiment, a method for treating bladder cancer with one or more FGFR gene alterations is provided, comprising, or substantially comprises: (a) assessing the presence of the one or more FGFR gene alterations in a tumor tissue sample from a bladder cancer patient, particularly assessing the presence of the one or more FGFR gene alterations in a tumor tissue sample from a bladder cancer patient using tissue-based PCR or NGS assays, or assessing the presence of the one or more FGFR gene alterations in a histopathological image of the tumor tissue from a bladder cancer patient by digital histopathological analysis; and (b) locally delivering erdatinib if the one or more FGFR gene alterations are present in the sample. In one embodiment, a method for treating bladder cancer with one or more FGFR gene alterations is provided, the method comprising locally delivering a therapeutically effective amount of erdatinib to the bladder of a patient in need, wherein the patient is selected for treatment based on the detection of the one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly wherein the patient is selected for treatment based on the detection of the one or more FGFR gene alterations in a tumor tissue sample from the patient using tissue-based PCR or NGS assay, or wherein the patient is selected for treatment based on the detection of the one or more FGFR gene alterations in a histopathological image of the tumor tissue by digital histopathological analysis. In one embodiment, a method for treating bladder cancer with one or more FGFR gene alterations is provided, the method comprising locally delivering a therapeutically effective amount of erdatinib to the bladder of a patient in need, wherein eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly wherein eligibility is determined by detecting the one or more FGFR gene alterations in a tumor tissue sample from the patient using tissue-based PCR or NGS assays, or wherein eligibility is determined by detecting the one or more FGFR gene alterations in a histopathological image of the tumor tissue using digital histopathological analysis.In one embodiment, the use of erdatinib in treating bladder cancer in a patient with one or more FGFR gene alterations is provided, wherein erdatinib is locally delivered to the patient's bladder, and wherein the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient, particularly wherein the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient by tissue-based PCR or NGS assay, or wherein the one or more FGFR alterations are detected in a histopathological image of the tumor tissue by digital histopathological analysis. In one embodiment, the use of erdatinib in treating bladder cancer in patients with one or more FGFR gene alterations is provided, comprising, or substantially comprising: (a) assessing the presence of one or more FGFR gene alterations in a tumor tissue sample from a bladder cancer patient, particularly by tissue-based PCR or NGS assays, or by assessing the presence of one or more FGFR gene alterations in histopathological images of tumor tissue from a bladder cancer patient via digital histopathological analysis; and (b) in the presence of one or more FGFR gene alterations in the sample, locally delivering erdatinib to the patient. In one embodiment, the use of erdatinib in treating bladder cancer in a patient with one or more FGFR gene alterations is provided, wherein erdatinib is locally delivered to the patient's bladder, and wherein the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly wherein the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a tumor tissue sample from the patient using tissue-based PCR or NGS assays, or wherein the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a histopathological image of the tumor tissue by digital histopathological analysis. In one embodiment, the use of erdatinib in treating bladder cancer in a patient with one or more FGFR gene alterations is provided, wherein erdatinib is locally delivered to the patient's bladder, and wherein eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly wherein eligibility is determined by detecting the one or more FGFR gene alterations in a tumor tissue sample from the patient using tissue-based PCR or NGS assays, or wherein eligibility is determined by detecting the one or more FGFR gene alterations in a histopathological image of the tumor tissue using digital histopathological analysis.In one embodiment, the use of erdatinib in the preparation of a medicament for treating bladder cancer in a patient having one or more FGFR gene alterations is provided, wherein erdatinib is locally delivered to the patient's bladder, and wherein the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient, particularly wherein the one or more FGFR gene alterations are detected in a tumor tissue sample from the patient by tissue-based PCR or NGS assay, or wherein the one or more FGFR alterations are detected in a histopathological image of the tumor tissue by digital histopathological analysis. In one embodiment, the use of erdatinib in the preparation of a medicament for treating bladder cancer in patients with one or more FGFR gene alterations is provided, comprising, or substantially comprising: (a) assessing the presence of one or more FGFR gene alterations in a tumor tissue sample from the bladder cancer patient, particularly by tissue-based PCR or NGS assays, or by assessing the presence of one or more FGFR gene alterations in histopathological images of tumor tissue from the bladder cancer patient by digital histopathological analysis; and (b) locally delivering erdatinib in the presence of one or more FGFR gene alterations in the sample. In one embodiment, erdatinib is provided in the preparation of a medicament for treating bladder cancer in a patient having one or more FGFR gene alterations, wherein erdatinib will be locally delivered to the patient's bladder, and wherein the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly wherein the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a tumor tissue sample from the patient using tissue-based PCR or NGS assay, or wherein the patient is selected for treatment based on the detection of one or more FGFR gene alterations in a histopathological image of the tumor tissue by digital histopathological analysis. In one embodiment, the use of erdatinib in the preparation of a medicament for treating bladder cancer in a patient having one or more FGFR gene alterations is provided, wherein erdatinib will be locally delivered to the patient's bladder, and wherein eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a tumor tissue sample from the patient, particularly wherein eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a tumor tissue sample from the patient using tissue-based PCR or NGS assay, or wherein eligibility for treatment is determined by detecting the one or more FGFR gene alterations in a histopathological image of the tumor tissue using digital histopathological analysis.This method or use may include the local delivery or administration of erdatinib (such as in any formulation described herein) to the bladder of a patient requiring treatment (particularly a cancer patient) at an amount effective for treating bladder cancer (e.g., about 2 mg / day to about 4 mg / day, as described herein). In one aspect, the patient (particularly a human) is a patient with recurrent HR-NMIBC who has undergone BCG. In another aspect, the patient (particularly a human) is a patient with recurrent BCG-treated, high-risk papillary NMIBC (high-grade Ta / T1) cancer who refuses or is ineligible for radical cystectomy (Rcy). In another aspect, the patient (particularly a human) is a patient with recurrent BCG-treated, high-risk papillary NMIBC (high-grade Ta / T1) cancer who is scheduled for Rcy. In another aspect, the patient (particularly a human) is a patient with recurrent, intermediate-risk NMIBC (Ta and T1) cancer who has only a prior history of low-grade disease.

[0309] In some embodiments, this document provides a method for treating a patient with recurrent non-homogeneous intra-arterial cystitis (HR-NMIBC) with a history of BCG, the method comprising deploying an intravesical drug delivery system into the patient's bladder, the intravesical drug delivery system comprising a shell defining a closed drug reservoir lumen and a drug formulation containing erdatinib disposed within the closed drug reservoir lumen, wherein the drug reservoir lumen is formed by a first wall structure and a second wall structure, the first wall structure being formed of a first material and the second wall structure being formed of a second material, the first wall structure and the second wall structure being joined together at two interface edges to form a tube defining the closed 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 erdatinib and the second wall structure is permeable to erdatinib, such that erdatinib can be released in vivo by diffusion through the second material forming the second wall structure, the tube defining a longitudinal axis, wherein the two interface edges are set at an arc angle of 45 degrees to 270 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. In some embodiments, the treatment method includes releasing erdatinib by diffusion through a second material forming a second wall structure but not through a first material forming a first wall structure. In some embodiments, the treatment method includes removing the drug delivery system after at least about 90 days, wherein such treatment results in a relapse-free rate of at least 50% in the patient population receiving such treatment. In some embodiments, the drug delivery system comprises a formulation 4B, wherein this disclosure covers a formulation 4B, wherein the solid pharmaceutical composition comprises: (a) 50 wt% of erdatinib free base; (b) 10 wt% of hydroxypropyl-β-cyclodextrin; (c) 1 wt% of meglumine; (d) 24.5 wt% of microcrystalline cellulose; (e) 6.0 wt% of silanized microcrystalline cellulose; (f) 6.0 wt% of vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5 wt% of colloidal silica; and (h) 2.0 wt% of magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In some embodiments, the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the end of the intravesical drug delivery system is closed.

[0310] In some embodiments, this document provides a method for treating a patient with recurrent non-homogeneous intra-arterial cystitis (HR-NMIBC) with a history of BCG, the method comprising deploying an intravesical drug delivery system into the patient's bladder, the intravesical drug delivery system comprising a shell defining a closed drug reservoir lumen and a drug formulation containing erdatinib disposed within the closed drug reservoir lumen, wherein the drug reservoir lumen is formed by a first wall structure and a second wall structure, the first wall structure being formed of a first material and the second wall structure being formed of a second material, the first wall structure and the second wall structure being joined together at two interface edges to form a tube defining the closed 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 erdatinib and the second wall structure is permeable to erdatinib, such that erdatinib can be released in vivo by diffusion through the second material forming the second wall structure, the tube defining a longitudinal axis, wherein the two interface edges are set at an arc angle of 45 degrees to 270 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. In some embodiments, the treatment method includes releasing erdatinib by diffusion through a second material forming a second wall structure but not through a first material forming a first wall structure. In some embodiments, the treatment method includes removing the drug delivery system after at least about 90 days, wherein such treatment results in a relapse-free rate of at least 50% in the patient population receiving such treatment. In some embodiments, the drug delivery system comprises formulation 4.1, wherein formulation 4.1 covered by this disclosure comprises: (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 17.5% by weight of microcrystalline cellulose; (d) 11.75% by weight of silanized microcrystalline cellulose; (e) 7.5% by weight of vinylpyrrolidone-vinyl acetate copolymer; (f) 0.25% by weight of colloidal silica; (g) 1.5% by weight of hydroxypropyl methylcellulose; and (h) 1.5% by weight of magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition.

[0311] In some embodiments, this document provides a method for treating a patient with recurrent non-homogeneous intra-arterial cystitis (HR-NMIBC) with a history of BCG, the method comprising deploying an intravesical drug delivery system into the patient's bladder, the intravesical drug delivery system comprising a shell defining a closed drug reservoir lumen and a drug formulation containing erdatinib disposed within the closed drug reservoir lumen, wherein the drug reservoir lumen is formed by a first wall structure and a second wall structure, the first wall structure being formed of a first material and the second wall structure being formed of a second material, the first wall structure and the second wall structure being joined together at two interface edges to form a tube defining the closed 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 erdatinib and the second wall structure is permeable to erdatinib, such that erdatinib can be released in vivo by diffusion through the second material forming the second wall structure, the tube defining a longitudinal axis, wherein the two interface edges are set at an arc angle of 45 degrees to 270 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube. In some embodiments, the treatment involves releasing erdatinib by diffusion through a second material forming the second wall structure but not through the first material forming the first wall structure. In some embodiments, the treatment involves removing the drug delivery system after at least about 90 days, wherein such treatment results in a relapse-free rate of at least 50% in the patient population receiving this treatment. In some embodiments, the drug delivery system comprises formulation 3.4, wherein formulation 3.4 covered by this disclosure comprises: (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 1% by weight of meglumine; (d) 17.5% by weight of microcrystalline cellulose; (e) 10.75% by weight of silanized microcrystalline cellulose; (f) 7.5% by weight of vinylpyrrolidone-vinyl acetate copolymer; (g) 0.25% by weight of colloidal silica; (h) 1.5% by weight of hydroxypropyl methylcellulose; and (i) 1.5% by weight of magnesium stearate, wherein these weight percentages are relative to the entire solid drug composition.

[0312] In some embodiments, a method of treating a patient with recurrent IR-NMIBC includes deploying an intravesical drug delivery system into the patient's bladder. The intravesical drug delivery system includes a shell defining a closed drug reservoir lumen and a drug formulation containing erdatinib disposed within the closed drug reservoir lumen. The drug reservoir lumen is formed by a first wall structure and a second wall structure, the first wall structure being formed of a first material and the second wall structure being formed of a second material. The first and second wall structures are joined together at two interface edges to form a tube defining the closed drug reservoir lumen. (i) the second wall structure or both the first and second wall structures are water-permeable, and (ii) the first wall structure is impermeable to erdatinib and the second wall structure is permeable to erdatinib, such that erdatinib can be released in vivo via diffusion through the second material forming the second wall structure. The tube defines a longitudinal axis, wherein the two interface edges are arranged at an arc angle of 45 to 270 degrees around the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube. In some embodiments, the treatment method includes releasing erdatinib by diffusion through a second material forming a second wall structure but not through a first material forming a first wall structure. In some embodiments, the treatment method includes removing the drug delivery system after at least about 90 days, wherein such treatment results in a complete response of at least 50% in the patient population receiving such treatment. In some embodiments, the drug delivery system comprises a formulation 4B, wherein this disclosure covers a formulation 4B, wherein the solid pharmaceutical composition comprises: (a) 50 wt% of erdatinib free base; (b) 10 wt% of hydroxypropyl-β-cyclodextrin; (c) 1 wt% of meglumine; (d) 24.5 wt% of microcrystalline cellulose; (e) 6.0 wt% of silanized microcrystalline cellulose; (f) 6.0 wt% of vinylpyrrolidone-vinyl acetate copolymer; (g) 0.5 wt% of colloidal silica; and (h) 2.0 wt% of magnesium stearate, wherein these weight percentages are relative to the entire solid pharmaceutical composition. In some embodiments, the delivery system comprises AC-4075A-B20 and EG-80-A as described herein. In some embodiments, the end of the intravesical drug delivery system is closed.

[0313] In some embodiments, a method of treating a patient with recurrent IR-NMIBC includes deploying an intravesical drug delivery system into the patient's bladder. The intravesical drug delivery system includes a shell defining a closed drug reservoir lumen and a drug formulation containing erdatinib disposed within the closed drug reservoir lumen. The drug reservoir lumen is formed by a first wall structure and a second wall structure, the first wall structure being formed of a first material and the second wall structure being formed of a second material. The first and second wall structures are joined together at two interface edges to form a tube defining the closed drug reservoir lumen. (i) the second wall structure or both the first and second wall structures are water-permeable, and (ii) the first wall structure is impermeable to erdatinib and the second wall structure is permeable to erdatinib, such that erdatinib can be released in vivo via diffusion through the second material forming the second wall structure. The tube defines a longitudinal axis, wherein the two interface edges are arranged at an arc angle of 45 to 270 degrees around the circumference of the tube in a cross-section perpendicular to the longitudinal axis of the tube. In some embodiments, the treatment method includes releasing erdatinib by diffusion through a second material forming a second wall structure but not through a first material forming a first wall structure. In some embodiments, the treatment method includes removing the drug delivery system after at least about 90 days, wherein such treatment results in a complete response of at least 50% in the patient population receiving such treatment. In some embodiments, the drug delivery system comprises formulation 4.1, wherein formulation 4.1 covered by this disclosure comprises: (a) 50% by weight of erdatinib free base; (b) 10% by weight of hydroxypropyl-β-cyclodextrin; (c) 17.5% by weight of microcrystallin...

Claims

1. A drug delivery system, the drug delivery system comprising: A housing defining a drug reservoir lumen defined by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises an aromatic thermoplastic polyurethane based on polycarbonate and the second material comprises a thermoplastic polyurethane based on aliphatic polyether; and A pharmaceutical preparation, disposed in the lumen of the drug reservoir, comprising erdatinib. Wherein (i) the second wall structure, or both the first and second wall structures, is water-permeable, and (ii) the first wall structure is impermeable to erdatinib and the second wall structure is permeable to erdatinib, such that erdatinib can be released in vivo by diffusion through the second material forming the second wall structure. The first wall structure and the second wall structure are adjacent to each other at the two interface edges and together form a tube. The drug delivery system is configured to release erdatinib at an average rate of about 2.5 mg / day to about 3.5 mg / day, and The two interface edges are set at an arc angle of about 125 degrees to about 145 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure.

2. A drug delivery system, the drug delivery system comprising: A housing defining a drug reservoir lumen defined by a first wall structure formed of a first material and a second wall structure formed of a second material, wherein the first material comprises an aromatic thermoplastic polyurethane based on polycarbonate and the second material comprises a thermoplastic polyurethane based on aliphatic polyether; and A pharmaceutical preparation disposed in the lumen of the drug reservoir, the pharmaceutical preparation comprising erdatinib. Wherein (i) the second wall structure, or both the first and second wall structures, is water-permeable, and (ii) the first wall structure is impermeable to erdatinib and the second wall structure is permeable to erdatinib, such that erdatinib can be released in vivo by diffusion through the second material forming the second wall structure. The first wall structure and the second wall structure are adjacent to each other at the two interface edges and together form a tube. The drug delivery system is configured to release erdatinib at an average rate of approximately 3 mg / day, and The two interface edges are set at an arc angle of approximately 135 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure.

3. The drug delivery system according to claim 1 or claim 2, wherein the drug delivery system comprises 42 to 46 erdatinib microtablets.

4. The drug delivery system of claim 3, wherein the drug delivery system comprises 43 erdatinib microtablets.

5. The 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, optionally wherein the first material comprises AC-4075A-B20.

6. The drug delivery system according to any one of claims 1 to 5, wherein the drug formulation comprises: (a) Erdatinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the pharmaceutical formulation. (b) Hydroxypropyl-β-cyclodextrin at a concentration of 10% by weight of the pharmaceutical preparation; (c) meglumine at a concentration of 1% by weight of the pharmaceutical preparation; (d) Microcrystalline cellulose at a concentration of 17.5% by weight of the pharmaceutical preparation; (e) Silicated microcrystalline cellulose at a concentration of 10.75% by weight of the pharmaceutical preparation; (f) A vinylpyrrolidone-vinyl acetate copolymer at a concentration of 7.5% by weight of the pharmaceutical preparation; (g) Colloidal silica at a concentration of 0.25% by weight of the pharmaceutical preparation; (h) Hydroxypropyl methylcellulose at a concentration of 1.5% by weight of the pharmaceutical preparation; and (i) magnesium stearate at a concentration of 1.5% by weight of the pharmaceutical preparation; or (a) Erdatinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the pharmaceutical formulation. (b) Hydroxypropyl-β-cyclodextrin; (c) meglumine; (d) Microcrystalline cellulose; (e) Silicified microcrystalline cellulose; (f) Vinylpyrrolidone-vinyl acetate copolymer; (g) Colloidal silica; (h) hydroxypropyl methylcellulose; and (i) Magnesium stearate.

7. The drug delivery system according to any one of claims 1 to 5, wherein the drug formulation comprises: (a) Erdatinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the pharmaceutical formulation. (b) Hydroxypropyl-β-cyclodextrin at a concentration of 10% by weight of the pharmaceutical preparation; (c) Microcrystalline cellulose at a concentration of 17.5% by weight of the pharmaceutical preparation; (d) Siliconized microcrystalline cellulose at a concentration of 11.75% by weight of the pharmaceutical preparation; (e) A vinylpyrrolidone-vinyl acetate copolymer at a concentration of 7.5% by weight of the pharmaceutical formulation; (f) Colloidal silica at a concentration of 0.25% by weight of the pharmaceutical preparation; (g) hydroxypropyl methylcellulose at a concentration of 1.5% by weight of the pharmaceutical preparation; and (h) magnesium stearate at a concentration of 1.5% by weight of the pharmaceutical preparation; or (a) Erdatinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the pharmaceutical formulation. (b) Hydroxypropyl-β-cyclodextrin; (c) Microcrystalline cellulose: (d) Silicified microcrystalline cellulose; (e) Vinylpyrrolidone-vinyl acetate copolymer; (f) Colloidal silica; (g) hydroxypropyl methylcellulose; and (h) Magnesium stearate.

8. The drug delivery system according to any one of claims 1 to 5, wherein the drug formulation comprises: (a) Erdatinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the pharmaceutical formulation. (b) Hydroxypropyl-β-cyclodextrin at a concentration of 10% by weight of the pharmaceutical preparation; (c) meglumine at a concentration of 1% by weight of the pharmaceutical preparation; (d) Microcrystalline cellulose at a concentration of 24.5% by weight of the pharmaceutical preparation; (e) Silicated microcrystalline cellulose at a concentration of 6% by weight of the pharmaceutical preparation; (f) A vinylpyrrolidone-vinyl acetate copolymer at a concentration of 6% by weight of the pharmaceutical preparation; (g) Colloidal silica at a concentration of 0.5% by weight of the pharmaceutical preparation; (h) Magnesium stearate at a concentration of 2% by weight of the pharmaceutical preparation; or (a) Erdatinib free base (N-(3,5-dimethoxyphenyl)-N'-(1-methylethyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]ethane-1,2-diamine) at a concentration of 50% by weight of the pharmaceutical formulation. (b) Hydroxypropyl-β-cyclodextrin; (c) meglumine; (d) Microcrystalline cellulose; (e) Silicified microcrystalline cellulose; (f) Vinylpyrrolidone-vinyl acetate copolymer; (g) colloidal silica; and (h) Magnesium stearate.

9. The 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 between about 0.2 mm and about 1.0 mm.

10. The drug delivery system according to any one of claims 1 to 9, wherein the second wall structure has a thickness, wherein the thickness of the second wall structure is from about 0.16 mm to about 0.24 mm, and wherein the first wall structure is impermeable to the erdatinib, and the second wall structure is permeable to the erdatinib.

11. The drug delivery system according to any one of claims 1 to 10, wherein the drug formulation comprises microtablets, wherein each microtablet has a weight between about 22 mg and about 24 mg.

12. The drug delivery system according to any one of claims 1 to 11, wherein the drug formulation comprises microtablets, wherein each microtablet has a weight of about 23 mg.

13. The drug delivery system according to any one of claims 1 to 12, wherein the drug formulation comprises microtablets, wherein each microtablet has a thickness between about 3.0 mm and about 3.4 mm.

14. The drug delivery system according to any one of claims 1 to 13, wherein the drug formulation comprises microtablets, wherein each microtablet has a thickness of about 3.2 mm.

15. The drug delivery system according to any one of claims 1 to 14, wherein the drug formulation comprises microtablets, wherein each microtablet has a diameter between about 2.60 mm and about 2.66 mm.

16. The drug delivery system according to any one of claims 1 to 15, wherein the drug formulation comprises microtablets, wherein each microtablet has a diameter of about 2.63 mm.

17. The drug delivery system according to any one of claims 1 to 16, wherein the housing has a first end and a second end, and defines a length between the first end and the second end, wherein the length is about 17 cm.

18. The 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 linear element disposed within the retaining frame lumen.

19. The drug delivery system of claim 18, wherein the linear element has a diameter of about 0.305 mm and a length of about 156 mm.

20. The drug delivery system of claim 18 or 19, wherein the linear element is a nitinol wire.

21. The drug delivery system according to any one of claims 1 to 20, the drug delivery system comprising a plurality of said microtablets arranged in series and defining a core length between a first face of a first microtablet and an opposite second face of a last microtablet.

22. The drug delivery system of claim 21, wherein the core length is about 15 cm.

23. The 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 of 0.2 ± 0.04 mm extending along the diameter of the lumen of the drug reservoir.

24. The drug delivery system according to any one of claims 1 to 23, wherein the drug reservoir lumen defines an inner diameter of 2.64 ± 0.05 mm.

25. The drug delivery system according to any one of claims 1 to 24, wherein the drug delivery system is capable of elastically deforming between a coiled retaining shape and a relatively straight insertion shape.

26. The drug delivery system of claim 25, wherein the coiled retaining shape comprises a bi-elliptical shape.

27. The drug delivery system according to claim 25 or 26, wherein, When in the curled-up shape, the drug delivery system has a maximum size equal to or less than about 6 cm in any direction.

28. The drug delivery system according to any one of claims 25 to 27, wherein, When in the curled-up shape, the drug delivery system has a maximum size equal to or less than about 5.5 cm in any direction.

29. The drug delivery system according to any one of claims 25 to 28, wherein, When in the curled-up shape, the drug delivery system fits into a 5.5cm × 4.5cm sleeve.

30. The drug delivery system according to any one of claims 1 to 29, wherein the erdatinib is the erdatinib free base.

31. The drug delivery system according to any one of claims 1 to 30, wherein both the first wall structure and the second wall structure are water-permeable.

32. A method for treating a patient with non-muscle-invasive bladder cancer, the method comprising: Deploy the drug delivery system according to any one of claims 1 to 31 into the patient's bladder; Erdatinib is released by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; as well as The drug delivery system will be removed after at least approximately 90 days.

33. The method of claim 32, wherein the cancer is intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC).

34. The method of claim 32, wherein the cancer is a newly diagnosed intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC).

35. The method of claim 32, wherein the cancer is recurrent intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC).

36. The method according to any one of claims 32 to 35, wherein the cancer carries an FGFR alteration.

37. The method of claim 35, wherein the FGFR change is an FGFR2 change or an FGFR3 change.

38. The method of claim 36 or 37, wherein the FGFR alteration is an FGFR3 alteration, particularly an FGFR3 mutation or an FGFR3 fusion.

39. The method of claim 38, wherein 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.

40. The method according to any one of claims 32 to 39, wherein the patient has not recently received BCG treatment.

41. The method according to any one of claims 32 to 40, wherein the patient has one or more of the following risk factors: multiple low-grade (LG) tumors, solitary LG tumors >3 cm, early recurrence of LG tumors (<1 year), frequent recurrence (>1 time per year), or recurrence after previous intravesical chemotherapy.

42. The method according to any one of claims 32 to 41, wherein such treatment results in a median duration of response of at least 12 months or about 12 months.

43. The 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 erdatinib, said complete response rate being assessed at 12 weeks.

44. The 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 erdatinib, said complete response rate being assessed at 12 weeks.

45. The method of claim 32, wherein the cancer is high-risk non-muscle-invasive bladder cancer (HR-NMIBC).

46. ​​The method of claim 45, wherein the cancer carries an FGFR alteration.

47. The method of claim 46, wherein the FGFR change is an FGFR2 change or an FGFR3 change.

48. The method of claim 46 or 47, wherein the FGFR alteration is an FGFR3 alteration, particularly an FGFR3 mutation or an FGFR3 fusion.

49. The method of claim 48, wherein 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.

50. The method according to any one of claims 45 to 49, wherein the recurrence-free survival (RFS) rate, and particularly the 12-month RFS rate, in the patient population treated with erdatinib at about 2 mg / day to about 4 mg / day, especially about 3 mg / day, is about 90%.

51. The method according to any one of claims 45 to 49, wherein the recurrence-free survival (RFS) rate and, in particular, the 12-month RFS rate in the patient population treated with erdatinib at about 2 mg / day to about 4 mg / day, especially about 3 mg / day, is about 75%, or about 79%, or about 80%.

52. A method for treating a patient with intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC), the method comprising administering erdatinib 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, wherein: i) The patient is newly diagnosed or has recurrent IR-NMIBC; ii) Determine that the patient has an intermediate risk of recurrence or progression; iii) The patient has a selected FGFR gene alteration; iv) The patient had not previously received BCG treatment; and v) The patient has one or more of the following risk factors selected from a list consisting of the following: a) Multiple low-grade (LG) tumors, b) Solitary LG tumors >3cm c) Frequent relapses (>1 time per year), and d) Relapse following previous intravesical chemotherapy.

53. The method of claim 52, wherein the patient and / or patient group has a histologically confirmed diagnosis of IR-NMIBC by at least one of the following disease characteristics: i) Ta LG / G1: Relapse; ii) Ta LG / G1: primary and (multifocal or ≥3cm); and / or iii) Ta G2: Primary or recurrent.

54. A method for treating a patient with recurrent intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC), the method comprising: Erdatinib was administered topically to the bladder of the patients for at least approximately 90 days, at a rate of approximately 2 mg / day to approximately 4 mg / day. This treatment resulted in a complete response rate of at least 50% among the patient population receiving it.

55. A method for treating a patient with recurrent intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC), the method comprising: An intravesical drug delivery system is deployed into a patient's bladder, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation containing erdatinib disposed within the closed drug reservoir lumen, wherein the drug reservoir lumen is formed by a first wall structure and a second wall structure, the first wall structure being formed of a first material and the second wall structure being formed of a second material, the first wall structure and the second wall structure being joined to each other at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are set at an arc angle of 45 degrees to 270 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure; Erdatinib is released by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; as well as The drug delivery system will be removed after at least approximately 90 days. This treatment resulted in a complete response rate of at least 50% among the patient population receiving it.

56. The method according to any one of claims 52 to 55, wherein such treatment results in a median duration of response of at least 12 months or about 12 months.

57. The 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 erdatinib, said complete response rate being assessed at 12 weeks.

58. The 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 erdatinib, said complete response rate being assessed at 12 weeks.

59. The method according to any one of claims 52 to 58, the method comprising administering erdatinib to the patient at a dose of about 2.5 mg / day to about 3.5 mg / day.

60. The method according to any one of claims 52 to 59, the method comprising administering about 3 mg / day of erdatinib to the patient.

61. A method for treating a patient with recurrent, high-risk non-muscle-invasive bladder cancer (HR-NMIBC) that has undergone BCG vaccination, the method comprising: Erdatinib was administered topically to the bladder of the patients for at least approximately 90 days, at a rate of approximately 2 mg / day to approximately 4 mg / day. This treatment results in a relapse-free rate of at least 50% among patients receiving it.

62. A method for treating a patient with recurrent, high-risk non-muscle-invasive bladder cancer (HR-NMIBC) that has undergone BCG vaccination, the method comprising: An intravesical drug delivery system is deployed into a patient's bladder, the intravesical drug delivery system comprising a housing defining a closed drug reservoir lumen and a drug formulation containing erdatinib disposed within the closed drug reservoir lumen, wherein the drug reservoir lumen is formed by a first wall structure and a second wall structure, the first wall structure being formed of a first material and the second wall structure being formed of a second material, the first wall structure and the second wall structure being joined to each other at two interface edges and together forming a tube defining the closed drug reservoir lumen, the tube defining a longitudinal axis, wherein the two interface edges are set at an arc angle of 45 degrees to 270 degrees around the circumference of the tube in a cross section perpendicular to the longitudinal axis of the tube, wherein the arc angle corresponds to the second wall structure; Erdatinib is released by diffusion through the second material forming the second wall structure but not through the first material forming the first wall structure; The drug delivery system will be removed after at least approximately 90 days. This treatment results in a relapse-free rate of at least 50% among patients receiving it.

63. The method according to any one of claims 61 or 62, wherein the recurrence-free survival (RFS) rate, and particularly the 12-month RFS rate, in the patient population treated with erdatinib at about 2 mg / day to about 4 mg / day, especially about 3 mg / day, is about 90%.

64. The method according to any one of claims 61 or 62, wherein the recurrence-free survival (RFS) rate and, in particular, the 12-month RFS rate in the patient population treated with erdatinib at about 2 mg / day to about 4 mg / day, especially about 3 mg / day, is about 75%, or about 79%, or about 80%.

65. The method according to any one of claims 61 to 64, the method comprising administering erdatinib to the patient at a dose of about 2.5 mg / day to about 3.5 mg / day.

66. The method according to any one of claims 61 to 65, the method comprising administering about 3 mg / day of erdatinib to the patient.

67. The method according to any one of claims 52 to 66, wherein the method further comprises using urine sample determination to select patients for treatment.

68. The method of claim 67, wherein the urine sample determination is a urine sample NGS or PCR determination, particularly a urine sample NGS determination.

69. The method according to claim 67 or 68, wherein the urine sample assay detects the presence of at least one FGFR2 gene alteration and / or FGFR3 gene alteration.

70. The method of claim 69, wherein the FGFR2 gene alteration and / or the FGFR3 gene alteration comprises activating tumor FGFR2 or FGFR3 mutations or fusions.

71. The method according to claim 69 or 70, wherein the FGFR2 gene alteration and / or the FGFR3 gene alteration is selected from FGFR3 S249C, FGFR3 Y373C, FGFR3 R248C, FGFR3 G370C, FGFR3-TACC3, particularly FGFR3-TACC3 V1 or FGFR3-TACC3 V3, FGFR3-BAIAP2L1, FGFR2-BICC1, FGFR2-CASP7 or any combination thereof, particularly wherein the FGFR2 gene alteration and / or the FGFR3 gene alteration is selected from FGFR3-TACC3 variant 1 (FGFR3-TACC3 V1), FGFR3 G370C, FGFR3 S249C, FGFR3 Y373C and FGFR3 R248C.

72. The 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 means of the urine sample are relapse-free or have achieved a complete response.

73. The 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 means of the urine sample are relapse-free or have achieved a complete response.

74. The method according to claim 55 or 62, wherein the pharmaceutical formulation comprises about 480 mg to about 510 mg of erdatinib, optionally wherein the erdatinib is a free erdatinib base.

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