Drug delivery system and method for treating bladder cancer with gemcitabine

Abstract

To provide improved drug delivery methods and systems for treating bladder cancer.SOLUTION: Provided herein are drug delivery device and method for administering gemcitabine to a patient in need of treatment of bladder cancer by intravesically administering gemcitabine into the bladder of the patient to obtain a sufficient sustained concentration of the gemcitabine in urine in the bladder so as to generate a therapeutically effective concentration of the gemcitabine in the tissues of the bladder. In embodiments, the local administration into the patient's bladder is at a mean average amount of from 1 mg / day to about 300 mg / day of the gemcitabine (FBE).SELECTED DRAWING: Figure 12

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority from U.S. Provisional Patent Application No. 61 / 949,215, filed March 6, 2014. No. 6,299,629, filed on Dec. 1, 2003, which application is incorporated herein by reference.

[0002] The present invention relates the development to the treatment of cancer, and more particularly to compositions for the treatment of bladder cancer. The present invention relates to articles, devices, and methods. [Background technology]

[0003] Bladder cancer is a significant medical challenge, and currently available treatment options are limited for many reasons. It is not very satisfactory.

[0004] Generally, bladder cancer can be classified as muscle-invasive bladder cancer (MIBC) or non-muscle-invasive bladder cancer (Non-Muscle Invasive Bladder Cancer). Bladder cancer is classified as non-metastatic bladder cancer (NMIBC). The pathological classification and staging of bladder cancer are as follows: pTa (urothelial lesion), pTis (high-risk urothelial lesion), pT1 (mucosal solid lesion) pT2 (muscle invasion), pT3 (perivesical fat invasion), and pT4 (pelvic organ invasion) Bladder cancer is also classified as grade 1 / 3 (well differentiated), grade 2 / 3 (moderately differentiated), or grade 3 / 3 (moderately differentiated). It can also be classified by grade as grade 3 / 3 (poorly differentiated) or grade 3 / 3 (well differentiated). Bladder cancer can also be classified by stage, ranging from stage 0 to stage IV. The cancer is a transitional cell carcinoma of epithelial origin, confined to the inner wall of the bladder, and is non-muscle invasive (NM) In the early stages, most bladder cancers are superficial NMIBC. , stage pTa, pTis, and pT1 disease. MIBC includes stage pT2, p These include T3 and pT4.

[0005] A common clinical protocol for early stage bladder cancer is cystoscopic visualization followed by endoscopy. The surgical removal of the tumor(s) is known as transurethral resection (TUR). However, there is a high rate of postoperative recurrence, and these cancers may progress to muscle-invasive disease. Therefore, surgery is often recommended to help prevent or delay the incidence and severity of recurrence. In some cases, adjunctive chemotherapy or immunotherapy may be administered into the bladder (via a catheter). Direct administration of chemotherapy into the bladder (BC) G) is one such immunotherapeutic agent, typically administered intravenously into the bladder after surgery. CG is ineffective in many patients, and furthermore, treatment with BCG is associated with various complications that lead to treatment discontinuation. Chemotherapeutic agents are usually used for patients who have not responded to BCG therapy. Chemotherapy is typically administered intravesically, concentrating chemotherapy at the tumor site. It removes any remaining tumor after resection while avoiding systemic exposure to the drug.

[0006] One such chemotherapy agent in clinical trials for treating bladder cancer is gemcitabine. Gemcitabine (2',2'-difluorodeoxycytidine) is a Gemcitabine is a pyrimidine analogue with activity against superficial bladder cancer. and clinical trials for the treatment of NMIBC using various weekly schedules. Gemcitabine has been used by instillation into the bladder. Doses ranging from 500 to 2000 mg are administered weekly or in a maximum of 100 ml of saline. It is given as a 1-2 hour infusion twice a day for several weeks.

[0007] Such formulations are known to be excreted from the bladder before their full effect is achieved.1 The short residence time of ~2 hours limits the therapeutic benefit. To overcome this limitation, high concentrations (40 mg / ml) and High doses (up to 2 grams per infusion) are used. High doses of intravesical administration of tabine lead to significant systemic absorption, with absorption from the gastrointestinal tract, bladder, and bone marrow. May cause toxicity, further limiting clinical usefulness in addition to local tolerability issues There is.

[0008] The literature also suggests that slow intravenous infusion over, say, 90 minutes is preferable to slow intravenous infusion over, say, 1 to 2 minutes. Systemic intravenous administration of gemcitabine as a bolus injection over 2 minutes was better tolerated by patients. This suggests that prolonged exposure to gemcitabine increases toxicity. This suggests that this should be avoided.

[0009] Therefore, there is a need for improved drug delivery methods and systems for treating bladder cancer. For example, toxicity and tolerability issues remain. Avoid or mitigate the toxicity and tolerability issues that have limited the clinical usefulness of tabine This reduces the need for patients to receive therapeutic concentrations of gemcitabine for a sustained period. It still exists. Summary of the Invention

[0010] In one embodiment, the method comprises administering gemcitabine locally into the bladder of a patient. and a sustained concentration sufficient to produce a therapeutic concentration of said gemcitabine in bladder tissue. by obtaining the gemcitabine in urine in the bladder, for use in the treatment of bladder cancer. The drug is administered locally into the bladder of the patient in a range of 1 mg / day to about 300 mg / day. The agent is provided in an average amount of gemcitabine free base equivalent (FBE). In an embodiment, the topical administration into the bladder of the patient is from 1 mg / day to 200 mg / day. The above gemcitabine (FBE), 5 mg / day to 100 mg / day of the above gemcitabine (FBE ), 10 mg / day to 50 mg / day of the above gemcitabine (FBE), or 15 mg / day to At an average dose of 25 mg / day of gemcitabine (FBE), Local administration into the patient's bladder provides approximately 20 mg / day of the gemcitabine (FBE The topical administration into the bladder of the patient was continuous or intermittent. In an embodiment, the continuous or intermittent administration may be for 1 day to 30 days, 1 day to 1 It can last 4 days or 1-7 days.

[0011] In a preferred embodiment, the gemcitabine is administered over a sustained period of time. The drug is delivered to the bladder from an intravesical drug delivery device that continuously releases the drug into the urine in the bladder. In another embodiment, the gemcitabine is released from a coating material applied to the bladder. into the bladder, where the coating material (e.g., mucoadhesive formulation) remains for a sustained period of time. In yet another embodiment, the liquid releases the gemcitabine into the urine in the bladder. The above-mentioned gemcitabine is administered via a urethral catheter or suprapubic catheter placed into the bladder. The fluid is pumped through the tube into the bladder for a sustained period of time.

[0012] In another embodiment, for administering gemcitabine to a patient in need of treatment for bladder cancer. 1. A drug delivery device for administering gemcitabine intravesically into the bladder of a patient, comprising: a sustained concentration sufficient to produce a therapeutically effective concentration of said gemcitabine in the tissues of the patient The device is adapted to administer the gemcitabine in a dose that is delivered to the bladder in urine. In certain embodiments, the drug delivery device is for intravesical insertion. and a dosage form containing gemcitabine, wherein the housing holds the dosage form. and configured to release the gemcitabine into the bladder in a therapeutically effective amount for treating the bladder. The device is configured to administer gemcitabine at an average dose of 1 mg / day to about 300 mg / day. In a preferred embodiment, the housing is configured to release the cytabine into the bladder. The gemcitabine is released without a predetermined release opening. In certain embodiments, the housing comprises a drug-permeable polymer wall material that expands through the polymer wall material. The gemcitabine is released by diffusion. the housing having a retention feature configured to retain the device in the patient's bladder; the device is elastically deformable between a configuration in which it is deployed for passage through the patient's urethra, Good too.

[0013] In yet another embodiment, the gemcitabine is administered locally into the bladder of a patient to provide a therapeutic effect in the bladder tissue. and providing a sustained concentration of said gemcitabine sufficient to produce a therapeutic concentration of said gemcitabine in a A method for treating bladder cancer by administering steroids to the bladder in urine is provided. The topical administration into the bladder of the patient is 1 mg / day to about 300 mg / day of gemcitabine. In one embodiment, the method comprises administering to the patient at least The method further comprises administering at least a second therapeutic agent to the bladder, the second therapeutic agent being administered intravesically. In another embodiment, the method further comprises adding urea or another solubility modifier to the gem into the bladder in an amount effective to enhance or otherwise modify the solubilization of cytabine. In embodiments, the second therapeutic agent and / or the soluble The modifying agent is released from the gemcitabine-releasing intravesical device. [Brief explanation of the drawings]

[0014] [Figure 1A] 1A-1B illustrate one embodiment of an intravesical drug delivery device described herein that can be used to administer gemcitabine. [Figure 1B] (As mentioned above.) [Figure 2A] 2A-2B illustrate another embodiment of an intravesical drug delivery device described herein that can be used to administer gemcitabine. [Figure 2B] (As mentioned above.) [Figure 3A] 3A-3C illustrate yet another embodiment of an intravesical drug delivery device described herein that can be used to administer gemcitabine. [Figure 3B] (As mentioned above.) [Figure 3C] (As mentioned above.) [Figure 4A] 4A-4B are diagrams illustrating a method of inserting an intravesical drug delivery device into a patient's bladder for local administration of gemcitabine, as described herein. [Figure 4B] (As mentioned above.) [Figure 5A] FIG. 1 illustrates a material applied to the inner surface of the bladder wall for local administration of gemcitabine, as described herein. [Figure 5B] FIG. 1 illustrates a method of applying a coating material onto the inner surface of the bladder wall for local administration of gemcitabine, as described herein. [Figure 6] FIG. 1 illustrates a method for applying a liquid drug or drug formulation into the bladder. [Figure 7] FIG. 1 illustrates the concentration of gemcitabine in the prostate after bladder irrigation and intravenous administration. [Figure 8] FIG. 1 illustrates bladder irrigation and plasma concentrations of gemcitabine after intravenous administration. [Figure 9] FIG. 1 illustrates bladder irrigation and 14C gemcitabine concentration in the bladder after intravenous administration. [Figure 10A] 10A-C illustrate one embodiment of an intravesical drug delivery device for releasing gemcitabine via a permeability disc. FIG. 10A is a plan view of the device. FIG. 10B is a cross-sectional view of one of the four drug storage modules of the device shown in FIG. 10A, showing the drug tablets and permeability disc in each module. FIG. 10C is a perspective view of a portion of the housing / body of the device shown in FIG. 10A prior to assembly with the other components of the device. [Figure 10B] (As mentioned above.) [Figure 10C] (As mentioned above.) [Figure 11] 10A-10C are graphs showing the cumulative amount of gemcitabine released in vitro from the devices shown in FIGS. [Figure 12] 10A-10C are graphs showing the cumulative amount of gemcitabine released in vitro from the devices shown in FIGS. [Figure 13] 1 is a graph showing the urinary concentrations of gemcitabine, dFdU, and a combination thereof in an animal experiment. [Figure 14] 1 is a graph showing the urinary concentrations of gemcitabine, dFdU, and a combination thereof in an animal experiment. DETAILED DESCRIPTION OF THE INVENTION

[0015] Continuous delivery of gemcitabine via intravesical administration results in significant plasma / systemic exposure. Unexpected drug distribution across the thickness of the bladder wall was obtained, with the drug distribution occurring in all layers of the bladder. It has been found that drug concentrations at or above the observed therapeutic threshold can be achieved. Therefore, the compositions, systems, and methods described herein may be used to treat bladder tissue where needed. can be used to obtain a therapeutically effective amount of gemcitabine while preserving normal bladder tissue It is well tolerated in humans and also minimizes systemic exposure.

[0016] The term "gemcitabine" as used herein refers to the compound gemcitabine as well as its derivatives. These include physiologically acceptable salts, esters, amides, solvates and prodrugs. The above-mentioned gemcitabine may be one or more suitable It can be formulated with a pharmaceutically acceptable excipient.

[0017] In certain embodiments, a therapeutic concentration of the drug is produced and maintained in the tissue of the bladder. A controlled amount of gel is delivered to the patient's bladder in sufficient concentration and for sufficient time to However, the bladder limits the absorption of urinary components into the general circulation. Systemic exposure to the drug is advantageously minimized.

[0018] A variety of methods can be used to obtain the desired urinary concentration of gemcitabine. In embodiments, the drug is delivered by instilling a simple solution directly into the bladder. For example, a solution of the drug can be administered by a urethral catheter or a suprapubic catheter. may be pumped into the bladder over a treatment period in a continuous or pulsed form through In another embodiment, the drug is released from a device or composition placed in the bladder. and the device or composition is adapted to reduce urinary concentrations of the desired drug over a specified treatment period. The drug is released (continuously or intermittently) at a rate effective to produce a desired effect. For example, the drug may be released into the bladder from an intravesical device, and then the drug is released into the bladder. At the end of the treatment period, the device may be retrieved from the bladder or The device may be absorbed, dissolved, excreted, or a combination of these. may be removed by

[0019] In a preferred embodiment, the gemcitabine is administered to the bladder from an intravesical device. Intravesical drug delivery can be adapted to achieve the dosing regimens described herein. Examples of devices and methods for placing them in the bladder are described in the following U.S. Patent Applications: The invention is described in US2012 / 0203203 (Lee et al.), US2012 / 0089122 (Lee et al.), US2012 / 0089121 (Lee et al.); US20 11 / 0218488 (Boyko et al.), US2011 / 0202036 (Boyko et al. ), US2011 / 0152839 (Cima et al.), US2011 / 0060309 (L ee et al.), US2010 / 0331770 (Lee et al.), US2010 / 0330149 (Daniel et al.), US2010 / 0003297 (Tobias et al.), US2009 / 0149833 (Cima et al.), US2007 / 0202151 (Lee et al.), WO2 014 / 144066 (Lee et al.), US2014 / 0276636 (Lee et al.), and WO2015 / 026813 (Lee et al.).

[0020] In embodiments where the gemcitabine is delivered from an intravesical drug delivery device, the drug The drug may be contained in the device in various forms, and the form may be such that the device The mechanism of action of the bladder may depend on the specific mechanism that controllably releases the bladder fluid (e.g., urine). In some embodiments, the agent is provided in a solid, semi-solid, or other non-liquid state; This allows for the drug to be stored stably before the device is used. and the drug payload of the device is increased by the drug being contained in the form of a liquid solution. Advantageously, this allows for a smaller storage volume than would otherwise be possible. In some embodiments, the non-liquid form may be a tablet, a granule, a semi-solid (e.g., , ointments, creams, pastes, or gels), capsules, and combinations thereof In one embodiment, the drug is selected from the group consisting of those described in U.S. Pat. No. 8,343,516. In other embodiments, the drug is in the form of one or more tablets, such as mini-tablets. or may be contained in a liquid state, such as a solution containing a plurality of pharmaceutically acceptable excipients. .

[0021] An embodiment of a drug delivery device 100 is shown in Figure 1A. The device 100 comprises: The device body includes a drug reservoir 102 and a holding frame 104. Thus, device 100 is shown in a relatively expanded configuration suitable for retention within the body. Following placement within the body cavity or lumen, device 100 may be configured to retain the drug delivery device within the body cavity or lumen. It may also have a relatively expanded shape for this purpose.

[0022] For purposes of this disclosure, "relatively widened shape," "relatively high profile shape," or Terms such as "retention shape" refer to a shape suitable for retaining the device in the bladder, as shown in FIG. The device is positioned at the intended implantation location, including, but not limited to, a pretzel shape. Similarly, the term "relatively low profile" generally refers to any shape suitable for holding a vise. Terms such as "configuration" or "deployment configuration" refer to the catheter, cystoscope, or or a straight line suitable for placing the device through the working channel of another placement tool. and a drug delivery device having a shape suitable for placement within the body, including a round or elongated shape. In embodiments, the drug delivery device is It can assume a relatively expanded shape and can be expanded either manually or with the aid of an external device. The device may be deformed into a relatively low profile shape for insertion into the body. When placed in the body, it spontaneously, i.e., naturally, assumes an initial, relatively expanded shape to accommodate its internal organization. can be restored to its original state.

[0023] In the illustrated embodiment, the drug reservoir and retaining frame portions of the drug delivery device 100 102, 104 are aligned longitudinally and connected to each other along their lengths. However, other configurations are possible. The drug delivery device 100 includes a drug reservoir lumen 108 (i.e., , drug housing) and a resilient or flexible device body defining a retaining frame lumen 110. 106. The drug storage lumen 108 is designed to contain a drug formulation containing the drug. In an illustrated embodiment, the drug formulation comprising gemcitabine is a multi-solid drug formulation. The support frame lumen 110 is in the form of a medical unit 112, which may be a tablet. It is designed to receive the holding frame 114 and forms the holding frame portion 104. The lumens 108, 110 are separated from one another, although other configurations are possible.

[0024] As shown in cross-section in FIG. 1B, device body 106 defines a drug reservoir lumen 108. A tube or wall 122 and a tube or wall 124 defining the support frame lumen 110 are provided. The tubing 122, 124 and lumens 108, 110 may be substantially cylindrical; The drug reservoir lumen 108 has a relatively larger diameter than the retaining frame lumen 110. and placement factors such as the amount of drug to be delivered, the diameter of the holding frame, and the inner diameter of the placement tool. Other configurations may be selected based on considerations of: As shown in the figure, the wall material 124 is formed such that the holding frame lumen 110 is similar to the drug storage lumen 108. and extending along the entire length of the wall material 122 defining the drug storage lumen 108 so as to have a length of However, in other embodiments, one wall member may be shorter than the other wall member. The two walls 122, 124 are, in the illustrated embodiment, spaced apart along the entire length of the device. However, intermittent bonding may also be used.

[0025] As shown in FIG. 1A, the drug reservoir lumen 108 contains multiple drug units (including gemcitabine). The containers 112 are filled in a serial arrangement. For example, depending on the size of the reservoir and drug unit, Essentially any number of drug units can be used. The drug unit 112 has a first end opening 130 and an opposite second opening 132. After filling, the locking plugs 120 are placed in the openings 130 and 132. In the embodiment, the fixing plug 120 is a cylindrical plug and is fixed in the openings 130, 132. In other embodiments, openings 130 and 132 are closed with other structures or materials. The structure or material may be configured to allow water or drugs to enter or leave the structure or material during use, depending on the particular embodiment. To facilitate ease of use, apertures or water- or drug-permeable wall materials may be included. do.

[0026] In other embodiments, the drug reservoir lumen contains gemcitabine other than the solid drug unit. Gemcitabine may be packaged in the form of, for example, an oily or aqueous vehicle. The formulation may take the form of a suspension, solution, or emulsion, and may contain suspending agents, stabilizers, and and / or may contain formulatory agents such as dispersants. The active ingredient may be incorporated into a suitable vehicle, such as a sterile, pyrogen-free vehicle, prior to use. By aseptic isolation of sterile solids or freezing from solution for constitution with fresh water It may be in the form of a powder obtained by drying.

[0027] In one embodiment, the gemcitabine is released from a release opening in the housing of the device. One or more excipients including a viscosity enhancing agent to control the release of the solubilized gemcitabine. In another embodiment, the reservoir of the device is formulated with gemcitabine and However, gemcitabine and the viscosity enhancing agent are not co-formulated, e.g. For example, they are supplied as separate tablets in separate areas within the reservoir. Suitable thickening agents are known in the art, including, but not limited to, polyethylene oxide (PEO). In some variations of the above embodiments, the thickening agent may be, for example, urea or another It may also be supplied formulated with an osmotic agent.

[0028] In one embodiment, the gemcitabine is administered to the patient with a solubility enhancer. In an embodiment, the solubility enhancer is urea. In one embodiment, the urea is or other solid form and placed in the drug reservoir of the intravesical drug delivery device. In some devices, the urea also acts as an osmotic agent, Osmotic pressure can be easily generated within the reservoir. Citabine and osmotic agents are disclosed in PCT WO2015 / 0 As described in 26813 (Lee et al.), different ion channels can be placed within different regions of the drug reservoir. It is comprised as individual tablets (or other solid forms).

[0029] The retaining frame lumen 110 is filled with a retaining frame 114, which may be, for example, a Nitto The holding frame 110 may be made of an elastic wire material such as a superelastic alloy such as tungsten. or those disclosed in the above-incorporated applications. , may be configured to naturally return to a retained shape, such as another coiled shape. In other words, the holding frame 114 can hold the device 100 within the body, such as in the bladder. For example, the retention frame 114 may allow the device 100 to be introduced into the body in a relatively low profile configuration. and returning to a relatively expanded shape after device 100 is inside the body. and the device is adapted to control the fluid dynamics associated with detrusor contraction and urination. and preventing the device from assuming a relatively low cross-sectional shape in the body in response to anticipated forces, such as mechanical forces. , elastic limit and elastic modulus. Thus, the device 100 is The present invention can limit or prevent the growth of erythrocytes and erythrocytes in the body and be retained in the body after implantation.

[0030] The material used to form, at least in part, the device body 106 A resilient or flexible support is provided to allow the chair 100 to move between the deployed and held configurations. When the device is in the holding configuration, the holding frame portion 104 is shown. As shown, the drug reservoir 102 may tend to be located inside the drug reservoir 102. In this case, the holding frame portion 104 may be positioned inside, outside, above, or below the drug reservoir portion 102. It is possible.

[0031] The material used to form the device body 106 may be The solubilizing fluid (e.g., urine) enters the drug reservoir 102 and solubilizes the drug unit 112. It may be water permeable so as to be solubilized, for example, silicone or another biocompatible elastomer. In another embodiment, the device body comprises at least a portion Alternatively, it may be made of a water-impermeable material.

[0032] FIG. 2A illustrates another embodiment of an intravesical drug delivery device 200, which contains a drug 21. 2 filled drug reservoir 202 and 2 filaments 220 connected by fasteners 230 , 222. As shown, the drug reservoir 202 includes a retention structure including the 2B and 2C. The drug reservoir 202 is an elongated tubular member that can be deformed between different shapes. may be packed into a flexible tubing so that it can move between the two shapes. For example, the medication 212 may be a number of solid medication tablets, liquids, or gels. The filaments 220, 222 are attached to both ends of the drug reservoir 202 and fasteners 23 The stopper 230 may be adjusted to change the position of one of the filaments 220. 222, thereby adjusting the position of one end of the drug reservoir 202 relative to the other. The filaments 220, 222 can be adjusted to deliver the drug By drawing the ends of reservoir 202 closer together, device 200 The filaments 220, 222 can then be attached by the fasteners 230. By preventing adjustment, the device 200 can be held in a held configuration. In some embodiments, the filament is manually removed after the device 200 is inserted into the bladder. By adjusting 220, 222, the device 200 is manually adjusted to the holding configuration. do.

[0033] In the illustrated embodiment, the fastener 230 is a cinch nut. The cinch nut is a filament 220 between both ends of the drug reservoir and the cinch nut. , 222 while allowing the filaments 220, 222 to be shortened. This prevents the filament from being stretched through the cinch nut. By pulling on one or both of the ports 220, 222, both ends of the drug reservoir 202 The portions can be drawn closer together, causing the device 200 to assume a holding shape. When the filaments 220, 222 are so adjusted, the cinch nut The members 220, 222 prevent stretching and hold the device in a retained configuration. In this way, manually adjusting the device 200 to a holding configuration after implantation is simply It is only necessary to pull on one or both of the filaments 220, 222. Other fasteners 230 that require separate operations may also be used. It is possible.

[0034] Another embodiment of an intravesical drug delivery device is illustrated in Figures 3A-3C. The device has a single continuous structure with multiple separate drug storage lumens 320. and optionally at least one holding frame 360 ​​disposed therein. The housing 300 includes a drug reservoir lumen 330. Each drug reservoir lumen 320 is shown in cross section in FIG. As shown in the figure, the device has two defined openings and at least one solid drug unit 3 For example, solid drug unit 340 may be a drug tablet or capsule. In another embodiment not shown, each drug reservoir lumen may be a single The housing may be formed from a flexible polymer such as silicone. FIG. 3B shows one of the drug storage lumens 320 of the housing shown in FIG. 3A along line 3B-3B. As shown in FIG. 3B, the one-piece housing 300 is Two defined openings exposing both ends of the solid drug unit 340 in the drug storage lumen 320. In this embodiment, the support frame lumen 33 has a mouth portion (350a, 350b). 0 is parallel to the longitudinal axis of the housing and perpendicular to the drug reservoir lumen 320 FIG. 3C is a perspective view of a portion of the embodiment of device 300 shown in FIG. When the device is placed in the support frame lumen 330, 1 is a perspective view of the drug storage lumen 3 in the housing of this embodiment in its retained shape. 20 and the holding frame 360, the drug storage lumen 320 is outside the arc of the holding frame 360. Alternatively, the housing of FIG. 3C may be oriented around the holding frame 360. The structure is rotated by 80 degrees so that the drug storage lumen 320 is positioned inside the arc of the holding frame 360. In this embodiment, the device is placed and retained within the bladder. When the device is in use, sufficient direct contact is achieved between the solid drug unit and the urine surrounding the device. In embodiments, release of drug from the device occurs via the surface of the solid drug unit. The rate of drug release from the drug delivery device is controlled by erosion of the exposed portion of the drug. The degree of adhesion is directly proportional to and limited by the total exposed surface area of ​​the solid drug unit. It is possible.

[0035] The release of gemcitabine from the intravesical devices described herein is driven by various mechanisms of action. In various embodiments, the drug can be diffused through the wall of the drug housing. By diffusion through one or more defined openings in the wall material of the drug housing. and one or more temporarily formed vesicles are formed by osmotic pressure through openings in the drug housing. The drug formulation is eroded by contact with urine in the bladder due to osmotic pressure passing through the microchannels. or a combination thereof may be released from the intravesical drug delivery device. In some embodiments, drug release is achieved by activating a drug-permeable polymer that defines a portion of the housing of the device. The drug is controlled by the diffusion of the drug through a drug-permeable matrix material. In embodiments, the device comprises a drug-permeable polymeric member.

[0036] In certain embodiments, the drug delivery device comprises a first wall structure and a hydrophilic second wall structure. a housing having a closed drug storage lumen surrounded by a wall structure of the above-mentioned a drug formulation containing gemcitabine contained within the first wall structure, the first wall structure being water-permeable or water-impermeable; The second wall structure is aqueous and impermeable to the drug, and the second wall structure is The wall surrounding and defining the drug reservoir of the device is permeable to a first a first material serving as a wall structure and a second material serving as a wall structure; two materials, so that drug release occurs substantially exclusively through the second material. In one embodiment, the device does not include an opening and drug release occurs through the second wall structure. As used herein, the term "non-drug" refers to a drug that is released from a tissue by diffusion through the tissue. "Permeable" and "water-impermeable" mean that the wall structure is substantially impermeable to the drug or water. Transient, so that the drug or water is substantially absorbed into the wall over the therapeutic release period. For use in the bladder, the drug is not released through the structure, which may cause discomfort to the patient. The device is flexible during detrusor contraction to avoid or reduce discomfort and irritation. (i.e., it is easy to bend and has a soft feel). The durometer of the first and second materials is a design consideration to ensure the device is adequately flexible in the bladder. High durometer is essential for constructing a device housing of a given size while maintaining flexibility. The percentage of material in the thermoplastic may be limited. For example, Tecophilic™ thermoplastic Plastic polyurethane (Lubrizol) is over 70A, and has a short resistance of 80A to 65D. While silicone tubing may have a Shore hardness of 50A to 70A. Rather than fabricating the entire device from a second, hydrophilic, drug-permeable material that swells in water, It may be advantageous to utilize a combination of these two different polymeric materials.

[0037] Continuing with this particular embodiment, the first wall structure may be formed of silicone. For example, the housing comprises a silicone tubing, the wall of which serves as a first wall structure. In other embodiments, the first wall structure may be made of other water-permeable materials. The drug is preferably in solid form (e.g., one tablet or multiple tablets). tablet), and the first wall structure prevents the inflow of the drug while the drug is in the drug storage lumen. The first wall structure is water permeable to allow for solubilization in vivo. For example, the first wall structure is water permeable to approximately 50 A. The second wall may be formed of silicone having a Shore durometer of about 70A. The structure may be a hydrophilic polymer designed to absorb water. The wall structure of at least partly comprises a hydrophilic polyurethane, a hydrophilic polyester, or It may be a hydrophilic elastomeric material made of hydrophilic polyamide. The second wall structure is Tecophilic™ thermoplastic polyurethane. , HydroThane™ thermoplastic polyurethane (AdvanSource Bi omaterials), Quadraphilic™ thermoplastic polyurethane ( Biomerics, LLC) (ALC grade is an aliphatic polycarbonate hydrophilic polymer ALE grade is aliphatic polyether-based hydrophilic polyurethane, Hydro roMed™ (AdvanSource Biomaterials), or Thermoplastic polyurethanes such as Dryflex® (HEXPOL TPE) Another hydrophilic polymer is the polyether block amide Pebax® MV 1074 SA 01 MED (Arkema), the polymer is flexible and It is a thermoplastic elastomer made of water-based polyether and rigid polyamide. For example, The hydrophilic material of the second wall structure has a Shore durometer value of about 70A to about 65D. The specific material and its thickness and wall area control the permeation rate of water and drugs, This allows selection to obtain a particular release profile of the gemcitabine. Cut.

[0038] The arrangement of the first and second wall structures can take a variety of forms. In this case, the first wall structure is a cylindrical tubular member, and the second wall structure is a portion of the cylindrical tubular member. an end wall member disposed at at least one end, or a first wall structure and a second wall structure The bodies are adjacent to each other and together form a cylindrical tube, i.e., drug release occurs within a closed The drug is controlled by diffusion through a drug-permeable member that defines a portion of the housing of the device. The drug-permeable wall structure provides a desired, controlled rate of drug diffusion from the device. The conductors may be arranged, sized, and have material properties to provide: In the example 4 described below, the first wall structure is a cylindrical pipe, and the second wall structure is a cylindrical pipe. The wall structure is an end wall disposed on at least one end of the cylindrical tubing.

[0039] Inserting an intravesical device 400 for subsequent controlled release of the drug into the bladder One embodiment is shown in Figures 4A and 4B, where a device 400 is shown, The device is shown with the suction tube 404 emerging from the placement tool 402 and in a holding configuration. The device 402 may be any suitable device. The placement device 402 may be a catheter, a urethral catheter, or the like. The placement instrument 402 may be a catheter or a tubular instrument such as a cystoscope. The device may be a device or a device specially adapted for the present drug delivery device. Illustrates insertion of 400 into the bladder, showing the anatomy of an adult male as an example. The device 400 is inserted through the urethra into the bladder, and the device 400 is by a stylet or a flow of lubricant, or a combination thereof, until it is released into the bladder. It may be driven and passed from / through the placement tool 402, The nozzle 400 is in a retaining configuration as shown.

[0040] From the study described in the Examples below, it was surprisingly found that the extremely small discharge opening, i.e. Embodiments of the device having holes are preferred, and devices that release drug without pre-set holes are also preferred. It has been found that the above embodiments are more preferred because these embodiments The incidence of urothelial lesions was significantly reduced compared to device embodiments utilizing relatively larger release holes. It has been observed that this can be effective to eliminate or at least substantially reduce Without being bound by any theory, it is believed that the larger pores The device is designed to localize gemcitabine on the urothelial tissue surface in the area adjacent to the release opening of the device. It is possible that localized high drug concentrations may form in these localized tissue areas, resulting in In contrast, the pre-set holes In device systems that utilize an ejection mechanism with no or very small ejection holes, Such localized high drug concentrations are less likely to occur. An example of such a suitable "non-porous" release system is P CT Patent Application Publication No. WO2014 / 144066 (TB 130) and U.S. Patent Application Publication No. and US Pat. No. 6,276,636 (TB 134), which are incorporated herein by reference. It is incorporated into the detailed text.

[0041] In some embodiments, the device comprises a drug in solid form. The elution of the drug occurs following dissolution of the drug within the device. enters the membrane, comes into contact with the drug, solubilizes the drug, and the dissolved drug then dissolves under osmotic pressure or by diffusion. For example, the device In cases where the drug is implanted into the bladder, the drug may be solubilized upon contact with urine. .

[0042] In various embodiments, the intravesical device delivers the drug continuously or intermittently. The drug is released to provide a sustained, therapeutically effective concentration of the drug for 1 hour to 1 month, for example, 2 hours to 1 month. In the bladder over a period of time such as 2 weeks, 6 hours to 1 week, or 24 hours to 72 hours. In certain embodiments, the intravesical concentration of the drug can be obtained in the bladder. The device can be used in doses ranging from 1 mg / day to 1000 mg / day, e.g., 20 mg / day to 300 mg / day or The formulation may release the gemcitabine in an amount of 25 mg / day to 300 mg / day. In this formulation, these release rates are provided over a treatment period of 14 to 21 days. .

[0043] In another embodiment, the coating material is applied to the bladder wall (e.g., the urothelium lining the bladder). The coating material may be applied intravesically to the bladder (region), and the coating material may be the gemcitabine or other a drug and one or more additive substances that promote adhesion of the coating material to the bladder wall The coating comprises a compound that provides a continuous, controlled release of the drug over a period of treatment. The formulations include gels, ointments, creams, pastes, films, emulsion gels, tablets, polymers, or a combination thereof. The polymers include hydrogels or hydrophilic polymers, polycarbophil (i.e., carbopoly chol, chitosan, polyvinylpyrrolidone (PVP), lectin, polyethylene glycol Examples of suitable polymers include cholesteric polymers, cellulose, and combinations thereof. Examples of suitable cellulose include methyl cellulose (MC) and carboxymethyl cellulose (CM). C), hydroxypropyl cellulose (HPC), or a combination thereof. The coating material may include a permeability enhancer. Non-limiting examples of permeability enhancers include: Examples include dimethyl sulfoxide (DMSO) and sodium carboxymethylcellulose. (NaCMC), lipids, surfactants, or a combination thereof. As shown, the coating material 500 is oriented such that the coating material 500 engages the bladder wall 552. The catheter may be positioned within the bladder 550 so as to

[0044] The coating material may be placed into the bladder using a placement tool. 5 is a sagittal section of the genitourinary system of a human being, being deployed to an implantation site via a deployment tool 502. Illustrated is a coating material 500 having various configurations. For illustrative purposes, the male anatomy is shown, and the The implantation site is shown as bladder 550. The coating material 500 may be any of the coating materials described herein. The placement tool 502 may be one embodiment of a coating material. It can be any instrument designed to pass through a cavity to reach the intended implantation site. For placement into the bladder 550, the placement device 502 is inserted into the patient's urethra as shown. 560 into the bladder 550. The placement instrument 502 is It may be a known device such as a catheter or cystoscope, or a specially designed device The placement tool 502 is used to place the coating material 500 inside the body. It is then removed from the body, leaving the coating material 500 completely implanted within the body. The coating material 500 is capable of releasing the drug into the body for a long period of time after being implanted in this manner. Using equivalent procedures, any of the devices or drugs described herein can be administered to other The device can be placed in other parts of the body through natural lumens. For example, as shown in FIG. Then, by using the placement tool 602 and passing the placement tool 602 through the urethra 660, A liquid drug or drug formulation 600 can be placed in the bladder 650 .

[0045] In one embodiment, a second therapeutic agent is administered to the patient. This second agent is a compound similar to that described above. Can be administered simultaneously, sequentially, or overlapping with administration of cytabine The second therapeutic agent may be administered intravesically. A second therapeutic agent may be administered intravesically. The second therapeutic agent may be a cytotoxic agent, an analgesic, The second therapeutic agent may be a gemcitabine or an anti-inflammatory agent, or a combination thereof. may function by a different mechanism of action than gemcitabine and / or may act synergistically with gemcitabine. In one embodiment, the second therapeutic agent may function to prevent, treat, or inhibit cystitis of the bladder. In yet another embodiment, the initial (e.g., first week following TURBT) During this period, gemcitabine is used as a chemoimmunotherapy agent, and then carboplatin is used as a subsequent agent. Bacillus Calmette-Guérin (BCG) is routinely administered. See, e.g., Cho et al., J. Int'l' See Med. Res. 37:1823-30(2009).

[0046] In various embodiments, the intravesical administration of gemcitabine to the patient is performed by TURBT. It can be performed before TURBT, after TURBT, both before and after TURBT, or without TURBT. This can be done.

[0047] In one embodiment, the intravesical gemcitabine is administered to treat non-muscle invasive bladder cancer (NMIBC). In another embodiment, the intravesical gemcitabine is used in the treatment of BC. In yet another embodiment, the intravesical gemcitabine is used in the treatment of refractory NMIBC. Tabine is available in a multiple dose form, with an induction period followed by a series of maintenance doses. For example, one week of treatment once a month for three months, followed by treatment every three months as needed. A maintenance dose is administered once a week.

[0048] As used herein, the term "patient" or "subject" refers to a human or, in veterinary, livestock, and other mammals such as in clinical research applications. In another embodiment, the patient or subject is an adult human. , cows, dogs, cats, goats, sheep, and pigs. [Example]

[0049] The present invention can be further understood with reference to the following non-limiting examples.

[0050] Example 1: Uptake of gemcitabine from the bladder in the prostate Intravesical cannulation in male Sprague-Dawley rats for 6 or 24 hours by continuous infusion or by a single intravenous (IV) bolus. 14 C Game Travel The 6-hour and 24-hour continuous perfusions were performed at 6.9 ml / min, respectively. The single IV bolus was administered in a 5-minute infusion of 26.6 mg of gemcitabine into the bladder. It contained 0.0 mg of gemcitabine.

[0051] Blood (Figure 8), urine, and tissue samples (e.g., bladder, prostate) (Figures 7 and 9) were collected. The gemcitabine content was analyzed. The results are illustrated in Figures 7 to 9. The subsequent urinary concentration of gemcitabine results in significant gemcitabine concentrations in bladder tissue. This gemcitabine concentration was found to be effective in treating bladder cancer cells in vitro. The results show that gemcitabine concentrations in the bladder are at or above therapeutic levels. 9, which also shows clinically relevant gemcitabine in the bladder 24 hours after IV administration. The bladder epithelium, lamina propria, muscularis, and adventitia each showed significantly lower concentrations of The observed gemcitabine concentrations are shown in Figure 14, which also shows the tissue concentrations of gemcitabine. This illustrates the target effective range for

[0052] Example 2: Gemcitabine in large mixed breed hunting dogs Two gems designed to release therapeutic concentrations (4 mg / day and 40 mg / day) into the urine A cytabine release system (the device shown in Figures 1A-1B) was screened and tested. , either laser-drilled or punched holes for the release of said gemcitabine. The tested system was designed to mimic the standard intravesical administration used clinically. The test animals were large, mixed-breed hounds, and each group was compared with a previously designed intravesical instillation method. The experiment was conducted with N=3.

[0053] Each system exhibited different release rates of gemcitabine in vitro. One system produced very low urinary and tissue concentrations, but performed poorly in test animals. The other system produced the target urinary concentration levels but was well tolerated in the test animals. The drug was poorly tolerated in patients with variable urinary profiles and prolonged drug release. The duration was unacceptably short. Intravesical administration resulted in symptoms consistent with those reported in the literature. Significant urothelial lesions were also observed.

[0054] In summary, this study demonstrated that the device / tablet formulation design significantly impacted gemcitabine urinary concentrations over time. demonstrated that steroids have a strong impact on both steroid use and bladder tolerance.

[0055] Example 3: Examination of gemcitabine bladder irrigation in minipigs Various concentrations of gemcitabine were administered to pigs for 7 days with N=5 (2 males and 3 females per treatment group). The animals were perfused with the steroids selected for classification of target doses for bladder cancer in humans. For comparison, large-diameter granules with moderate in vitro release rates were administered at selected concentrations. The end cap (a stopper for fixing the drug) has a large diameter opening for drug release passing through it. a gemcitabine-releasing device (as shown in FIGS. 1A-1B) having a stopper (above) having a closure portion. All perfusion groups received gemcitabine, including the highest perfusion dose. In contrast, the gemcitabine-releasing device demonstrated moderate to severe vasoconstriction. Although it produced urinary concentrations, it was not well tolerated.

[0056] Example 4: Modular device releasing gemcitabine by a permeation system Gemcitabine HCl was injected into the four-module device 1000 illustrated in Figures 10A-C. FIG. 10A shows a device 1000 having four drug storage modules 1010A, 1010B, 1010C, 1010D, 1010E, 1010F, 1010H ... For clarity, FIG. 10C shows the same components as those shown in FIG. 10B, 1010C, and 1010D. only the housing portion of the device for the drug storage modules 1010A and 1010D. FIG. 10C shows drug storage modules 1010A and 1010B. Respective reservoir sidewalls 1040A and 1040D of wall segments 1012 and 1014 are Illustrated is a configuration in which the retaining frame is integrally joined by a lumen 1014. The wall material segments 1040A and 1040D, as well as the wall material segments 1012, and the retaining frame lumen 1 014 was formed by cutting a section from double lumen silicone tubing. (The four-module device is constructed from a double-lumen silicone tubing with spaced apart Each drug storage module had an inner diameter of 2.64 mm. A silicone MED-4750 (Nusil) with dimensions of 0.5 mm and a wall thickness of 0.20 mm was used. The silicone tubing had an inner diameter of 0.51 mm and a wall thickness of 0.20 mm. The Nitinol support frame was provided with a support frame lumen 1. 10B shows the structure of the membrane through which the solubilized drug is released by diffusion. 1 illustrates the structure of a drug storage module 1010A having a disk 1060 (the other three The drug storage module of this disk was identical in structure to module 1010A. 60 sandwiches the disk 1060 between an outer washer 1100 and an inner washer 1120. Each disk 106 is stabilized within the lumen of the cylindrical tube sidewall material 1040A by the insertion of the disks 106. 0 is HP-93A-100 (Tecophilic® thermoplastic polyurethane) Each disk 1060 was approximately 0.5 mm thick and 3.0 mm in outer diameter. The outer diameter of the disk (3.0 mm) was smaller than the inner diameter of the silicone tube (2.64 mm). The disk was larger than the silicone tubing, so that it frictionally fitted into the silicone tubing. Inner and outer silicone washers 1120 and 1100 are MED-4780 (Nusil) ) and silicone adhesive is applied around these washers 1120 and 1100 to secure the device. Place these washers adjacent to the disk 1060 and install them within the silicone tubing 1040A. The silicone outer washers 1100 are approximately 2.5 mm, 3.2 mm, and and 2 mm inner diameter, outer diameter, and length, and the silicone inner washer 1120 The inner diameter, outer diameter, and length dimensions are approximately 1.58 mm, 2.77 mm, and 2 mm, respectively. had.

[0057] A number of drug tablets 1080 with an outer diameter of 2.6 mm were placed in silicone tubing 1040A. and then secured by disk 1060 and inner and outer washers 1120 and 1100. The tablet formulation was 90% gemcitabine HCl, 5% P VP, 2.5% Neusilin, and 2.5% magnesium stearate. The total mass of the tablets packed in the device of the module was approximately 800 mg.

[0058] In vitro release tests were conducted using three devices (R204-4 to 6) at 37 °C. The release medium was deionized water, and samples were taken at each time point. The release of gemcitabine was measured at T Controlled by diffusion through the ecophilic disk. Free base equivalent (FBE) The cumulative amount and release rate, expressed as , are shown in Figures 11 and 12, respectively. Each error bar represents the mean value (N The standard deviation is centered around the error bar (=3). Some error bars are smaller than the symbols representing the measurement points. stomach.

[0059] Devices of the same design were tested in vivo in three Göttingen minipigs. Each device was non-surgically inserted into the bladder of each animal via a cystoscope through the urethra. Urinary concentrations of tabine and 2',2'-difluoro-2'-deoxyuridine (dFdU) were Measurements were taken over an 8-day period. After this 8-day study, each device was examined using a cystoscope and forceps. The combined urinary concentration of gemcitabine and dFdU was The medium concentration is shown in FIG.

[0060] Example 5: Screening study of gemcitabine delivery devices in minipigs Based on the inherent tolerability of gemcitabine found in the minipig perfusion study described above, To refine the design of this drug delivery system, a series of prototype screening studies were conducted. In the study, three prototype devices were designed to release therapeutic concentrations of gemcitabine into the urine. Two types of devices were designed as shown in Figures 1A-1B (large diameter end cap for drug release) One type of device is shown in Figure 10A- The device was designed as 10C (drug-permeable disc for drug release). Each study tested one prototype design in three minipigs for 7 days. Blood and urine samples were collected intensively over a period of 10 min.

[0061] The device design of Figures 1A-1B with a larger diameter end cap for drug release provides consistent It was found that the above-mentioned gemcitabine induces urothelial lesions in the animals. 1A-1B with laser-drilled holes containing a thickening agent along with cytabine. It was found that the non-porous design of Figures 10A-10C reduced the incidence of urothelial lesions. The device was found to completely eliminate the occurrence of urothelial lesions. It is believed that this contributes to the development of urothelial lesions (near the drug release opening of the device). This is thought to prevent transient high local concentrations of gemcitabine (at the tissue surface).

[0062] Example 6: Screening study of gemcitabine delivery devices in minipigs In this study, an osmotic prototype device was designed to release therapeutic concentrations of gemcitabine into urine. The device was designed to: A separate location within the drug reservoir, as generally described in O2015 / 026813. The device was configured to use a gemcitabine tablet and an osmotic agent tablet placed in the Each of the devices in one subset is a silicone tubing having a tubing between both ends of the tubing. A centrally located area has 75 micron laser-drilled holes for drug release. The silicone tubing had a lumen with a central region near the release hole. The lumen is filled with tablets of a mixture of gemcitabine and urea, and both end regions of the lumen are filled with urea / Lub The second subset of devices were each filled with a silicone tube. a tubular material having a 150 mm diameter tubular material for drug release in a region centrally located between both ends of the tubular material; The silicone tubing had a laser-drilled hole in it. The tablet is filled with a mixture of gemcitabine and urea in the central area near the release hole. The urea / PEO tablets were filled into both end regions of the lumen. Cumulative and in vitro studies were performed in minipigs and in vitro, and the cumulative and in vivo released data were analyzed over a 7-day period. The average gemcitabine release rate was measured. Approximately 120 mg was obtained from the device over a 7-day period, and approximately 120 mg was obtained from the 150 micron pore device. The urinary concentration over time was approximately 140 mg. A slightly lower rate was observed with the urea / PEO formulation when compared to the tab formulation. Therefore, the viscosity of the solution of solubilized drug in the lumen of the device controls drug release. This can be a factor in determining whether

[0063] Conclusions from the examples A literature review providing target concentrations—in vitro concentrations across tumor cell lines—was conducted. Generally, for responsive cell lines, the doses are 0.5 μg / g and 3.0 μg / g (micrograms per gram). (Jeon et al., J. Urol. 18(1):189-200) 6(5):2084-93(2011). The literature is also However, high urinary concentrations (e.g., 2000 mg in up to 50 mL) are required for However, intravesical instillation to achieve such concentrations has been shown to be effective in reducing safety and tolerability, systemic toxicity, and adverse reactions. It has been suggested that this is associated with problems with lower urinary tract symptoms (LUTS) (Cattel et al., Annals s Oncol. 17(Suppl 5):v142-47(2006)).

[0064] However, from the studies described in the above examples, the urine required to achieve these therapeutic tissue concentrations The concentration of gemcitabine in the tissue is measured and the concentration is found to be tolerable to the urothelium. In other words, it is not necessary to have a high concentration in the urine of the bladder. Intravesical systems delivering 100 mg / 100 ml (e.g., 20 mg in up to 50 ml) are effective. It was found that this is possible.

[0065] Also, contrary to what the literature teaches regarding intravenous infusion of gemcitabine, This study demonstrated that long-term intravesical delivery of gemcitabine can be achieved without damaging the bladder. It was found that:

[0066] Publications cited herein and the material for which they are cited are incorporated by reference. Modifications and variations of the methods and devices described herein will be apparent to those skilled in the art from the foregoing detailed description. Such modifications and variations are intended to fall within the scope of the appended claims. The inventions described in the original claims of this application are listed below. [Invention 1] 1. A medicament for use in treating bladder cancer, comprising gemcitabine, by locally administering said gemcitabine into the bladder of a patient to achieve a sustained concentration of said gemcitabine in urine within the bladder sufficient to produce a therapeutic concentration of said gemcitabine in bladder tissue, comprising: The agent is locally administered into the patient's bladder in an average amount of 1 mg / day to about 300 mg / day of gemcitabine (FBE). [Invention 2] The agent according to Invention 1, wherein the gemcitabine (FBE) is administered locally into the patient's bladder in an average amount of 1 mg / day to 200 mg / day. [Invention 3] The agent according to Invention 1, wherein the gemcitabine (FBE) is administered locally into the patient's bladder in an average amount of 5 mg / day to 100 mg / day. [Invention 4] The agent according to Invention 1, wherein the gemcitabine (FBE) is administered locally into the patient's bladder in an average amount of 10 mg / day to 50 mg / day. [Invention 5] The drug according to invention 1, wherein the gemcitabine (FBE) is administered locally into the patient's bladder in an average amount of 15 mg / day to 25 mg / day. [Invention 6] The agent according to invention 1, wherein the local administration into the patient's bladder is at an average dose of about 20 mg / day of gemcitabine (FBE). [Invention 7] 7. The agent according to any one of Inventions 1 to 6, wherein the local administration into the patient's bladder is continuous for a period of 1 to 30 days. [Invention 8] 7. The agent according to any one of Inventions 1 to 6, wherein the local administration into the patient's bladder is intermittent over a period of 1 to 30 days. [Invention 9] 7. The agent according to any one of claims 1 to 6, wherein the local administration into the patient's bladder is intermittent or continuous over a period of 1 to 14 days. [Invention 10] 7. The agent according to any one of Inventions 1 to 6, wherein the local administration into the patient's bladder is continuous over a period of 1 to 7 days. [Invention 11] 7. The agent according to any one of claims 1 to 6, wherein the gemcitabine is delivered into the bladder from an intravesical drug delivery device that continuously releases the gemcitabine into the urine in the bladder over a sustained period of time. [Invention 12] 12. The method of claim 11, wherein the intravesical drug delivery device continuously releases the gemcitabine into the urine in the bladder over a period of 1 to 14 days. [Invention 13] The agent of invention 12, wherein the intravesical drug delivery device comprises a housing that is elastically deformable between a retention shape configured to contain and controllably release the gemcitabine and to retain the device in the patient's bladder, and a deployment shape for passing the device through the patient's urethra. [Invention 14] The drug according to Invention 13, wherein the gemcitabine contained in the housing is in a non-liquid state. [Invention 15] The drug according to invention 14, wherein the non-liquid form is selected from the group consisting of tablets, granules, semisolids, capsules, and combinations thereof. [Invention 16] 7. The agent according to any one of Inventions 1 to 6, wherein the gemcitabine is delivered into the bladder from a coating material applied to the bladder, and the coating material releases the gemcitabine into urine in the bladder over a sustained period of time. [Invention 17] 17. The medicament according to claim 16, wherein the coating material comprises a mucoadhesive formulation. [Invention 18] 18. The agent according to claim 17, wherein the local administration into the patient's bladder is continuous for a period of 1 to 14 days. [Invention 19] 18. The agent according to claim 17, wherein the local administration into the patient's bladder is continuous over a period of 1 to 7 days. [Invention 20] The agent according to any one of Inventions 1 to 6, wherein the local administration comprises pumping the gemcitabine in a liquid state into the bladder through a urethral catheter or a suprapubic catheter placed into the bladder. [Invention 21] 21. The agent according to claim 20, wherein the local administration into the patient's bladder is continuous or intermittent over a period of 1 to 7 days. [Invention 22] A drug delivery device comprising an agent according to any one of the preceding inventions, the device being configured to release the gemcitabine when the drug delivery device is inserted into the bladder. [Invention 23] A method for administering a drug to a patient in need of treatment for bladder cancer, comprising: The method comprises intravesically administering gemcitabine into the bladder of the patient to achieve a sustained concentration of said gemcitabine in the urine within the bladder sufficient to produce a therapeutically effective concentration of said gemcitabine in the tissue of the bladder. [Invention 24] 24. The method of claim 23, further comprising administering to said patient at least a second therapeutic agent. [Invention 25] 25. The method of claim 24, wherein the second therapeutic agent is administered intravesically. [Invention 26] 24. The method of claim 23, further comprising administering urea or another solubility-modifying agent into the bladder in an amount effective to enhance or otherwise modify the solubilization of said gemcitabine. [Invention 27] 27. The method of claim 26, wherein the urea or other solubility modifier is released from an intravesical device that releases the gemcitabine. [Invention 28] a housing configured for intravesical insertion; and Gemcitabine-containing dosage forms Equipped with the housing is configured to hold the dosage form and release the gemcitabine into the bladder in a therapeutically effective amount for treating the bladder; configured to release gemcitabine into the bladder at an average dose of 1 mg / day to about 300 mg / day of said gemcitabine. Drug delivery devices. [Invention 29] 29. The device of claim 28, wherein the housing releases the gemcitabine by diffusion through a drug-permeable polymer wall material. [Invention 30] 29. The device according to claim 28, wherein the housing releases the gemcitabine without having a preset release opening. [Invention 31] 29. The device according to claim 28, wherein the housing has a release hole communicating with a drug reservoir in which the gemcitabine is contained together with (i) a viscosity increasing agent, (ii) an osmotic agent, or (iii) a combination of a viscosity increasing agent and an osmotic agent. [Invention 32] 32. The device of claim 31, wherein the gemcitabine is provided in a first region comprising one or more tablets, and the osmotic agent and / or viscosity increasing agent is provided in a second region comprising one or more tablets, the first and second regions being separate spaces within the drug reservoir.

Claims

1. 1. A medicament for use in treating bladder cancer in a patient, comprising gemcitabine, by locally administering said gemcitabine into the bladder of the patient to achieve a sustained concentration of said gemcitabine in urine within the bladder sufficient to produce a therapeutic concentration of said gemcitabine in bladder tissue, comprising: locally administering into the patient's bladder in an average amount of 1 mg / day to 300 mg / day of the gemcitabine free base equivalent (FBE); wherein the gemcitabine is delivered to the bladder from an intravesical drug delivery device that continuously releases the gemcitabine into the urine in the bladder over a period of 1 to 30 days; the intravesical drug delivery device comprising: Gemcitabine or gemcitabine HCl, a housing that contains and controllably releases the gemcitabine; The drug comprising:

2. The method of claim 1, wherein the intravesical drug delivery device is elastically deformable between a retention configuration configured to retain the device in the bladder and a deployment configuration for passing the device through the patient's urethra.

3. The drug of claim 1 or 2, wherein the housing is configured to release the gemcitabine by osmotic pressure.

4. The drug according to any one of claims 1 to 3, wherein the housing releases the gemcitabine by osmotic pressure so as to achieve a urinary concentration of gemcitabine in the bladder that is well tolerated by the urothelium.

5. The method of any one of claims 1 to 4, wherein the local administration into the bladder is at an average amount of 5 mg / day to 100 mg / day of gemcitabine (FBE).

6. The method of any one of claims 1 to 4, wherein the local administration into the bladder is at an average amount of 1 mg / day to 50 mg / day of gemcitabine (FBE).

7. The method of any one of claims 1 to 4, wherein the local administration into the bladder is at an average amount of 1 mg / day to 25 mg / day of gemcitabine (FBE).

8. The method of any one of claims 1 to 4, wherein the gemcitabine is released into the urine in the bladder in an average amount of 1 mg / day to 15 mg / day over a period of 1 to 30 days.

9. The method of any one of claims 1 to 4, wherein the gemcitabine is released into the urine in the bladder in an average amount of 15 mg / day to 25 mg / day over a period of 1 to 14 days.

10. The method of any one of claims 1 to 4, wherein the gemcitabine is released into the urine in the bladder in an average amount of 25 mg / day to 50 mg / day over a period of 1 to 7 days.

11. The method of any one of claims 1 to 4, wherein the gemcitabine is released into the urine in the bladder in an average amount of 20 mg / day.

12. 12. The method of claim 11, wherein the gemcitabine is released into the urine in the bladder at an average amount of 20 mg / day for 7 days.

13. The method of any one of claims 1 to 4, wherein the gemcitabine is released into the urine in the bladder over a period of 1 to 14 days.

14. The method of any one of claims 1 to 4, wherein the gemcitabine is released into the urine in the bladder over a period of 1 to 7 days.

15. The method of any one of claims 1 to 4, wherein the gemcitabine is released into the urine in the bladder over a period of 7 to 30 days.

16. The method of any one of claims 1 to 4, wherein the gemcitabine is released into the urine in the bladder over a period of 14 to 30 days.

17. The method of any one of claims 1 to 4, wherein the gemcitabine is released into the urine in the bladder in an average amount of 10 mg / day over a period of 7 to 30 days.

18. The method of any one of claims 1 to 4, wherein the gemcitabine is released into the urine in the bladder in an average amount of 1 mg / day to 50 mg / day over a period of 7 days.

19. The method of any one of claims 1 to 4, wherein the gemcitabine is released into the urine in the bladder in an average amount of 1 mg / day to 50 mg / day over a period of 7 to 30 days.

20. The method of any one of claims 1 to 4, wherein the gemcitabine is released into the urine in the bladder in an average amount of 1 mg / day to 50 mg / day over a period of 14 to 30 days.

21. The method of any one of claims 1 to 4, wherein the gemcitabine is released into the urine in the bladder in an average amount of 15 mg / day to 25 mg / day over a period of 7 days.

22. The method of any one of claims 1 to 21, wherein the cancer is non-muscle invasive bladder cancer (NMIBC).

23. The method of any one of claims 1 to 22, wherein the patient has undergone a transurethral resection of the bladder tumor (TURBT) prior to placement of the intravesical drug delivery device in the bladder.

24. The method of any one of claims 1 to 23, wherein the patient has undergone transurethral resection of bladder tumor (TURBT) after placement of the intravesical drug delivery device in the bladder.

25. The drug according to any one of claims 1 to 24, wherein the gemcitabine contained in the housing is in a non-liquid state.

26. 26. The method of claim 25, wherein the non-liquid form is selected from the group consisting of tablets, granules, semi-solids, capsules, and combinations thereof.

27. The drug according to any one of claims 1 to 26, wherein the housing is provided with a release hole communicating with a drug reservoir in which the gemcitabine is contained together with a viscosity-increasing agent and an osmotic agent.

28. 28. The method of claim 27, wherein the release hole is a laser-drilled release hole.

29. 29. The method of claim 28, wherein the laser-drilled emission holes are 150 micron holes.

30. The method of any one of claims 27 to 29, wherein the osmotic agent is urea.

31. The drug of any one of claims 27 to 30, wherein the drug reservoir contains a urea tablet.

32. a housing configured for intravesical insertion; and Gemcitabine-containing dosage forms A drug delivery device comprising: the housing is configured to hold the dosage form and release the gemcitabine into the bladder in a therapeutically effective amount for the treatment of bladder cancer; The drug delivery device, wherein the device is configured to continuously release the gemcitabine free base equivalent (FBE) into the urine of the bladder at an average amount of 1 mg / day to 100 mg / day of the gemcitabine over a period of 1 day to 30 days.

33. 33. The device of claim 32, wherein the intravesical drug delivery device is elastically deformable between a retention configuration configured to retain the device in the bladder and a deployment configuration for passing the device through the urethra.

34. 34. The device of claim 32 or 33, wherein the housing is configured to release the gemcitabine by osmotic pressure.

35. 35. The device of any one of claims 32 to 34, wherein the housing releases the gemcitabine by osmotic pressure to achieve a urinary concentration of gemcitabine in the bladder that is well tolerated by the urothelium.

36. 36. The device of claim 35, wherein the device is configured to release gemcitabine into the bladder continuously for a period of 1 to 30 days, at an average amount of 1 mg / day to 50 mg / day of the gemcitabine (FBE).

37. 37. The device of any one of claims 32 to 36, wherein the device is configured to release gemcitabine into the urine of the bladder in an average amount of 5 mg / day to 50 mg / day of gemcitabine (FBE).

38. 37. The device of any one of claims 32 to 36, wherein the device is configured to release gemcitabine into the urine of the bladder in an average amount of 1 mg / day to 50 mg / day of gemcitabine (FBE).

39. 37. The device of any one of claims 32 to 36, wherein the device is configured to release gemcitabine into the urine of the bladder in an average amount of 1 mg / day to 25 mg / day of gemcitabine (FBE).

40. 37. The device of any one of claims 32 to 36, wherein the device is configured to release gemcitabine into the urine in the bladder at an average amount of 1 mg / day to 15 mg / day of the gemcitabine (FBE) over a period of 1 to 30 days.

41. 37. The device of any one of claims 32 to 36, wherein the device is configured to release gemcitabine into the urine in the bladder at an average amount of 15 mg / day to 25 mg / day of the gemcitabine (FBE) over a period of 1 to 14 days.

42. 37. The device of any one of claims 32 to 36, wherein the device is configured to release gemcitabine into the urine in the bladder at an average amount of 25 mg / day to 50 mg / day of the gemcitabine (FBE) over a period of 1 to 7 days.

43. The device of any one of claims 32 to 36, wherein the device is configured to release gemcitabine into the urine in the bladder at an average amount of 20 mg / day of the gemcitabine (FBE).

44. 37. The device of any one of claims 32 to 36, wherein the device is configured to release gemcitabine into the urine in the bladder at an average amount of 20 mg / day of the gemcitabine (FBE) for 7 days.

45. 37. The device of any one of claims 32 to 36, wherein the device is configured to release gemcitabine into the urine in the bladder over a period of between 1 and 14 days.

46. 37. The device of any one of claims 32 to 36, wherein the device is configured to release gemcitabine into the urine in the bladder over a period of 1 to 7 days.

47. 37. The device of any one of claims 32 to 36, wherein the device is configured to release gemcitabine into the urine in the bladder over a period of between 7 and 30 days.

48. 37. The device of any one of claims 32 to 36, wherein the device is configured to release gemcitabine into the urine in the bladder over a period of between 14 and 30 days.

49. 37. The device of any one of claims 32 to 36, wherein the device is configured to release gemcitabine into the urine in the bladder at an average amount of 10 mg / day of the gemcitabine (FBE) over a period of 7 to 30 days.

50. 37. The device of any one of claims 32 to 36, wherein the device is configured to release gemcitabine into the urine in the bladder at an average amount of 1 mg / day to 50 mg / day of the gemcitabine (FBE) for 7 days.

51. 37. The device of any one of claims 32 to 36, wherein the device is configured to release gemcitabine into the urine in the bladder at an average amount of 1 mg / day to 50 mg / day of the gemcitabine (FBE) over a period of 7 to 30 days.

52. 37. The device of any one of claims 32 to 36, wherein the device is configured to release gemcitabine into the urine in the bladder at an average amount of 1 mg / day to 50 mg / day of the gemcitabine (FBE) over a period of 14 to 30 days.

53. 37. The device of any one of claims 32 to 36, wherein the device is configured to release gemcitabine into the urine in the bladder at an average amount of 15 mg / day to 25 mg / day of the gemcitabine (FBE) over a period of 7 days.

54. The device of any one of claims 32 to 53, wherein the housing comprises a release hole communicating with a drug reservoir in which the gemcitabine is contained together with an osmotic agent.

55. 55. The device of claim 54, wherein the gemcitabine is provided in a first region comprising one or more tablets, and the osmotic agent and / or viscosity increasing agent is provided in a second region comprising one or more tablets, the first and second regions being separate spaces within the drug reservoir.

56. 56. The device of claim 54 or 55, wherein the osmotic agent is urea.

57. 57. The device of any one of claims 54 to 56, wherein the drug reservoir comprises a urea tablet.

58. 58. The device of any one of claims 54 to 57, wherein the drug reservoir further comprises a viscosity increasing agent.

59. 59. The device of any one of claims 54 to 58, wherein the emission holes are laser-drilled emission holes.

60. 60. The device of claim 59, wherein the laser-drilled emission holes are 150 micron holes.

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