Drug delivery devices with drug-permeable component and methods

Abstract

To provide implantable devices that can deliver drugs to different various drugs by an effective release rate.SOLUTION: Implantable drug delivery devices include a housing having a closed drug reservoir lumen bounded by a first wall structure and a hydrophilic second wall structure, and a drug contained in the drug reservoir lumen, wherein the first wall structure is impermeable to the drug and the second wall structure is permeable to the drug. Methods of providing controlled release of drug to a patient include deploying a drug delivery device in the patient releasing a drug from the drug reservoir lumen via diffusion through the second wall structure.SELECTED DRAWING: Figure 8A

Description

Technical Field

[0001] [Cross - Reference to Related Applications] This application claims priority to U.S. Provisional Patent Application 61 / 799,733, filed on March 15, 2013, and is hereby incorporated by reference herein in its entirety.

[0002] This disclosure generally relates to the field of implantable medical devices, and more particularly to drug delivery devices having drug - permeable components.

Background Art

[0003] Implantable medical devices and methods are known for targeted, e.g., local or partial, drug delivery to avoid problems associated with systemic drug delivery. However, there is room for improvement with respect to local delivery of drugs to a particular tissue site, especially with regard to extended drug delivery by minimally invasive devices and methods for minimizing patient discomfort resulting from the presence of the device itself. The problem is particularly important for certain treatments where a drug, e.g., one that is relatively poorly water - soluble, and / or a device needs to be kept small enough to avoid unwanted discomfort and pain during and after device deployment in a patient, while still providing controlled release of the drug at therapeutic levels over a long period of days or weeks.

[0004] U.S. Patent Application Publication Nos. 2012 / 0203203 (TB121), 2012 / 0089122 (TB117), 2011 / 0060309 (TB108), 2011 / 0152839 (TB112), and 2010 / 0331770 (TB101) of TARIS Biomedical provide for controlled release of drugs from a housing. (TB121), 2012 / 0089122 (TB117), 2011 / 0060 309 (TB108), 2011 / 0152839 (TB 112), and 20 10 / 0331770 (TB101) provide for controlled release of drugs from a housing. describes various drug delivery devices. While releasing the drug locally over a long period of time , the device can freely float in the patient's bladder and still be tolerable and completely retained in the patient's bladder. However, a new design of the intravesical drug delivery device , and for different drugs, it is desirable to provide other implantable devices capable of delivering drugs at an effective release rate . SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0005] In one aspect, an implantable drug delivery device is provided that includes a closed drug reservoir lumen surrounded by a first wall structure and a hydrophilic second wall structure , and a drug contained in the drug reservoir lumen, where the first wall structure is impermeable to the drug and the second wall structure is permeable to the drug. In one embodiment, the first wall structure is a cylindrical tube and the second wall structure is an end wall disposed at at least one end of the cylindrical tube. In another embodiment , the first wall structure and the second wall structure are adjacent to each other and together form a cylindrical tube .

[0006] In another aspect, a method for providing controlled drug release to a patient is provided, the method comprising: (i) disposing in the patient's body a drug delivery device including a closed drug reservoir lumen surrounded by a first wall structure and a hydrophilic second wall structure , and (ii) releasing the drug from the drug reservoir lumen via diffusion through the second wall structure , where the first wall structure is impermeable to the drug and the second wall structure is permeable to the drug . including. In one embodiment, the first wall structure is a cylindrical tube, and the second wall structure is an end wall disposed at at least one end of the cylindrical tube. In another embodiment, the first wall structure and the second wall structure are adjacent to each other and together form a cylindrical tube.

Brief Description of the Drawings

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DETAILED DESCRIPTION OF THE INVENTION

[0008] An improved implantable drug delivery device is provided. In certain embodiments, the device is configured for intravesical insertion and sustained drug delivery, and preferably provides a zero-order release rate of a therapeutically effective amount of the drug.

[0009] It has been found that for certain drugs, it may be difficult to achieve a zero-order release rate for more than 3 days and up to 4 days by an osmotic delivery mechanism. In experiments, from 3 days to 4 days later, the drug release rate drops sharply, which results in the urinary concentration of the drug in the bladder being at the end of the treatment period ​previously, it would be possible to reduce it below the minimum effective concentration. For example, due to the limited size of the overall implant system, simply providing more or more densely packed osmotic agents with the drug may not necessarily be practical to extend the period of zero-order release rate is not necessarily practical by providing them. Instead, providing an overall first-order drug release rate throughout the entire treatment period is also not necessarily practical. Because as the treatment period approaches the end, even if the drug release rate is attenuated, the release rate is still not necessarily safe to have an initial peak drug release rate that is high enough to be above the minimum effective concentration of the drug. Therefore, the special device described herein has been developed, where instead of an osmotic drug release mechanism, drug release is controlled by diffusion of the drug through a drug-permeable polymer or a matrix member that defines the device housing portion. In one embodiment, the device comprises a drug-permeable polymer member.

[0010] In one aspect, an implantable drug delivery device is provided that includes a closed drug reservoir lumen surrounded by a first wall structure and a hydrophilic second wall structure, and a housing having the drug contained in the drug reservoir lumen, where the first wall structure is permeable or impermeable to water, and the second wall structure is permeable to the drug. The walls surrounding and defining the drug reservoir of the device are made of a first material provided as the first wall structure and a second material provided as the second wall structure, and drug release occurs essentially only through the second material. In one embodiment, the device does not include an opening, and drug release is through the second material only. In one embodiment, the device comprises a drug-permeable polymer member. In one aspect, an implantable drug delivery device is provided that includes a closed drug reservoir lumen surrounded by a first wall structure and a hydrophilic second wall structure, and a housing having the drug contained in the drug reservoir lumen, where the first wall structure is permeable or impermeable to water, and the second wall structure is permeable to the drug. The walls surrounding and defining the drug reservoir of the device are made of a first material provided as the first wall structure and a second material provided as the second wall structure, and drug release occurs essentially only through the second material. In one embodiment, the device does not include an opening, and drug release is through the

[0011] second material only. In one aspect, an implantable drug delivery device is provided that includes a closed drug reservoir lumen surrounded by a first wall structure and a hydrophilic second wall structure, and a housing having the drug contained in the drug reservoir lumen, where the first wall structure is permeable or impermeable to water, and the second wall structure is permeable to the drug. The walls surrounding and defining the drug reservoir of the device are made of a first material provided as the first wall structure and a second material provided as the second wall structure, and drug release occurs essentially only through the second material. In one embodiment, the device does not include an opening, and drug release is through the second material only. second wall structure. The walls surrounding and defining the drug reservoir of the device are made of a first material provided as the first wall structure and a second material provided as the second wall structure, and drug release occurs essentially only through the second material. In one embodiment, the device does not include an opening, and drug release is through the second wall structure only. second wall structure only. In one embodiment, the device does not include an opening, and drug release is through the It is generated only by diffusion through the two wall structures. As used herein, the terms "impermeable to drugs" and "impermeable to water" mean that during the therapeutic release period, substantially no drug or water is released through the wall structure, i.e., a wall structure that is substantially impermeable to drugs or water.

[0012] For use in the bladder, to avoid or alleviate discomfort and irritation for the patient, during contraction of the urinary muscles, it is important that the device is compliant (i.e., easily bendable and soft to the touch). Therefore, the durometer hardness of the first and second structural materials is important, and there is a limit to the proportion of materials with high durometer hardness when constructing a device housing of a given size while maintaining proper compliance of the device housing within the bladder. It is pointed out that, for example, Tecophilic® thermoplastic polyurethane (manufactured by Lubrizol) has a shore hardness greater than 70A, such as 80A - 65D, while silicone forms tubes with a shore hardness of 50A - 70A. Thus, rather than making the device entirely of a water-swellable, hydrophilic, drug-permeable second material, it may be beneficial to utilize a combination of these two different polymeric materials.

[0013] In a preferred embodiment, the device is elastically deformable between a relatively linear shape suitable for insertion into the patient's bladder through the patient's urethra and a retention shape suitable for retaining the device within the bladder. In one embodiment, the device further includes a retention frame lumen and a retention frame located within the retention frame lumen. In an embodiment, the retention frame ​​may include two or more housing units.

[0014] The first wall structure can be formed of silicone. For example, the housing can include a silicone tube, and the wall of the silicone tube serves as the first wall structure. In other embodiments, the first wall structure may be formed of other water-permeable materials. In a preferred embodiment, the drug is in solid form (e.g., a single tablet or multiple tablets), and the first wall structure is water-permeable to enable solubilization of the drug in vivo while the drug is in the drug reservoir lumen. For example, the first wall structure can be formed of silicone having a Shore durometer hardness of from about 50A to about 70A.

[0015] The second wall structure is a hydrophilic polymer designed to absorb water. For example, the second wall structure may be a hydrophilic elastomeric material formed at least in part of hydrophilic polyurethane, hydrophilic polyester, or hydrophilic polyamide. In a preferred embodiment, as the second wall structure, Tecophilic® thermoplastic polyurethane, HydroThane® thermoplastic polyurethane (manufactured by AdvanSource Biomaterials); Quadraphilic® thermoplastic polyurethane (manufactured by Biomerics, LLC) (the ALC grade is based on aliphatic polycarbonate and the ALE grade is a hydrophilic polyurethane based on aliphatic polyether); HydroMed® (manufactured by AdvanSource Biomaterials) or Dryflex® (manufactured by HEXPOL Examples of the thermoplastic polyurethane include those such as TPE). As other hydrophilic polymers, poly ether block amide, Pebax (registered trademark) MV 1074 SA 01 MED (manufactured by Arkema), which is a thermoplastic elastomer made from a flexible and hydrophilic polyether and a rigid po lyamide. For example, the hydrophilic material of the second wall structure may have a Shore durometer hardness of from about 70A to about 65D. The specific material and its thickness and wall area can be selected to achieve a specific drug release profile, such as water and drug permeation rates.

[0016] The arrangement of the first and second wall structures can take various forms. As non-limiting examples, FIGS. 1 to 12C are shown. In one embodiment, the first wall structure is a cylindrical tube and the second wall stru cture is an end wall disposed at at least one end of the cylindrical tube, or the first wall structure and the second wall structure are adjacent to each other and together form a cylindrical tube. That is, drug release is controlled by drug diffusion through a drug-permeable component that defines a portion of the closed device housing. The drug-permeable wall structure can be positioned, dimensioned, and have material properties to provide a desirable rate of controlled drug diffusion from the device.

[0017] In one embodiment shown in FIGS. 1 to 8B, the first wall structure is a cylindrical tube and the second wall structure is an end wall disposed at at least one end of the cylindrical tube. In one embodiment, the first wall structure is a cylindrical tube and the second wall structure is an end wall disposed at at least one end of the cylindrical tube, and the second wall structure is a disk-shaped body stabilized in the lumen of the cylindrical tube. ​​​​​There is. As shown, the first wall structure may be in the form of a cylindrical tube, and the second wall structure may be in the form of a disk at one or both ends. The disk may be stabilized in the lumen of the cylindrical tube using various mechanical or adhesive means. For example, the disk may be frictionally engaged between the disk and the tube; notches in the inner wall of the tube; a suitable adhesive; or one or more washers, or other structural stabilizing members, to be stabilized in the lumen of the cylindrical tube can. In certain embodiments, the first wall structure, one or more washers, or stabilizing members, and / or the adhesive are made of silicone.

[0018] Figures 1 - 3 show an implantable drug delivery device 100 having a housing 102 with a closed drug reservoir lumen surrounded by a first wall structure 104 and a hydrophilic second wall structure 106; and a plurality of drug tablets in the form of drugs 108 contained in the drug reservoir lumen, where the first wall structure 104 is impermeable to the drug, and the second wall structure 106 is permeable to the drug. The second wall structure 106 is an end wall disposed at at least one end of the first wall structure which is a cylindrical tube 104. The second wall structure 106 is in the form of a disk stabilized within the lumen of the cylindrical tube 10 4. As shown in Figure 1, the disk 106 may be in frictional fit or adhered to the lumen of the cylindrical tube 104. As shown in Figure 2 the external washer 110 is adjacent to the disk 106 and stabilizes it within the lumen of the cylindrical tube 104 . As shown in Figure 3, the external washer 110 and the internal washer 112 sandwich the disk 106 and stabilize it within the lumen of the cylindrical tube 104 . As shown in Figure 3 sandwich the disk 106 and stabilize it within the lumen of the cylindrical tube 104 As shown in Figure 3, the drug tablet 109 adjacent to the inner washer 112 has a smaller tablet diameter than the other drug tablets 108 in order to fit within the inner diameter of the inner washer 1 12. The drug tablet 109 may be omitted, and in such a case, there may be a void space within the inner washer 112, which may introduce or delay the delay time before drug release begins. Depending on the void space within the inner washer 112, the delay time can be varied or controlled.

[0019] The components of the disk stabilizing washer can take on a variety of forms. Non-limiting examples are shown in Figures 4A - 7. As shown in Figures 4A - 4D, the inner and outer washers 412, 4 10 can sandwich the disk 406. The drug tablet 409 adjacent to the inner washer 412 may have a smaller tablet diameter than the other drug tablets 408 in order to fit within the inner diameter of the inner washer 412. Therefore, the washers 410, 412, the disk 406, and the drug tablets 40 8, 409 may be disposed within a cylindrical tube (i.e., a first wall structure). For example, the inner and outer washers may be made of silicone, and the hydrophilic disk may be Tecop hilic (registered trademark). In one embodiment, the washer has an inner diameter of 2.1 6 mm and an outer diameter of 2.77 mm, and the drug tablets have diameters of 2.16 mm and 2.64 mm In certain embodiments, as shown in Figures 4A - 4C, the washers 410, 412 include one or more screw grooves 413 for receiving an adhesive (e.g., room temperature vulcanizing (RTV) silicone). In one embodiment, the screw groove has a diameter of 0.3 mm For example, the adhesive may be applied to one or both of the inner and outer washers. Out​​​​​​​ When the inner surface of the partial washer 410 comes into contact with water or body fluid, the initial wetting of such a surface may be assisted by being covered with a hydrophilic material. For example, the inner surface of the outer washer is salt sodium chloride, urea, polyvinylpyrrolidone (PVP), or polyethylene glycol (PEG) and other water-soluble excipients, and may be covered with either a powder form or a tablet form that can fit into the void space within the outer washer. Further, the inner surface of the outer washer may be coated with a hydrophilic polymer used to construct the second wall structure. The appropriate method of coating the hydrophilic polymer varies depending on the substrate conditions of the inner surface of the outer washer. As shown in FIG. 5, in one embodiment, the first wall structure 504 is a cylindrical tube having an inner diameter at the end of the tube that is smaller than the inner diameter of the rest of the tube. As shown in FIG. 5, the inner diameter at the end of the cylindrical tube 504 may be smaller than the diameter of the disk 506 so that the end of the cylindrical tube 504 stabilizes the disk 506 at one end. The inner washer 512 may be used to stabilize the disk 506 at the other end.

[0020] As shown in FIG. 5, in one embodiment, the first wall structure 504 is a cylindrical tube having an inner diameter at the end of the tube that is smaller than the inner diameter of the rest of the tube. As shown in FIG. 5, the inner diameter at the end of the cylindrical tube 504 is, in order for the end of the cylindrical tube 504 to stabilize the disk 506 at one end, smaller than the diameter of the disk 506. The inner washer 512 may be used to stabilize the disk 506 at the other end. for. used.

[0021] As shown in FIG. 6, in one embodiment, the first wall structure is a cylindrical tube 604 having a housing insert 620 . The housing insert 620 is fixed within the cylindrical tube 604 to stabilize the disk 606 at one end. As shown in FIG. 6, the housing insert 620 may be cylindrical in shape and may have an outer diameter such that the insert 620 can be fixed within the cylindrical tube 604. The inner diameter at the end of the cylindrical housing insert 620, such that the end of the insert 620 stabilizes the disk 606 at one end, is the inner diameter at the end of the cylindrical housing insert 620 such that the end of the insert 620 stabilizes the disk 606 at one end, is the disk 606 It may also be smaller than the diameter of. The outer washer 610 may be disposed within the housing insert 620 to stabilize the disk 606 at the other end. The drug tablet 608 may be provided within the lumen of the cylindrical tube 604. For stabilization, it may be placed within the housing insert 620. The drug tablet 608 may be provided within the lumen of the cylindrical tube 604. It may be provided within the lumen of the cylindrical tube 604.

[0022] Figure 7 illustrates another embodiment of a device having a housing insert 720. The housing insert 720 is fixed to the cylindrical tube 704 to stabilize the disk 706 at one end. The inner washer 712 stabilizes the disk 706 at the other end. The drug tablet 708 is provided by the lumen of the cylindrical tube 704 and the insert 720. The housing insert 720 is fixed to the cylindrical tube 704 to stabilize the disk 706 at one end. The inner washer 712 stabilizes the disk 706 at the other end. The drug tablet 708 is provided by the lumen of the cylindrical tube 704 and the insert 720. It is provided by the lumen of the cylindrical tube 704 and the insert 720.

[0023] Figure 8 illustrates an embodiment of a drug delivery device 800 having a disk 806 stabilized by washers at each end of the device. The disk 806 is stabilized between the inner washer 812 and the outer washer 810. The drug tablet is the drug tablet 809 adjacent to the disk 806 having a diameter smaller than the tablet 808 and is provided within the lumen of the cylindrical tube 804. The disk 806 is stabilized between the inner washer 812 and the outer washer 810. The drug tablet is the drug tablet 809 adjacent to the disk 806 having a diameter smaller than the tablet 808 and is provided within the lumen of the cylindrical tube 804. It is provided within the lumen of the cylindrical tube 804.

[0024] Therefore, an assembly of a device in which a closed housing is formed by a first wall structure of a cylindrical tube and a second wall structure of an end wall can take many forms. Given a particular drug formulation, the following parameters: disk material, wall thickness, and diameter; inner diameter, outer diameter, and length of the inner washer; Inner diameter, outer diameter, and length of the outer washer; initial void space within the inner washer (e.g., large voids may result in a long release delay time.) may be adapted to affect the drug release profile. For example, the inner washer and the outer washer May be fixed to a silicone tube to stabilize the disk in both the longitudinal directions. In one embodiment Inner diameter, outer diameter, and length of the outer washer; initial void space within the inner washer (e.g., large voids may result in a long release delay time.) may be adapted to affect the drug release profile. For example, the inner washer and the outer washer May be fixed to a silicone tube to stabilize the disk in both the longitudinal directions. In one embodiment May be fixed to a silicone tube to stabilize the disk in both the longitudinal directions. In one embodiment May be fixed to a silicone tube to stabilize the disk in both the longitudinal directions. In one embodiment In one form, the washer is made of high durometer silicone (e.g., MED-4780 manufactured by Nusil Technology LLC), and a silicone adhesive (e.g., MED3-4213 manufactured by Nusil Technology LLC) is applied to the interface between the washer and the tube.

[0025] The hydrophilic polymer wall structure has a tendency to absorb and swell water, and the degree of swelling depends on the water absorption behavior of the polymer. Therefore, the thickness of the disk can be selected based on the type of hydrophilic polymer used and its water absorption to achieve the desired drug release rate. The initial void space in the inner washer can also be used to program the delay time in the drug release profile. Overall, to reduce the drug release rate through the disk, the diameter of the disk, the inner diameter of the inner washer, and the inner diameter of the outer washer can be reduced and the length of one or more of the outer and / or inner washers and the thickness of the disk can be increased.

[0026] In other embodiments, as shown in FIGS. 9-12C, the first wall structure and the second wall structure are adjacent to each other and together form a cylindrical tube. For example, such a device may be formed by coextrusion. In one embodiment, the coextruded first and second wall structures are thermoplastic polymers that retain the desired properties.

[0027] As shown in FIG. 9, the first wall structure 904 and the second wall structure 906 together form a cylindrical tube having a lumen containing the drug formulation 908. The second wall structure 906 is at least the first It is in the shape of a strip extending along the length portion of the wall structure 904 and is permeable to the drug, while the first wall structure 904 is impermeable to the drug. In certain embodiments, various hydrophilic strips or regions may be used in a single device.

[0028] Figures 10A - 10C illustrate another embodiment of a device in which the first wall structure 1004 forms a closed cylindrical tube with the second wall structure 1006. In Figures 10A - 10C, the first wall structure 1004 is a tubular body having an opening in its side wall. The hydrophilic band 1 006 is sized and shaped to fit within a sleeve 1005 having an opening sized similarly to that of the first wall structure 1004. The hydrophilic band 1006 is disposed around the tube 1004 such that the hydrophilic material covers the opening within the tube 1004, thereby forming the closed tube 1004. The sleeve 1005 may be disposed on the band 1006 to stabilize the band 1006, while the opening of the sleeve 1005 is aligned with the opening of the first wall structure 1004 to expose the band 1006 in order to allow for drug release. For example, an adhesive may be applied to the lumen of the sleeve to adhere the sleeve and the band assembly to the first wall structure. As shown in Figure 10C, the inner diameter of the hydrophilic second wall band 1006 may be flush with the inner diameter of the sleeve 1005 having a notch for housing the band 1006 therein. In certain embodiments, the tube, sleeve, and / or adhesive of the first wall structure are made of silicone, while the hydrophilic band is a thermoplastic polymer such as Tecophilic (registered trademark). It is made of urethane.

[0029] Figures 11A - 11B illustrate another embodiment of a device for forming a cylindrical tube in which a first wall structure 1104 is closed by a second wall structure 1106. The first wall structure 1104 is tubular in shape and has three openings in its sidewall. The first wall structure 1104 is in the shape of a tube having three openings in its sidewall. The hydrophilic second wall structure 1106 is tubular in shape and contains a drug tablet 110 8. The hydrophilic tube 1106 is sized and shaped to fit within the first wall structure tube 1104 such that the hydrophilic material of the tube 1106 is disposed at each opening of the first wall structure body 1104, thereby forming a closed cylindrical tube. For example, the first wall structure tube may have one or more openings therein. In certain embodiments, the first wall structure has one, two, three, or more openings therein. openings therein.

[0030] Figures 12A - 12C illustrate another embodiment of a device for forming a cylindrical tube in which a first wall structure 1204 is closed by a hydrophilic second wall structure 1206. The first wall structure 1204 is tubular in shape and has three openings in its sidewall. The hydrophilic second wall structure 1206 is sized and shaped to fit within the interior of the tube 1204 such that the hydrophilic second wall 1206 is disposed at each opening of the tube 1204, thereby forming a closed cylindrical tube that is a semi - cylindrical insert. The hydrophilic second wall structure may take the form of a thin strip sized to extend only along the perimeter of the tube including the openings.

[0031] Alternatively, the hydrophilic second wall structure extends about 50% to about 100% of the circumference of the tube including the openings.​​​​​​ It may be long. In certain embodiments, the tube is silicone, while the hydrophilic inser tion structure is a thermoplastic polyurethane such as Tecophilic®.

[0032] Therefore, in order to achieve a desired drug release rate, the size, shape, wall thickness and material properties of the second wall structure can be selected. Moreover, in embodiments utilizing the second wall structure with exposed openings, the size and number of the single or multiple openings can also be selected in order to achieve a desired drug release rate.

[0033] In embodiments where the first and second wall structures together form a cylindrical tube, any suitable end plugs or closures can also be used to seal the ends of the tube after the drug is loaded. These end plugs / closures ensure that the hydrophilic polymer portion exposed on the outer surface of the tube (e.g., by forming a portion of the outer tube or by being exposed through an opening in the outer tube) is the only path for drug release. In embodiments where the second wall structure forms the end wall of the tube, the end plugs or closures are not present at the single or multiple ends including the single or multiple second wall structures. That is, in embodiments where the second wall structure forms the end of the device, end caps or closures are not used so as not to block the second wall structure from providing a drug release path.

[0034] In a preferred embodiment, the device is configured to release a therapeutically effective amount of the drug, where the release rate of the drug from the drug delivery device is zero order over at least 36 hours. In one embodiment, the release rate of the drug from the drug delivery device is at least 7 days. is essentially zero order over time. In certain embodiments, the device is configured such that drug release begins, for example, after a delay time due to void space within an inner wall of the device. In certain embodiments, the delay time can be at least about 30 minutes, about 12 hours to about 24 hours, or up to about two days.

[0035] In a preferred embodiment, the drugs are gemcitabine hydrochloride and tropisetron chloride. In one embodiment, at least 25 mg / day of gemcitabine is released over 7 days. In another embodiment, at least 1 mg / day of tropisetron chloride is released over 7 days to 3 months. In other embodiments, other drugs can be delivered by the devices described herein.

[0036] Other aspects of implantable drug delivery devices The devices and methods disclosed herein are described in U.S. Patent Nos. 8,182,464 and 8,343,516, as well as U.S. Patent Application Publication Nos. 2009 / 0149833 (MIT12 988); 2010 / 0331770 (TB101); 2010 / 0060309 (TB108); 2011 / 0 202036 (TB107); 2011 / 0152839 (TB 112); PCT / US11 / 46843, filed August 5, 2011 (TB 113); U.S. Patent Application No. 13 / 267,560, filed October 6, 2011 (TB116); U.S. Patent Application No. 13 / 267,469, filed October 6, 2011 (TB117); and U.S. Patent Application No. 13 / 347,513, filed January 10, 2012 (TB120). ​​​No. 6,399,411, each of which is incorporated herein by reference. do.

[0037] In one embodiment, the device is configured for insertion and retention within a patient's bladder. For example, the device may be configured in a configuration suitable for transluminal insertion into a body cavity of a patient, as shown in FIG. 8A. The device is elastically variable between a substantially straight shape and a retained shape suitable for retaining the device within the body cavity. In the retained configuration after placement in the bladder, for example, the device may , or may resist excretion in response to urination or another force. Because they are designed to be retained within the cavity, they are convenient and convenient for use with traditional procedures, such as those involving the bladder. The devices described herein overcome some of the deficiencies of the prior art. and can release the drug over a desired period of time without surgery or frequent intervention. As a result, the device can be delivered locally or locally into the bladder, reducing the chance of infection and side effects. Increase the amount of drug delivered locally or improve the patient's quality of life during the treatment process. After release of the drug, the device can be removed, for example, by cystoscope or forceps, or It may be, at least in part, biodegradable to avoid retrieval procedures.

[0038] The device may contain one or more solid drug units, such as tablets, capsules, or pellets. The drug is in the form of a capsule and can be filled with at least one drug. It is often beneficial to provide the drug in a solid form. A solid drug can reduce the volume of the overall device. It is possible to provide a relatively large drug payload and to reduce the time required for shipment, storage, and use. The stability of the drug before use or before drug release can potentially be enhanced. However, solid drugs should be solubilized in vivo in order to diffuse a therapeutically effective amount through the drug-permeable components and into the patient's surrounding tissues.

[0039] Each drug reservoir lumen may hold one or several drug tablets or other solid drug units. In one embodiment, the device holds about 10 to 100 cylindrical drug tablets, such as minitablets, between many individual drug reservoir lumens. In certain embodiments, the minitablets may each have a diameter of about 1.0 to about 3.3 mm, such as about 1.5 to about 3.1 mm, and a length of about 1.5 to about 4.7 mm, such as about 2.0 to about 4.5 mm.

[0040] The device can be inserted into a patient using a cystoscope or catheter. Generally, an adult cystoscope has an outer diameter of about 5 mm and an operating channel with an inner diameter of about 2.4 mm to about 2.6 mm. In embodiments, the cystoscope may have an operating channel with an inner diameter of 4 mm or greater. Thus, the device can be relatively small. Thus, when the device is elastically deformed relative to a relatively linear shape, the device for adult patients can be less than about 2.6 mm, such as between about 2.0 mm to about 2.4 mm, in overall outer diameter. For pediatric patients, the dimensions of the device should be smaller, for example, proportionally smaller, based on, for example, differences in anatomical size and / or differences in drug dosage between adult and pediatric patients. In addition to enabling insertion, making the device relatively small in size may also reduce patient discomfort and trauma to the bladder. ​

[0041] In one embodiment, the overall configuration of the device promotes biocompatibility in vivo for the majority of patients. In a particular embodiment, the device is configured for biocompatibility based on the characteristics of the bladder and the design considerations described in U.S. Patent Application Publication No. 2011 / 0152839 (TB112), which is hereby incorporated by reference.

[0042] Within the three-dimensional space occupied by the device, in the retention shape, the maximum dimension of the device in any direction is approximately the diameter of the bladder when full, preferably 10 cm or less. In some embodiments, the maximum dimension of the device in any direction may be about 9 cm or less, such as about 8 cm, 7 cm, 6 cm, 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 cm, or less. In certain embodiments, the maximum dimension of the device in any direction is about 7 cm or less, such as about 6 cm, 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 cm, or less. In a preferred embodiment, the maximum dimension of the device in any direction is about 6 cm or less, such as about 5 cm, 4.5 cm, 4 cm, 3.5 cm, 3 cm, 2.5 cm, or less. More specifically, the three-dimensional space occupied by the device is defined in three perpendicular directions. Along one of these directions, the device has its maximum dimension, and along the other two directions, it may have smaller dimensions. For example, the smaller dimensions in the other two directions may be about 4 cm or less, such as about 3.5 cm, 3 cm, 2.5 cm, or less. In a preferred embodiment, the device has, within these directions, at least ​ One has a dimension of 3 cm or less.

[0043] In some embodiments, due to the non-uniform shape of the device, the device may have different dimensions in at least two directions out of three directions, and in some cases, in each of the three directions. Due to the non-uniform shape, the device can achieve a reduced compression orientation within the empty bladder, which is also because the shape is non-uniform. In other words, a particular orientation of the device within the empty bladder reduces the contact pressure against the bladder wall and can be more tolerable to the patient. The overall shape of the device can allow the device to reorient itself within the bladder itself to reduce its engagement or contact with the bladder wall. For example, the overall outer shape of the device may be curved, and all or most of the outer or exposed surfaces of the device may be substantially rounded. The device may also be substantially lacking sharp ends, and the outer surface may be formed from a material that experiences a reduced frictional engagement with the bladder wall. Such a configuration allows the device to reposition itself within the empty bladder to provide a low contact pressure against the bladder wall. In other words, the device may slip or roll to a low energy position against the bladder wall, which means the device experiences less compression. In one embodiment, even if the device occupies a three-dimensional space, the device is generally planar in shape. Such a device can define a minor axis that is substantially symmetric around it and a major axis that is substantially perpendicular to the minor axis around it. The device is over about 6 cm.

[0044]

[0045] ​​​​​​​​​​​​​​ The maximum longitudinal dimension may be greater than about 4. Less than 5 cm, such as 5 cm, about 4 cm, about 3.5 cm, about 3 cm, or less. The device may have a maximum dimension along its minor axis not exceeding about 4.5 cm, and in particular In certain embodiments, less than 4 cm, such as about 3.5 cm, about 3 cm, or less. The device has a thickness of about 1 mm around substantially its entire circumference in both the long and short axis cross sections. In other words, the overall shape of the device is curved and the cross-sectional shape of the device is rounded. Therefore, when you place the device on a flat surface, there are two fully protected compartments inside the device. Except for the flat end edges, the device is substantially free of edges. These features include: When the device is in an empty bladder, it is designed to reorient itself to a lowered, compressed position. Make it possible.

[0046] The device may also be small enough in the retained configuration to allow mobility within the bladder. In particular, the device, when deployed, is designed to deliver blood through the entire bladder under most conditions of bladder fullness. , it may be small enough to move freely and smoothly, and it may be suitable for the patient's device. Supports tolerance to

[0047] The device also uses low density materials for the structural members in the housing components. and / or by, for example, the methods described in U.S. Patent Application Publication No. 2012 / 0089121 (TB 116) gas or gas generating material is introduced into the housing to provide buoyancy. The present invention can be adapted to assist in the provision of a method for detecting and determining whether a particular component is a cellular component, which is incorporated herein by reference. The dry and drug-loaded devices had a concentration of about 0.7 g / mL to about 1.3 g / mL. It may have a density in the range of about 0.5 g / mL to about 1.5 g / mL, such as in the range of In some embodiments, the device in the dry and drug-loaded state has a density less than 1 g / mL and has the smallest density.

[0048] The implantable drug delivery device does not require explantation or retrieval of the device following drug release from the formulation, and can thus be made to be fully or partially biodegradable. In some embodiments, when the device is partially eroded, it is partially biodegradable such that it breaks down into sufficiently small non-erodible fragments for excretion from the bladder. As used herein, the term "biodegradable" means that the device or a portion thereof breaks down in vivo by dissolution, enzymatic hydrolysis, erosion, resorption, or a combination thereof. In one embodiment, this breakdown occurs when it does not interfere with the intended rate of response of drug release from the device. For example, substantial erosion of the device does not occur until the drug formulation has been substantially or fully released. In another embodiment, the device is erodible and the release of the drug formulation is at least partially controlled by the degradation or erosion characteristics of the erodible device body. The devices described herein are designed to be compatible with those described in U.S. Patent Application Publication No. 2012 / 0089122 (TB117), which is hereby incorporated by reference herein. Useful biocompatible, erodible materials for the construct are known in the art. Examples of such suitable materials include poly(amides), poly(esters), poly(ester amides), In some embodiments, when the device is partially eroded, it is partially biodegradable such that it breaks down into sufficiently small non-erodible fragments for excretion from the bladder. As used herein, the term "biodegradable" means that the device or a portion thereof breaks down in vivo by dissolution, enzymatic hydrolysis, erosion, resorption, or a combination thereof. In one embodiment, this breakdown occurs when it does not interfere with the intended rate of response of drug release from the device. For example, substantial erosion of the device does not occur until the drug formulation has been substantially or fully released. In another embodiment, the device is erodible and the release of the drug formulation is at least partially controlled by the degradation or erosion characteristics of the erodible device body. The devices described herein are designed to be compatible with those described in U.S. Patent Application Publication No. 2012 / 0089122 (TB117), which is hereby incorporated by reference herein. and occurs when it does not interfere with the intended rate of response of drug release from the device. For example, substantial erosion of the device does not occur until the drug formulation has been substantially or fully released. In another embodiment, the device is erodible and the release of the drug formulation is at least partially controlled by the degradation or erosion characteristics of the erodible device body. The devices described herein are designed to be compatible with those described in U.S. Patent Application Publication No. 2012 / 0089122 (TB117), which is hereby incorporated by reference herein. For example, substantial erosion of the device does not occur until the drug formulation has been substantially or fully released. In another embodiment, the device is erodible and the release of the drug formulation is at least partially controlled by the degradation or erosion characteristics of the erodible device body. The devices described herein are designed to be compatible with those described in U.S. Patent Application Publication No. 2012 / 0089122 (TB117), which is hereby incorporated by reference herein. Useful biocompatible, erodible materials for the construct are known in the art. Examples of such suitable materials include poly(amides), poly(esters), poly(ester amides), which is hereby incorporated by reference herein.

[0049] Useful biocompatible, erodible materials for the construct are known in the art. Examples of such suitable materials include poly(amides), poly(esters), poly(ester amides), Poly(anhydrides), poly(orthoesters), polyphosphazenes, pseudo-poly(amino acids ), poly(glycerol sebacate) (PGS), its copolymers, and mixtures thereof Selected synthetic polymers include. In one embodiment, the resorbable synthetic polymer Is selected from poly(lactic acid), poly(glycolic acid), poly(lactic acid-co-glycolic acid), poly(c Prolactone), and mixtures thereof. Other curable bioresorbable Elastomers include poly(caprolactone) (PC) derivatives, amino alcohol-based Based poly(ester amide) (PEA), and poly(octanediol citrate ester Stel) (POC). Polymers based on PC have elastomeric properties To obtain, additional cross-linking agents such as lysine diisocyanate, or 2,2-bis(ε-caprolactone-4-i Ru) propane are required.

[0050] Alternatively, the implantable drug delivery device may be at least partially non-biodegradable It may be made of a medical grade silicone tube known in the art . Other examples of suitable non-resorbable materials include ethylene vinyl acetate (EVA), p Li (ether), poly(acrylate), poly(methacrylate), poly(vinylpyrrol Don), poly(vinyl acetate), poly(urethane), cellulose, cellulose acetate, Poly(siloxane), poly(ethylene), poly(tetrafluoroethylene), polyamide , and other fluorinated polymers, poly(siloxane), its copolymers, and combinations thereof Selected synthetic polymers include. Following the release of the pharmaceutical formulation, the device, and / Or, the retention frame can be removed substantially completely or in multiple parts.

[0051] The drug delivery device can be sterilized before insertion into a patient. In one embodiment, the device may use other sterilization processes, but is sterilized using a suitable process such as gamma irradiation or ethylene oxide sterilization.

[0052] Retention of the device within a body cavity The devices described herein are elastically deformable between a relatively linear shape suitable for insertion through a lumen into a patient's bladder (or other body cavity) and a retention shape suitable for holding the device within the bladder (or other body cavity). In certain embodiments, the drug delivery device naturally assumes the retention shape and can be deformed manually or with the assistance of an external device into a relatively linear shape for insertion into the body. Once placed, the device can spontaneously or naturally assume its initial retention shape for retention within the body.

[0053] For purposes of the present disclosure, the term "retention shape" generally means any shape suitable for holding the device in an intended implantation location and includes, but is not limited to, the coiled or "screw-like" shape shown in FIG. 8A that is suitable for holding the device within the bladder. Similarly, the term "relatively linear shape" generally means any shape suitable for placement of the drug delivery device within the body and includes, but is not limited to, a linear or elongated shape suitable for other equipment disposed within a lumen of the body such as an operating channel of a catheter, a cystoscope, or the urethra.

[0054] In some embodiments, the drug delivery device is elastic between a relatively linear shape and a retention shape ​​​​​​​​​​​do not require a retention frame that is deformable in nature. In these embodiments, the material from which the housing is formed renders the device elastically deformable between two shapes.

[0055] In other embodiments, the drug delivery device includes a retention frame associated with the housing. The nature of the retention frame causes the device to function as a spring, deforming in response to a compressive load and returning to its initial shape simultaneously when the load is removed.

[0056] As shown in FIGS. 8A-8B, 9, 11A-11B, and 12A-12C, the housing may each include one or more retention frame lumens 822, 922, 1122, and 1222 through which at least portions of the retention frames 824, 924, 1124, 1224 are respectively screwed. In some embodiments, the housing does not include discrete retention frame lumens and the retention frame is fixed to the housing by any other means such as an adhesive, or the retention frame and the drug occupy the same lumen.

[0057] In certain embodiments, a retention frame such as the device itself may naturally assume a retention shape, may deform to a relatively linear shape, and may return to the retention shape simultaneously upon insertion into the body. The retention frame in the retention shape may be of a shape that can be retained within a body cavity, and the relatively linear retention frame may be of a shape for insertion into the body through the working channel of a placement device such as a catheter or a cystoscope. To obtain such a result, the retention frame is selected with an elastic limit, modulus of elasticity, and / or or so as to prevent the device from assuming a relatively low-profile shape immediately upon implantation. may have a spring constant. Such a configuration can limit or prevent accidental expulsion of the device under expected forces. For example, the device can be retained within the bladder during urination or contraction of the detrusor muscle.

[0058] In a preferred embodiment, the device is relatively linearly shaped to fit through a catheter or cystoscope extending through the patient's urethra and is curved or coiled to fit within the bladder after release of the device from the end of the catheter or cystoscope, i.e., during urination, to prevent expulsion from the bladder, and is elastically deformable . In a particular configuration of this embodiment, the device has an elastic wire or strip that serves as a retaining frame, and the elastic wire or strip acts as a spring to maintain the device in a curved or coiled shape when no compressive load is present and when the device is under compression from the bladder wall during urination or other contractions of the patient's detrusor muscle.

[0059] In some embodiments, the retaining frame includes or consists of an elastic wire or an elastic strip. In one embodiment, the elastic wire includes a biodegradable shape memory material or a biodegradable shape memory polymer known in the art. The elastic wire may also include a relatively low modulus elastomer, which can relatively less likely cause irritation or ulcers within the bladder or other implantation sites and may be biodegradable so that there is no need to remove the device. The low modulus elastomer Examples of polymers include polyurethane, silicone, styrene-based thermoplastic elastomers, and poly(glycerol sebacate) (PGS). The elastic wire may be coated with a biocompatible polymer such as one or more of silicone, polyurethane, styrene-based thermoplastic elastomers, Silitek , Tecoflex, C-flex, and Percuflex.

[0060] In some embodiments, the retention frame lumen may contain a filling material such as a silicone adhesive such as MED3-4213 from Nusil Technology LLC, but other filling materials may be used. The filling material is optional and may be omitted. However, its inclusion may fill the retention frame lumen around the retention frame, extend along or twist or rotate around the drug reservoir lumen, while maintaining the drug reservoir lumen in a selected direction relative to the retention frame.

[0061] A retention frame having a helical shape is relatively resistant to compressive forces. The helical shape substantially includes two semi-circles, each of which includes its own small arch and shares a large arch. When the helical shape is first compressed, the large arch absorbs most of the compressive force and begins to deform. However, with continued compression, the small arches overlap, and then all three arches resist the compressive force. The resistance of the device as a whole to compression increases when the two semi-circles overlap and the bladder contracts during urination, preventing the device from collapsing and creating voids.

[0062] The retention frame (or the housing itself in embodiments without a retention frame) is In embodiments that include a shape memory material, the material used to form the frame "remembers its shape" and, when placed within the bladder and exposed to body temperature, takes on its retained shape when heat is applied to the device. The windings, coils, or spirals of the frame can take many configurations. For example, the frame may be a curl configuration that includes one or more loops, curls, or semicircles. The ends of the resilient wire may be made soft, not sharp, bent inward, combined together, or otherwise configured to avoid tissue

[0063] inflammation and scarring. The retention frame may have a two-dimensional structure that is limited to a plane, a three-dimensional structure that occupies the interior of an ellipsoid of revolution, or some combination thereof. The frame may be linearly or radially connected, bent in the same or another direction, and include one or more loops, curls, or semicircles that overlap or do not overlap. The frame may include one or more circles or ellipses arranged in a two-dimensional or three-dimensional configuration, where the circles or ellipses may be closed or open, have the same or different sizes, overlap or not overlap, and are combined together at one or more connection points. The retention frame portion may also be a three-dimensional structure that occupies or encircles a space having an ellipsoidal shape, such as a spherical space, a space having

[0064] The retaining frame portion is formed to occupy the spherical space or wrap around its periphery. This may be the case. The retaining frame portion generally consists of two intersecting circles on different planes, two intersecting circles on different planes with an end portion that curls inward, three intersecting circles on different planes, or may take the shape of a spherical spiral. In each of these examples, the retaining frame portion can be extended in a linear shape for placement through the placement device. The retaining frame portion may wrap around or pass through the spherical space or the space of other ellipsoidal shapes in various other ways. One or both of the retaining frame and the retaining frame inner cavity may be omitted if the housing itself can assume or be deformed into any of the retaining shapes described herein. Further examples of configurations are described in the U.S. patent applications incorporated by reference herein.

[0065] Drug Formulations and Solid Drug Tablets Generally, a drug formulation is formed in a solid drug unit loaded within a device housing. Each solid drug unit is a solid (during assembly, storage, and handling prior to implantation, under the temperature and pressure conditions to which the delivery device is normally exposed) that substantially retains a selectively imparted shape and is a separate object. The drug unit may have other configurations but may be in the form of a tablet, capsule, pellet, or bead.

[0066] The solid drug unit can be formed using a stable and measurable manufacturing process. In particular, a drug tablet can be loaded into the housing of a drug delivery device that can be placed into a patient's bladder or another cavity, lumen, or tissue site using minimally invasive techniques and stored efficiently. ​ is sized and shaped.

[0067] The solid drug unit may be made by direct powder compression, or by tableting processes, molding processes, or other processes known in the pharmaceutical arts field. Suitable methods for forming drug tablets are described in U.S. Patent Application Publication No. 2010 / 0330149 (TB102), which is hereby incorporated by reference and made a part hereof. The drug formulation may also be loaded into the device housing in a workable form and solidified therein. For example, in embodiments where the drug formulation is melted and solidified, the drug formulation may be melted and injected into the device housing in a molten form and then solidified. The drug formulation may also be extruded from the device housing, solidified within the housing, and then cut at spaced positions along the length of the housing to form segments at the exposed surface of the drug. The solid drug unit contains a drug formulation, which contains a drug content and may contain an excipient content. In a preferred embodiment, the drug content contains one or more drugs or pharmaceutically active ingredients (APIs), while the excipient content contains one or more pharmaceutically acceptable excipients. The drug formulation is essentially a therapeutic agent, a prophylactic agent, or a diagnostic agent, such as being useful for local delivery to or partial delivery into a body cavity or lumen. The drug formulation may contain only the API or may contain one or more excipients. As used herein, the term "drug" referring to any particular drug described herein includes salt forms, free acid forms, and may be cut at spaced positions along the length of the housing to form segments at the exposed surface of the drug. The solid drug unit contains a drug formulation, which contains a drug content and may contain an excipient content. In a preferred embodiment, the drug content contains one or more drugs

[0068] or pharmaceutically active ingredients (APIs), while the excipient content contains one or more pharmaceutically acceptable excipients. The drug formulation is essentially a therapeutic agent, a prophylactic agent, or a diagnostic agent, such as being useful for local delivery to or partial delivery into a body cavity or lumen. The drug formulation may contain only the API or may contain one or more excipients. As used herein, the term "drug" referring to any particular drug described herein includes salt forms, free acid forms, and may be cut at spaced positions along the length of the housing to form segments at the exposed surface of the drug. The solid drug unit contains a drug formulation, which contains a drug content and may contain an excipient content. In a preferred embodiment, the drug content contains one or more drugs or pharmaceutically active ingredients (APIs), while the excipient content contains one or more pharmaceutically acceptable excipients. The drug formulation is essentially a therapeutic agent, a prophylactic agent, or a diagnostic agent, such as being useful for local delivery to or partial delivery into a body cavity or lumen. The drug formulation may contain only the API or may contain one or more excipients. As used herein, the term "drug" referring to any particular drug described herein includes salt forms, free acid forms, It includes free base forms and their alternative forms such as hydrates. The term "excipient" is known in the art and representative examples of excipients useful in the present drug unit include components such as binders, lubricants, flow promoters disintegrants, colorants, fillers, diluents, coating agents, or preservatives, and other non-active components for assisting in manufacturing , stability, dispersibility, wettability, and / or drug release kinetics, or drug delivery of the drug unit may also include others. The drug may be a small molecule, a macromolecule, or a biological metabolite among other forms / types of the active ingredient.

[0069] Stored in a drug delivery device given a selected (small) size and released therefrom To maximize the amount of drug that can be released, the drug unit preferably has a high weight fraction of drug or API, along with a reduced or small weight fraction of excipients when required for the manufacture of solid drug units and device assembly, and considerations in use For the purposes of this disclosure, terms such as "weight fraction", "weight percent", and "percent by weight" related to a drug or API refer to the drug or API in the form adopted, such as a salt form, free acid form, free base form, or hydrate form For example, a solid drug unit having 90% by weight of a drug in salt form will contain 90% by weight or less of that drug in free base form .

[0070] . In one embodiment, the solid drug unit is 50% by weight or more of drug. In another embodiment , 75% by weight or more of the weight of the solid drug unit is drug having the remaining weight including excipients such as lubricants and binders that assist in the manufacture of the solid drug unit . For the purposes of this disclosure, the term "high weight fraction" related to a drug or API means that the excipient is solid ​ Comprising 25% by weight or less of the drug unit, preferably 20% by weight or less, more preferably 15 % by weight or less, and even more preferably 10% by weight or less. In some cases, the drug content comprises about 75% by weight or more of the solid drug unit or more. More specifically, the drug content comprises about 80% by weight or more of the drug tablet. For example, the drug content comprises between about 85% by weight and about 99.9% by weight of the solid drug unit. In some embodiments, the excipient content can be completely omitted.

[0071] In one embodiment, the drug and excipient are selected, and the solid drug unit is formulated to be water-soluble so that it can be solubilized when the device is positioned in the bladder to release the solubilized drug. When the device is positioned in the bladder to release the solubilized drug, the solid drug unit can be solubilized. For this purpose, it is formulated to be water-soluble.

[0072] Each individual solid drug unit may essentially have any selected shape and dimensions that fit within the device described herein. In one embodiment, the solid drug unit is sized and shaped such that the drug reservoir lumen in the housing is substantially filled with a selected number of solid drug units. Each solid drug unit may have a cross-sectional shape that substantially corresponds to the cross-sectional shape of the drug reservoir lumen of a particular housing. For example, the drug unit may be substantially cylindrical in shape to be positioned within the lumen of a substantially cylindrical drug reservoir. When loaded, the solid drug units, in some embodiments, substantially fill the drug reservoir lumen and form the drug housing portion. For example, the drug unit may be substantially cylindrical in shape to be positioned within the lumen of a substantially cylindrical drug reservoir. When loaded, the solid drug units, in some embodiments, substantially fill the drug reservoir lumen and form the drug housing portion. When loaded, the solid drug units, in some embodiments, substantially fill the drug reservoir lumen and form the drug housing portion. When loaded, the solid drug units, in some embodiments, substantially fill the drug reservoir lumen and form the drug housing portion.

[0073] In one embodiment, the solid drug units are in a single row when the device is in its deployed configuration. It takes an aligned shape. For example, each solid drug unit may have a cross-sectional shape corresponding to the cross-sectional shape of the drug reservoir lumen in the housing, and each solid drug unit may have an end face shape corresponding to the end face of an adjacent solid drug unit. Cracks or fissures between the solid drug units can accommodate deformation or movement of the device during placement while still allowing each drug unit to be held in a solid form. Therefore, the drug delivery device is relatively flexible or deformable despite being loaded with solid drugs because each drug unit can move relative to adjacent drug units. In embodiments where the solid drug unit is designed for insertion or implantation into a body lumen or cavity such as the bladder via a drug delivery device, the drug unit may be a "mini-tablet" that is appropriately sized and shaped for insertion through a natural body lumen such as the urethra. For the purposes of this disclosure, the term "mini-tablet" generally refers to a solid drug unit that is substantially cylindrical, having an end face and a generally cylindrical side surface. The mini-tablet has a diameter that extends along the end face in the range of about 1.0 to about 3.2 mm, such as between about 1.5 and about 3.1 mm. The mini-tablet has a length that extends along the side surface in the range of about 1.7 to about 4.8 mm, such as between about 2.0 and about 4.5 mm. The abrasion rate of the tablet may be about 2% or less. Embodiments of the solid drug unit and system and methods of making the same are further described below in connection with the U.S. patent application incorporated herein by reference.

[0074]

[0075] ​​​​​​​​​​​​​​​​​In one embodiment, the pharmaceutical formulation is in solid form. In another embodiment, the pharmaceutical formulation is , in semi-solid form such as an emulsion or suspension, gel or paste. For example, the pharmaceutical formulation may be a highly viscous emulsion or suspension. As used herein, solid form includes semi-solid form unless otherwise indicated. In one embodiment, the pharmaceutical formulation is in liquid form .

[0076] The drug may be a poorly soluble drug. As used herein, the term "poorly soluble" refers to a drug having a solubility in water at 37°C of about 0.01 mg / mL to about 10 mg / mL . In other embodiments, the drug is a highly soluble drug. As used herein, the term "highly soluble" refers to a drug having a solubility in water at 37°C of about 10 mg / mL or more. For example, the approximate solubility of certain pharmaceutical formulations is: trospium chloride: 500 mg / mL; lidocaine hydrochloride: 680 mg / mL; lidocaine base: 8 mg / mL; gemcitabine hydrochloride : 80 mg / mL; gemcitabine base: 15 mg / mL; oxybutynin hydrochloride: 50 mg / mL; oxybutynin base: 0.012 mg / mL; and tolterodine tartrate: 12 mg / mL.

[0077] In one embodiment, the drug delivery device is used to treat kidney or urinary tract cancers such as bladder cancer and prostate cancer. Drugs that may be used include anti-proliferative agents, cytotoxic agents, chemotherapeutic agents, or combinations thereof. Representative examples of drugs that may be suitable for the treatment of urinary tract cancers include Calmette-Guérin bacillus (BCG) vaccine, docetaxel, cisplatin, doxorubicin, valrubicin , gemcitabine, mycobacterium cell wall-DNA complex (MCC), methotrexate , vinblastine, thiotepa, mitomycin (e.g., mitomycin C), flu rouracil, leuprorelin, diethylstilbestrol, estramustine, megestrol roll acetate, cyproterone, flutamide, selective estrogen receptor modulator (i.e., SERM, tamoxifen, etc.), botulinum toxin, and cyclophosphamide are included. The drug may include monoclonal antibodies, TNF inhibitors, anti-ILs, etc. The drug may be an immunomodulator such as imiquimod or other TLR agonists including TLR7 agonists. The drug may also be a fibroblast growth factor receptor-3 (FGFR3)-selective tyrosine kinase inhibitor, a phosphatidylinositol 3 kinase (PI3K) inhibitor, or , a mitogen-activated protein kinase (MAPK), especially a kinase inhibitor such as a combination thereof. Other examples include celecoxib, erlotinib, gef itinib, paclitaxel, polyphenone E, valrubicin, neocarzinostatin, a padicon, belinostat, ingenol mebutate, uridine (MCC), prox nium (VB4845), BC819 (manufactured by BioCancell Therapeutic s), keyhole limpet hemocyanin, LOR2040 (manufactured by Lorus Ther apeutics), urocanic acid, OGX427 (manufactured by OncoGenex), and SCH721015 (manufactured by Schering-Plough). Drug treatment may be combined with conventional radiation therapy or surgical treatment targeting cancerous tissue.

[0078] In one embodiment, the devices described herein contain anesthetics, analgesics, and combinations thereof. The anesthetic agent may be an aminoamide, an aminoester, or a combination thereof. Representative of the aminoamide, or amide class of anesthetics are alticarb, , bupivacaine, carticaine, cinchocaine, etidocaine, levobupivacaine, These include docaine, mepivacaine, prilocaine, ropivacaine, and trimecaine. Anesthetics of the amino ester or ester class include amylocaine, benzocaine, , butacaine, chloroprocaine, cocaine, cyclomethylcaine, dimethocaine, hexa Silcaine, Larocaine, Meprylcaine, Metabutoxycaine, Orthocaine, Pipero Caine, procaine, proparacaine, propoxycaine, proxymetacaine, lysocaine These anesthetics are generally weak bases and The anesthetics may also be used in free base or hydrate form, but must be modified to make them water soluble. Other anesthetics, such as rontocaine, may also be formulated as salts, such as the hydrochloride salt. Drugs may also be used, such as anesthetics such as oxybutynin, or propiverine. The drug may also be an antimuscarinic compound that exhibits an intoxicating effect. Other drugs may be included either alone or in combination with the local anesthetic.

[0079] In certain embodiments, the analgesic comprises an opioid. Representative examples of opioid agonists include: , alfentanil, allylprozine, alphaprozine, anileridine, benzyl mol Fin, benzitramide, buprenorphine, butorphanol, clonitadine, codeine N-desomorphine, dextromoramide, desocine, diamidone, diamorphine , dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, di methylthiambuten, dioxaphetyl butyrate, dipipanone, eptazocine, ethohepta dine, ethylmethylthiambuten, ethylmorphine, etonitazene fentanyl, hero in, hydrocodone, hydromorphone, hydroxypeptidine, isomethadone, ketobemi done, levorphanol, levophenacylmorphan, lofentanyl, meperidine, me ptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbufi ne, narceine, nicomorphine, norlevorphanol, normetazone, nalorphine , normorphine, norpipanone, opium, oxycodone, oxymorphone, papave retum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperi dine, piminodine, pirtramide, proheptazine, promedol, propethidine, pro piram, propoxyphene, sufentanyl, tilidine, tramadol, pharmaceutically acceptable salts thereof, and mixtures thereof are included. Other opioid drugs such as μ, κ, δ and nociceptive opioid receptor agonists are also contemplated.

[0080] Representative examples of other suitable pain relievers include agents such as salicyl alcohol, phenazopyridine hydrochloride salt, acetaminophen, acetylsalicylic acid, flufenizal, ibuprofen, indoprofen, indomethacin, and naproxen.

[0081] In certain embodiments, the drug delivery device is for interstitial cystitis, radiation cystitis, bladder pain syndrome It is used to treat inflammatory symptoms such as groups, prostatitis, urethritis, postoperative pain, and kidney stones. Non-limiting examples of specific drugs for these symptoms include lidocaine, glycosaminogly cans (e.g., chondroitin sulfate, sodexide), pentosan sodium poly sulfate (PPS), dimethyl sulfoxide (DMSO), oxybutynin, mitomycin C, heparin, flavoxate, ketorolac, cyclosporine, or a combination thereof. For kidney stones, one or more drugs may be selected to treat pain and / or promote the dissolution of kidney stones.

[0082] Other non-limiting examples of drugs that can be used in IC treatment include nerve growth factor monoclonal clonal antibody (MAB) antagonists such as tanezumab, and calcium α-2-δ modulators such as PD-299685 or gabapentin. Evidence shows that exogenous delivery of NGF to the bladder induces bladder overactivity and increases the excitability of dissociated bladder afferent neurons, suggesting that the bladder locally expresses nerve growth factor (NGF) (Nature Re v Neurosci 2008;9:453~66). Therefore, it may be beneficial to locally deliver MAB or other agents against NGF using the described drug delivery device, significantly reducing the total dose required for therapeutic efficacy. Evidence also shows that binding to voltage-sensitive calcium channel units such as gabapentin is effective in treating neuropathic pain diseases such as fibromyalgia, and suggests that there may be a common mechanism between IC and neuropathic pain (see: Tech U ). In addition, pain (see: Tech U (vol. 2001 Mar,7(1):47~49). Therefore, for the described delivery device it may be beneficial to locally deliver a calcium channel α-2-δ modulator such as PD-299685 or gabapentin to minimize systemic toxicity associated with the dose of IC treatment. It may be beneficial.

[0083] Other bladder cancer treatments include small molecules such as apaziquone, adriamycin, AD-32, doxorubicin, docetaxel, epirubicin, gemcitabine, HTI-286 (hemasterlin homolog), idarubicin, γ-linolenic acid, mitozantrone, meglumine, and thiotepa; macromolecules such as EGF-dextran, HPC-doxorubicin, IL-12, IFN-a2b, IFN-γ, α-lactalbumin, p53 adenovector, TNFα; combinations such as epirubicin + BCG, IFN + farmorubicin, doxorubicin + 5-FU (oral), BCG + IFN, and pertussis toxin + cystectomy; activated cells such as macrophages and T cells; intravesical instillations such as IL-2 and doxorubicin; chemosensitizers such as epirubicin + BCG, IFN + farmorubicin, doxorubicin + 5-FU (oral), BCG + IFN, and pertussis toxin + cystectomy; BCG + antifibrinolytic agents (paramethylbenzoic acid or aminocaproic acid) and doxorubicin + verapamil; diagnostic / imaging agents such as hexylaminolevulinate, 5-aminolevulinic acid, iododeoxyuridine, HMFG1 Mab + Tc99m; and local toxicity management agents such as formalin (hemorrhagic cystitis).

[0084] Drug delivery devices can be used to treat urinary incontinence, frequency, or urgency, including, for example, stress incontinence and neurogenic incontinence, as well as trigonitis. Drugs that can be used include ​​​​, anticholinergic agents, antispasmodics, antimuscarinic agents, β-2 agonists, α-adrenergic agonists , anticonvulsants, norepinephrine receptor inhibitors, serotonin receptor inhibitors, calcium channel blockers, potassium channel openers, and muscle relaxants. Representative examples of suitable drugs for the treatment of urinary incontinence include oxybutynin, S-oxybutynin, emepronium , verapamil, imipramine, flavoxate, atropine, propantheline, tolterodine , rociverine, clenbuterol, darifenacin, terodiline, trospium , hyoscyamine, pipopromazine, desmopressin, bamifylline, clidinium bromide , dicyclomine hydrochloride, glycopyrrolate amino alcohol ester, ipratropium bromide , mepenzolate bromide, methscopolamine bromide, scopolamine hydrobromide salt, tiotropium bromide, fesoterodine fumarate, YM-46303 (manufactured by Yamanouchi Pharmaceutical Co., Ltd., Japan), lanperisone (manufactured by Nippon Kayaku Co., Ltd., Japan), inaperisone, NS- 21 (manufactured by Nippon Shinyaku-Orion, Formenti, Japan / Italy), NC-1800( manufactured by Nippon Chemifa Co., Ltd., Japan), ZD-6169 (manufactured by Zeneca Co., Ltd., UK), and styrylpyridinium iodide. In yet another embodiment, the present intravesical drug delivery device is used to treat infections including the bladder, prostate, kidney, and urethra. Antibiotics, antibacterial, antifungal, antiprotozoal drugs, antiseptics, antiviral drugs and other anti-infective drugs can be administered for the treatment of such infections. Representative examples of drugs for the treatment of infections include mitomycin, ciprofloxacin

[0085] , norfloxacin, ofloxacin, methenamine, nitrofurantoin, ampicillin ​ Cillin, amoxicillin, nafcillin, trimethoprim, sulfonamide, trimethoprim Sulfamethoxazole, erythromycin, doxycycline, metronidazole, te Tetracycline, kanamycin, penicillin, cephalosporin, and aminoglycoside are included.

[0086] In other embodiments, the drug delivery device is used to treat fibrosis in urogenital sites such as the bladder or uterus. Representative examples of drugs for treating fibrosis include pent xifylline (xanthine homolog), anti-TNF, anti-TGF agonist, GnRH homolog, exogenous progestin, antiprogestin, selective estrogen receptor modulator, danazol and NSAIDs.

[0087] The implantable drug delivery device can also be used to treat spastic or flaccid neurogenic bladder. Representative examples of drugs for treating neurogenic bladder include lidocaine, bupivacaine, mepivacaine, prilocaine, articaine, and ropivac aine and other analgesics and anesthetics; anticholinergic drugs; antimuscarinic drugs such as oxybutynin or pirpipeline; vanilloids such as capsaicin or resiniferatoxin; antimuscarinic agents that act on M3 muscarinic acetylcholine receptors (mAChR); antispasmodics containing GABA agonists such as baclofen; baclofen; botulinum toxin ; capsaicin; α-adrenergic antagonists; antiepileptic drugs; serotonin reuptake inhibitors such as amitriptyline; and nerve growth factor antagonists. In various embodiments B ​​​​​As described in Reitz et al., Spinal Cord 42:267~72(200 4), the drug may act on the afferent nerves of the bladder or on the efferent cholinergic transmission.

[0088] In one embodiment, the drug is selected from those known for the treatment of incontinence based on overactivity of the neuro-urinary muscles and / or low-compliance urinary muscles. Representative examples of this type of drug include anticholinergic drugs (e.g., oxybutynin (an antimuscarinic drug with significant muscle relaxation and local anesthetic activity), propiverine, imipratropium, tiotropium, tropicamide, terodiline, tolterodine, propantheline, oxyphencyclimine, flavoxate, and tricyclic antidepressants); drugs for blocking the nerves that innervate the bladder and urethra (e.g., vanilloids (capsaicin, resiniferatoxin), botulinum-A toxin); or drugs that regulate the urinary muscle contraction strength, micturition reflex, and sphincter dyssynergia (e.g., GABAb agonists (baclofen), benzodiazepines). In another embodiment, the drug is selected from those known for the treatment of incontinence based on neurogenic sphincter deficiency. Examples of this drug include α-adrenergic agonists, estrogen, β-adrenergic agonists, tricyclic antidepressants (imipramine, amitriptyline). In yet another embodiment, the drug is selected from those known to be able to empty the bladder easily (e.g., α-adrenergic antagonists (phentermine) or cholinergic agonists). Further, in another embodiment , the drug is an anticholinergic drug (e.g., dicyclomine), a calcium channel blocker (e.g., verapamil), a tropane alkaloid (e.g., atropine, scopolamine), nosicep Selected from among chin / orphanin FQ and bethanechol (e.g., M3 muscarinic agonist, choline ester).

[0089] In certain embodiments, the drug is a steroid such as triamcinolone, budesonide, or prednisone.

[0090] In certain embodiments, the drug is lidocaine, gemcitabine, docetaxel, carboplatin, cisplatin, oxaliplatin, tolterodine, trospium, mitomycin C.

[0091] Other device features The devices described herein may include a radiopaque portion or structure to facilitate detection or visualization (e.g., by x-ray imaging or fluoroscopy) of the device by a healthcare provider as part of an implantation or retrieval procedure. In one embodiment, the housing is composed of a material that includes a radiopaque filler, such as barium sulfate, or other radiopaque material known in the art. Some housings may be made radiopaque by incorporating a radiopaque filler, such as barium sulfate or other suitable material, during the processing of the material forming the housing.

[0092] The radiopaque material may be associated with the retention frame in these embodiments that include a retention frame. Ultrasonic imaging or fluoroscopic images can be used to image the device in vivo.

[0093] The housing of the implantable drug delivery device may further include a string, loop, or from the body cavity​​​​​​​​​​​​ Facilitating removal of the device, for example, following release of a pharmaceutical formulation from a solid drug unit may include a retrieval function such as other structures for removal of a non-absorbable device. In some cases the device can be removed from the bladder by engaging a string that pulls the device through the urethra and retrieving the device within the lumen of a catheter or cystoscope, or within the urethra. When retrieving the device, the device is configured to be relatively narrow or to assume a linear shape.

[0094] Methods of drug delivery The devices and methods disclosed herein can be adapted for use in humans, male or female, adult or child, or for use in animals such as veterinary or livestock applications. Accordingly, the term "patient" refers to a human or other mammalian subject.

[0095] In one embodiment, a method of providing controlled release of a drug to a patient comprises: (i) placing a drug delivery device in the patient, the device including a closed drug reservoir lumen surrounded by a first wall structure and a hydrophilic second wall structure; and (ii) releasing the drug from the drug reservoir lumen via diffusion through the second wall structure, where the first wall structure is impermeable to the drug and the second wall structure is permeable to the drug. In one embodiment, the first wall structure is a cylindrical tube and the second wall structure is an end wall disposed at at least one end of the cylindrical tube, or the first wall structure and the second wall structure are adjacent to each other and together form a cylindrical tube. For example, the device may include any of the functions or combinations of functions described herein.

[0096] The device is implanted non-surgically, and the drug can be delivered for several days, weeks, months, or longer after the implantation procedure is complete. In one embodiment, implanting a drug delivery device into a patient involves inserting the device into a body cavity or lumen of the patient via a placement device. For example, the device can be placed into a body cavity such as the bladder through a placement device such as a catheter located in a natural lumen of the body such as the urethra or a cystoscope. The placement of the device is generally removed from the body cavity,

[0097] while the drug delivery device remains in the bladder or other body cavity for a predetermined treatment period. In some embodiments, the device can be placed into the patient's bladder by an independent procedure, or in combination with another urological or other procedure, or in combination with surgery, either before, during, or after any

[0098] other procedure. The device can release one or more drugs for local and / or partial tissue delivery for treatment or prevention, either before, after, or both before and after surgery. In one example, the device is implanted by passing the drug delivery device through a placement device and releasing the device from the placement device into the body. When the device is placed into a body cavity such as the bladder, the device expands or assumes a retention shape such as a high profile shape as it In an embodiment, placing the drug delivery device in a patient comprises (i) elastically deforming the device into a relatively linear shape; (ii) inserting the device through the patient's urethra; and (iii) releasing the device within the patient's bladder to assume a retention shape suitable for retaining the device within the bladder.

[0099] The drug delivery device can pass through a placement device that drives the drug delivery device until it exits the lumen of the instrument when passing through, for example, by a probe or by the flow of a lubricant or other fluid into the bladder. Thus, the device can be implanted in the bladder of a human patient, adult or child, male or female, depending on the need for treatment. Once placed in vivo, the device can release one or more drugs for the treatment of one or more conditions, substantially locally, to one or more tissues at the placement site and / or, in part, to other tissues distal to the placement site. The release is

[0100] controlled and can release the drug in an effective amount over a long period of time. The device can then be removed, absorbed, excreted, or a combination thereof. In some embodiments, the device remains in the bladder and releases the drug for a predetermined period, such as two weeks, three weeks, four weeks, one month, or longer. Once implanted, the device can provide long-term, continuous, intermittent, or periodic release of a desired amount of drug for a predetermined period of time as desired. In embodiments, the device can release the drug for 12 hours, 24 hours, five days, seven days, ten days, fourteen days, etc.

[0101] ten days, fourteen days, or longer. In embodiments, the device can release the drug for 12 hours, 24 hours, five days, seven days, ​​​can deliver a desirable dosage of a drug over a long period, such as 20, 25, 30, 45, 60, or 90 days or more. The delivery rate and dosage of the drug can be selected depending on the drug to be delivered, the disease or condition to be treated. In one embodiment, the rate of drug release from the drug delivery device is zero order over at least 36 hours. In one embodiment the rate of drug release from the drug delivery device is essentially zero order over at least 7 days and is.

[0102] In certain embodiments, elution of the agent from the device occurs following dissolution of the agent within the device, wherein body fluid enters the device, contacts the drug, and dissolves the drug, and then the dissolved drug diffuses from the device. For example, in the case where the device is implanted within the bladder the drug can dissolve when it contacts urine. In one embodiment, releasing the drug from the device comprises dissolving the drug in water absorbed through a second wall structure, or both the first and second wall structures.

[0103] The device can be used to treat interstitial cystitis, radiation cystitis, pelvic pain, cystitis, overactive bladder syndrome, bladder cancer neurogenic bladder, neurogenic or non-neurogenic bladder-sphincter dysfunction, infections, postoperative pain or other diseases, disorders, conditions treatable with a drug delivered to the bladder. The device can release the drug locally to the bladder and partially to other sites in the vicinity of the bladder. The device can deliver a drug that improves bladder function such as bladder volume, compliance, and / or frequency of uninhibited contractions, reduces pain and discomfort in the bladder or other surrounding areas, or has other effects or combinations thereof. When placed in the bladder, the de vice The vice can also be used between the kidneys, urethra, ureter, penis, testis, seminal vesicle, vas deferens, ejaculatory duct, prostate, vagina, uterus, ovary, or fallopian tube, or other organs, or combinations thereof, at other positions within the urogenital system, such as other urogenital sites within the urological or genital systems of the body, to deliver a therapeutically effective amount of one or more drugs. For example, the drug delivery device can be used for the treatment of kidney stones or fibrosis, erectile dysfunction, among other diseases, disorders, and symptoms.

[0104] In one embodiment, the device may have two effective payloads released at different times. The first effective payload can be applied to relatively rapid release, while the second effective payload can be applied to continuous release.

[0105] Subsequently, the device can be retrieved from the body if it is non-absorbable or otherwise requires removal. Retrieval devices for this purpose are known in the art or can be specially manufactured. The device can also be completely or partially biodegradable, absorbable, or biocompatible in the body, such that retrieval is unnecessary when the entire device is absorbed or when the device is sufficiently degraded, for example, to be excreted from the bladder in urine. The device may not be retrieved or absorbed until some drugs, or preferably most or all of the drugs, are released. If necessary, during or after the same procedure as retrieval, a device loaded with new drugs may be substantially implanted.

[0106] The present invention will be further understood by reference to the following non-limiting examples.

Examples

[0107] [Example 1] A port formed of Tecophilic (registered trademark) film and loaded with gemcitabine (GEM) was subjected to an in vitro drug permeability test. The effect of γ-ray irradiation on this port was also investigated.

[0108] The port was made of HP-93A-100 and HP-60D-60 films with a thickness of 0.5 mm (the films were provided by Lubrizol). (http: / / www.lubrizol.com / Medical / Product s / Tecophilic.html) These thermoplastic polyurethanes (TPUs) were selected based on biocompatibility, the ability to absorb up to 100% by weight of the equilibrium moisture content of the dry resin, and other properties. The material properties of the film materials used are shown in Table 1 below.

Table 1

[0109] Each port was made from two films with all four ends heat-sealed after loading a single tablet of gemcitabine hydrochloride or the base formulated as follows into each port: (1) Gemcitabine hydrochloride: 89% GEM HCl, 10% isomalt, 1% Lu britab (water-insoluble); or (2) Gemcitabine base: 90% GEM base, 5% PEG8k, 5% PVP. Some ports were γ-ray irradiated (25 kGy). The ports were then placed in 21 mL of deionized water at 37°C. Then, at each time point, they were inverted 5 times, 1 mL of the sample was taken, and then 1 mL of deionized water was refilled.

[0110] The accumulated amount of the released drug (in mg FBE, or free base equivalent), and the percentage amount were illustrated in FIGS. 13 to 24. The results showed that for both the hydrochloride or base form, gemcitabine had permeated through a 0.5 mm thick Tecophilic® film. For HP-93A-100 (low durometer hardness), faster release was observed than for HP-60D-60 (high durometer hardness). Gemcitabine hydrochloride (high solubility) was released faster than gemcitabine base (low solubility). No adverse effects were observed from gamma-ray irradiation. [Example 1A]

[0111] Pouches were constructed as in Example 1, except that each pouch was loaded with 1 tablet of gemcitabine (GEM) HCl and 4 tablets of urea. The pouches were then placed in 21 mL of deionized water at 37°C. Thereafter, at each time point, they were inverted 5 times, 1 mL of sample was taken, and then 1 mL of deionized water was refilled. The percentage amounts of drug and urea released from the samples are illustrated in Tables 2 to 4 below. The results

[0112] showed that gemcitabine and urea had permeated through a 0.5 mm thick Tecophilic® film in 1 day. For HP-93A-100 (low durometer hardness), faster release was observed than for HP-60D-60 (high durometer hardness). [Table 2] [Table 3] [Table 4] ​​ [Example 1B]

[0113] HP-93A-100 and HP-60D-60 films with a thickness of 0.020″ (films were provided by Lubrizol) were cut into squares (0.5 inches × 0.5 inches) and placed in 50 mL of deionized water at 37°C. The mass of each film was measured at T = 0 and again at T = 1 day to determine the film's water absorption rate. The area of each film was also measured at T = 0 and again at T = 1 day to measure the increase in film area based on water absorption. The results are shown in Table 5 below. HP-93A-100 (low durometer hardness) had an increase in mass and swelling by water, or an expansion of area, observed compared to HP-60D-60 (high durometer hardness). and placed in 50 mL of deionized water at 37°C. The mass of each film was measured at T = 0 and again at T = 1 day to determine the film's water absorption rate. The area of each film was also measured at T = 0 and again at T = 1 day to measure the increase in film area based on water absorption. The results are shown in Table 5 below. HP-93A-100 (low durometer hardness) had an increase in mass and swelling by water, or an expansion of area, observed compared to HP-60D-60 (high durometer hardness). and placed in 50 mL of deionized water at 37°C. The mass of each film was measured at T = 0 and again at T = 1 day to determine the film's water absorption rate. The area of each film was also measured at T = 0 and again at T = 1 day to measure the increase in film area based on water absorption. The results are shown in Table 5 below. HP-93A-100 (low durometer hardness) had an increase in mass and swelling by water, or an expansion of area, observed compared to HP-60D-60 (high durometer hardness). and placed in 50 mL of deionized water at 37°C. The mass of each film was measured at T = 0 and again at T = 1 day to determine the film's water absorption rate. The area of each film was also measured at T = 0 and again at T = 1 day to measure the increase in film area based on water absorption. The results are shown in Table 5 below. HP-93A-100 (low durometer hardness) had an increase in mass and swelling by water, or an expansion of area, observed compared to HP-60D-60 (high durometer hardness). and placed in 50 mL of deionized water at 37°C. The mass of each film was measured at T = 0 and again at T = 1 day to determine the film's water absorption rate. The area of each film was also measured at T = 0 and again at T = 1 day to measure the increase in film area based on water absorption. The results are shown in Table 5 below. HP-93A-100 (low durometer hardness) had an increase in mass and swelling by water, or an expansion of area, observed compared to HP-60D-60 (high durometer hardness). and placed in 50 mL of deionized water at 37°C. The mass of each film was measured at T = 0 and again at T = 1 day to determine the film's water absorption rate. The area of each film was also measured at T = 0 and again at T = 1 day to measure the increase in film area based on water absorption. The results are shown in Table 5 below. HP-93A-100 (low durometer hardness) had an increase in mass and swelling by water, or an expansion of area, observed compared to HP-60D-60 (high durometer hardness). -60D-60 (high durometer hardness). expansion of area, observed compared to HP-60D-60 (high durometer hardness). [Table 5] [Example 2]

[0114] The silicone tube made of MED-4750 (manufactured by Nusil) had dimensions of ID: 2.64 mm and wall thickness: 0.20 mm. Multiple gemcitabine hydrochloride tablets with a 2.6 mm: OD were loaded into the silicone tube with an effective loading amount of approximately 380 mg of total gemcitabine hydrochloride. Each end of the tablet drug core had a 0.5 mm thick disk made of HP-60D-60 (Tecophilic®: thermoplastic polyurethane). The diameter of the disk is shown in Figure 25. The disks were larger in size compared to the ID of the silicone tube, and thus, they were frictionally fitted inside the tube. The layout of each device inside the silicone tube was disk - tablet - disk. Three devices were assembled for in vitro release experiments. and wall thickness: 0.20 mm. Multiple gemcitabine hydrochloride tablets with a 2.6 mm: OD were loaded into the silicone tube with an effective loading amount of approximately 380 mg of total gemcitabine hydrochloride. Each end of the tablet drug core had a 0.5 mm thick disk made of HP-60D-60 (Tecophilic®: thermoplastic polyurethane). The diameter of the disk is shown in Figure 25. The disks were larger in size compared to the ID of the silicone tube, and thus, they were frictionally fitted inside the tube. The layout of each device inside the silicone tube was disk - tablet - disk. Three devices were assembled for in vitro release experiments. and wall thickness: 0.20 mm. Multiple gemcitabine hydrochloride tablets with a 2.6 mm: OD were loaded into the silicone tube with an effective loading amount of approximately 380 mg of total gemcitabine hydrochloride. Each end of the tablet drug core had a 0.5 mm thick disk made of HP-60D-60 (Tecophilic®: thermoplastic polyurethane). The diameter of the disk is shown in Figure 25. The disks were larger in size compared to the ID of the silicone tube, and thus, they were frictionally fitted inside the tube. The layout of each device inside the silicone tube was disk - tablet - disk. Three devices were assembled for in vitro release experiments. and wall thickness: 0.20 mm. Multiple gemcitabine hydrochloride tablets with a 2.6 mm: OD were loaded into the silicone tube with an effective loading amount of approximately 380 mg of total gemcitabine hydrochloride. Each end of the tablet drug core had a 0.5 mm thick disk made of HP-60D-60 (Tecophilic®: thermoplastic polyurethane). The diameter of the disk is shown in Figure 25. The disks were larger in size compared to the ID of the silicone tube, and thus, they were frictionally fitted inside the tube. The layout of each device inside the silicone tube was disk - tablet - disk. Three devices were assembled for in vitro release experiments. thermoplastic polyurethane). The diameter of the disk is shown in Figure 25. The disks were larger in size compared to the ID of the silicone tube, and thus, they were frictionally fitted inside the tube. The layout of each device inside the silicone tube was disk - tablet - disk. Three devices were assembled for in vitro release experiments. The diameter of the disk is shown in Figure 25. The disks were larger in size compared to the ID of the silicone tube, and thus, they were frictionally fitted inside the tube. The layout of each device inside the silicone tube was disk - tablet - disk. Three devices were assembled for in vitro release experiments. The diameter of the disk is shown in Figure 25. The disks were larger in size compared to the ID of the silicone tube, and thus, they were frictionally fitted inside the tube. The layout of each device inside the silicone tube was disk - tablet - disk. Three devices were assembled for in vitro release experiments. The diameter of the disk is shown in Figure 25. The disks were larger in size compared to the ID of the silicone tube, and thus, they were frictionally fitted inside the tube. The layout of each device inside the silicone tube was disk - tablet - disk. Three devices were assembled for in vitro release experiments. Me was placed in deionized water at 37 °C. The results are shown in Fig. 25. The Y-axis represents the release of gemcitabine rate, and the unit was mg FBE (free base equivalent) / day. [Example 3]

[0115] The silicone tube made of MED-4750 (manufactured by Nusil) had an ID: 2.64 mm, wall thickness: 0.20 mm. A plurality of gemcitabine hydrochloride tablets with an OD of 2.6 mm were loaded into the silicone tube with an effective loading amount of about 200 mg of all gemcitabine hydrochloride loaded. Each device had a disk made of HP-93A-100 (Tecoph ilic (registered trademark): thermoplastic polyurethane) at each end of the tablet drug core. Each disk had dimensions of wall thickness: about 0.5 mm, OD: 3.0 mm. The OD of the disk (3.0 mm) was larger than the ID of the silicone tube (2.64 mm), so the disk was frictionally fitted into the silicone tube. Further, a silicone washer made of MED-4780 (manufactured by Nusil) was positioned next to each disk with a silicone adhesive (MED3-4213) applied around the washer to stabilize the outward migration of the disk. The silicone washer had approximate dimensions of ID, OD, and length of 2.5 mm , 3.2 mm, and 2 mm, respectively. The layout of each device in the silicone tube was: silicone washer - disk - tablet - disk - silicone washer. Six devices were assembled and placed in deionized water at 37 °C for an in vitro release experiment. They were divided into two groups. In one group, the release jar rotated at 4 rpm within a rotating body (labeled "rotating body") in contrast to the other group (labeled "static"). The results are shown in Fig. 26. Each error bar shown below is the standard deviation around the mean value (n = 3 for each group). The Y-axis indicates the gemcitabine release rate, and the unit is mgF BE (free base equivalent) / day. [Example 4]

[0116] The silicone tube made of MED-4750 (manufactured by Nusil) had an ID of 2.64 mm and a wall thickness of 0.20 mm. A plurality of gemcitabine hydrochloride tablets with an OD of 2.6 mm were loaded into the silicone tube with an effective loading amount of about 97 mg of the total gemcitabine hydrochloride. The device had a disk made of HP-93A-100 (Tecophilic (registered trademark ): thermoplastic polyurethane) at one end of the drug core, and the other end was sealed with a silicone adhesive. The dimensions of each disk were a wall thickness of about 0.5 mm and an OD of 3.0 mm. Since the OD of the disk (3.0 mm) was larger than the ID of the silicone tube (2.64 mm), the disk was frictionally fitted into the silicone tube. Furthermore, there were polyimide washers located at both ends of the disk. The dimensions of the polyimide washers were an ID of 2.67 mm, a wall thickness of 0.064 mm, and a length of about 1 - 2 mm. The layout of each device in the silicone tube was: sealed, polyimide outer washer - disk - polyimide inner washer - tablet. Three devices were assembled and placed in deionized water at 37 °C for an in vitro release experiment. The results are shown in Fig. 27. Each error bar shown below is the standard deviation around the mean value (n = 3). The Y-axis indicates the gemcitabine release rate, and the unit is mgFBE (free base equivalent) / day. is the standard deviation around the mean value. is mgFBE (free base equivalent) / day. [Example 5]

[0117] Three experimental groups were experimented: 1) One with a release jar rotating within the rotor at 4 rpm with two module devices (the "rotor"); 2) One module device without a rotating jar (the "static"); and 3) Four module devices without a rotating jar (the "static") were present Each module included a silicone tube made of MED -4750 (manufactured by Nusil) with dimensions of ID: 2.64 mm and wall thickness of 0.20 mm. A plurality of gemcitabine hydrochloride tablets with an OD of 2.6 mm were loaded into the silicone tube in each module with an effective loading amount of gemcitabine hydrochloride of approximately 190 mg in total. The formulation of the tablets was 90% gemcitabine hydrochloride, 5% PVP, 2.5% Neusilin, and 2.5% magnesium stearate . Each module had discs made of HP-93A- 100 (Tecophilic®: thermoplastic polyurethane) at each end of the core of the tablet drug. The dimensions of each disc were a wall thickness of approximately 0.5 mm and an OD of 3.0 mm. Since the OD of the disc (3.0 mm) was larger than the ID of the silicone tube (2.64 mm), the disc was frictionally fitted into the silicone tube. Each module had a silicone external washer made of MED-4780, which was wet with a silicone adhesive (MED3-4213) around it to stabilize the outward movement of the disc and then positioned on each disc . The silicone external washer had dimensions of ID, OD, and length of approximately 2.5 mm, 3.2 mm, and 2 mm, respectively. Furthermore, each module had a polyimide internal washer with an ID of 2.67 mm, a wall thickness of 0.064 mm, and a length of approximately 4 mm . The internal washer was filled with tablets so that the disc was initially in contact with the tablets . ​ The layout of each module in the recone tube was silicone external washer - disk - poly imide internal washer - tablet - polyimide internal washer - disk - silicone external washer .

[0118] The cumulative amount and percentage amount of the released drug, as well as the drug release rate, are shown in FIGS. 28 - 31 for: one module device (static), one module device (rotor), and also four module devices (static) (n = 3 / each group). In FIG. 31 , each error bar is the standard deviation around the mean value, and the Y - axis indicates the release rate of gemcitabine, with the unit being mmgFBE (free base equivalent) / day. Some error bars are smaller than the symbol. There was no significant difference in the gemcitabine release rate between the release media of the non - stirred group and the stirred group (static and rotor). Also, the gemcitabine release rate of the four modules was approximately 4 times that of one module device. [Example 6]

[0119] Gemcitabine hydrochloride was tested in four module devices. Each module contained a silicone tube with an ID of 2.64 mm and a wall thickness of 0.20 mm, made of MED - 4750 (manufactured by Nusil). A plurality of tablets with an OD of 2.6 mm were loaded into the silicone tube. The tablet formulation was 90% gemcitabine hydrochloride, 5% PVP, 2.5 % Neusilin, and 2.5% magnesium stearate. The mass of the tablets loaded into the four module devices was approximately 800 mg. The silicone tube had an additional lumen with an ID of 0.51 mm and a wall thickness of 0.20 mm as shown in FIG. 5A , and was maintained by nitinol The holding frame was inserted into the inner cavity. Each module was HP-9 at both ends of the core of the tablet drug. made of 3A-100 (Tecophilic®: thermoplastic polyurethane) had a disk. Each disk had a thickness of about 0.5 mm and an OD of 3.0 mm. The OD of the disk (3.0 mm) was larger than the ID of the silicone tube (2.64 mm), and therefore, the disk was frictionally fitted into the silicone tube. Each module was positioned next to the disk with silicone adhesive applied around the washer to fix it in the silicone tube, and had internal and external silicone washers made of MED-4780 (manufactured by Nusil). The silicone external washer had dimensions of about 2 .5 mm, 3.2 mm, and 2 mm for ID, OD, and length, respectively, and the silicone internal washer had dimensions of about 1.58 mm, 2.77 mm, and 2 mm for ID, OD, and length, respectively. The layout of each module in the silicone tube was: silicone external washer - disk - silicone internal washer - tablet - silicone internal washer - disk - silicone external washer.

[0120] Three in vitro release experiments (R204-4 to 6) were carried out at 37°C. The release medium was deionized water, and time-point samples were collected over 14 days. The cumulative amount of the released drug and the urine concentration of the samples were measured. The results are shown in Figure 32. Each error bar is the standard deviation around the mean value (n = 3). Some error bars are smaller than the symbols.

[0121] Devices with the same design were subjected to in vivo tests in Göttingen minipigs. Each ​The vice was inserted into the animal's bladder non-surgically through the urethra using a cystoscope. Gemcitabine +2′,2′-difluoro-2′-deoxyuridine (dFdU) and the urinary concentration of its final metabolite were measured over 8 days. The results are shown in Figure 33. After 8 days of investigation, each device was removed non-surgically through the urethra using a cystoscope and forceps.

[0122] The results are shown in Figure 33. After 8 days of investigation, each device was removed non-surgically through the urethra using a cystoscope and forceps. The results are shown in Figure 33. After 8 days of investigation, each device was removed non-surgically through the urethra using a cystoscope and forceps. [Example 7]

[0123] Trosupium chloride was tested in a single-module device. The module was made of MED-47 50 (manufactured by Nusil) and included a silicone tube with an ID of 2.64 mm and a wall thickness of 0.20 mm. A plurality of trosupium tablets with an OD of 2.6 mm were loaded into the silicone tube. The tablet formulation was trosupium chloride without excipients, and the mass of the tablets loaded into each module was approximately 330 mg, and the tablet core length was 5 cm. The silicone tube had an additional lumen with an ID of 0.51 mm and a wall thickness of 0.20 mm, and a nitinol retaining frame was inserted into the lumen. Each module had a disk made of HP- 93A-100 (Tecophilic® thermoplastic polyurethane) at one end of the tablet drug core, while the other end was sealed with a silicone adhesive. The dimensions of each disk were approximately 0.5 mm in wall thickness and 3.0 mm in OD. The OD of the disk (3.0 mm) was larger than the ID of the silicone tube (2.64 mm), and therefore the disk was frictionally fitted into the silicone tube. Each module was made of MED-4780 (manufactured by Nusil) and positioned next to each disk with a silicone adhesive applied around the washer. The mass of the tablets loaded into each module was approximately 330 mg, and the tablet core length was 5 cm. The silicone tube had an additional lumen with an ID of 0.51 mm and a wall thickness of 0.20 mm, and a nitinol retaining frame was inserted into the lumen. Each module had a disk made of HP- 93A-100 (Tecophilic® thermoplastic polyurethane) at one end of the tablet drug core, while the other end was sealed with a silicone adhesive. The dimensions of each disk were approximately 0.5 mm in wall thickness and 3.0 mm in OD. The OD of the disk (3.0 mm) was larger than the ID of the silicone tube (2.64 mm), and therefore the disk was frictionally fitted into the silicone tube. Each module was made of MED-4780 (manufactured by Nusil) and positioned next to each disk with a silicone adhesive applied around the washer. 93A-100 (Tecophilic® thermoplastic polyurethane) at one end of the tablet drug core, while the other end was sealed with a silicone adhesive. The dimensions of each disk were approximately 0.5 mm in wall thickness and 3.0 mm in OD. The OD of the disk (3.0 mm) was larger than the ID of the silicone tube (2.64 mm), and therefore the disk was frictionally fitted into the silicone tube. Each module was made of MED-4780 (manufactured by Nusil) and positioned next to each disk with a silicone adhesive applied around the washer. The mass of the tablets loaded into each module was approximately 330 mg, and the tablet core length was 5 cm. The silicone tube had an additional lumen with an ID of 0.51 mm and a wall thickness of 0.20 mm, and a nitinol retaining frame was inserted into the lumen. Each module had a disk made of HP- 93A-100 (Tecophilic® thermoplastic polyurethane) at one end of the tablet drug core, while the other end was sealed with a silicone adhesive. The dimensions of each disk were approximately 0.5 mm in wall thickness and 3.0 mm in OD. The OD of the disk (3.0 mm) was larger than the ID of the silicone tube (2.64 mm), and therefore the disk was frictionally fitted into the silicone tube. Each module was made of MED-4780 (manufactured by Nusil) and positioned next to each disk with a silicone adhesive applied around the washer. 93A-100 (Tecophilic® thermoplastic polyurethane) at one end of the tablet drug core, while the other end was sealed with a silicone adhesive. The dimensions of each disk were approximately 0.5 mm in wall thickness and 3.0 mm in OD. The OD of the disk (3.0 It had a silicone washer. The silicone washer had dimensions of approximately 2.5 mm, 3.2 mm, and 2 mm for ID, OD, and length, respectively. The layout of each module in the silicone tube was: silicone washer - disk - tablet - seal.

[0124] The in vitro release experiments for the three units were carried out at 37°C. The release medium was a 150 mM ammonium acetate buffer at pH 4.5 over 0 to 14 days. Next, from 14 to 21 days, each unit of L104 - 1 to L104 - 3 was transferred to one of different pH and osmotic pressures: pH 8 and 1000 mmol / kg, pH 4 and 450 mmol / kg, pH 8 and 450 mmol / kg of human urine. After that, from 21 days on, the release medium was a 150 mM ammonium acetate buffer at pH 4.5 for all units. The cumulative amount of the released drug is shown in Figure 34. [Example 8]

[0125] Trosupium chloride was tested in a single - module device. The module was made of MED - 4 750 (manufactured by Nusil) and included a silicone tube with an ID of 2.64 mm and a wall thickness of 0.20 mm . A plurality of trosupium tablets with an OD of 2.6 mm were loaded into the silicone tube. The tablet formulation was trosupium chloride (80.75 wt%), Plasdone K - 29 / 32 (4.25 wt%), PROSOLV SMCC50 (14.0 wt %), and magnesium stearate (1 wt%). The tablet mass loaded into each module was approximately 900 mg, and the tablet core length was 14 cm. The silicone tube had an additional lumen with an ID of 0.5 -1 mm and a wall thickness of 0.20 mm and had a nitinol retention flange The modules were inserted into the lumen. Each module was fitted with an HP-93A-10 The disk is made of Tecophilic® 0 (thermoplastic polyurethane). The disks had a diameter of about 0.5 mm and the other end was sealed with silicone adhesive. The disk had a wall thickness of 1.5 mm and an OD of 3.0 mm. The OD of the disk (3.0 mm) was measured using a silicone tube. (2.64 mm) so that the disk fits frictionally into the silicone tube. Each module was fitted with a silicone washer around it to hold it in place. Each disk was then attached with adhesive, and made of MED-4780 (Nusil). The silicone washers had ID, OD, and length of The dimensions of the modules were approximately 2.5 mm, 3.2 mm, and 2 mm. The layout of the tool was: silicone washer-disc-tablet-seal.

[0126] In vitro experiments were performed at 37°C and the release medium was 150 mM ammonium acetate at pH 4.5. The release medium was buffered with sodium and samples were taken over a period of three months. Fresh release medium was added every two weeks. The results are shown in Figure 35. Each error bar represents the standard deviation ( (n = 3). Some error bars are smaller than the symbols. [Example 9]

[0127] Lidocaine hydrochloride was tested in a single module system. The module was MED-47 50 (Nusil) and has dimensions of 2.64mm ID and 0.20mm wall thickness. The silicone tube contained multiple lidocaine hydrochloride tablets with an OD of 2.64 mm. The drug was loaded into a silicone tube. The tablet formulation consisted of lidocaine hydrochloride monohydrate (89.5 (% by weight), Plasdone K-29 / 32 (2.5% by weight), and polyglycol 8000 PF (8.0% by weight), and the tablet mass loaded in each module was about 32 0 mg, and the tablet core length was 5 cm. Each module had an HP- 93A-100 (Tecophilic®: thermoplastic polyurethane) disk at one end of the tablet drug core, while the other end was sealed with a silicone adhesive. The dimensions of each disk were a wall thickness of about 0.5 mm and an OD of 3.0 mm. The OD of the disk (3.0 mm) was larger than the ID of the silicone tube (2.64 mm), so the disk was frictionally fitted into the silicone tube. Each module had a MED-4780 (manufactured by Nusil) silicone washer positioned next to each disk with a silicone adhesive applied around the washer to fix it. The silicone washer had dimensions of about 2.5 mm, 3.2 mm , and 2 mm. The layout of each module in the silicone tube was: silicone washer - disk - tablet - seal.

[0128] The in vitro release experiment was carried out in deionized water at 37 °C, and samples were collected over 8 days. The results are shown in Figure 36. Each error bar was the standard deviation around the mean value (n = 2 ). Some error bars were smaller than the symbols. [Example 10]

[0129] Lidocaine hydrochloride was tested in a side hole device having the following layout: an internal silicone tube with 2 holes - a hydrophilic polymer band - an external silicone sleeve with 2 holes. The internal silicone tube was made of MED-4750 (manufactured by Nusil). ​​​manufactured, having an ID of 1.52 mm, a wall thickness of 0.2 mm, and containing lidocaine tablets. The tablets formulation was lidocaine hydrochloride monohydrate (89.5 wt%), Plasdone K-29 / 32 (2.5 wt%), and polyglycol 8000 PF (8.0 wt%). The loaded tablet mass was about 105 mg, and the tablet core length was 5 cm. The two holes were about 1.2 mm in diameter and were made with a manual punch. Both the internal silicone tube and the external silicone sleeve were used. The two punch holes were positioned opposite each other. The hydrophilic polymer band was made of HP-93A-100 (Tecophilic® thermoplastic urethane), had an OD of 2.64 mm, a wall thickness of 0.2 mm, and a length of 1 cm . The external silicone sleeve had an ID of 3.05 mm, a wall thickness of 0.2 mm, and a length of 2 cm . The external silicone sleeve had an ID of 3.05 mm, a wall thickness of 0.2 mm, and a length of 2 cm . A silicone adhesive was applied between the internal silicone tube and the external silicone sleeve . The holes between the internal silicone tube and the external silicone sleeve were aligned. The in vitro release experiments were carried out in deionized water at 37 °C, and samples were collected over 7 days

[0130] . The results are shown in Figure 37. Each error bar is the standard deviation around the mean value (n = 2 ). Some error bars are smaller than the symbols. The publicly available information cited in this specification, and the materials that cite them, are specifically incorporated by reference. Modifications and variations of the methods and devices described in this specification will be apparent to those skilled in the art from the foregoing

[0131] detailed description. Such modifications and variations are intended to fall within the scope of the appended claims . ​

Claims

1. 1. An implantable drug delivery device comprising: a first wall structure and a closed drug reservoir lumen surrounded by a hydrophilic second wall structure; Housing; and a drug contained within said drug reservoir lumen; The first wall structure is impermeable to the drug, and the second wall structure is the structure is permeable to the drug; (i) the first wall structure is a cylindrical tube, and the second wall structure is a cylindrical tube an end wall disposed at at least one end; or (ii) the first wall structure and the second wall structure are adjacent to each other and together form a cylindrical Forming tubes, Drug delivery devices.

2. The device of claim 1 , wherein the device is configured for insertion and retention within the bladder.

3. The device has a relatively linear configuration suitable for insertion through the patient's urethra and into the patient's bladder. and a retention configuration suitable for retaining the device within the bladder.

3. The device of claim 2.

4. The device of claim 3 further comprising a support frame bore and a support frame disposed therein. Vice.

5. The device of claim 1 , wherein the first wall structure comprises silicone.

6. The device of claim 1 , wherein the second wall structure comprises a thermoplastic polyurethane.

7. The first wall structure is a cylindrical tube, and the second wall structure is at least one of the cylindrical tube. an end wall disposed at one end of the cylindrical tube, and the second wall structure is stabilized in the bore of the cylindrical tube; The device of claim 1 , wherein the device is in the shape of a square.

8. The device of claim 7 , wherein the disk is sandwiched between an inner washer and an outer washer. 。

9. the first wall structure and the second wall structure are adjacent to one another and together form a cylindrical tube; 10. The device of claim 1, wherein said first and second wall structures are formed by a coextrusion process. 。

10. The device of claim 1 , wherein the drug is in the form of one or more solid drug units.

11. The device of claim 1 , wherein the drug is a low-solubility drug.

12. The device of claim 1 , wherein the drug is a highly soluble drug.

13. The drug is lidocaine, gemcitabine, docetaxel, carboplatin, cisplatin , oxaliplatin, trospium, tolterodine, oxybutynin, or mitomycin The device of claim 1 , further comprising a syn-C.

14. 1. A method for providing a controlled release of a drug to a patient, comprising: A drug delivery device is placed within the patient, the device comprising a first wall structure and a hydrophilic first wall structure. a closed drug reservoir lumen surrounded by two wall structures; releasing a drug from said drug reservoir lumen via diffusion through said second wall structure; The first wall structure is impermeable to the drug and the second wall structure is permeable to the drug. is permeable to; (i) the first wall structure is a cylindrical tube, and the second wall structure is at least one of the cylindrical tubes. an end wall disposed at one end of the (ii) the first wall structure and the second wall structure are adjacent to each other and together form a cylindrical tube; Form; method.

15. Implantation of the drug delivery device into a patient includes implanting the device into the patient through a placement instrument.

15. The method of claim 14, comprising inserting the catheter into a body cavity or lumen of the body.

16. Placing the drug delivery device within the patient includes: elastically deforming said device into a relatively linear configuration; Inserting the device through the patient's urethra; and The device is inserted into the patient's bladder so as to assume a retention shape suitable for retaining the device within the bladder. Release the service; The method of claim 14, comprising:

17. The drug delivery device has a release rate of 0.01% or more for at least 36 hours.

15. The method of claim 14, wherein:

18. The rate at which the drug is released from the drug delivery device is essentially constant over a period of at least 7 days. The method of claim 14, wherein the eigenvalue is essentially zero order.

19. The drug is lidocaine, gemcitabine, docetaxel, carboplatin, cisplatin , oxaliplatin, trospium, tolterodine, oxybutynin, or mitomycin The method of claim 18, further comprising the step of:

20. The release of the drug may further comprise the second wall structure or the first and second wall structures.

15. The method of claim 14, further comprising solubilizing the drug with water that is absorbed through both the 。

21. 21. The method of claim 20, wherein the drug is in the form of one or more solid drug units.

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