In vivo drug delivery devices and methods for drug delivery

Abstract

To provide drug delivery devices and methods for administering drugs to patients.SOLUTION: A device 50 includes a reservoir 60 containing a drug 58. The reservoir 60 is defined by a wall 64 having a water-permeable portion, so that the water-permeable portion permits water to enter the device and contact the drug. A restraining plug 56 closes off an opening of the device so that transient micro-channels 62 form between an elastic portion 54 of the device and the restraining plug, upon the generation of a sufficient pressure within the reservoir, to release the drug from the device. Methods of treating patients for neurogenic detrusor overactivity resulting from a spinal cord injury and / or for idiopathic overactive bladder and urinary incontinence are also described.SELECTED DRAWING: Figure 2

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 62 / 453,333, filed February 1, 2017. No. 62 / 480,744, filed April 3, 2017. The benefit of these claims is claimed, the disclosures of which are incorporated herein by reference. [Background technology]

[0002] The present disclosure generally relates to in vivo deployable medical devices for controlled drug delivery. and more particularly, a water-permeable wall portion for providing controlled drug release from the device. and to such devices having one or more features.

[0003] Many current drug delivery devices have one or more orifices in the sidewall or end of the device. and relying on one or more orifices to permit release of the drug therefrom. However, such orifices, especially those disposed in the sidewalls of the device, may be difficult to separate from the drug. After the delivery device is deployed within a patient, it may be susceptible to encrustation or blockage. A blocked orifice often results in less reproducible drug release or slower drug release. In addition, the ori disposed within the edge of the device may prevent the device from escaping completely, which is undesirable. The face provides release only at the distal end of the device, which is consistent with all device configurations and and drug formulations.

[0004] In other cases, the drug delivery device may not have a release orifice, and the release of the drug may The drug may be released by diffusion from the matrix material and / or through the walls bounding the drug reservoir. However, such configurations that rely on diffusion limit the drug release that can be achieved. The drug may limit release kinetics and / or provide desirable biocompatibility, stability, sterility, and manufacturing properties. A range of suitable materials of construction for those lacking in mechanical properties including sturdiness, wall thickness, flexibility, etc. The range may be limited.

[0005] Therefore, there exists a need for a drug delivery device that overcomes one or more of these drawbacks. Patients with idiopathic overactive bladder and urinary incontinence, as well as those with neurological disorders resulting from spinal cord injury, Improved methods and drug delivery systems for treating patients with neurogenic detrusor overactivity There is also a need to provide systems. Summary of the Invention

[0006] In one aspect, a drug delivery device includes a body having a reservoir defined therein. a wall bounding the at least one preformed through hole disposed therein; and a drug formulation comprising a body having a water-permeable portion, the body including an elastic portion, and a drug. The drug formulation disposed in the reservoir and the elastic portion of the body seal the opening of the body. at least one constraining plug contacting the reservoir, the opening being in fluid communication with the reservoir; and at least one constraining plug, wherein the water-permeable portion of the wall allows water to pass through the drug delivery device. and configured to allow the drug formulation located in the reservoir to enter the reservoir and contact the drug formulation located in the reservoir; Release of the drug from the device occurs (i) through at least one preformed perforation in the wall. (ii) a release of the drug between the elastic portion of the body and at least one of the restraining plugs. The one or more microchannels forming the one or more microchannels When a hydrostatic pressure effective for the microchannel is generated in the reservoir, the microchannel extends to the opening. and release of the drug through the controlled formation of the drug delivery device.

[0007] In another aspect, a drug delivery device includes a tubular body having a rib defined therein. a wall bounding the reservoir, the wall having a water-permeable portion and at least one water-permeable portion disposed therein; a tubular body having a resilient portion with a preformed release port; and a drug containing drug. The drug formulation is disposed within the reservoir, and the water-permeable portion of the wall allows water to penetrate the drug delivery device. and a drug formulation, which allows the drug formulation to enter the chair and contact the drug formulation located in the reservoir. At least one captive plug in the reservoir that contacts the resilient portion of the body. and secured adjacent to at least one preformed ejection port, thereby wherein the confining plug is in a reservoir of hydrostatic pressure effective to form one or more microchannels. a resilient portion of the body extending to at least one preformed discharge port upon occurrence of and at least one confining plug by temporary formation of one or more microchannels between the thereby controlling the release of the drug from the device through at least one preformed release port. and at least one constraining plug controlling the drug delivery.

[0008] In yet another embodiment, one of the devices described above is used to administer a drug to a patient. A method for administering a drug delivery device to a patient, the method comprising: inserting a drug delivery device into a lumen or body cavity of a patient; Water ingress into the reservoir allows the drug to flow from the reservoir out of the device and into the lumen or body cavity. and enabling a pressure to be generated in the reservoir effective to cause the provide.

[0009] In yet another aspect, neurogenic detrusor overactivity (ND) resulting from spinal cord injury (SCI) is O) over a treatment period of 30 to 60 days. and subsequently locally administering an effective amount of trospium into the patient's bladder. provide.

[0010] In yet another embodiment, a patient in need of treatment for idiopathic overactive bladder (iOAB) and urinary incontinence is 1. A method of treating a patient, comprising administering to the patient's bladder continuously for a treatment period of 30 to 60 days. The present invention provides a method for treating a rheumatoid arthritis, comprising topically administering an amount of trospium effective to treat the rheumatoid arthritis. [Brief explanation of the drawings]

[0011] FIG. 1 is a block diagram of a computer system for use in a computer-implemented system; Reference will now be made to the accompanying drawings, which illustrate examples of the present disclosure. , where the use of the same reference numerals indicates similar or identical items. The embodiments may include elements, components, and / or structures other than those illustrated in the drawings. Some of the elements, components, and / or structures illustrated in the drawings may represent specific embodiments. may not exist in

[0012] [Figure 1A] FIG. 12 is a cross-sectional side view of one embodiment of a resilient portion of a device including a captive end plug. [Figure 1B] FIG. 1B is a cross-sectional end view of the embodiment of FIG. 1A. [Figure 1C] FIG. 1B is a cross-sectional side view of the device of FIG. 1A in which the reservoir is not under osmotic pressure. [Figure 1D] FIG. 1B is a cross-sectional side view of the device of FIG. 1A with the reservoir under osmotic pressure. [Figure 2] FIG. 1C is a cross-sectional side view of one embodiment of a device having a pre-formed sidewall orifice and two captive end plugs. [Figure 3A] FIG. 1 is a plan view of one embodiment of a device having a preformed sidewall orifice and two captive end plugs. [Figure 3B] FIG. 3B is a cross-sectional enlarged view of one of the end plugs of FIG. 3A. [Figure 3C] FIG. 3C is an exploded perspective view of the end plug of FIG. 3B. [Figure 4] FIG. 1 is a cross-sectional end view of an embodiment of a drug delivery device. [Figure 5] 1 illustrates various embodiments of a constraining plug according to the present disclosure. [Figure 6] 6 is a cross-sectional view illustrating the constraining plug of FIG. 5 in use as an end plug of a drug delivery device. [Figure 7] 1 illustrates the deployment of a drug delivery device from a deployment instrument. [Figure 8] 1 illustrates the deployment of a drug delivery device in a patient. [Figure 9A] FIG. 1 is a plan view of one embodiment of a drug delivery device having a constraining plug and a pre-formed release port. [Figure 9B] FIG. 9B is an enlarged cross-sectional view of the device of FIG. 9A. [Figure 10A] FIG. 1 is a plan view of one embodiment of a drug delivery device having a constraining plug and a pre-formed release port. [Figure 10B] FIG. 10B is an enlarged cross-sectional view of the device of FIG. 10A. [Figure 11] 1 is a graph showing drug release rates over time for the drug delivery devices tested in the Examples. [Figure 12] 1 is a graph showing drug release rates over time for the drug delivery devices tested in the Examples. [Figure 13] 1 is a graph showing drug release rates over time for the drug delivery devices tested in the Examples. [Figure 14]1 is a graph showing drug release rates over time for various drug delivery devices tested in the Examples. [Figure 15] 1 is a graph showing cumulative drug release over time for various drug delivery devices tested in the Examples. [Figure 16] 1 is a graph showing drug release rates over time for various drug delivery devices tested in the Examples. [Figure 17] 1 is a graph showing cumulative drug release over time for various drug delivery devices tested in the Examples. [Figure 18] 1 is a graph showing drug release rates over time for various drug delivery devices tested in the Examples. [Figure 19] 1 is a graph showing drug release rates over time for various drug delivery devices tested in the Examples. [Figure 20] 1 is a graph showing drug release rates over time for various drug delivery devices tested in the Examples. [Figure 21] 1 is a graph showing drug release rates over time for various drug delivery devices tested in the Examples. [Figure 22] 1 is a graph showing cumulative drug release over time for various drug delivery devices tested in the Examples. [Figure 23] 1 is a graph showing percent drug release over time for various drug delivery devices tested in the Examples. [Figure 24] 1 is a graph showing drug release rates over time for various drug delivery devices tested in the Examples. DETAILED DESCRIPTION OF THE INVENTION

[0013] A payload such as a drug formulation may be administered along with a method for delivering the payload 58 from the device 50. A reservoir 60 (referred to herein as the "reservoir lumen" or "drug reservoir lumen") containing a drug reservoir 58. The drug delivery device 50 is described herein as having a water-permeable wall portion 64 that bounds a water-permeable wall portion 64 (also referred to as a water-permeable wall portion 64). As shown in FIG. 2, the water-permeable wall portion 64 generally prevents water from entering the device. , contacting the drug formulation (i.e., payload) 58 located within the reservoir 60, For example, the drug 58 may be configured to facilitate release of the drug 58 from the Osmotic pressure-driven water intrusion into reservoir 60 causes one or more functional Pressure may be generated within reservoir 60 that drives the release of drug 58 through the mechanism. In the embodiments described herein, the release of drug 58 from the device is controlled by one or more preformed through a pre-formed sidewall orifice 66 (see FIG. 2) and / or One or more micropipes leading to a discharge port 68 or other opening (see FIG. 9) This can occur through the transient formation of chloro channels 62. In some embodiments, a combination of these release mechanisms may be used to provide the desired drug release profile. In devices that rely solely on one or more preformed orifices for drug release, and overcome the shortcomings discovered.

[0014] Specifically, pre-formed orifices in the side or end walls of the device allow air to escape from the device. An implantable intravesical drug delivery device utilized for the release of a drug is deployed intravesically or orifice encrustation and occlusion after implantation. In certain embodiments, as shown in FIG. 2, the drug delivery device 50 of the present disclosure includes a Upon generation of hydrostatic pressure effective to form one or more microchannels within reservoir 60, One or more microchannels 62 leading to an outlet port or other opening formed for One or more valve structures within the sidewall or end of the device in combination with a one-way valve structure with temporary formation Include a predetermined orifice 60 on the surface, e.g., for temporary formation of a microchannel 62. The development of hydrostatic pressure in the reservoir 60 above a threshold pressure of When the orifice(s) 66 are partially or completely blocked, or when the orifice(s) 66 This can occur when the release does not occur quickly enough to relieve the hydrostatic pressure within reservoir 60 . In some embodiments, the sidewalls or edges of the device may be coated with a protective film, as shown in FIGS. A pre-formed discharge port 68 is provided in the nozzle 100. The pre-formed discharge port 68 is provided with one or more microchannels extending to the discharge port 68. There is no hydrostatic pressure generated in the reservoir to form the channel 62, and the discharge port 68 It is provided in combination with a captive plug 56 that blocks access.

[0015] Controlled release of drugs can be achieved by devices with improved one-way valve release mechanisms. It has been discovered that this can be achieved by combining with other release mechanisms, for example: Controlled release of drugs can be achieved by micro-dispensing fluidized drugs from a delivery device. This can be achieved by the temporary formation of microchannels. The device components interface in response to hydrostatic pressure generated within the cavity. Inducing such a microchannel (i.e., separate from the preformed orifice) and drug delivery devices configured to utilize the same have been developed, which reduce component costs and may increase the risk of blockage or by diffusion through or from another material. Potential problems associated with conventional drug release mechanisms, including small, precise orifices that are restricted by Avoid or mitigate.

[0016] In an embodiment, the drug delivery device 50 includes a drug reservoir 60 defined within the body 52. The device includes a device body 52 having at least one water-permeable wall portion 64 bounding the device body. The drug formulation 58 containing the drug is loaded into a defined drug reservoir 60. The device 50 further includes a resilient portion 54 in fluid communication with the reservoir 60. contacting the portion 54 and providing a gap between the resilient portion 54 of the body 52 and at least one captive plug 56 Release of drug 58 from device 50 by temporary formation of one or more microchannels 62 It includes a captive plug 56 that controls egress.

[0017] As used herein, the term "microchannel" refers to a channel through which a drug is introduced as described herein. In embodiments, the term "immersion" refers to a passageway or passage system through which a device mounted thereon can exit. In response to hydrostatic pressure built up within the permeable body due to osmotic-driven water intrusion, Microchannels are formed and expand when hydrostatic pressure increases beyond a certain threshold. A reservoir is formed, thereby urging at least a portion of the drug out of the device and leaving the drug reservoir. This relieves the buildup of hydrostatic pressure within the microchannel. The microchannels will then move slightly as the hydrostatic pressure is relieved. This process may result in the release of all or a substantial portion of the drug. or the osmotically driven water intrusion is insufficient to continue the process. It is repeated until it becomes

[0018] The microchannels may be formed anywhere along the interior surface of the elastic portion of the permeable body. , thereby reducing the possibility of complete blockage even when insoluble excipients are used in drug formulations. Advantageously, unlike orifices, microchannels Reduces or eliminates the potential risk of sudden drug ejection when the device is compressed or deformed For example, the drug delivery device may be surrounded by bodily fluids, providing a gentle The device is exposed to external mechanical stresses (such as the intravesical drug delivery device in which the device is deployed). When the device is placed in a wheelchair (e.g., during urination while sitting), the drug is released through the microchannels. It is unlikely that this will happen.

[0019] 1A-1D show one embodiment of a microchannel in a drug delivery device. The vise 50 has the resilient portion 54 with the captive plug 56 inserted into the opening in the body 52. a body or housing 52 having a resilient portion 54 outside a captive plug 56 As shown by the dashed arrows, the water is The drug may diffuse through the water-permeable wall 64 of the body 52 and enter the drug reservoir 60, e.g., Forming a fluidized drug solution 58, which may be an aqueous solution containing the drug 58 initially loaded into the reservoir 60 Hydrostatic pressure within reservoir 60 causes fluidized drug 58 to move, e.g., against the interface surface. By elastic deformation of one or both of them, through the microchannel 62 formed therebetween , is pushed out of the reservoir 60 between the elastic portion 54 and the captive plug 56. The hydrostatic pressure in the reservoir causes any microchannels to form between the elastic portion 54 and the constraining plug 56. 1A, 1B, and 1C illustrate a device in a state where the threshold is not reached. In the embodiment illustrated in FIG. 1D, the microchannel 62 connects the reservoir 60 and the device 50. 1. Although shown as being formed between the distal (pre-formed) opening 72, As described below, in some embodiments, device 50 includes microchannel 6 2 between the reservoir 60 and a discharge port 68 defined in the side wall or closed end of the device. The structure is configured to be formed as follows.

[0020] The devices, systems, and methods disclosed herein are, in relevant part, incorporated by reference. The following patent application publications are incorporated herein by reference: US2016 / 0199544 (Le e et al.), US2012 / 0089122(Lee et al.), US2 012 / 0089121(Lee et al.), US2011 / 0152839(C ima et al.), US2010 / 0331770(Lee et al.), U S2010 / 0330149(Daniel et al.), US2009 / 0149 833 (Cima et al.), and US2007 / 0202151 (Lee e Some features and aspects of the devices, systems, and methods described in is based on.

[0021] Drug Delivery Devices An embodiment of a drug delivery device is illustrated in Figures 3 and 4. The device includes a drug reservoir portion. The water-permeable body 52 includes a portion 78 and a retaining frame portion 76. When used in a drug reservoir, the term "drug reservoir portion" is interchangeable with "drug reservoir" or "drug reservoir tube." As such, these terms refer to the portions of the device that form and define the "cavity." In FIG. 3A, device 50 is It is shown in a relatively expanded configuration suitable for retention within a body, for example, within the bladder. As shown, device 700 also includes a deployment instrument 7, such as a cystoscope or other catheter. The device can be arranged with a relatively low profile for deployment through the channel of the O2. After opening, the device retains the drug delivery device within the bladder or other body cavity or lumen. Therefore, it can assume a relatively expanded shape.

[0022] In some embodiments, the intravesical device comprises a deployed configuration and a retained configuration. As shown in FIG. 7, device 700 is suitable for insertion through a patient's lumen into the bladder. A relatively straight or uncoiled shape (deployed configuration) and suitable for retaining the device within the bladder. For purposes of this disclosure, a "retained configuration" may be resiliently deformable between a retained configuration and a retained configuration. The term "pretzel" generally refers to any shape including, but not limited to, a coil or "pretzel" shape. means any shape suitable for retaining the device in the bladder. 3A. The retention configuration allows the device to be taken up in urine and excreted when the patient urinates. "relatively expanded shape", "relatively high profile" The term "file shape" can be used interchangeably with "holding shape." The term "relatively low profile configuration" may be used interchangeably with "deployed configuration." and generally involves the use of a catheter, cystoscope, or other device placed within a body lumen, such as the urethra. 7 suitable for deploying the device through the working channel of a deployment instrument. or any shape suitable for deploying the drug delivery device in the body, including an elongated shape. In embodiments, the drug delivery device necessarily assumes a relatively expanded shape. Obtain and insert into the body, either manually or with the help of an external device, relatively Once deployed, the device can be elastically deformed into a low-profile shape. Spontaneously or naturally (e.g., elastically) expands to an initial relatively expanded shape for retention within the body. In some embodiments, the device behaves like a spring, It deforms in response to a compressive load (e.g., deforming the device into a deployed shape), but does not deform when the load is removed. In some embodiments, such an intravesical device spontaneously returns to its retained shape when removed. Such shape-changing functionality can be achieved by providing a shape-retaining frame within the device, as described herein below. This is provided by including a support frame (i.e., a "holding frame").

[0023] In the illustrated embodiment of FIG. 4, the drug reservoir and holding frame of the drug delivery device The sections 78, 76 are longitudinally aligned and connected to one another along their lengths (also are integrally formed together), but other configurations are possible. For example, 8 may be attached to the retaining frame portion 76 at discrete points, or alternatively, 76.

[0024] As shown in FIG. 4, the drug delivery device includes a drug reservoir lumen 60 and a retention frame. The device includes a resilient or flexible device body 52 defining a drug reservoir lumen 60. The drug reservoir portion 78 contains a drug formulation, such as several solid drug tablets 158. The support frame lumen 80 is designed to accommodate the support frame 74. , designed to form a retaining frame portion 76. The illustrated lumens 78, 76 are , are discrete from each other, although other configurations are possible.

[0025] As shown in cross section in FIG. 4, device body 52 defines a drug reservoir lumen 60. and a tube or wall 84 defining the retaining frame lumen 80. The tubes 82, 84 and lumens 60, 80 may be substantially cylindrical and may contain a drug reservoir. The support lumen 60 has a relatively larger diameter than the support frame lumen 80, e.g., Based on deployment considerations such as the amount of drug to be delivered, the diameter of the holding frame, and the inner diameter of the deployment instrument. Other configurations may be selected based on the device body 52. ​​The device body 52 may be molded or extruded. Although the tubes 82, 84 may be integrally formed via a separate structure and assembly, The wall 84 defining the retention frame lumen 80 may be the same as the wall defining the drug reservoir lumen 60. The retaining frame lumen 80 can extend along the entire length of the wall 82 shown. In other embodiments, the lumen has the same length as the drug reservoir lumen 60 as shown, but in other embodiments, one wall In addition, the two walls 82, 84 may be shorter than the other wall. The device is attached along the entire length, but temporary attachments can also be used. In one example, the wall 82 of the drug reservoir lumen 60 has an inner diameter of about 1.5 mm and a thickness of about 1.9 mm. The wall 84 of the retaining frame lumen 80 has an outer diameter of about 0.5 mm and an inner diameter of about 0.9 mm. In another example, the wall 82 of the drug reservoir lumen 60 has an outer diameter of about 2.16 mm. However, the wall 8 of the drug reservoir lumen 60 has an inner diameter of about 2.56 mm and an outer diameter of about 2.56 mm. 2 and the inner and outer diameters of the wall 84 of the retaining frame lumen 80 may be any suitable diameter. The overall cross-sectional area of ​​the body of device 52 is approximately 0.035 cm 2 However, However, the cross-sectional area of ​​the overall body of device 52 can be of any suitable size.

[0026] As shown in FIG. 3A, the drug reservoir lumen includes several drug units 158. The drug units may be tablets, such as mini-tablets. For example, about 30 to about 70 drug units, or more specifically, about 50 to 60 drug units For example, about 10 to about 100 drug units can be loaded. Essentially any number of drug units may be used, depending on the size of the server and drug unit. The drug reservoir lumen may be formed by relatively circular grooves at opposite ends of the drug reservoir lumen. These openings allow for easy loading and assembly of the device. The catheter provides an entrance for a drug unit to be placed into the drug reservoir lumen.

[0027] As described herein, the constraining plug allows access to the reservoir through the end opening of the device. The restraining plug and elastic portion may be disposed within any portion along the length of the drug delivery device. In certain embodiments, the restraints, as described herein, may be disposed in any suitable location. The plug may be disposed at or near the end of the device. The bundle plug may be disposed at or near the center of the device. One of the end device openings has a captive plug, and the opposite opening has a plug or or other material that does not allow the formation of microchannels.

[0028] In some examples, as shown in FIGS. 1C and 1D, each of the constraining plugs 56 As described herein, the drug reservoir lumen 60 may have an outer diameter that is larger than the inner diameter. In some embodiments, as shown in Figures 9A and 10A, the constraining plug 56 The end or opening of the device 50 is secured to the surface, such as by adhesive 70 or other suitable fastening means. It may be sealed and secured within the drug reservoir lumen 60 at the distal end of the device 50. In this embodiment, as shown in FIGS. 1C-1D, the constraining plug 56 is secured by adhesive 70. may be secured within the drug reservoir lumen 60 without sealing the lumen. In one embodiment, the constraining plug is secured by an external clamp disposed around the drug reservoir lumen. The constraining plug can be fixed within the drug reservoir lumen to allow the desired formation of microchannels. Drug release by any of the means or combinations disclosed herein is acceptable. It can be fixed within the reservoir lumen.

[0029] In certain embodiments, each of the captive plugs has a cavity for receiving an end portion of the retention frame. In some cases, some constraining plugs may be placed in the openings or cavities of the device. It may be placed anywhere else along the length. Constraining plugs include silicone plugs, ethylene vinyl The plugs may be either acid-vinyl plugs, or a combination of both. In the illustrated embodiment, openings that do not have a constraining plug may be made of any other suitable biocompatible material. In one example, the material is placed in the drug reservoir lumen in a workable form, In some embodiments, the constraining plug is a drug reservoir. The other opening of the drug reservoir lumen is sealed with adhesive. In other embodiments, both ends of the drug reservoir lumen may be sealed and one or more constraining plugs , which may be located within the device near the sealed end or away from the sealed end. The distances may be spaced apart as follows:

[0030] As shown in FIG. 4, the retention frame lumen 80 is formed from a retention frame lumen that may be elastic wire. The retaining frame 74 is mounted on the support frame 74 as identified above and incorporated herein by reference. Illustrated examples include "pretzel" shaped or other shapes, such as those disclosed in the patent application publications The retaining flange may be configured to spontaneously return to a retaining shape, such as a coiled shape. The frame 74 can hold the device in the body, such as in the bladder. The system 74 allows the device 50 to be introduced into the body in a relatively low profile configuration. Once inside the body, the device allows the device to return to a relatively expanded shape, The device responds to anticipated forces, such as those associated with bladder contractions and fluid forces associated with urination, They may have elastic limits and moduli that prevent them from assuming relatively low profile shapes. Thus, once deployed, the device can be retained within the body, limiting or minimizing accidental expulsion. is prevented.

[0031] The material used at least in part to form the device body 52 has a deployed shape and It may be resilient or flexible to allow movement of the device into and out of the holding configuration. When the vise is in the holding configuration, the holding frame portion 76 is positioned inside the drug reservoir portion 78. Although there may be a tendency for the retaining frame portion 76 to be present, the retaining frame portion 76 may otherwise be present. 78. At least a portion of the material used is also water permeable, thereby allowing the solubilizing fluid (e.g. , urine or other bodily fluids) enter the drug reservoir 60 once the device is deployed. For example, silicone, ethylene acetate, Vinyl (EVA), thermoplastic polyurethane, or another biocompatible elastomeric material It can also be used to form the device body.

[0032] In one embodiment where the drug delivery device is designed to be inserted into the bladder, The delivery device is inserted through the bladder and into the urethra by a cystoscope (and optionally The device is designed to be removed from the bladder (or urinary bladder). Sized and shaped to fit through the narrow tubular passage of a deployment instrument such as a cystoscope It can be done.

[0033] The exact configuration and shape of the drug delivery device will depend on the specific site of deployment, route of insertion, drug, The dosage regimen and therapeutic application of the device can be selected depending on various factors. The device design allows for the delivery of a therapeutically effective dose of drug to a patient's tissue site (e.g., the urothelium). can be delivered locally to the tissue while minimizing pain and discomfort to the patient .

[0034] Device body / drug reservoir As shown in FIGS. 1-3, 9, and 10, the drug delivery device 50 includes a body 52, e.g., a For example, a drug reservoir 60 may be provided that includes a water-permeable wall 64 and engages one or more restraining plugs 56. The drug reservoir 60 has a housing including a resilient portion 54 for retaining the drug. That is, the device comprises a "water-permeable body" As that term is sometimes used herein, this refers to at least one material that is water permeable. In an embodiment, the water-permeable body is made entirely of a water-permeable material. In other embodiments, the water-permeable body is made from a water-permeable material and a water-impermeable material. In a further embodiment, the water-permeable body comprises at least one water-permeable portion and Made from a material having at least one water-impermeable portion. The wall or material may be such that fluid enters the drug delivery device, for example, by diffusion through the wall. , when allowing the drug formulation located in a reservoir within the device body to be contacted. "Water permeability".

[0035] The body 52 of the drug delivery device 50 described herein also includes at least one elastic The elastic portion 54 of the device body 52 is the same as the device body described in the previous paragraph. 1A. As shown, the constraining plug 56 is secured to at least one resilient portion 54 of the device body 52. , closing the opening in the body, where the opening is the drug reservoir 60 within the device. In fluid communication therewith, the drug reservoir 60 contains the drug 58 .

[0036] In some embodiments, all of the elastic portions of the device body are elastically resilient as described herein. In another embodiment, the device is contacted with a constraining plug that allows for drug release as desired. One or more of the elastic portions of the body may be configured to allow for drug release as described herein. The remaining resilient portion of the body is then contacted with a cap, adhesive, heat seal, solder, or The seal may be by other suitable means such as gluing, welding, or a combination thereof.

[0037] Generally, the length of the elastic portion is the length of the portion of the constraining plug that contacts the elastic portion of the device body. The length should be at least 100 mm, so that the formation / use of the microchannels can be achieved by, for example, It is not obstructed by the non-elastic part of the body.

[0038] In an embodiment, the elastic portion 54 of the body 52 is configured to act as a barrier against hydrostatic pressure buildup within the drug reservoir 60. Sometimes, a microchannel 62 or It is formed from a material that allows for the formation of microchannels. The microchannels run along the surface of the constraining plug / elastic portion from the drug reservoir, as shown in Figure 1- 3 or the unsealed distal opening of the device body as shown in Figs. 9-10 The resilient portion may extend to any of the pre-formed release ports adjacent to the restraining plug. may include materials that are water permeable, water impermeable, or a combination thereof.

[0039] In a first embodiment, as shown in FIGS. 1A-1D, the drug delivery device described herein No. 50,600,500 to Lee, which is incorporated herein by reference in relevant part. As described in Patent Application Publication No. 2016 / 0008271, the distal opening of the device body To allow drug release through the port(s), the elastic portion(s) of the device body 52 may be The captive plugs 56 may be in contact with the captive plugs 54. However, The orifice-less (i.e., predetermined hole) of U.S. Patent Application Publication No. 2016 / 0008271 In contrast to systems without such a filter, in certain embodiments, as shown in FIGS. 2 and 3A, The device has at least one pre-formed penetration disposed within the wall of the device body 52. It includes a hole (ie, an orifice) 66 .

[0040] Thus, in certain embodiments, as shown in FIGS. 1-4, the drug delivery device 50 comprises: a body (52) having a wall bounding a reservoir (60) defined within the body (52), the wall comprising: The water-permeable portion 64 has at least one preformed through-hole 66 disposed therein. The body 52 includes an elastic portion 54, and a drug formulation 58 containing a drug. The opening of the body 52 is sealed, and the drug formulation 58 disposed in the reservoir 60 is sealed. At least one captive plug 56 contacting the two resilient portions 54, the opening of which is and at least one captive plug 56 in fluid communication with the reservoir 60. 64 indicates that water enters the drug delivery device 50 and dissolves the drug formulation 58 located in the reservoir 60. and the release of drug 58 from device 50 is determined by: (i) contacting at least The drug 58 is injected through a single preformed through-hole 66 (i.e., hole, orifice). and (ii) between the resilient portion 54 of the body 52 and at least one captive plug 56. One or more microchannels 62, forming one or more microchannels 62 The microchannel 62 extends to the opening upon the generation of hydrostatic pressure effective to The release of the drug through the formation of the polymer is controlled by at least one of the following: In the embodiment, the captive plug 56 is partially or completely sealed at the distal end opening of the device 50. Such systems may not function properly when the through-hole is partially or completely blocked. Consistent and reproducible drug delivery while providing a safety valve system that beneficially delivers drug release It has been found that the device provides a release profile of the drug in the drug reservoir. Unless and until the hydrostatic pressure reaches the threshold pressure of the confining plug(s), the preformed The device is operable to release the drug through the orifice, at which point the drug is released through the restraining plug. For example, the release of the drug through the at least one pre-formed through-hole may be It can be driven by osmotic pressure.

[0041] Advantageously, this device design allows for drug release on the sides and / or in the center of the device. This provides a device in which drug release occurs only through the distal opening of the device. In comparison, it offers increased device design flexibility as well as potential manufacturability.

[0042] In a second embodiment, as shown in Figures 9-10, the drug delivery device described herein The tube 50 includes a sealed distal end (shown sealed with adhesive 70) and one or more The captive plug 56 contacts the elastic portion(s) 54 of the device body 52, and the captive plug 56 Pre-formed ejection port(s) in the device body 52 (e.g., sidewall) adjacent to 68. Elastic portion 54 may be attached to the end of device 50 or It may be near the center of the device (as shown in Figures 9-10) or otherwise. Restraining plugs may be disposed along the length of the device, such as at or near the Optionally, 56 is adjacent to one or more pre-formed ejection port(s) in device body 52. The constraining plug(s) 56 may be positioned adjacent to the drug reservoir 60. If the threshold hydrostatic pressure is not reached, the preformed discharge port(s) 68 are covered. In such an embodiment, the constraining plug 56 and the elastic portion of the device 54 is one or more molecules that are temporarily formed when the drug reservoir 60 reaches a threshold hydrostatic pressure. The microchannels 62 extend from the drug reservoir 60 through pre-formed release port(s) 68. No. 2016 / 0030000 filed on Dec. 1, 2016, except as may be extended to the present application. The method may be similar to that described in US Pat. No. 6,271,621.

[0043] Thus, in certain embodiments, as shown in FIGS. 9-10, the drug delivery device 50 a tubular body 52 having a wall bounding a reservoir 60 defined therein, the wall , a water-permeable portion 64 and at least one pre-formed discharge port 68 disposed therein. and a resilient portion 54 having a through-hole, a hole, an orifice, or a notch. A body 52 and a drug formulation 58 containing a drug, the drug formulation 58 being disposed within a reservoir 60. The water-permeable portion 64 of the wall allows water to enter the drug delivery device and enter the reservoir 60. The drug formulation 58 and at least one restraining plate are provided to allow access to the drug formulation 58. At least one lug 56 in a reservoir 60 in contact with the resilient portion 54 of the body 52. and secured adjacent to the preformed discharge port 68 of the The plug 56 provides a reservoir of hydrostatic pressure effective to form one or more microchannels 62. 60, extending to at least one preformed discharge port 68. one or more microchannels between the elastic portion 54 and at least one constraining plug 56 62 temporarily forming at least one preformed ejection port from the device. and at least one constraining plug 56 that controls the release of the drug via 68. In certain embodiments, at least one pre-formed ejection port 68 is located in the body 52. The through holes or notches are disposed in the wall of the

[0044] Any suitable number and location of restraint plates may be used to achieve the desired drug release profile. A gag 56 and a pre-formed ejection port 68 may be used. For example, as shown in FIG. 9B Thus, the device 50 is configured such that a single captive plug 56 is positioned adjacent both holes. Two pre-existing holes, shown here as holes 180 degrees apart from each other in the tubular device body 52, are As shown in FIG. 9B, a pair of holes 68 and a corresponding A constraining plug 56 may be provided at or near each distal end of the device. For example, as shown in FIG. 10B, a single preformed A port 68 may be disposed adjacent each captive plug 56. As shown in FIG. , a preformed port 68 and corresponding restraining plug 56 are provided at each distal end of the device. It may be provided at or near the

[0045] In such an embodiment, a suitable adhesive 70 or other sealing means as described herein may be used. Steps can be used to seal the ends of the device body. The plug 56 may be attached to an adhesive 70 or other sealing means that seals the end(s) of the device body. The device is sealed in place via a step or via another adhesive. Chamfers used when emission occurs from at least a partially unsealed end opening of the device Reducing the complexity and variability associated with manufacturing and assembling the end plugs Additionally, such ejection ports can be located on the sides and / or in the middle of the device. allowing the creation of a check valve at the device, allowing drug release from any location along the device; This reduces design constraints. In addition, it allows for positioning drug release away from the ends of the device. Positioning can advantageously be achieved with rounded (i.e., non- Edge (edging) allows the device edge to act as a nucleation point for the crust formation at the edge. Furthermore, such a device design advantageously reduces defects that can cause malfunction. This allows for increased flexibility and bending of the distal end of the vise.

[0046] In certain embodiments, the device also includes a pre-formed release port adjacent to the constraining plug. and at least one pre-loaded device disposed within the wall of the body, as described above, in combination with the and a through hole formed therethrough so that release of the drug from the device occurs through at least one of the walls. Further control is provided by the release of the drug through a single preformed through-hole.

[0047] In embodiments where the drug formulation is a solid or semi-solid, as described in more detail below, The device is designed to allow water to diffuse into the reservoir through the permeable portion of the wall in vivo, releasing the drug It may be configured to allow the agent to be solubilized.

[0048] The devices described herein advantageously can be used alone or in conjunction with a previously untreated graft that may be subject to occlusion. These improved features, combined with other release mechanisms such as formed sidewall orifices, It has been discovered that the present invention provides a controlled release of a drug via a valve-directed release mechanism. The devices described herein have only sidewall discharge orifices that may be susceptible to encrustation. provides a longer duration of drug delivery compared to devices having

[0049] In particular, the controlled release of the drug may be achieved through an opening at the distal end of the device or through a constraining plug. the fluidized drug is delivered either through one or more preformed delivery ports adjacent to the This can be achieved by the temporary formation of microchannels through which the delivery device can dispense. The microchannels act as device components in response to hydrostatic pressure generated within the drug reservoir. formed at the interface, whereby a certain threshold hydrostatic pressure is reached within the drug reservoir. Only then can the device parameters be adjusted to release the drug.

[0050] To facilitate the formation of microchannels, the elastic portion 54 of the device body 52 and The constraining plug 56 may be formed from a material having a particular elasticity or hardness. , the shore durometer of the resilient portion of the body is lower than the shore durometer of the captive plug In one embodiment, the shore durometer of the resilient portion of the body is about 40A to about 60A. In another embodiment, the Shore durometer of the constraining plug is about 70A to about 100A. The Shore durometer of the elastic part of the main body is about 45A to about 55A, and the shell of the restraining plug In a further embodiment, the elastic portion of the body has a durometer of about 75 A to about 85 A. The shore durometer of the part is approximately 50A, and the shore durometer of the captive plug is approximately 80A. In yet another embodiment, the Shore Durometer of the resilient portion of the body is from about 40A to about The shore durometer of the captive plug is approximately 97A. at or near the end of the device, and a preformed release port in the device body is In some embodiments, the durometer of the constraining plug is This can be further reduced to reduce the stiffness at the ends of the tube.

[0051] In embodiments, the device body 52 is configured with two or more constraining plugs 56 having different elasticities. It may include two or more elastic portions 54 that are in contact and have different elasticities. Drug release from two or more different reservoirs with different drug solubilities and desired release rates For example, the permeable bodies may be 45A and 55A, respectively. First and second elastic portions made from two different materials having Shore durometers and two different materials having Shore durometers of 75A and 85A, respectively. First and second restraining plugs made of a material are inserted into the first and second elastic portions. It is possible.

[0052] In one embodiment, the device body is made entirely from an elastic material. The body is made from at least one elastic material and at least one non-elastic material. In a further embodiment, the body comprises at least one elastic portion and at least one It is made from a material that has an inelastic portion.

[0053] The resilient portion 54 of the device body 52 is adapted to allow insertion of the captive plug 56 and the resilient portion 54 and the plug It may be any shape that allows for the creation of an interference fit between the spring 56. The lumen of the sexual portion may be non-polygonal. For example, the cross section may be round, substantially round, or In some embodiments, the shape of the lumen of the elastic portion is such that the constraining plug The shape of the .

[0054] The device body 52 generally can be any suitable material, so long as at least a portion of the body 64 is water permeable. The resilient portion 54 of the body 52 that contacts the constraining plug 56 may be made of a biocompatible material. causes the formation of one or more microchannels 62 through which the drug may exit the device 50. It may be made from any biocompatible material that allows for this.

[0055] In one embodiment, the device body 52 comprises an elongated tube. The drug formulation 58 may define one or more drug reservoirs 60, and the drug formulation 58 may be disposed within the drug reservoir(s) 60. For example, the elongated tube may be housed in an annulus, i.e., a tube that acts as a drug reservoir. In other embodiments, the drug reservoir portion may be annular in shape, i.e., including the lumen of a tube. The drug reservoir portion may be in a form other than a tube. The release rate of the drug from the drug reservoir portion is generally Among other things, materials, dimensions, surface area, pre-formed ejection ports / through-holes, and including, but not limited to, the total mass of the confining plug and the specific drug formulation and drug load. The design of the device components is not controlled by the temperature and humidity.

[0056] An example of a drug reservoir portion 78, i.e., the device body, is shown in Figure 4. As shown, The reservoir portion 78 may include a body formed from an elastomeric tube 82. Tube 82 defines a reservoir 60 containing several drug units 158. Insert a captive plug into the opening in the end of 2.

[0057] In an embodiment, drug reservoir portion 78 and drug reservoir 60 are configured as an osmotic pump. In such embodiments, the drug reservoir portion is at least partially water permeable. In a preferred embodiment, the water-permeable material is silicone. After insertion / implantation into the drug reservoir, water or urine permeates through the wall of the drug reservoir. enters the reservoir and contacts the drug formulation to form a fluidized drug (e.g., drug solution). This in turn creates a microchamber formed between the constraining plug and the elastic portion of the drug reservoir portion. The fluid can be dispensed through the channel and out of the reservoir at a controlled rate. and overall performance depends, among other factors, on the surface area of ​​the drug reservoir; the liquid permeability of the materials used to form the cover; The relative size, shape, and location of the release port / through-hole; the restraining plug, and the drug reservoir lumen the relative size, shape, and elasticity or hardness of the elastic portion of the drug formulation; and the drug formulation dissolution profile. In some embodiments, the device may initially exhibit a zero-order release rate, and then may exhibit a reduced non-zero-order release rate, In this case, the overall drug release profile is determined by the initial zero-order release rate and the total payload. The equations for selecting an osmotic pump design and such a design can be determined by: Representative examples are those described in U.S. Patent Application Publication No. 2009 / 0149833 to Cima et al. It is listed.

[0058] The drug reservoir portion may be formed, at least in part, from an elastomeric material, to the patient during its deployment, for example, through a deployment instrument such as a cystoscope or catheter. It may be possible to elastically deform the device for its insertion. For example, a tube The bladder support includes an elastic support member along with a retaining frame for insertion into the bladder, as described in more detail below. can be dynamically transformed.

[0059] In one embodiment, the drug reservoir portion is made from a material that is both elastomeric and water permeable. Examples of materials that are both elastomeric and water permeable are silicones and the like. Other materials, including non-elastomeric biocompatible materials, include thermoplastic polyurethanes known in the art. Any suitable biocompatible material may be used.

[0060] The length, diameter, and thickness of the drug reservoir portion may be determined, among other things, by the size and thickness of the drug formulation contained therein. volume, desired drug delivery rate, intended deployment site of the device within the body, Desired mechanical integrity, desired release rate or permeability to water and urine, initial release time Selection based on desired induction time before initiation and desired method or route of insertion into the body The tube wall thickness may be adjusted so that excessively thin tube walls do not have sufficient mechanical integrity. In some cases, an excessively thick tube wall may result in an unnecessarily long initial drug release from the device. The induction period may be determined based on the mechanical properties and water permeability of the tubing material. do.

[0061] In one embodiment, the device body is non-absorbable, as is known in the art. Other suitable non-absorbable materials may be used. In other embodiments, the device body is at least partially bioerodible. In one embodiment of the bioerodible device, the drug reservoir portion is bioerodible or is formed of a bioabsorbable polymer. Any suitable biocompatible polymer may be used. .

[0062] In embodiments in which the drug reservoir portion is tubular, the tube of the drug reservoir portion , which may be substantially linear, and in some cases have a circular or elliptical cross section. It can be cylindrical, but also has square, triangular, hexagonal, and other polygonal cross sections, among others. Surface shapes can also be used.

[0063] In one embodiment, the drug reservoir portion 78 has multiple reservoirs. The drug reservoir may be defined by a portion of the interior surface of the drug reservoir and at least one partition. In embodiments where the reservoir portion is tubular, the partition may be, among other things, a cylinder. A partition structure or plug, such as a sphere or disk, inserted into a tube. In this case, the partition structure may have a larger cross section than the tube, and the partition structure may be held in place. The partition can be fixed and separate adjacent reservoirs. The partition can be non-porous or semi-porous. The constraining plug may be made of any of the materials described herein for the constraining plug. The partition may also be formed in the tube, such as by molding. For example, One or more webs separate axial reservoirs extending along the length of the tube. The divider may also function as a separate reservoir. It can be a structure that joins two different tubes.

[0064] Multiple reservoirs may be used to separate two or more different drug formulations in different reservoirs or to separate the two or more different drug formulations after deployment. A single drug may be delivered from different reservoirs at different rates or times, or For example, two different reservoirs may be combined as described herein. As shown, two different restraining plugs with different configurations can be combined, thereby This allows the drugs in the two different reservoirs to be released at different rates. The reservoirs may also contain the same or different forms (such as liquid, semi-solid, and solid) of the same or different substances. It may contain different drug formulations, or combinations thereof. Also, the same or different drug formulations may be used along different portions of a single drug reservoir. The drug reservoir may be provided along with a different drug reservoir containing the drug. These embodiments can be combined and It can be modified to achieve the desired release profile of the desired drug.

[0065] For example, the onset of release of two doses in different reservoirs defines different reservoirs. Using different materials for sections of the tube (e.g., materials with different water permeabilities) By placing drugs with different solubilities in the reservoir, or by immediate Different forms, such as a liquid form for release and a solid form that is solubilized in vivo before release The device can be configured accordingly, such as by placing a drug having Thus, the device may release some drug relatively quickly after deployment. The drug may be released in a short time, while other drugs may have an induction period before release begins.

[0066] Preformed release holes / ports In some embodiments, the device comprises a drug reservoir as described herein. One or more ports (e.g., holes, or openings) for dispensing drugs, such as through the generation of osmotic pressure. The holes include orifices, notches, etc., which are designed to provide a passageway for the release of the drug formulation. The holes or orifices may be disposed through the sidewall of the tube. The holes may be one or more reservoirs (exemplified by orifices 66 in FIGS. 2 and 3A). ) or as described herein, a constraining plug (such as and 10 ports 68).

[0067] An embodiment of the holes 66 is shown in the drug reservoir portion 78 of Figure 3A. may be located around the middle of the reservoir portion 78 or adjacent to the end of the drug reservoir 60; This allows the solid drug unit 158 ​​to be loaded into the drug reservoir portion 78 as described below. The holes may affect the ease with which the membrane can be degraded. The tubing may be spaced apart from the portion of the tube that is folded during insertion.

[0068] The size, number, and placement of the holes can be selected to provide a controlled rate of drug release. Devices that primarily operate as osmotic pumps rely on the diffusion of drugs through the pore(s). small enough to reduce the pressure, but large enough to reduce the buildup of hydrostatic pressure within the tube. These restrictions may include one or more holes appropriately spaced along the tube. Within a few minutes, you can vary the size and number of holes for a single device (or reservoir) to select In an exemplary embodiment, the diameter of the holes is about 25 20 μm to about 500 μm, such as 20 μm to about 300 μm, and more specifically, about In one specific example, the holes are about 1 μm to about 200 μm. In one specific example, the holes have a diameter of about 75 μm to about 200 μm. A single device may have two or more different sizes. The holes may be circular, although other shapes are possible and contemplated. Typically, it depends on manufacturing considerations. An example of a process for forming holes is mechanical drilling. Holes include holes, laser drilling, laser ablation, and shaping. Holes are formed from the outside of the tube to the inside. It may be slightly tapered, and the hole may be opened either before or after the drug is loaded into the tube. can be generated.

[0069] In some embodiments, as shown in FIG. 10, a pre-formed ejection port 68 Upon the generation of sufficient pressure to stretch the elastic portion 54 of the body 52, an outlet for the drug 58 is provided. A notch in device body 52 configured to provide an opening, where port 6 8 is formed to open the notch, thereby providing a through hole for the drug solution Such notches may be configured to act as one-way valves, allowing internal pressure to When opened, it allows fluid to escape from the device, otherwise allowing external fluid to escape from the device. remains closed to prevent the passage of

[0070] Restraint Plug The constraining plug 56 allows for the formation of the microchannel 62 as described herein. However, the elastic portion 54 may have any shape suitable for placement in one or more elastic portions 54 of the body 52 . In an embodiment, the constraining plug 56 is cylindrical or substantially cylindrical. When used in conjunction with a cylindrical object, the term "substantially cylindrical" refers to any object that is non-polygonal when viewed in cross section. In other embodiments, the constraining plug is partially cylindrical or substantially cylindrical. The groove has at least one portion that is dovetailed, wedge-shaped, tapered, angled, or rounded. In the present invention, the captive plug is solid rather than hollow.

[0071] FIG. 6 shows a series of constraining plugs 502, 503, 504, 505, and 7 illustrates the elastic portion 506 inserted into the tube-shaped elastic portion 501 of the device body. Illustrated are captive plugs 502, 503, 504, 505, and 506. If the surface has a wedge-shaped, tapered, angled, or rounded surface, these surfaces are This may allow the microchannels described herein to be formed more easily. Without wishing to be bound by any particular theory, it is contemplated that wedge, tapered, angled, or rounded shapes may be used. A rough surface provides a preferential path for seepage flow along or near such a surface. As a result, the lower hydrostatic pressure will allow the confining plug and the permeable body to It may be necessary to create one or more microchannels between the elastic portions. The captive plug may have one or more wedge-shaped tapered portions on one or both sides of the longitudinal axis of the captive plug. In an embodiment, the longitudinal surface of the constraining plug may be shaped, angled, or rounded. The angle between the face and the surface of the wedge, tapered, angled, or rounded part is about 30° to about It can be 60°.

[0072] As shown in FIG. 7, the wedges of the constraining plugs 502, 503, 504, 505, and 506 The tapered, angled, or rounded surface is inserted into the end of the tube-shaped elastic portion 501. The constraining plug may have a wedge-shaped, tapered, angled, or rounded surface, which may facilitate drug delivery. In Figure 7, the base of the device is opposite the constraining plug. faces outward as the outer surface of the drug delivery device. The wedge-shaped, tapered, angled, or rounded surface of the bundle plug is in contact with the outer surface of the drug delivery device. The base of the constraining plug faces outward and communicates with the inside of the drug delivery device (drug reservoir). In this position, the wedge-shaped, tapered shape of the captive plug Contoured, angled, or rounded surfaces may create voids at or near the ends of the elastic portion. The cavity or a portion thereof may be filled with adhesive, clamps, or plastic as exemplified in Figures 3A-3C. It may accept lugs or other known means for securing a captive plug.

[0073] In certain embodiments, the resilient portion of the body and the restraining plug may be used in devices other than the distal end. The device may be disposed at a location.

[0074] The restraining plug 56 may be used to compress the device 50 within the body after deployment and / or to restrain the device. When hydrostatic pressure is applied to the bundle plug 56, the captive plug 56 is ejected from the elastic portion 54. The elastic portion 54 of the water-permeable body 52 should contact the elastic portion 54 in a manner that prevents the elastic portion 54 from contacting the water-permeable body 52. In this example, the captive plug 56 and the resilient portion 54 are held together by an interference fit, e.g., by frictional engagement. Thus, they are secured together, either alone or optionally with the aid of an adhesive. The restraining plug 56 allows the device 50 to resiliently move between its retained configuration and a relatively straight configuration. When the water-permeable body 52 is deformed, the elastic portion 54 of the water-permeable body 52 should be maintained.

[0075] In a preferred embodiment, the constraining plug 56 is attached to the device body 5 after deployment and during drug release. In other embodiments, the restraining plug 56 does not move within the resilient portion 54 after deployment and The restraining plug 56 does not move within the elastic portion 54 of the water-permeable body 52 during drug release. This is acceptable as long as drug release is not unnecessarily affected.

[0076] In an embodiment, the cross-sectional shape of the constraining plug 56 is such that it fits within the resilient portion 54 of the device body 52 . In other embodiments, the outer diameter 56 of the constraining plug substantially corresponds to the dimensions of the device body 5 The inner diameter of the elastic portion 54 of the second elastic portion 54 is greater than the inner diameter of the elastic portion 54 of the second elastic portion 54. As used herein, the phrase "inner diameter" means It is not intended to imply that the elastic portion is always circular when viewed in cross section, but instead Rather, the term refers to the maximum diameter or major axis of the lumen of the elastic portion of the water-permeable body. As used in the specification, the phrase "outer diameter" means the diameter at which the restraining plug is always It is not intended to imply circularity; instead, the term refers to a captive plug or It refers to the maximum diameter or major axis of the cross section of the base.

[0077] In one embodiment, the outer diameter of the constraining plug is at least 3 times larger than the inner diameter of the elastic portion of the device body. In another embodiment, the outer diameter of the constraining plug is greater than or equal to 1 / 2 of the elastic portion of the device body. In yet another embodiment, the outer diameter of the constraining plug is at least 5 percent greater than the inner diameter. In a further embodiment, the inner diameter of the elastic portion of the vise body is at least 10 percent greater than the inner diameter of the elastic portion of the vise body. The outer diameter of the restraining plug is at least 15 percent greater than the inner diameter of the elastic portion of the device body. In still further embodiments, the outer diameter of the constraining plug is greater than the inner diameter of the elastic portion of the device body. In a specific embodiment, the outer diameter of the captive plug is at least 20 percent greater than the outer diameter of the body. At least 25 percent greater than the inside diameter of the elastic portion.

[0078] In one embodiment, the outer diameter of the constraining plug is approximately 5 percent smaller than the inner diameter of the elastic portion of the device body. The inner diameter of the elastic part of the device body is 2.1 to 2.2 mm (e.g., 2.16 mm). m), and the outer diameter of the restraining plug is 2.2 to 2.3 mm (e.g., 2.27 mm). In this embodiment, the constraining plug has a length of about 2.5 mm to about 5 mm.

[0079] In another embodiment, the outer diameter of the constraining plug is about 28 percent larger than the inner diameter of the elastic portion of the water-permeable body. For example, in one case, the inner diameter of the elastic part of the permeable body is 2.1 to 2.2 mm. m (e.g., 2.16 mm), and the outer diameter of the restraining plug is 2.7 to 2.8 mm (e.g., In this embodiment, the constraining plug is approximately 2.5 mm or 5 mm. It has a long length.

[0080] The constraining plug may be configured to form a microchannel between the constraining plug and the elastic portion of the device body. The outer surface of the constraining plug may be of any suitable length to allow for The elastic portion of the device body along its entire length or only a portion of the length of the restraining plug For example, the outer surface of a cylindrically shaped confining plug may contact the inner surface of the confining plug. The interior surface of the opening may be contacted at a resilient portion of the permeable portion along the entire length of the bundle plug. However, the outer surface of the constraining plug may have one or more wedged, angled, or tapered surfaces. The surface of the captive plug may extend over a portion of the overall length of the captive plug, as shown, for example, in FIGS. The inner surface of the elastic portion of the water-permeable body along the

[0081] In embodiments, the length of the constraining plug is about 2 mm to about 10 mm, about 2 mm to about 8 mm, about It can be 2 to about 6 mm, or about 2.5 mm to about 5 mm.

[0082] Generally, the resilient portion of the water-permeable body and the inner surface of the constraining plug are The elastic portions of the elastic body may be shaped so that they remain in contact with each other during deployment. In an embodiment, as shown in FIG. 3, adhesive 70 is used to secure the elastic portion of the water-permeable body 52. The part 54 and the captive plug 56 can be secured together in a single part or in one or more The adhesive of the discrete portions of the adhesive may be such that the amount and placement of the adhesive is such that it affects drug release as described herein. In other embodiments, the captive plug may be used as long as it is not unnecessarily affected. For example, an external clamp may be used to secure the elastic portion of the water-permeable body and The clamp and the captive plug can be secured together. Any suitable clamp can be used, as described herein. as long as it does not unnecessarily affect the acceptability of the device to the patient or drug release as expected. If the captive plug is secured mechanically with adhesive or both, To ensure the formation of microchannels, a softer material is used to form the elastic or restraining plates. It may be necessary to form a lug or both.

[0083] The constraining plug allows for the release of the drug from the device as described herein. It may be made from any biocompatible material or combination of biocompatible materials. The plug may be made of silicone or ethylene vinyl acetate, ceramic, adhesive, or The polymer may be a combination of the above.

[0084] In certain embodiments, the constraining plug may be sterilized when the combined device is sterilized, e.g., For example, the internal surface of the elastic part may be damaged, such as can occur with certain polymer materials due to gamma irradiation. Coated with a material to prevent unwanted bonding between the surface and the constraining plug. For example, the constraining plug can be silicone and coated with a parylene, such as Parylene C. It is possible.

[0085] Retaining frame part In a preferred embodiment, as shown in FIGS. 3 and 4, the drug delivery device 50 includes a storage The retaining frame portion 76 is associated with a drug reservoir portion 78. This allows the drug reservoir portion 78 to be retained within the body, such as in the bladder. The tubular portion 76 is a support that is deformable between a relatively expanded shape and a relatively low profile shape. For example, the support frame 74 may include a relatively expanded shape. and can be manipulated into a relatively low profile shape for insertion into the body, The retention frame may spontaneously return to the relatively expanded shape upon insertion of the retaining frame. The support 74 may be shaped for retention within a body cavity and may have a relatively low profile. The frame 74 is inserted into the body through the working channel of a deployment instrument such as a catheter or cystoscope. To achieve such a result, the retaining frame 74 may be shaped to fit within the Once unfolded, it prevents the device from assuming a relatively low profile shape. Such a configuration may have an elastic limit, modulus, and / or spring constant selected to: Limit or prevent accidental expulsion of the device from the body under anticipated forces For example, the device may be retained in the bladder during urination or detrusor muscle contractions.

[0086] In a preferred embodiment, the retaining frame 74 comprises or consists of elastic wire. For example, in the embodiment shown in Figures 3 and 4, the retaining frame 74 is made of a material such as Nitinol. which is formed from a superelastic alloy and forms a protective sheath around the retaining frame 74 The frame lumen 80 is an elastic wire surrounded by a wall 84. The wall 84 is made of silicone. In some other embodiments, the support frame may be formed from a polymeric material such as: It is covered with a polymer coating such as a silicone sheath and attached to the drug reservoir. The wire may be made of a superelastic alloy such as Nitinol. In embodiments, the elastic wire may be formed from a relatively low modulus elastomer.

[0087] In some embodiments, the support frame lumen 80 is connected to the support frame 74 and the polymer-filled An exemplary filler material is Nusil Technology Silicone adhesives such as MED3-4213 by NY LLC, but other filler materials may be used. The filler material may be used to fill the voids within the support frame lumen 80 around the support frame 74. For example, the filler material may completely or partially fill the retaining frame 74. The filler material may be injected into the frame lumen 80 and allowed to harden therein. 0 in a selected orientation relative to the retaining frame 74, the drug reservoir lumen 60 Stretch along, or twist or rotate around, the retaining frame 74 However, the filler material is not necessary and may be omitted. stomach.

[0088] When the holding frame 74 is in a relatively expanded shape, such as the coiled shape shown in FIG. 3A, When the device 50 is in the bladder, it can occupy a space having dimensions suitable to prevent bladder emptying. If the holding frame has a relatively low profile shape, such as the elongated shape shown in FIG. The device 700 is inserted into the body, such as through a working channel of a deployment instrument 702. Due to the properties of the elastic wire, the device acts as a spring, It deforms in response to a compressive load, but spontaneously returns to its original shape once the load is removed. Return to.

[0089] A retaining frame that assumes a pretzel shape can be relatively resistant to compressive forces. The tzel shape essentially contains two small circles, each with its own smaller arc. , share a common larger arch. When the pretzel shape is first compressed, the larger The smaller bow absorbs most of the compressive force and begins to deform, but with continued compression, the smaller bow The larger arcuate segments overlap, and then all three arcuate segments resist the compressive force. The overall resistance increases once the two small circles overlap and decreases as the bladder contracts during urination. Prevents the device from collapsing and expelling.

[0090] In embodiments where the support frame comprises a shape memory material, the The material exhibits a comparatively high thermal conductivity upon application of heat to the device, such as when exposed to body heat upon entry into the bladder. The fluid can "remember" and spontaneously assume a specific expanded shape.

[0091] The retention frame has a spring constant high enough to retain the device within a body cavity such as the bladder. High modulus or low modulus materials may be used. When using low modulus materials, the support frame must have a spring constant that would otherwise prevent urination. Diameter and / or shape that provides a spring constant such that the frame will deform significantly under force For example, the retaining frame may have a configuration similar to that described in U.S. Patent Application Publication No. 2003 / 0129998 to Cima et al. Designed to achieve desired spring orientation as described in patent application Ser. No. 009 / 0149833. The wire may include one or more windings, coils, spirals, or combinations thereof. do.

[0092] The holding frame is a two-dimensional structure substantially limited to a plane, a structure occupying the interior of an ellipsoid. or some combination thereof.

[0093] Drug preparations As used herein, the term "drug" includes any suitable pharmaceutically active ingredient. Drugs include small molecules, macromolecules, biologics, among other forms / types of active ingredients. The drugs described herein may be in salt form, free acid form, or a metabolite. The drug may be in any form known in the art, including the base form and its alternative forms, such as hydrates. Non-limiting examples of drugs include gemcitabine, cefotaxime, and cefotaxime. tabin, oxaliplatin, and / or another chemotherapy agent; trospium and / or or another antimuscarinic agent; and / or lidocaine and / or another anesthetic agent In one embodiment, the first compartment is configured to deliver a combination of drugs. , may be filled with more than one type of drug tablet (e.g., different drugs).

[0094] In embodiments, the drug is one used to treat pain. Various anesthetics, Analgesics, analgesics, and combinations thereof may also be used. In one embodiment, the drug is an anesthetic. The anesthetic may be a cocaine analogue. The anesthetic may be an aminoamide, an amino ester, or or a combination thereof. Representative examples include anticaine, bupivacaine, carticaine, cinchocaine, ethi Docaine, levobupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine Alternatives to anesthetic agents of the amino ester or ester class include Typical examples are amylocaine, benzocaine, butacaine, chloroprocaine, and cocaine. cyclomethicaine, dimethocaine, hexylcaine, larocaine, meprylcaine , metabutoxycaine, orthocaine, piperocaine, procaine, proparacaine, pro These include lopoxycaine, proxymetacaine, lisocaine, and tetracaine. Drugs also include antimuscarinic compounds that exhibit anesthetic effects, such as oxybutynin or propiverine. In embodiments, the analgesic comprises an opioid. Representative opioid agonists include: Examples include alfentanil, allylprozine, alphaprozine, anileridine, and benzamidine. benzoylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, Codeine, desomorphine, dextromoramide, dezocine, diampromide, diamol fin, dihydrocodeine, dihydromorphine, dimenoxadol, dimeheptanol , dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, Toheptadine, ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl , heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, keto Bemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine , meptazinol, metazocine, methadone, metopon, morphine, mirofine, nalbufen morphine, narceine, nicomorphine, norlevorphanol, normetadone, nalorphine , normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretu Lun, pentazocine, phenadoxone, fenomorphan, phenazocine, fenoperidine phenytoin, piminodine, piritramide, proheptadine, promedol, properidine, propionate ram, propoxyphene, sufentanil, tilidine, tramadol, and their pharmaceutical Acceptable salts, and mixtures thereof include mu, kappa, delta, and thiamin. Other opioid drugs, such as opioid receptor agonists, are contemplated. Representative examples of agents include salicylic alcohol, phenazopyridine hydrochloride, and acetaminophen. , acetylsalicylic acid, flufenisal, ibuprofen, indoprofen, indometacin These include drugs such as tacrolimus and naproxen.

[0095] In certain embodiments, the drug is used to treat interstitial cystitis, radiation cystitis, painful bladder syndrome, To treat inflammatory conditions such as benign prostatic hyperplasia, urethritis, post-surgical pain, and kidney stones Non-limiting examples of medications used for these conditions include lidocaine, Glycosaminoglycans (e.g., chondroitin sulfate, sulodexide), pentosan polysaccharides Sodium sulfate (PPS), dimethyl sulfoxide (DMSO), oxybutynin, Itomycin C, heparin, flavoxate, ketorolac, or a combination thereof Other non-limiting examples of drugs that can be used to treat IC include tanezumab, nerve growth factor monoclonal antibody (MAB) antagonists, and PD-299685 or Calcium channel alpha-2-delta modulators such as gabapentin.

[0096] In certain embodiments, the medication is for the treatment of urge incontinence and neurogenic incontinence, as well as trigonitis. These drugs are used to treat frequent or urgent urinary incontinence, including: These include anticholinergics, antispasmodics, antimuscarinics, beta-2 agonists, alpha-adrenergics, and anti Convulsants, epinephrine uptake inhibitors, serotonin uptake inhibitors, calcium channel blockers These include urinary incontinence medications, including urinary blockers, potassium channel openers, and muscle relaxants. Representative examples of drugs include oxybutynin, S-oxybutyrin, emepronium, and benzamidine. Rapamil, imipramine, flavoxate, atropine, propantheline, tolterodine , rosiverine, clenbutrol, darifenacin, terodiline, trospium, henbane Thiamine, propiverine, desmopressin, vamicamide, clidinium bromide, dicyclohexyl Glycopyrrolate amino alcohol ester, ipratropium bromide, Mepenzolate bromide, methscopolamine bromide, scopolamine hydrobromide, iotropin bromide Fesoterodine fumarate, YM-46303 (Yamanouchi Co., Ltd., Japan) (Nippon Kayaku Co., Japan), Lanperisone (Nippon Kayaku Co., Japan), Inaperisone, N S-21 (Nippon Shinyaku Orion, Formenti, Japan / India Talia), NC-1800 (Nippon Chemiphar Co., Japan), ZD -6169 (Zeneca Co., UK), and stylonium iodide.

[0097] In certain embodiments, the drug is used to treat urinary tract cancers, such as bladder cancer and prostate cancer. Drugs that may be used include antiproliferative drugs, cytocidal drugs, chemotherapeutic drugs, or Representative examples of drugs that may be suitable for treating urinary tract cancer include: The vaccines include Bacillus Calmette-Guérin (BCG), cisplatin, doxorubicin, and valproicin. Vicine, gemcitabine, mycobacterial cell wall-DNA complex (MCC), methotrexate Cetirizine, vinblastine, thiotepa, mitomycin, fluorouracil, leuproreductase inhibitors diethylstilbestrol, estramustine, megestrol acetate, cysteine roterone, flutamide, selective estrogen receptor modulators (i.e., tamoxifen, etc.) These include steroid medications (e.g., steroid antibiotics), botulinum toxin, and cyclophosphamide. The drug may be a pharmaceutical preparation and may include monoclonal antibodies, TNF inhibitors, anti-leukins, etc. also with immune modulators such as TLR agonists, including imiquimod or another TLR7 agonist. Drugs may also inhibit, among other things, fibroblast growth factor receptor-3 (FGFR3) -Selective tyrosine kinase inhibitor, phosphatidylinositol 3-kinase (PI3K) inhibitors, or kinase inhibitors such as mitogen-activated protein kinase (MAPK) inhibitors Other examples include celecoxib, eltrombopag, erythropoietin ... Lotinib, gefitinib, paclitaxel, Polyphenon E, valrubicin, neocarcin Nostatin, Apaziquone, Belinostat, Ingenol Mebutate, Urocidi n(MCC), Proxinium(VB 4845), BC 819(BioCanc ell Therapeutics), Keyhole Limpet Hemocyanin, LOR 2 040 (Lorus Therapeutics), urocanic acid, OGX 427 (O ncoGenex), and SCH 721015 (Schering-Plough). Other treatments for intrabladder cancer include apaziquone, adriamycin, and AD-3. 2. Doxorubicin, docetaxel, epirubicin, gemcitabine, HTI-286 Miastarin analogue), idarubicin, gamma-linolenic acid, mitoxantrone, meglumine , and small molecules such as thiotepa; activated macrophages, activated T cells, EGF dextrose Ran, HPC-doxorubicin, IL-12, IFN-a2b, IFN-γ, α-lacto Large molecules such as albumin, p53 adenovector, TNFα; epirubicin + BCG , IFN + Farmorubicin, Doxorubicin + 5-FU (oral), BCG + IFN, and and pertussis toxin + cystectomy combinations; activation of macrophages and T cells cells; intravesical instillation of IL-2 and doxorubicin; BCG plus antifibrinolytic drugs (paramethylpropional) benzoic acid or aminocaproic acid) and chemosensitizers such as doxorubicin plus verapamil ;Hexaaminolevulinic acid, 5-aminolevulinic acid, iododeoxyuridine, HMFG 1 Diagnostic agents / contrast media such as MAb+Tc99m; and formalin (hemorrhagic cystitis) These include agents for the management of local toxicities such as:

[0098] In certain embodiments, the drug is used to treat infections involving the bladder, prostate, and urethra. It is used as an antibiotic, antibacterial, antifungal, antiprotozoal, antiseptic, and antiviral. Drugs and other anti-infective agents can be administered to treat such infections. Representative examples of drugs for the treatment of infections include mitomycin and ciprofloxacin. , norfloxacin, ofloxacin, methanamine, nitrofurantoin, ampicillin , amoxicillin, nafcillin, trimethoprim, sulfonamide trimethoprim sulf Amethoxazole, erythromycin, doxycycline, metronidazole, tetracycline These include cyclosporins, kanamycin, penicillins, cephalosporins, and aminoglycosides. can be done.

[0099] In certain embodiments, the drug treats fibrosis in urogenital areas such as the bladder or uterus. Representative examples of drugs for the treatment of fibroids include pentobarbital, pentazocine, and pentazocine. Xifylline (xanthine analogue), anti-TNF, anti-TGF drugs, GnRH analogues, exogenous protease inhibitors Progestins, antiprogestins, selective estrogen receptor modulators, danazol, and N SAID is one example.

[0100] In certain embodiments, the drug is one used to treat neurogenic bladder. Representative examples of such drugs include lidocaine, bupivacaine, mepivacaine, and privacaine. Analgesics or anesthetics such as locaine, anticaine, and ropivacaine; anticholinergics antimuscarinics such as oxybutynin or propiverine; capsaicin or Vanilloids such as siniferatoxin; M3 muscarinic acetylcholine receptors (mAC antimuscarinic agents such as those acting on the thymus (hR); GABAergic agents such as baclofen B Contains agonists Antispasmodic; Botulinum toxin; Capsaicin; Alpha-adrenergic antagonist; Anticonvulsant; Amino Serotonin reuptake inhibitors such as liptiline; and nerve growth factor antagonists. In various embodiments, the drug is a compound selected from the group consisting of benzodiazepines, ... 42:267-72 (2004), those that act on the bladder afferent pathway or may act on efferent cholinergic transmission.

[0101] In certain embodiments, the drug is used to treat neurological detrusor hyperresponsiveness and / or hypocompliant detrusor. Examples of these types of medications include: Bladder relaxants (e.g., oxybutynin (an anti-inflammatory drug with significant muscle relaxant and local anesthetic properties) muscarinics), propiverine, ipratropium, tiotropium, trospium, Lodiline, tolterodine, propantheline, oxyphencyclamine, flavoxate , and tricyclic antidepressants; drugs to block the nerves that innervate the bladder and urethra (e.g., vanilloids (capsaicin, resiniferatoxin, botulinum toxin-A); or excretory Urinary muscle contraction strength, micturition reflex, detrusor-sphincter dyssynergia (e.g., GABAβ agonists (Baclofen) In another embodiment, the drug is a drug that modulates It is selected from those known for the treatment of urinary incontinence due to urinary sphincter deficiency. Examples of these drugs include alpha-adrenergic agonists, estrogens, beta-adrenergic agonists, Tricyclic antidepressants (imipramine, amitriptyline) are included. Drugs include those known to promote urination (e.g., alpha-adrenergic antagonists (FLU)). In another embodiment, the drug is selected from: Anticholinergics (e.g., dicyclomine), calcium channel blockers (e.g., verapamil Tropane alkaloids (e.g., atropine, scopolamine), nociceptin / ol Fannin FQ, and bethanechol (e.g., M3 muscarinic agonists, choline esters) is selected from.

[0102] In some embodiments, an agent that increases osmotic pressure may be disposed within the water-permeable body. or may be included in a drug formulation, or in some embodiments, the drug itself may be osmotically For example, the drug and osmotic agent may be homogeneously mixed or may be combined into a tablet. As another example, a drug tablet may be placed near the confining plug and The osmotic agent may be arranged adjacent to the drug tablet. Non-limiting examples of osmotic agents include urea, citric acid, , L-tartaric acid, lactose-fructose, glucose-fructose, sucrose-fructose Lactose, Mannitol-Fructose, Sodium Chloride, Fructose, Lactose -Sucrose, potassium chloride, lactose-glucose, mannitol-glucose, bud Sugar-sucrose, mannitol-sucrose, sucrose, mannitol-lactose Sugar, glucose, potassium sulfate, mannitol, tribasic sodium phosphate 12H2 O, dibasic sodium phosphate·7H2O, dibasic sodium phosphate anhydrous, and monosodium salt Examples include basic sodium phosphate·H2O.

[0103] Device Use and Intended Use The device can be deployed into a body cavity or lumen and then used to treat one or more symptoms. one or more drugs for the purpose of administering the drug to one or more tissues at the deployment site and / or The release can be controlled over a long period of time. The device can then be used to remove, absorb, excrete, or some combination thereof. It can be done.

[0104] In one example, the device includes passing a drug delivery device through a deployment instrument and discharging the drug from the deployment instrument. The device is inserted into the body by releasing it into the body. In the case of deployment, the device is deployed once the device emerges from the deployment instrument into the cavity. and assume a retention shape such as an extended or higher profile shape. 7, which shows the device assuming a retained configuration upon exiting the deployment instrument 702. 7 shows a deployment device 700. The deployment device 702 may be a catheter, a urinary catheter, or a cystoscope. The deployment instrument 702 may be any suitable endoluminal device. For example, the method described in U.S. Patent Application Publication No. 2011 / 0202036 to Boyko et al. The drug delivery device may be a device specifically adapted for use in the drug delivery device of the present invention, such as

[0105] Once inserted into the body, the device releases the drug in a controlled manner. The drug may be administered chronically, continuously, intermittently, or in a desired quantity for a desired, predetermined period of time. In embodiments, the device may provide periodic release. , 10 days, 14 days, or longer periods such as 20, 25, 30, 45, 60, or 90 days or more In a preferred embodiment, the device can deliver a desired dose of drug over a period of time. The chair is administered over a selected treatment period ranging from 7 to 60 days, e.g., 14 to 30 days. An intravesical drug delivery device that continuously releases therapeutic amounts of a drug into the urine in the bladder. The delivery rate and dose of the drug are selected depending on the drug being delivered and the disease or condition being treated. It is possible.

[0106] In embodiments where the device contains a drug in solid form, elution of the drug from the device may be achieved by dissolving the drug in the device. This occurs after dissolution of the drug within the device. Body fluids enter the device, come into contact with the drug, and solubilize it. The dissolved drug is then delivered to the device via the microchannels described herein. For example, if the device is deployed in the bladder, the drug may be released upon contact with urine. It can be solubilized.

[0107] The device must then be non-absorbable, non-disintegrating, or otherwise removable. In some cases, it may be recovered from the body.

[0108] The device may also be fully or partially bioabsorbable so that retrieval is unnecessary. In one case, the device may be configured to be absorbed or removed from the bladder during urination. In some embodiments, the device is degraded sufficiently to be excreted. No. 8,690,840 to Lee et al., which is incorporated herein by reference. As shown in Figure 1, the device may collapse into a shape that allows it to pass through the urethra during urination. The device may contain a portion of the drug, or preferably a majority of the drug. It may not be recovered or absorbed until some or all of it has been released.

[0109] FIG. 8 illustrates the deployment of device 800 into the bladder, here in adult human male anatomy. Illustrated by way of example, a deployment instrument 802 can be inserted into the bladder through the urethra, and the device The device 800 may be inserted, for example, with a stylet and / or lubricant, until the device 800 is positioned within the bladder. The fluid may be passed through the deployment instrument 802 driven by a stream of water or other fluid. The device is then deployed within the bladder of a male or female human patient in need of treatment.

[0110] The device may be used as a standalone procedure or as part of another urological or other procedure or surgical procedure. It may be deployed in a patient's bladder in conjunction with other procedures, either before, during, or after the procedure. The chair is used for treatment or prevention, intraoperatively, postoperatively, or both, in local and and / or may release one or more drugs that are delivered to localized tissue.

[0111] In one embodiment, the drug delivery device having a self-contained drug payload is fully deployed. and administering at least one drug to the bladder in a therapeutically effective amount to the target tissue in need of treatment. It provides sustained delivery of an agent to the bladder itself or locally adjacent to the bladder. Such localized delivery may be accompanied by undesirable side effects or result in inadequate drug delivery. The device may provide an alternative to systemic administration that may result in sufficient bioavailability. After in vivo deployment of the drug, at least a portion of the drug payload remains substantially constant over an extended period of time. The device continuously delivers therapy to the urothelium and possibly surrounding tissue. In a preferred embodiment, the drug is released in an amount effective to improve bladder function in a patient. The drug is present in the bladder for a predetermined period of time, such as 2 weeks, 3 weeks, 4 weeks, or a month or more. Release the drug.

[0112] In such cases, the device can be used to treat interstitial cystitis, radiation cystitis, pelvic pain, and hyperactivity. Motor bladder syndrome, bladder cancer, neurogenic bladder, neurogenic or non-neurogenic bladder-sphincter dysfunction Injury, infection, post-surgical pain or other diseases, disorders and conditions treated with drugs delivered to the bladder The device can treat pain and symptoms in the bladder or other surrounding areas. bladder capacity, compliance, and / or The present invention may deliver drugs that improve bladder function, such as the frequency of uninhibited contractions, or a combination thereof. Devices deployed in the bladder may also be used to treat one or both kidneys, the urethra, among other conditions. , one or both ureters, the penis, testicles, one or both seminal vesicles, one or both vas deferens Both, one or both of the ejaculatory ducts, the prostate, vagina, uterus, or ovaries, or Any part of the body's urinary or genital system, including one or both fallopian tubes, or a combination thereof other urogenital sites in the body, such as other locations within the reproductive system, in therapeutically effective amounts of one or more For example, intravesical drug delivery devices can be used to treat other diseases, disorders, and conditions. It may be used to treat kidney stones or fibrosis, erectile dysfunction, among others.

[0113] In one embodiment, the intravesical drug delivery device is deployed within the bladder to, among other things, treat urogenital disorders. Pain arising from any source, such as disease or injury of organ tissue, or from surgery, catheterization, Any bladder procedure such as tube insertion, cauterization, medical device implantation, or stone or foreign body removal Lidocaine or another anesthetic is delivered locally to manage pain caused by

[0114] In embodiments, the drug delivery device is prepared after the device is manufactured / assembled and after the device is In some cases, the device is sterilized, such as before it is deployed in a patient. After the chair is packaged, the package is not subjected to gamma irradiation, electron beam irradiation, or acid irradiation. Gamma irradiation can be used in certain embodiments of the present invention. Although this may affect the performance of the drug delivery device, as described herein, any adverse effects Materials and construction can be selected to eliminate or substantially nullify the effects of can.

[0115] In one aspect, a method of administering a drug to a patient comprises administering a drug to a patient using a drug delivery device as described herein. Insertion of either into a lumen or body cavity of a patient and water ingress into the reservoir may cause from the reservoir, through any pre-formed through-holes present in the device body, and One or more microchannels formed between the plug and the elastic portion of the device body. (i) a drug reservoir and at least one pre-formed release port; or (ii) ) through one or more microchannels originating from the drug reservoir and an opening at the end of the device; and a reservoir effective to allow drug flow out of the device and into the lumen or body cavity. and allowing pressure to be generated within the body cavity. The patient's bladder.

[0116] In some specific embodiments, trospium is used to treat spinal cord injury (SCI) resulting from spinal cord injury. It is administered locally into the patient's bladder for the treatment of non-transferable detrusor overactivity (NDO). In some embodiments, the patient has suffered from traumatic or non-traumatic suprasacral spinal cord injury for a period of more than six months. Those diagnosed with a history of SCI and NDO. Such patients also: It may be necessary to use an intravesical catheter (non-indwelling) to empty the bladder. In some of these embodiments, local administration of trospium to the patient's bladder is This is accomplished using one of the drug delivery systems described herein. In a specific embodiment, the device (containing a payload of trospium, e.g., trospium chloride) (including tablets containing the drug) is placed into the bladder through an insert, and then after 30 to 60 days, such as after 42 days, The device is then removed. The device gradually and continuously releases trospium during the in-place period. In some of these embodiments, the device releases from about 2 mg / day to about 3 mg / day. about 50 mg / day, for example, about 5 mg / day to about 15 mg / day, or about 10 mg / day, mg / day to about 25 mg / day, for a treatment period of, for example, 42 days. In some other embodiments, the trospium is released over time. See, for example, U.S. patent application to Giesing, which is incorporated herein by reference.

[0013] The present invention relates to a method for producing a medicament for the treatment of malaria, which is known in the art, such as that described in Publication No. 2015 / 0182516. The compound may be administered locally to the bladder by other delivery systems.

[0117] In some specific embodiments, trospium is used to treat idiopathic overactive bladder (iOAB) and and administered locally to the patient's bladder for the treatment of urinary incontinence. Patients must have had urge incontinence or mixed urinary incontinence with a predominant urge component for at least 6 months. Those diagnosed with OAB (frequency / urgency) symptoms. In some of these, local administration of trospium to the patient's bladder is performed using the methods described herein. This is achieved using one of the drug delivery systems described in some specific embodiments. In this case, the device (including tablets containing a payload of trospium, e.g., trospium chloride) ) into the bladder through an insert, and then after 30 to 60 days, such as after 42 days, the device The device gradually and continuously releases trospium during the indwelling period. In some of these embodiments, the device provides a dose of about 2 mg / day to about 30 mg / day, e.g. For example, about 5 mg / day to about 2 mg / day, such as about 5 mg / day to about 15 mg / day, or about 10 mg / day. At an average daily rate of 5 mg / day over the course of treatment, e.g., over a 42-day indwelling period In some other embodiments, the trospium is released, e.g., U.S. Patent Application Publication No. 2015 to Giesing, which is incorporated herein by reference. Other delivery systems known in the art, such as those described in US Pat. No. 6,251,616, are also disclosed. The drug may be administered locally to the bladder by a system.

[0118] The present invention can be further understood by reference to the following non-limiting examples.

[0119] Example 1 Fabricating a prototype of the device with a central laser-drilled orifice and placing a trospium chloride tablet One set of devices had two spacer orifices at each end (i.e., a plug having a longitudinal orifice formed therein, and a second set of devices It has two constraining plugs. Prototype examples are shown in Figures 11 and 12. The device in Figure 11 , has three drug release holes: two on opposing ends and one on the side wall. The device has 2. The drug reservoir lumen had an inner diameter of 64 mm and a wall thickness of 0.2 mm. The device of Figure 12 had a durometer sufficient to form microchannels. It has one release hole plus two opposing ends that can provide release when pressurized. The device has a drug reservoir lumen with an inner diameter of 2.64 mm and a wall thickness of 0.2 mm. The walls had a durometer of 50A.

[0120] The device was placed in a container of deionized water and the amount of trospium chloride released was measured over time. The results of the in vitro tests (five times for each prototype design) are shown in the graphs in Figures 11 and 12. As can be seen, the constraining plug allows for more repeatable spacer orifice devices. Achieving consistent and reproducible release profiles compared to lower release profiles The differences observed between the two systems were unexpected.

[0121] Example 2 The device illustrated in Figure 3 was fabricated as follows. The device had a laser-machined orifice. a drug lumen containing a drug, and a passage for forming a one-way valve at each end of the drug compartment within the drug lumen; Silicone elastomer plug coated with Rylene C, and a protective film to hold the plug in place White silicone adhesive in a large lumen for holding the device in place. Superelastic Nitinol wireform formed for implant placement and sealed with translucent silicone adhesive The tube was a double-lumen silicone tube with a retaining lumen end. (Pharmaceutical active ingredient), Povidone (Polyvinylpyrrolidone (PVP)) K29 / 32 (Binding as a tablet containing polyethylene glycol 8000 (lubricant excipient) and polyethylene glycol 8000 (lubricant excipient) Each device contained 850 mg of trospium chloride. , small size (long axis less than 5 cm) to minimize potential irritation and inflammation The drug reservoir lumen has an inner diameter of 2.64 mm and a thickness of 0.4 mm. The Nitinol wire had a wall thickness of 0.279 mm.

[0122] The device body acts as an osmotic pump, passively transporting the drug when filled with the drug. Provides controlled release and the Nitinol wireform allows the system to move freely within the bladder The device provides bladder retention for the duration of treatment while maintaining the osmotic pump. Trospium mini-tablets deliver therapeutic agents at a controlled rate by osmotic action. The silicone tubing wall that contains the tubing acts as a semi-permeable membrane, and the wall thickness allows water The flow of the drug can be adjusted, ultimately controlling the drug release rate. There are drug release channels, one in the middle of the system and the other at the ends. The rate is controlled by the permeability of the semipermeable membrane and the osmotic properties of the therapeutic agent and osmotic agent in the lumen. Trospium chloride is highly water soluble and is an osmotic agent in its own right, providing additional This particular device contains trospiru chloride at a rate of approximately 10 mg / day. It was designed to deliver

[0123] The systems were placed in deionized water at 37°C and the release rate of trospium was determined. The in vitro results (mean ± SD, n=3) are shown in Figure 13. As can be seen, the mean daily release rate The concentration was approximately 10 mg / mL. Therefore, the desired daily release profile of trospiru chloride was obtained. It has been determined that the system can be tailored to provide a

[0124] Example 3 Trospium release bladder for in vitro release characterization according to the parameters in Table 1. The device was fabricated using one of two types of silicone housing parts. One type (RW) had a 0.2 mm wall thickness that bounded the drug reservoir lumen. The other type (TW) included an annular tube having a durometer of 50A. having a wall thickness of 0.4 mm bounding the drug reservoir lumen and having a durometer of 35A Both types of silicone components contained a drug-reducing tube with an inner diameter of 2.64 mm. All of the devices had a 150 μm diameter laser-drilled orifice. The silicone part had a hole in it, which was approximately centered on the side wall of the silicone part. The system was assembled using the piping. The system included one of two plugs. One plug on each end or one plug with a spacer seals the end of the reservoir on the other end of the system (i.e., the end at which the microchannels are formed). The drug reservoir lumen of each system was filled with 97:3 (percent w / w) 95 percent trospium chloride-polyvinylpyrrolidone (PVP) granules, and and 5 weight percent polyglycol 8000 PF (PEG 8k). , filled with approximately 996 mg trospium chloride tablets. Trospium chloride is the active agent and This in vitro stability was confirmed by acting both as an osmotic agent and as a driving force for the osmotic drug release mechanism. A total of 42 device systems were used for characterization. All systems were irradiated. did.

[0125] For the RW system, after an initial peak release rate of approximately 18–24 mg / day at 7 days, First-order trospium release kinetics were observed. The TW system was administered for 10 days over the next 35 days. It has a constant release rate of ~14 mg / day with an initial peak release rate of 10-15 mg / day. The RW system showed a higher cumulative release than the TW system, but the amount of chlorine present in the system was The number of plugs and the length of the plugs did not affect the release rate of the system. [Table 1]

[0126] All irradiated units were used for in vitro release testing. , placed in a glass filled with 300.00 + / - 0.05 g of degassed deionized water and heated to 37°C. The animals were placed in an environmental chamber maintained at 100°C. Samples were taken from each bottle at 1, 28, 35, and 42 days. At each time point, the release bottles were Day 14: The plate was inverted once and 1 mL of sample was removed and replaced with 1 mL of fresh release medium. On days 1 and 28, the release medium was completely replaced. Trospium time-point samples were analyzed using high performance liquid chromatography (HPLC). .

[0127] The trospium chloride release rate (mg / day) at a given time point T(i) is calculated using Equation 1: Release rate at T(i) (mg FBE / day) = {M(i)-M(i-1)} / {T( i)-T(i-1)}(Equation 1) Predict using different methods according to where M(i) and M(i-1) are the current time T(i) and the previous time T(i The cumulative amount of trospium released in Figure 22 is shown in Figure 22. was used to generate the trospium chloride rate release profiles seen in Figures 18-21. Using the initial drug load, the percent of trospium released can be seen in Figure 23. The mean cumulative percent trospium released for each formulation was: This can be seen in Table 2. [Table 2]

[0128] RW and TW systems with two plugs (see Figure 18). After the release experiments were initiated for RW systems with different plug lengths of 16 mm and 17 mm. After an initial release rate of approximately 18-20 mg / day on approximately day 7, the first trospium release kinetics After 7 days, a steady decrease in the release rate of the RW system was observed. At the end of the experiment, the release rate averaged 5-6 mg / day. The initial release rate was observed to be approximately 12-13 mg / day. After the first 10 days, release The rate remained roughly constant at about 11-13 mg / day for the first 35 days. After 5 days, first-order trospium release kinetics were observed. At the end of the 42-day experiment, the release rate The average release rate was 8-9 mg / day. The release rate changed with the change in plug length. All RW systems with plug lengths of 5, 8, or 16 mm All exhibited the same release profile and had plug lengths of 5, 8, or 16 mm. The TW system showed the same release profile.

[0129] 5. A system with one plug and one spacer (see Figure 19). After the release experiment was initiated for the RW system with different plugs of 8 and 16 mm. After an initial release rate of approximately 20-23 mg / day on approximately day 7 of The kinetics were observed. After 7 days, a steady decrease in the release rate of the RW system was observed. At the end of the experiment, the release rate averaged 5-6 mg / day. The initial release rate was observed to be approximately 13-15 mg / day. After the first 10 days, release The output rate remained fairly constant at about 10-13 mg / day for the first 35 days. After 35 days, first-order trospium release kinetics were observed. At the end of the 42-day experiment, the release rate The average dose was 8-9 mg / day. The release rate varied with the length of the plug. All RW systems with plug lengths of 5, 8, or 16 mm All showed the same release profile and had plug lengths of 5, 8, or 16 mm. The TW systems showed the same release profile.

[0130] A system with one plug and one spacer compared to a two plug system (See Figure 20). All models with plug lengths of 5, 8, or 16 mm. The RW system exhibited the same release profile and was available with plug lengths of 5, 8, or 16 mm. All TW systems with RW and TW showed the same release profile. The system consists of one plug system and two plugs from a lot tested in minipigs. The current plug length showed no change in release rate when compared to the 8mm system. Both the change in length and the number of plugs did not change the release rate of the trospium chloride system. It was.

[0131] System with 8mm plug (see Figure 21). Approximately 7 days after the release experiment started for the RW system with a lag volume, approximately 19 First-order trospium release kinetics were observed after an initial release rate of 24 mg / day. After 7 days, A steady decrease in the release rate of the RW system was observed. At the end of the 42-day experiment, the release rate The initial release rate for the TW system was approximately 1.5 mg / day. After the first 10 days, the release rate was observed to be 0-13 mg / day. The dose remained roughly constant at about 10-14 mg / day. After the first 35 days, the first trospiu At the end of the 42-day experiment, the release rate averaged 8-10 m / s. g / day. The release rate varied with the number of plugs each system contained, which were 8 mm long. No change in velocity occurred. All RW systems with 8mm plug length were When there were one or two plugs in the stem, they showed the same release profile and were 8 mm All TW systems with plug lengths of 1 or 2 plugs in the system showed the same release profile.

[0132] In conclusion, a 0.2 mm wall thickness (R Osmotic trospium-releasing devices were fabricated with a wall thickness of 0.4 mm (W) and 0.4 mm (TW). The RW system was constructed and an in vitro release experiment was carried out using DI water at 37°C as the release medium. The maximum dose of approximately 18-24 mg / day was reached approximately 7 days after the release experiment began. First-order trospium release kinetics were observed after the initial release rate. The initial release rate was approximately 10-15 mg / day. For the TW system, the release rate was It remained fairly constant at about 10-14 mg / day for the first 28 days. After the first 35 days, First-order trospium release kinetics were observed. Therefore, the RW system was had an initial high peak release rate and a higher cumulative release overall drug load The TW system had a more consistent release rate and lower cumulative release overall over the first 35 days. The release rate profile was significantly increased with the number of plugs or the length of the plugs. All RW systems had approximately the same release rate and cumulative release profile. All TW systems showed approximately the same release rate, cumulative The release and percent release were shown.

[0133] Example 4 For in vitro release testing, a trospium-releasing bladder with drug-releasing orifice(s) is prepared. An intravesical device was fabricated. The system was constructed using a double-lumen silicone tube. The small lumen contains two oval wireforms, and the large lumen contains 92 percent A combination of 100% trospium chloride, 3% PVP, and 5% PEG 8k Each system was loaded with trospium minitablets having the following composition (percent w / w): The amount of trospium chloride administered was approximately 910-920 mg.

[0134] Four Perforation Configuration. Figures 9A-9B show a configuration in which there are four perforations, two of which are Within the side walls of the housing near each end of the drug core are 5 mm long and 2.77 mm A Parylene C-coated silicone constraining plug with an outer diameter (OD) of The hole was positioned using the silicone adhesive on the back of the captive plug to secure it in place. The two oval wireforms were attached to the tube, and adhesive sealed the ends of the lumen. Insert into the small lumen and apply silicone adhesive to the small lumen to secure the wireform in place. The end was then hemmed 5 mm from the end of the restraining plug. The silicone constraining plug is oversized, and the inner diameter of the silicone tube is 2.64 mm. The silicone confining plug had an outer diameter of 2.77 mm. Gamma irradiation-induced changes in silicone-to-silicone joints after the use of gamma irradiation A parylene coating was used on the constraining plug to prevent adhesion. Perforations were placed 2-3 mm from the edge. Perforations across the oversized confining plug allowed for drug testing. The chamber was designed to act as a drug release outlet when osmotic pressure was built up inside the chamber. .

[0135] The location and number of holes will depend on the number and location of the captive plugs located along the length of the tube. For example, there may be only one constraining plug and two perforations in the middle of the tube. If present, there will be two drug release openings in the middle of the tube.

[0136] Two notch opening configurations 10A-10B show the two notches present in the device. 1 illustrates a configuration in which one notch is in the side wall of the housing near each end of the drug core. A Parylene C-coated silicone tube with a length of 5 mm and an outer diameter of 2.77 mm was used. A cone restraining plug was inserted into the tube, and then an incision was made with a razor blade. The razor blade passed through the tube wall and partially penetrated the captive plug, causing damage to the wall. Silicone material from the hole was not removed, in contrast to the hole where wall material was removed. Use the silicone adhesive on the back of the plug to secure the constraining plug in place and allow the adhesive to penetrate the lumen. The ends of the drug core were sealed. An incision was made 2-3 mm from each end of the drug core. An oval wireform is inserted into the small lumen of the tube and a small amount of silicone adhesive is applied. The wireform is applied to the umbilical lumen to secure it in place and allowed to cure for approximately 24 hours, after which the restraint The ends of the bundle plug were hemmed up to 5 mm from the end. The silicone constraining plug was oversized and The inner diameter of the silicone tube is 2.64 mm and the outer diameter of the silicone restraining plug is 2.7 After using gamma irradiation to sterilize the product, the silicone and To prevent gamma radiation induced adhesion at the joint with the tubing, parylene was applied to the restraining plug. A small piece of paper was inserted into each notch to test the adhesive potential and the illuminating The oversized restraining plug prevented wall closure during irradiation and was then removed in subsequent irradiations. The inlet acts as a drug release outlet when osmotic pressure builds up inside the drug chamber. It was designed to be.

[0137] The location and number of cuts will determine the number and location of the captive plugs along the length of the tube. For example, if only one captive plug is present in the middle of the tube, , there may be one notch in the middle of the tube.

[0138] Three orifice systems (one laser-drilled orifice and two plugs). and 3A have a laser drilled hole with a diameter of 150 microns in the middle of the tube and a 2.77 Two plugs with an outer diameter of 1 mm and a length of 8 mm (see Figures 3B and 3C) The plugs are made of silicone and Parylene C. Each plug contained a bevel at one end (see Figures 3A-3C). Apply silicone adhesive to the beveled end and the area created by the large lumen. The plug was secured in place, but the adhesive did not seal the end of the lumen. C shows one end of a three-opening system and shows a plug. The diagram shows a one-way valve with oversized plugs in the large lumen. Once osmotic pressure is established, a one-way valve is formed.

[0139] Perforations across the oversized constraining plug (Figures 9A-9B), as well as oversized constraining plugs (Figure 10 Unlike the incisions across the lamina (Figs. 1A-1B) and plugs (Figs. 1C, 1D, 3B, and 3C), The drilled holes are used to prevent osmotic pressure changes within the drug reservoir (i.e., the large lumen or drug compartment lumen). A hole having a predefined opening that is present regardless of the presence of a

[0140] In vitro release testing. Six systems were tested for in vitro release according to the parameters in Table 3. The stems tested were of two ellipses in shape. the number and configuration of drug release openings, the wall thickness of the silicone tube (RW or TW), and silicone tubing hardness (50A and 35A) depending on the system type. All of the systems were gamma irradiated before being tested for in vitro release. The patient was given a radiation dose of 25-40kGy. [Table 3]

[0141] In vitro release through 0.20 mm wall (RW) tubing. 300 g release at 37 °C. The system was placed in ionized water and time-point samples were collected at predetermined time points to generate an in vitro release profile. Figures 14 and 15 show the time course of types 1, 2, and 3 in Table 3. The release rate and cumulative amount of trospium chloride released are shown. The drug release characteristics between the four-opening system (with perforations) and the four-opening system (with indentations) were compared. No significant difference was observed, which supports osmotic controlled drug release. However, three openings with predefined laser drilled holes and two plugs The system has a higher overall performance compared to the two-aperture and four-aperture systems. The cumulative release amount was

[0142] In vitro release with 0.41 mm wall (TW) tubing. 300 g at 37°C. The system was placed in deionized water and time-point samples were collected at predetermined time points to assess the in vitro release profile. Figures 16 and 17 show the time course of types 4, 5, and 6 in Table 3. The release rate and cumulative amount of trospium chloride released in the two open-ended systems ( The drug release characteristics between the four-opening system (with perforations) and the four-opening system (with notches) were No significant difference was observed, which supports osmotic controlled drug release. However, three openings with predefined laser drilled holes and two plugs are used. The mouth system has a higher overall The cumulative release amount was shown.

[0143] Example 5 A system with two end restraining plugs and no sidewall orifices (see Lee et al. (as disclosed in US Patent Application Publication No. 2016 / 0008271) with a restraining plug a system having a preformed port in the sidewall adjacent to the nozzle and no sidewall orifice ( A device was fabricated for comparison with the device parameters (as illustrated in Figure 9). is shown below in Table 4.

[0144] The device was immersed in deionized water, and the drug release rate was measured over time. The results are shown in Figure 24. Illustratively, this has perforations with adjacent confining plugs to form microchannels between them. The plug-forming system exhibited in vitro release compared to the prior art plug-only system. Tests have demonstrated that it produces similar release profiles over 84 days. In fact, systems with perforations with captive plugs have shown significant improvements compared to systems with only plugs. , exhibiting a smoother release profile. [Table 4]

[0145] Publications cited herein and the material for which they are cited are specifically incorporated by reference. Variations and modifications of the methods and devices described herein will be apparent to those skilled in the art from the foregoing detailed description. Such variations and modifications are intended to fall within the scope of the appended claims. The present invention also provides the following. [1] 1. A drug delivery device comprising: a body comprising a wall bounding a reservoir defined within the body, the wall having at least one preformed through hole disposed therein and comprising a water-permeable portion, the body comprising an elastic portion; a drug formulation comprising a drug, the drug formulation being disposed within the reservoir; and at least one constraining plug sealing an opening in the body and contacting the resilient portion of the body, the opening being in fluid communication with the reservoir; the water-permeable portion of the wall is configured to allow water to enter the drug delivery device and contact the drug formulation located in the reservoir; A drug delivery device, wherein release of the drug from the device is controlled by (i) release of the drug through the at least one pre-formed through hole in the wall, and (ii) release of the drug through temporary formation of one or more microchannels between the elastic portion of the body and the at least one constraining plug, the microchannels extending to the opening upon the generation of hydrostatic pressure in the reservoir effective to form the one or more microchannels. [2] The drug delivery device described in [1], wherein the release of the drug through the at least one preformed through-hole is driven by osmotic pressure. [3] the at least one constraining plug has an outer diameter; the resilient portion of the body defines an opening having an inner diameter; The drug delivery device described in [1], wherein the outer diameter of the constraining plug is at least 3 percent greater than the inner diameter of the elastic portion of the body. [4] [3] The drug delivery device described in [3], wherein the outer diameter of the constraining plug is at least 5 percent, at least 10 percent, at least 15 percent, at least 20 percent, or at least 25 percent greater than the inner diameter of the elastic portion of the body. [5] The drug delivery device described in [1], wherein the main body further comprises an inelastic portion. [6] The drug delivery device described in [1], wherein the at least one constraining plug is fixed within the opening in the elastic portion of the body with an adhesive. [7] The drug delivery device described in [1], wherein the drug formulation is in a solid form. [8] The drug delivery device of [7], wherein the device is configured to allow water to diffuse through the water-permeable portion of the wall and into the reservoir in vivo to solubilize the solid drug formulation. [9] The drug delivery device described in [1], wherein the drug comprises trospium or another antimuscarinic agent.

[10] The drug delivery device according to [1], further comprising an osmotic agent.

[11] The drug delivery device described in

[10] , wherein the osmotic agent is a component of the drug formulation.

[12] The drug delivery device described in [1], wherein the at least one constraining plug is substantially cylindrical.

[13] The drug delivery device of [1], wherein the at least one constraining plug has a wedge-shaped, tapered, angled, or rounded surface.

[14] The drug delivery device described in [1], wherein the Shore durometer of the elastic portion of the main body is about 40A to about 60A, and the Shore durometer of the at least one constraining plug is about 70A to about 100A.

[15] The drug delivery device described in [1], wherein the Shore durometer of the elastic portion of the main body is about 45A to about 55A, and the Shore durometer of the at least one constraining plug is about 75A to about 85A.

[16] The drug delivery device described in [1], wherein the Shore durometer of the elastic portion of the body is approximately 50A and the Shore durometer of the at least one constraining plug is approximately 80A.

[17] The drug delivery device described in [1], wherein the device is elastically deformable between a relatively straight shape suitable for insertion into a body cavity through a patient's lumen and a retained shape suitable for retaining the device within the body cavity.

[18] The drug delivery device described in [1], wherein the main body is formed from an elastomer tube.

[19] The drug delivery device described in [1], wherein the elastic portion of the body is formed from a water-permeable material.

[20] The drug delivery device described in [1], wherein the one or more microchannels are not preformed orifices. [twenty one] The drug delivery device described in [1], wherein the at least one constraining plug has a parylene coating. [twenty two] 1. A method of administering a drug to a patient, comprising: Inserting the drug delivery device according to any one of [1] to

[21] into a lumen or body cavity of a patient; allowing water entry into the reservoir to generate pressure within the reservoir effective to cause the drug to flow from the reservoir through the preformed through-hole and at least one of the one or more microchannels, out of the device, and into the lumen or body cavity. [twenty three]

[22] The method according to

[22] , wherein the body cavity is the patient's bladder. [twenty four] 1. A drug delivery device comprising: a tubular body comprising a wall bounding a reservoir defined within the body, the wall comprising a water-permeable portion and a resilient portion having at least one preformed release port disposed therein; a drug formulation comprising a drug, the drug formulation being disposed within the reservoir, the water-permeable portion of the wall allowing water to enter the drug delivery device and contact the drug formulation located within the reservoir; and and at least one constraining plug secured within the reservoir in contact with the elastic portion of the body adjacent to the at least one preformed release port, whereby the at least one constraining plug controls release of the drug from the device through the at least one preformed release port by temporary formation of one or more microchannels between the elastic portion of the body and the at least one constraining plug, the microchannels extending to the at least one preformed release port upon the occurrence of hydrostatic pressure within the reservoir effective to form the one or more microchannels. [twenty five] 24. The drug delivery device of claim 23, wherein the at least one preformed release port comprises a through hole or incision disposed in the wall.

[26] the at least one constraining plug has an outer diameter; the resilient portion of the body has an inner diameter;

[24] The drug delivery device described in

[24] , wherein the outer diameter of the constraining plug is at least 3 percent greater than the inner diameter of the elastic portion of the body.

[27]

[24] The drug delivery device of

[24] , wherein the outer diameter of the constraining plug is at least 5 percent, at least 10 percent, at least 15 percent, at least 20 percent, or at least 25 percent greater than the inner diameter of the elastic portion of the body.

[28] The drug delivery device described in

[24] , wherein the body further comprises an inelastic portion.

[29]

[24] The drug delivery device described in

[24] , wherein the at least one constraining plug is fixed within the elastic portion of the body with an adhesive.

[30] The drug delivery device described in

[24] , wherein the drug formulation is in a solid form.

[31] 30. The drug delivery device of claim 30, wherein the device is configured to allow water to diffuse through the water-permeable portion of the wall and into the reservoir in vivo to solubilize the solid drug formulation.

[32]

[24] The drug delivery device of

[24] , wherein the drug comprises trospium or another antimuscarinic agent.

[33]

[24] The drug delivery device according to

[24] , further comprising an osmotic agent.

[34] The drug delivery device of

[33] , wherein the osmotic agent is a component of the drug formulation.

[35] The drug delivery device described in

[24] , wherein the at least one constraining plug is substantially cylindrical.

[36] The drug delivery device described in

[24] , wherein the Shore durometer of the elastic portion of the main body is about 40A to about 60A, and the Shore durometer of the at least one constraining plug is about 70A to about 100A.

[37] The drug delivery device described in

[24] , wherein the Shore durometer of the elastic portion of the main body is about 45A to about 55A, and the Shore durometer of the at least one constraining plug is about 75A to about 85A.

[38]

[24] The drug delivery device described in

[24] , wherein the Shore durometer of the elastic portion of the body is about 50A and the Shore durometer of the at least one constraining plug is about 80A.

[39]

[24] A drug delivery device as described in

[24] , wherein the device is elastically deformable between a relatively straight shape suitable for insertion into a body cavity through a patient's lumen and a retained shape suitable for retaining the device within the body cavity.

[40]

[24] A drug delivery device as described in

[24] , wherein the elastic portion of the body is formed from a water-permeable material.

[41] The drug delivery device according to

[24] , wherein the one or more microchannels are not preformed orifices.

[42] 24. The drug delivery device of claim 23, wherein the at least one constraining plug has a parylene coating.

[43]

[24] The drug delivery device described in

[24] , further comprising at least one preformed through hole disposed within the wall of the body, wherein release of the drug from the device is further controlled by release of the drug through the at least one preformed through hole within the wall.

[44] 43. The drug delivery device of claim 43, wherein the release of the drug through the at least one preformed through-hole is driven by osmotic pressure.

[45] 1. A method of administering a drug to a patient, comprising: Inserting the drug delivery device according to any one of

[24] to

[44] into a lumen or body cavity of a patient; allowing water entry into the reservoir to generate hydrostatic pressure within the reservoir effective to form one or more microchannels between the elastic portion of the body and the at least one constraining plug extending to the at least one preformed release port, thereby causing the drug to flow from the reservoir through the microchannels, out of the device and into the lumen or body cavity.

[46]

[45] The method according to

[45] , wherein the body cavity is the patient's bladder.

[47] 1. A method of treating a patient in need of treatment for neurogenic detrusor overactivity (NDO) resulting from a spinal cord injury (SCI), comprising: 3. A method comprising administering an effective amount of trospium topically to the bladder of the patient continuously for a treatment period of 30 to 60 days.

[48] 47. The method of claim 47, wherein locally administering the effective amount of trospium comprises releasing the trospium into urine in the bladder from a drug delivery device located in the patient's bladder.

[49]

[47] The method according to

[47] , wherein the treatment period is 42 days.

[50] 47. The method of claim 47, wherein the trospium is released into the bladder at an average daily rate of about 2 mg / day to about 30 mg / day over the treatment period.

[51] 47. The method of claim 47, wherein the trospium is released into the bladder at an average daily rate of about 5 mg / day to about 25 mg / day over the treatment period.

[52] 47. The method of claim 47, wherein the trospium is released into the bladder at an average daily rate of about 5 mg / day to about 15 mg / day over the treatment period.

[53]

[47] The method of

[47] , wherein the trospium is released into the bladder at an average daily rate of about 10 mg / day over the treatment period.

[54] 1. A method of treating a patient in need of treatment for idiopathic overactive bladder (iOAB) and urinary incontinence, comprising: 3. A method comprising administering an effective amount of trospium topically to the bladder of the patient continuously for a treatment period of 30 to 60 days.

[55] 54. The method of claim 54, wherein locally administering the effective amount of trospium comprises releasing the trospium into urine in the bladder from a drug delivery device located in the patient's bladder.

[56] The method according to

[54] , wherein the treatment period is 42 days.

[57] 54. The method of claim 54, wherein the trospium is released into the bladder at an average daily rate of about 2 mg / day to about 30 mg / day over the treatment period.

[58] 54. The method of claim 54, wherein the trospium is released into the bladder at an average daily rate of about 5 mg / day to about 25 mg / day over the treatment period.

[59] 54. The method of claim 54, wherein the trospium is released into the bladder at an average daily rate of about 5 mg / day to about 15 mg / day over the treatment period.

[60] 54. The method of claim 54, wherein the trospium is released into the bladder at an average daily rate of about 10 mg / day over the treatment period.

Claims

1. 1. A drug delivery device for treating a patient in need of treatment for neurogenic detrusor overactivity (NDO) resulting from spinal cord injury (SCI), or for treatment of idiopathic overactive bladder (iOAB) and urinary incontinence, comprising: configured to administer an effective amount of trospium locally to the patient's bladder continuously for a treatment period of 30 to 60 days. a body comprising a wall bounding a reservoir defined within the body, the wall having at least one preformed through hole disposed therein and comprising a water-permeable portion, the body comprising an elastic portion; a drug formulation comprising the trospium, the drug formulation being disposed within the reservoir; and a captive plug sealing an opening in the body and contacting the resilient portion of the body, the opening being in fluid communication with the reservoir; water diffuses into the reservoir through the water-permeable portion of the wall to contact the drug formulation and generate hydrostatic pressure within the reservoir effective to cause the trospium to flow from the reservoir, out of the drug delivery device and into the patient's bladder; A drug delivery device, wherein the release of the trospium from the drug delivery device is controlled by (i) the release of the trospium through the at least one pre-formed through hole in the wall, and (ii) the release of the trospium through the temporary formation of one or more microchannels between the elastic portion of the body and the restraining plug, extending along the inner surface of the elastic portion of the body to the opening.

2. 1. A drug delivery device for treating a patient in need of treatment for neurogenic detrusor overactivity (NDO) resulting from spinal cord injury (SCI), or for treatment of idiopathic overactive bladder (iOAB) and urinary incontinence, comprising: configured to administer an effective amount of trospium locally to the patient's bladder continuously for a treatment period of 30 to 60 days; a body comprising a wall bounding a reservoir defined within the body, the wall having at least one preformed through hole disposed therein and comprising a water-permeable portion, the body comprising an elastic portion; a drug formulation comprising the trospium, the drug formulation being disposed within the reservoir; and a captive plug sealing an opening in the body and contacting the resilient portion of the body, the opening being in fluid communication with the reservoir; water diffuses into the reservoir through the water-permeable portion of the wall to contact the drug formulation and generate hydrostatic pressure within the reservoir effective to cause the trospium to flow from the reservoir, out of the drug delivery device and into the patient's bladder; A drug delivery device wherein the constraining plug controls the release of the trospium from the drug delivery device through the at least one preformed through hole by temporary formation of one or more microchannels between the elastic portion of the body and the constraining plug, which extend along the inner surface of the elastic portion of the body to the at least one preformed through hole upon the generation of the hydrostatic pressure.

3. The drug delivery device of claim 1 or 2, which is placed in the patient's bladder.

4. The drug delivery device of any one of claims 1 to 3, wherein the treatment period is 42 days.

5. 5. The drug delivery device of claim 1, wherein the trospium is released into the bladder at an average daily rate of 2 mg / day to 30 mg / day over the treatment period.

6. 6. The drug delivery device of claim 1, wherein the trospium is released into the bladder at an average daily rate of 5 mg / day to 25 mg / day over the treatment period.

7. 7. The drug delivery device of claim 1, wherein the trospium is released into the bladder at an average daily rate of 5 mg / day to 15 mg / day over the treatment period.

8. 8. The drug delivery device of claim 1, wherein the trospium is released into the bladder at an average daily rate of about 10 mg / day over the treatment period.

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