Drug delivery device with drug-permeable component and method

Abstract

To provide a drug delivery device (1000) having a drug-permeable component and a method for producing and using the same.SOLUTION: A drug delivery device includes a housing (1002) having a first wall structure (1012) and a second wall structure (1014) that are adjacent to each other and together form a tube (1010) defining a drug reservoir lumen (1004). The second wall structure or both the first wall structure and the second wall structure is or are permeable to water, and the first wall structure is impermeable to a drug while the second wall structure is permeable to the drug, such that the drug is releasable in vivo by diffusion through the second wall structure.SELECTED DRAWING: Figure 10A

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is incorporated herein by reference in its entirety. US Provisional Patent Application No. 62 / 151,982, filed February 9, 2016. Priority is claimed from patent application Ser. No. 62 / 293,232.

[0002] The present disclosure is generally in the field of medical devices, and more specifically, but not limited to: and devices for controlled release of drugs, including devices that can be placed in the bladder to administer the drug into the bladder. The present invention relates to a drug delivery device for insertion into the body of a patient for administering a drug to a subject.

[0003] Intravesical drug delivery devices are known. An example of such a device is described in Cima et al. U.S. Patent No. 8,679,094 to Lee et al., U.S. Patent No. 9,017,312 to Lee et al. No. 9,107,816 to Lee et al., and U.S. Pat. In some embodiments, the method is described in application publication no. 2012 / 0089121A1. wherein the intravesical device defines a drug storage lumen that contains a solid or semi-solid formulation. The device includes a water-permeable housing, and water from the bladder diffuses into the drug storage lumen to solubilize the drug. Drug release occurs in vivo by the release of the drug, which then rises in the drug storage lumen. The resulting osmotic pressure forces the solubilized drug out of the device through the release orifice.

[0004] For example, in cases involving a particular drug and therapeutic application, the period during which a therapeutic amount of drug is released. It may be desirable to extend the time and / or prevent the drug from being released too quickly. One way to achieve this is by slowing the rate at which water can enter the drug reservoir. U.S. Patent Application Publication No. 2009 / 0149822A1 to Cima et al. a conformal coating on at least a portion of the exterior surface of the housing to reduce water permeability to the body; Alternatively, adding a sheath is disclosed. However, this approach complicates manufacturing. Additionally, the device housings of these intravesical devices are typically designed to be elastically deformable. This prevents the coating from peeling and / or cracking during deformation of the device. This can undesirably alter the release kinetics and adversely affect the reproducibility of results. As such, maintaining an effective coating can be difficult.

[0005] U.S. Patent Application Publication No. 2014 / 0276636A1 to Lee et al. describes a first wall structure. a first wall structure that is impermeable to the drug and a second wall structure that is permeable to the drug; The present invention discloses a device in which a drug is released from a housing made of a hydrophilic second wall structure. It provides a device capable of delivering a variety of different drugs at effective release rates. and to allow greater flexibility and flexibility regarding the relative size and position of the two wall structures. To provide a method for fabricating these devices with control, It would be desirable to provide improvements and / or alternative embodiments to the system. Summary of the Invention

[0006] In a first embodiment, the drug delivery devices are adjacent to each other and together form a drug storage loop. a housing having a first wall structure and a second wall structure forming a tube defining a body; and a drug contained within the second wall structure, or the first wall structure and the second wall structure. Both the first wall structure and the second wall structure are permeable to water and impermeable to the drug, The second wall structure is permeable to the drug, so that the drug is absorbed by diffusion through the second wall structure. The second wall structure is releasable in vivo by the occupying less than 90 percent of the cross-sectional area of ​​the tube, and the first wall structure is made of a first polyurethane composition. Includes things.

[0007] In a second embodiment, the drug delivery device has a first closed end and a second closed end. an elongated elastic housing having an extending drug storage lumen; The housing includes a first material that is entirely impermeable to the drug. and a second annular segment formed at least in part of the second material that is permeable to the drug. and the drug is released in vivo by diffusion through the second material in the second annular segment. and a second annular segment configured to release the substance. The first annular segment is integrally formed with and connected to the first end of the second annular segment. The first end has a first end.

[0008] In a third embodiment, the drug delivery device contains at least one thermoplastic material. a tubular housing having a closed drug storage lumen surrounded by a wall structure; At least a portion of the wall structure is water permeable, and the wall structure At least some of the wall structure is permeable to the drug, so that the drug can pass through the drug-permeable portion of the wall structure. The tubular housing is adapted to release the device in vivo by diffusion through the bladder of a patient. The device is inserted through the patient's urethra and into the bladder from a coiled retention configuration suitable for retaining the device. The tubular housing can be elastically deformed to a non-coil shape suitable for inserting a chair, and the tubular housing is a coil-type retaining type. The thermal shape is set to have a shape.

[0009] In a fourth embodiment, the device has a drug storage lumen extending between a first end and a second end. A method for making a drug delivery device having an elongated elastic housing includes: (i) pressing a first material against a substrate; The extrusion process involves introducing the extruded material into an outlet channel, making the extruded material impermeable to the drug to be delivered. (ii) forming a first annular segment entirely from a first material; and A pipe having one or more first annular segments integrally connected to a second annular segment. and dispensing a second material into an extrusion channel containing the first material at a preselected location effective to form a first or second shaped structure. By intermittently introducing a second material, a second material that is permeable to the drug to be delivered is formed. and at least partially forming the second annular segment from the material.

[0010] In a fifth embodiment, a method of administering a drug to a patient in need thereof comprises: (i) administering adjacent a first wall structure and a second wall structure that abut and together form a tube that defines a drug storage lumen; and (ii) a drug contained in a drug storage lumen. and inserting the first wall structure into the patient, the first wall structure being impermeable to the drug and comprising a polymer. The second wall structure comprises a urethane, the second wall structure being permeable to the drug and comprising a urethane-containing second wall structure having an outer surface area of ​​the tube. Occupying less than 90 percent of the space and including the second wall structure or both the first and second wall structures The method involves using only the second wall structure to solubilize the drug. absorbing water through the first wall structure or through both the first wall structure and the second wall structure; and releasing the solubilized drug from the device by diffusion through the wall structure of the two. .

[0011] In a sixth embodiment, a method of administering a drug to a patient in need thereof comprises: (i) providing a tubular wall structure; and a drug storage lumen extending between a first closed end and a second closed end. and (ii) administering to the patient a device comprising an elongated elastic housing and a drug contained within the drug storage lumen. the wall structure being entirely made of a first material that is impermeable to the drug. a first annular segment formed therein and a second material permeable to the drug; and a partially formed second annular segment, the first annular segment being The method includes: imbibing water through the tubular wall structure to solubilize the drug; and and releasing the solubilized drug from the device by diffusion through the annular segment. include.

[0012] The detailed description will be described with reference to the accompanying drawings, in which the use of the same reference numerals indicates similar or Various embodiments may include elements and / or components other than those shown in the drawings. Some elements and / or components may be present in various embodiments. Elements and / or components in the figures are not necessarily drawn to scale. [Brief explanation of the drawings]

[0013] [Figure 1A] 1 is a longitudinal cross-sectional view of one embodiment of a coiled retention-shaped drug delivery device according to the present disclosure. FIG. [Figure 1B] 1B is a cross-sectional view of the drug delivery device of FIG. 1A according to the present disclosure. [Figure 2] 1 is a cross-sectional view of an embodiment of a drug delivery device according to the present disclosure. [Figure 3] 1 is a cross-sectional view of an embodiment of a drug delivery device according to the present disclosure. [Figure 4] 1 is a cross-sectional view of an embodiment of a drug delivery device according to the present disclosure. [Figure 5] 1 is a cross-sectional view of an embodiment of a drug delivery device according to the present disclosure. [Figure 6] 1 is a cross-sectional view of an embodiment of a drug delivery device according to the present disclosure. [Figure 7A] FIG. 10 is a perspective view of another embodiment of a drug delivery device in a relatively straight shape according to the present disclosure, with no drug disposed therein or within a resilient retaining frame. [Figure 7B] 7B is a longitudinal cross-sectional view of the drug delivery device shown in FIG. 7A taken along line 7B-7B. [Figure 7C] 7C is a cross-sectional view of the drug delivery device shown in FIG. 7A taken along line 7C-7C. [Figure 8A] FIG. 10 is a perspective view of another embodiment of a drug delivery device in a relatively straight shape according to the present disclosure, with no drug disposed therein or within a resilient retaining frame. [Figure 8B] 8B is a longitudinal cross-sectional view of the drug delivery device shown in FIG. 8A taken along line 8B-8B. [Figure 8C] 8C is a cross-sectional view of the drug delivery device shown in FIG. 8A taken along line 8C-8C. [Figure 8D] 8D is a cross-sectional view of the drug delivery device shown in FIG. 8A taken along line 8D-8D. [Figure 9A] FIG. 10 is a partial top view of another embodiment of a drug delivery device in a relatively straight shape according to the present disclosure, without any drug disposed therein. [Figure 9B] 9B is a partial longitudinal cross-sectional view of the drug delivery device shown in FIG. 9A taken along line 9B-9B. [Figure 10A]FIG. 1 is a perspective view of another embodiment of a drug delivery device according to the present disclosure. [Figure 10B] 10B is a longitudinal cross-sectional view of the drug delivery device shown in FIG. 10A taken along line 10B-10B. [Figure 10C] 10C is a cross-sectional view of the drug delivery device shown in FIG. 10A taken along line 10C-10C. [Figure 10D] 10D is a cross-sectional view of the drug delivery device shown in FIG. 10A taken along line 10D-10D. DETAILED DESCRIPTION OF THE INVENTION

[0014] Improved implantable drug delivery devices, methods for their manufacture, and methods for drug delivery are provided. In a specific embodiment, the device is configured for intravesical insertion and sustained release drug delivery. and preferably provides a zero order release rate of a therapeutically effective amount of the drug.

[0015] Diffusion-Based Drug Delivery Devices

[0016] For certain drugs, osmotic delivery mechanisms are used to achieve zero-order release rates over 3-4 days. In experiments, the drug release rate decreased after 3-4 days. may decrease rapidly, causing urinary drug concentrations in the bladder to fall below the minimum effective concentration before the end of the treatment period. For example, due to size constraints on the overall implant system, more and extends the period of zero-order release by simply providing a more densely packed permeant with the drug. It is not always feasible to achieve this, and instead, the overall drug Providing first-order release is also not always feasible, because even at the end of the treatment period Even if the drug release rate decreases toward the minimum effective concentration of the drug, the release rate will still be higher than the minimum effective concentration of the drug. Therefore, it may not be safe to have a sufficiently high initial peak drug release rate. That's why.

[0017] Thus, instead of an osmotic drug release mechanism, a drug permeable membrane defining a portion of the device housing is used. Drug release is controlled by the diffusion of the drug through the polymer or matrix component. In one embodiment, the device comprises: , drug-permeable polymer components or moieties. For example, the size of the drug-permeable wall structure, The shape (e.g., arc angle), thickness, and material properties are adjusted to achieve the desired drug release rate. As may be selected, the drug permeable component or portion of the device may be separated from the remainder of the housing ( For example, one or more strips of material extending along at least a portion of the length of the housing. In certain embodiments, the housing may be made of a different material than the housing. (i) controlled diffusion of drug from the device; (ii) desired mechanical properties (e.g., compliance); (iii) a device that can be thermally configured to have a desired retention shape. and / or (iv) a device that can be advantageously manufactured in a coextrusion process. To provide a drug-permeable portion, a drug-impermeable portion, or a drug-permeable and drug-impermeable portion, Both components are formed of a polyurethane composition.

[0018] In one embodiment, as shown in FIGS. 1A and 1B, a closed A drug delivery device 100 is provided that includes a tubular housing having an open drug storage lumen 106. (i) at least a portion of the wall structure 104 is water permeable; and (ii) at least a portion of the wall structure Some of the solid drug units 108 are permeable to the drug, so that the drug , releasable in vivo by diffusion through the drug-permeable portion of the wall structure 104. In certain embodiments, as will be discussed in more detail below, the wall structures together form an enclosure. As used herein, "drug permeation" refers to a drug delivery system that includes a first and second wall structure that forms a body. Diffusion through a transient segment (e.g., a "second wall structure," a "second annular segment," or The phrase "through another drug-permeable portion" refers to an opening or aperture extending through that wall. Drugs penetrate the walls by molecular diffusion rather than by passing through the free-flowing structure. This means that the

[0019] In one embodiment, as shown in FIG. 2, adjacent to each other and together form a drug storage lumen. A housing having a first wall structure 206 and a second wall structure 205 forming a tube defining a cavity 208. A drug delivery device 200 is provided that includes a body, (i) a second wall structure 205, or a first (ii) both the first wall structure 206 and the second wall structure 205 are permeable to water; The first wall structure 206 is impermeable to the drug, and the second wall structure 205 is permeable to the drug. Being permeable, the drug is released in vivo by diffusion through the second wall structure 205. As used herein, the term "drug-impermeable" Over the course of the treatment period while the device is in vivo, a significant amount of solubilized drug is released into the wall. The wall is substantially impermeable to the solubilized drug so that it cannot diffuse through This refers to the following:

[0020] In certain embodiments, the tube is cylindrical or has another suitable shape or design. As used herein, the term "cylindrical" refers to a tubular housing. When used herein, it refers to a housing having a substantially cylindrical outer wall. The device does not contain any orifices and drug release is solely by diffusion through the second wall structure.

[0021] In some embodiments, as shown in FIGS. 2 and 3, the first wall structure 206 / 3 06 and the second wall structure 205 / 305 are adjacent to each other and together form a cylindrical tube. For example, such a device may include a first wall structure and a second wall structure that are integrally formed. In one embodiment, the co-extruded The first and second wall structures are thermoplastic polymers having desired properties.

[0022] As shown in FIG. 3, the first wall structure 306 and the second wall structure 306 together , forming a cylindrical tube having a lumen 308 in which the formulation is contained. The second wall structure 305 in the form of a strip extending along at least a portion of the length of the first wall structure 306; permeable to the drug, while the first wall structure 306 is not permeable to the drug. In certain embodiments, multiple drug-permeable strips are used in a single device. Therefore, the size, shape, thickness, and material properties of the second wall structure may be selected as desired. The drug release rate may be selected to achieve a drug release rate of 0.15 to 1.0001.

[0023] In a preferred embodiment, as will be discussed in more detail below, the device is configured to collect urine from a patient. A relatively straight shape that is suitable for insertion through the bladder and into the patient's bladder, and In one embodiment, the flexible support is elastically deformable between a suitable holding shape and a suitable holding shape. As shown in Figures 7A-7C, 8A-8D, and 10A-10D, the device includes a retaining frame. In certain embodiments, the retention frame further comprises a retention frame lumen 734, 834, 1034. The frame lumen contains an elastic wire, such as a nitinol wire. Thus, the retention frame lumen is filled with a shape-setting elastic polymer. As shown in FIGS. 1A-1B and 2-6, the device is inserted into the retaining frame lumen or Instead, the housing material does not include any retaining frame or wires. is configured to be elastically deformable between a straightened shape and a retained shape in the absence of a wire. In certain embodiments, the tubular housing has a coil shape or other retention shape. Thus, in such an embodiment, the device The design and manufacture of the device is simplified and the overall size of the device is minimized (or (If the size of the reservoir remains constant, the drug loading can be increased). In embodiments without a lumen, the tubular housing material (i) forms a drug storage lumen, ii) to control drug release, and (iii) to retain the device in the bladder once placed. Perform Noh.

[0024] In one embodiment, as shown in FIGS. 7A-7C, the first end 706 and the second end a drug storage lumen 704 extending between the elongated elastic housing 702 and the drug storage lumen 704; A drug delivery device 700 is provided. Elastic housings 702 are adjacent to each other and together hold the drug. The first wall structure 716 and the second wall structure 72 form a tube that defines the storage lumen 704. 4, and (i) a second wall structure 724, or a first wall structure (ii) both the first wall structure 716 and the second wall structure 724 are permeable to water; The first wall structure 716 is impermeable to the drug, and the second wall structure 724 is permeable to the drug. , so that the drug is releasable in vivo by diffusion through the second wall structure 724. is.

[0025] In embodiments where the first and second wall structures together form a cylindrical tube, any suitable Suitable end plugs or closures or thermoformed seals close the ends of the tubes after the drug is inserted. These end plugs / closures form part of the outer tube. The drug-permeable polymeric moiety ensures that this is the only route of drug release.

[0026] In some embodiments, as shown in FIGS. 2 and 3, walls 206, 205 / 30 6, 305 has a substantially constant thickness around its periphery. The wall structure 206, 205 / 306, 305 (together forming a cylindrical tube) has an inner diameter 21 The outer diameters 0 / 310 and 212 / 312 are the same.

[0027] In other embodiments, the wall is, for example, Figures 4 to 6 show thicknesses less than the drug-impermeable portions (406 / 506 / 606). The wall may have a varying thickness around its circumference, as shown in FIG. The drug-permeable wall structure (405 / 505 / 605) is adjacent to a thicker drug-impermeable wall. They may be placed in various positions relative to the wall structure (406 / 506 / 606). As shown, the thinner drug-permeable wall structure 405 is a drug-impermeable wall that forms a drug storage lumen. 5, the inner surface of the flexible wall structure 406 may be flush with the inner surface of the flexible wall structure 406. The thin drug-permeable wall 505 may be centered relative to the thickness of the drug-impermeable wall structure 506. As shown in FIG. 6, a thinner drug-permeable wall structure 605 forms the drug storage lumen. The outer surface of the drug-impermeable wall structure 606 may be flush with the outer surface of the drug-impermeable wall structure 606 opposite the surface forming the .

[0028] That is, drug release occurs through a drug-permeable component that defines a portion of the closed drug housing. The drug-permeable wall structure allows the drug to be released from the device at a desired rate and controlled by the drug's diffusion. The drug diffusion barrier may be positioned, sized, and have material properties to provide for enhanced drug diffusion.

[0029] The particular material and arc angle of the drug permeable portion or wall structure may determine a particular drug release profile. , i.e., water and drug permeation rates. In this embodiment, as shown in FIGS. 2 and 3, the second wall structure 205 / 305 is aligned with the longitudinal axis of the tube. In a vertical cross section, it occupies less than 90 percent of the cross-sectional area of ​​the tube. The second wall structure occupies less than 50 percent of the cross-sectional area of ​​the pipe in a cross section perpendicular to the longitudinal axis of the pipe. In one embodiment, the second wall structure is accounts for less than 25 percent of the total.

[0030] In one embodiment, as shown in FIG. 2, the second wall structure 205 has, in cross section: The circumference of the cylindrical tube 200 has an arc angle 214 of approximately 60 degrees. As such, the second wall structure 305 extends in cross section through approximately 30 degrees of the circumference of the cylindrical tube 300. In one embodiment, the second wall structure has an arc angle 314 between about 10 degrees and about 170 degrees. In one embodiment, the second wall structure has an arc angle of about 15 degrees to about 90 degrees. As used herein, the term "about" in relation to the arc angle of the second wall structure The expression refers to an arc angle of ±3 degrees. The second wall structure is used when the device is in a holding configuration as shown in FIG. When the shape is formed as an inner bend (0 degrees), an outer bend (180 degrees), and an upper The upper (90 degrees) position may be located at the top of the second wall structure. , may be preferred if formed from a material that swells significantly once it absorbs water.

[0031] In a second embodiment, a drug storage lumen extends between the first closed end and the second closed end. The drug delivery device has an elongated elastic housing having a first section that is impermeable to the drug. a first annular segment formed entirely of a material and a second annular segment formed entirely of a material that is permeable to the drug; and a diffusion barrier formed at least in part of the second material in the second annular segment. and a second annular segment configured to release the drug in vivo by The first annular segment has a tubular wall structure including a first end of the second annular segment. Such a device has a first end formed and connected to a conventional extrusion process. This overcomes certain problems associated with the process, for example, the use of tubular structures with two walls. In using certain conventional extrusion processes to fabricate the device body, the drug-permeable material A smaller portion of the wall structure containing the material (when viewed in a cross section perpendicular to the lumen axis, the arc angle defining the wall) (which can be quantified by This wall structure cannot be narrowed down even at the narrowest arc angle that can be reliably manufactured. For a particular drug in a device of a given length, the area for drug diffusion remains constant. It has become clear that in some cases the drug release rate is too high (i.e., the drug is released too quickly). Many other variables or devices can be used to modify the drug release kinetics in such situations. Specifications may be considered; however, changing these variables may affect mechanical and tolerability. , the available drug payload, or other desirable characteristics of the device. Therefore, it is necessary to press the device so that the drug-permeable material does not need to run the entire length of the device body. It has been found that the extrusion process can be modified, i.e., the extrusion process can be performed by During the process of extruding the drug-impermeable wall material of the body, discontinuous (or In this way, the entire pipe structure can be Not only can the physical dimensions be maintained, but advantageously the drug diffusion selection for release can be achieved. The length and thickness of the diffusion portion of the wall structure of the device are adjusted to provide a controlled area and therefore velocity. Both the length and width can be controlled.

[0032] Therefore, the mechanical properties and dimensions favorable for device placement and tolerance are adversely altered. Tubular devices designed to slow or control the drug release rate without changing the In embodiments, this design allows the length of the drug permeable region(s) to be determined. By shortening the length so that it extends along only a portion of the total length of the device, the drug release rate can be increased. Therefore, advantageously, a drug permeable region(s) with a larger arc angle These may be used to slow the rate of drug release from the device. By shortening the length of the region, less drug-permeable material is required compared to conventional devices. A slower drug release rate can be achieved using materials, particularly when the device is in the bladder. This is beneficial to the mechanical properties of the device when used in

[0033] In one embodiment, as shown in FIGS. 8A-8D, the first end 806 and the second end a drug storage lumen 804 extending between the elongated elastic housing 802 and the drug storage lumen 804; A substance delivery device 800 is provided. The resilient housing 802 includes a first annular segment 812 and a second annular segment 814. and a second annular segment 814. In this embodiment, the first and second annular segments 812, 814 are extruded together in the extrusion process. are formed together.

[0034] The first annular segment 812 contains a drug (not shown) disposed within the drug storage lumen 804. The first annular segment is formed entirely of a first material 816 that is impermeable to The annular portion 812 is integrally formed with and connected to a first end 820 of the second annular segment 814. The second annular segment 814 has a first end 818 that is formed from a first material 816. a second material 824 that is permeable to the drug disposed within the drug storage lumen 804; The drug is released in vivo by diffusion through the second material 824. It is possible to obtain it.

[0035] In the embodiment shown in FIGS. 8A-8D, the second annular segment 814 is a tubular wall structure. The structure 810 includes a central portion 826 extending between an outer surface 828 and an inner surface 830. The core portion 826 is formed entirely of the second material 824 .

[0036] having a drug-permeable portion extending along its length (e.g., as shown in Figures 7A-7C). As discussed in relation to the drug permeable second wall structure in the device, The specific materials and arc angles within the cavity will result in a specific drug release profile, i.e., the amount of water and drug released. For example, in certain embodiments, the second material may be selected to achieve a desired permeation rate. The portion of the second annular segment including the tubular wall structure of the central portion has a cross-sectional area of ​​less than about 25%. In one embodiment, the portion of the second annular segment that includes the first material is A portion of the second annular segment forming the arcuate portion and comprising the second material is disposed adjacent the outer periphery of the tubular wall structure. The first and second arches form a second arch portion having an arc angle of about 15 degrees to about 120 degrees. The shaped portions are integrally connected and together define an annulus of the second annular segment. In one embodiment, the portion of the second annular segment including the second material is angled between about 30 degrees and It has an arc angle of approximately 60 degrees.

[0037] Once the drug is placed in the drug storage lumen 804, any suitable end plug or A closure or thermoformed seal is formed at the first and second ends of the resilient housing 802. 6, 808. These end plugs / closures can be used to seal / close The second material forming part of the elastic housing ensures that this is the only pathway for drug release.

[0038] In certain embodiments, as shown in Figures 8A-8D, the tubular wall structure comprises a second annular a third annular portion integrally formed with and connected to the opposing second end 822 of the segment 814; In one embodiment, the second and third annular segments 8 14, 832 are formed together in an extrusion process. The annular segment 832 is formed entirely of the first material 816 .

[0039] 9A-9B show a variation of the drug delivery device 800 shown in FIGS. 8A-8D. 9A-9B show only a partial longitudinal plan view and a cross-sectional view of device 900. The drug delivery device 900 includes an elongated, resilient housing 902 formed of a tubular wall structure. The wall structure includes a first annular segment 912, a second annular segment 914, and a third annular segment 916. The first annular segment is formed of a first material 916 and includes a first annular segment 932. The second annular segment 914 is formed of a first material 916 and a second material 924, and the third The annular segment 932 is formed from the first material 916 .

[0040] In this embodiment, the second annular segment 914 is positioned on the outer surface of the tubular wall structure 910. The central portion 926 extends between the first surface 928 and the inner surface 930. The second annular segment 914 is formed entirely of the first and third materials 924. It is shown to include a transition region leading to each of the annular segments 912, 932. As such, all of the second material 924 within the second annular segment 914 is disposed inside and adjacent to the tubular wall structure. The outer surfaces 928, 930 do not extend from the ends 918 of 912 and 91 The joint formed by the end of 4, 920, may be angled or straight. obtain.

[0041] In some embodiments, the tubular wall structure is permeable to a second material or drug. For example, in one embodiment, the annular segment includes one or more additional annular segments that include another material. wherein the tubular wall structure is integrally formed with and joined to the opposing second end of the second annular segment. The annular segment has an additional annular segment connected thereto. The tubular wall structure is formed on the opposing side of the second annular segment. In one embodiment including a third annular segment connected to the second end, the tubular wall structure an additional annular segment integrally formed with and connected to the opposing free end of the third annular segment; It has a segment.

[0042] In an alternative embodiment, the absence of the second material may result in one or more of the tubular wall structures The second material of the device is omitted so that an opening is defined. Such openings may be substantially round, square, rectangular, or cutouts. Emission can occur by diffusion through openings or, if small enough, by ionization from the device. Their drug release can occur by osmotic pressure.

[0043] Another embodiment of a drug delivery device is shown in Figures 10A-10D. 1000 includes a drug storage lumen extending between a first end 1006 and a second end 1008. The resilient housing 1002 includes an elongated resilient housing 1002 having a first annular center 1004. The annular wall structure 1010 includes a first annular segment 1012 and a second annular segment 1014. In a preferred embodiment, the first and second annular segments 1012, 1014 are , are formed together in the extrusion process.

[0044] The first annular segment 1012 is configured to accommodate a drug disposed within the drug storage lumen 1004. The first annular segment 1016 is formed entirely of a first material 1016 that is impermeable to the outside. 1012 is integrally formed with and connected to the first end 1020 of the second annular segment 1014. The second annular segment 1014 has a first end 1018 that is spaced apart from the drug storage lumen. The second material 1024 is permeable to the drug and is disposed within the cavity 1004. The drug is then transported in vivo by diffusion through the second material 1024. The second annular segment is formed exclusively of the second material at the center. and a graduated combination of the first and second materials within transition regions at opposing ends around the central portion. The second annular segment, formed in combination, may include a transition region.

[0045] Once the drug is placed in the drug storage lumen 1004, any suitable end plug or A closure or thermoformed seal is formed between the first and second ends 1006 of the elastomeric housing 1002, These end plugs / closures can be used to seal / close the 1008. This ensures that the second material forming part of the flexible housing is the only route for drug release.

[0046] In certain embodiments, as shown in FIGS. 10A-10D, the tubular wall structure 1010 , integrally formed with and connected to the opposing second end 1022 of the second annular segment 1014 In one embodiment, the second and third annular segments 1032 are The annular segments 1014, 1032 are formed together in the extrusion process. In an embodiment, the third annular segment 1032 is formed entirely of the first material 1016. will be done.

[0047] In a variation of the embodiment shown above, a drug-impermeable wall structure (e.g., a first annular cell) a drug-permeable wall structure (e.g., a second annular segment), or a drug reservoir loop. At least one end plug closing the member is provided with an opening or notch. In such embodiments, drug release in vivo is achieved by diffusion (across the wall) and permeation. If the drug has a relatively low solubility, it may penetrate through holes or incisions. However, the contribution of osmotic release through the holes or incisions may not be significant. It can act as a pressure relief valve to prevent unwanted expansion of the extruded housing. can.

[0048] In an embodiment, the length (L) of the second annular segment is equal to the overall length (L) of the elastic housing. T )Yo This beneficially maintains the drug release rates provided by conventional devices. or by increasing the arc angle of the second material without increasing the length of the device. In fact, in certain embodiments, the drug release rate remains low or The overall length of the device can be reduced while still having a reduced drug release rate.

[0049] In one embodiment, the length of the second annular segment is about 5% to about 5% of the length of the elastic body. In another embodiment, the length of the second annular segment is 0% of the length of the elastic body. In one embodiment, the second annular segment relative to the elastic body is about 10% to about 30%. In another embodiment, the ratio of the length of the second elastic body to the length of the elastic body is less than about 0.1. The ratio of the lengths of the annular segments is less than about 0.4. The term "about" in relation to a length refers to the length of the stated value plus or minus 10 percent. In one embodiment, the length of the second annular segment is from about 1 cm to about 8 cm.

[0050] Unless otherwise indicated, as used herein, the length of a particular element is the length of that element. The longitudinal distance such an element extends between its opposing ends. The length of each annular segment is the longitudinal distance between its first end and second end. For example, in one embodiment, the length of the resilient body is such that its opposed first and second ends are is the length between the ends of the

[0051] In the above embodiment, the first material or first wall structure, the second material or first In a preferred embodiment, the drug is A solid form (e.g., tablet or tablets) that allows the drug to be released while in the drug storage lumen. At least a portion of the tubular body is water permeable to allow in vivo solubilization of In an embodiment, the first material or first wall structure is the only water-permeable portion. In other embodiments, both the first and second materials / wall structures may be water permeable. It is also possible.

[0052] The material(s) of the wall structure and / or annular segment of the device of the present invention may be any of a variety of suitable materials. Suitable materials include silicone, polyurethane, ethylene vinyl acetate (EVA), thermoplastics, Plastic silicone polyether polyurethane, aliphatic thermoplastic silicone polyether polyurethane Urethane, segmented polyether polyurethane, thermoplastic polyether polyurethane , thermoplastic polycarbonate polyurethane, Bionate® PCU, Bio Span® SPU, CarboSil® TSPCU, Elasth ane™ TPU, PurSil® TSPU (DSM), aliphatic and aromatic Other thermoplastic polyurethanes (TPUs) containing the hydroxyl group, polycarbonate-based thermoplastic polyurethanes Carbothane™ TPU, Tecoflex™ TPU, Tecothane(TM) TPU, Tecothane(TM) Soft TPU, P ellethane® TPU and Tecophilic™ TPU, etc. and combinations or blends thereof.

[0053] permeable to the second material or wall structure or to the drug contained in the drug reservoir; Other materials include hydrophilic polymers, such as hydrophilic polyurethanes, hydrophilic polyesters, and In one embodiment, the drug-permeable wall structure is a Teco philic (trademark) TPU, HydroThane (trademark) TPU (Advan Sou rce Biomaterials Corp.), Quadraphilic (trademark) TPU (Biomerics, LLC) (ALC grade is an aliphatic polycarbonate type, ALE grade is an aliphatic polyether-based hydrophilic polyurethane, Hydro Med(TM) (AdvanSource Biomaterials Corp.), or Dryflex® (HEXPOLTPE). Another hydrophilic polymer that may form the wall structure(s) is polyether block copolymer. Quamide Pebax® MV 1074 SA 01 MED (Arkema) which is a thermoplastic elastomer made from flexible and hydrophilic polymers and rigid polyamides. It is a lastomer.

[0054] In certain embodiments, the first material and / or the second material or the first wall structure and The wall structure and / or the second wall structure may comprise at least one thermoplastic material. In the present invention, the first material or first wall structure, the second material or second wall structure, or both In certain embodiments, the polyurethane composition may comprise a polyurethane composition such as a thermoplastic polyurethane. The first wall structure / material comprises a first polyurethane composition and the second wall structure / material comprises a first and a second polyurethane composition different from the first polyurethane composition.

[0055] In one embodiment, the first material or first wall structure is Tecoflex™ ( e.g., EG-80A), Tecothane™ Soft (e.g., AR-62A ), Carbothane™ TPU (e.g., AC-4075A and PC-357 5A), or a combination or blend thereof, and The wall structure of the 2 is made of Tecophilic™ TPU (e.g., HP-60D-20, H P-60D-35, HP-60D-60, and HP-93A-100), another hydrophilic TP U, or combinations or blends thereof.

[0056] In one embodiment, the inner diameter of the cylindrical tube may be from about 1.0 mm to about 2.5 mm. In one embodiment, the cylindrical tube has an outer diameter of about 2.0 mm to about 4.1 mm. wherein the thickness of the first wall structure, the second wall structure, or both, is between about 0.2 mm and about 1.0 mm. In certain embodiments, the thickness of the second wall structure is 1 / 2 mm thick. different.

[0057] Therefore, it is necessary to use homogenous materials (e.g., permeable and impermeable) to form a drug-permeable tube. Compared to drug delivery systems using a blend of soluble thermoplastic materials, The mechanical properties of the wall (e.g., in embodiments of the drug-permeable strip) advantageously affect the drug release ( For example, in a single-material tube, the tube material can be separated from the The modification essentially affects both the mechanical and diffusion properties of the device. Additionally, the drug release properties of the blended polymers may not be easily predictable. When mixing two thermoplastics, it can be difficult to obtain a truly homogeneous blend. Therefore, in order to adjust the drug release rate using such a tubular drug delivery system, Experiments are needed.

[0058] For use in the bladder, it is used to prevent or reduce discomfort and irritation to the patient. The device is flexible during muscle contraction (i.e., easily bent and soft to the touch). Therefore, the durometer of the first and second constituent materials is important. Constructing a device enclosure of a given size while maintaining adequate flexibility within the bladder In some cases, the proportion of high durometer material may be limited. For example, Tecophilic (trademark) thermoplastic polyurethane (Lubrizol Corp.) exceeds 70A, For example, it may have a Shore hardness of 80A to 65D, while being compatible with other drug-impermeable thermoplastic polymers. The urethanes may have a lower or higher Shore hardness than Tecophilic™, e.g. Therefore, to achieve the desired mechanical properties of the pipe, it is necessary to swell it with water. Rather than constructing the entire device from a second, hydrophilic, drug-permeable material, two different It may be advantageous to use a combination of polymeric materials.

[0059] In one embodiment, the first material or first wall structure has a Shore A of about 50 A to about 70 A. In one embodiment, the first material or first wall structure has a durometer of 90 In certain embodiments, the second material or the first material has a Shore durometer value of less than 1.0. The wall structure of the two has a Shore durometer value of about 70A to about 65D. and its thickness and wall area, e.g., arc angle, determines a particular drug release profile, i.e., It can be selected to achieve water and drug permeation rates.

[0060] In one embodiment, the first and second materials / wall structures each comprise a thermoplastic polyurethane. The tubular wall structure includes a lumen that is configured to retain the device in a suitable shape for retaining the device within the bladder. The tubular wall structure is elastically deformable to a relatively straight shape suitable for insertion into the bladder through a is thermoformed to have a retaining shape.

[0061] The drug-impermeable portion occupies the majority of the cross-sectional area of ​​the tube and is highly permeable to water. (e.g., Tecoflex EG-80A), in embodiments where the tube has an opening, The contents of the reservoir (e.g., API and excipients) form an osmotic gradient across the wall of the tube To the extent possible, the system should be engineered to release the drug by both diffusion and osmosis. Therefore, the presence of permeable openings may be due to storage conditions that may be caused by osmotic pressure. This may help reduce swelling of the area.

[0062] In a preferred embodiment, the devices described herein release a therapeutically effective amount of a drug. and the drug release rate from the drug delivery device is In one embodiment, the release rate of the drug from the drug delivery device is at least zero order. In embodiments, the device is essentially zero order for at least 7 days. Treatment over a 90-day period, e.g., 7 to 30 days, or 7 to 14 days. The drug delivery device is configured to release an effective amount of the drug. The release rate may be over a period of at least 7 days, e.g., 7 to 14 days or longer. In certain embodiments, the device is, for example, a gap in the inner washer. Due to this, the drug is configured to start releasing after a delay time. The delay time is at least approximately 30 minutes, approximately 12 to 24 hours, or a maximum of approximately 2 days. could be.

[0063] In a preferred embodiment, the drugs are gemcitabine hydrochloride and trospium chloride. In one embodiment, at least 25 mg / day of gemcitabine is released for 7 days. In another embodiment, at least 1 mg / day of trospium chloride is administered for 7 to 10 days. In other embodiments, the compounds described in more detail herein are released over a 3-month period. As such, other drugs may be delivered using the devices described herein.

[0064] Other aspects of the drug delivery device

[0065] The devices and methods disclosed herein are disclosed in U.S. Pat. No. 8,182,464 and U.S. Pat. No. 8,343,516 and U.S. Patent Application Publication No. 2009 / 0149833 (M IT12988); U.S. Patent Application Publication No. 2010 / 0331770 (TB101); U.S. US Patent Application Publication No. 2010 / 0060309 (TB108); US Patent Application Publication No. 20 11 / 0202036 (TB107); U.S. Patent Application Publication No. 2011 / 0152839 No. (TB112); PCT / US11 / 46843 (T filed August 5, 2011) B113); U.S. Application No. 13 / 267,560 filed October 6, 2011 (T B116); and U.S. Application No. 13 / 267,469, filed October 6, 2011 (TB117), each of which is incorporated herein by reference. will be incorporated into

[0066] In certain embodiments, the device is configured for insertion into the bladder and retention within the patient. For example, the device may be configured to have a suitable ratio for insertion through the lumen into a body cavity of a patient. A relatively straight shape and a flexible closure suitable for holding the device within a body cavity, as shown in FIG. 1A. For example, in the retained configuration after placement in the bladder, The device may resist expulsion by the force of urination or other forces. Because they are designed to be retained within a body cavity, they are not compatible with conventional treatments such as those involving the bladder. The devices described herein can overcome some of the deficiencies of the prior art. Once inserted, it releases the drug for a desired period of time without surgery or frequent interventions. As a result, the device may reduce the chance of infection and side effects or may be used locally in the bladder. or may increase the amount of drug delivered locally or to improve patient well-being during the treatment process. After drug release, the device can be removed, for example, with a cystoscope and forceps. The implant may be removable or may be at least partially biodegradable to avoid retrieval procedures.

[0067] The device contains one or more solid drug units, e.g., tablets, capsules, or pellets. The drug may be provided to the patient in one or more solid forms. It is often advantageous to provide a solid drug that is relatively large in relation to the overall volume of the device. The drug can be delivered in a convenient manner during transport, storage, before use, or before drug release. However, the solid drug may be transported through the drug-permeable component. Therefore, it must be solubilizable in vivo to diffuse into the surrounding tissues of a patient in therapeutically effective amounts. It should be.

[0068] The drug storage lumen may hold one or several drug tablets or other solid drug units. In one embodiment, the device contains about 10 to 100 cylindrical drug tablets, e.g., mini The tablets are maintained among a number of individual drug storage lumens. The tablets each have a diameter of about 1.0 to about 3.3 mm, for example, about 1.5 to about 3.1 mm, and It may have a length of about 1.5 to about 4.7 mm, for example, about 2.0 to about 4.5 mm.

[0069] The device may be inserted into the patient using a cystoscope or a catheter. A cystoscope for an adult human has an outer diameter of approximately 5 mm and an inner diameter of approximately 2.4 mm to 2.6 mm. In embodiments, the cystoscope has a larger inner diameter, e.g., 4 mm. The device may have a working channel with an inner diameter of 1 mm or more. For example, if the device is elastically deformed into a relatively straight shape, The patient device has an overall outer diameter of less than about 2.6 mm, for example, about 2.0 mm to about 2.4 mm. For pediatric patients, the dimensions of the device may be, for example, between those of an adult patient and a pediatric patient. may be proportionally smaller based on differences in anatomical size and / or drug dose. In addition to making insertion possible, the relatively small size of the device also allows for easier access to the patient. It can also reduce discomfort and trauma to the bladder for the patient.

[0070] In one embodiment, the overall configuration of the device is such that it is in vivo compatible for most patients. In a specific embodiment, the device is a device as described herein by reference. No. 2011 / 0152839 (TB112), which is incorporated herein by reference. The bladder is configured for tolerability based on the characteristics and design considerations of the bladder.

[0071] Within the three-dimensional space occupied by the device in its holding shape, the device in any direction The maximum dimension of the pouch is preferably less than 10 cm, which is the approximate diameter of the bladder when full. In some embodiments, the largest dimension of the device in any direction is less than about 9 cm; For example, approximately 8cm, 7cm, 6cm, 5cm, 4.5cm, 4cm, 3.5cm, 3cm , 2.5, or even less. The maximum dimension of the device in the cm, 3.5 cm, 3 cm, 2.5 cm, or less. The maximum dimension of the device in any direction is less than about 6 cm, e.g., about 5 cm, 4 0.5cm, 4cm, 3.5cm, 3cm, 2.5cm, or less. Essentially, the three-dimensional space occupied by a device is defined by three perpendicular directions. Along one of these directions, the device has its largest dimension and along the other two directions, Along one direction, the device may have a smaller dimension, e.g., a larger size than in the other two directions. A smaller dimension is less than about 4 cm, e.g., about 3.5 cm, 3 cm, 2.5 cm, or less. In a preferred embodiment, the device is At least one has a dimension of less than 3 cm.

[0072] In some embodiments, the device is In some cases, the surface may have different dimensions in each of the three directions, so Because of this, the device has a non-uniform shape. A reduced compression orientation can be achieved in an empty bladder that is uniform in shape. Due to the specific orientation of the device in the bladder, the device exerts a lower contact pressure against the bladder wall. This allows for a more comfortable experience, making the device more tolerable for patients.

[0073] The overall shape of the device allows the device to change its orientation within the bladder and interact with the bladder wall. It may be possible to reduce that engagement or contact, for example by reducing the overall profile of the device. The device may be curved, and all or most of the outer or exposed surface of the device may be substantially The device may also be substantially free of sharp edges, The surface may be formed from a material that provides reduced frictional engagement with the bladder wall. The device is positioned in an empty bladder so that the device applies a lower contact pressure to the bladder wall. In other words, the device slides or rolls relative to the bladder wall. and choose a lower energy position, i.e., a position where the device is subjected to less compression. It is possible.

[0074] In one embodiment, the device is substantially flat, even though it occupies three-dimensional space. Such a device has a minor axis about which the device is substantially symmetric. , and a major axis that is substantially perpendicular to the minor axis. Not more than 6 cm, and in a specific embodiment, less than 5 cm, e.g., about 4.5 cm , about 4 cm, about 3.5 cm, about 3 cm, or less. The device is no larger than about 4.5 cm along its minor axis, and in a specific embodiment: having a greatest dimension that is less than 4 cm, e.g., about 3.5 cm, about 3 cm, or less; The device may have a diameter of 10 mm or more around substantially its entire circumference in both the long and short axis cross sections. In other words, the overall profile of the device is curved, and the cross section of the device is The shape is rounded. Thus, the device is essentially edgeless, with the exception of There are edges on the two flat ends that hold the device in place when it is placed in a plane. These features ensure that the device is fully protected inside the chair. , allowing it to change direction to be in a position of reduced compression.

[0075] The device can also be small enough in the retained configuration to allow mobility within the bladder. Specifically, when deployed, the device is designed to provide a bladder that is responsive to, for example, most bladder filling conditions. Enough to move within the bladder so that it moves freely or unhindered throughout the bladder The device can be small, facilitating patient tolerance of the device. It also promotes uniform drug delivery throughout the bladder.

[0076] The device may also be used in conjunction with, for example, U.S. Patent Application Publication No. 2004 / 0149994, which is incorporated herein by reference. As described in 12 / 0089121 (TB116), low density configurations for housing components By using materials and / or incorporating gas or gas generating materials into the housing, It may be configured to promote buoyancy. Generally, dry and medicated The device may have a concentration of about 0.5 g / mL to about 1.5 g / mL, for example, about 0.7 g / mL to about 1. In some embodiments, the dry and drug The loaded device has a density of less than 1 g / mL.

[0077] The implantable drug delivery device does not require explantation or retrieval of the device after release of the formulation They can be made to be fully or partially biodegradable, such as In some embodiments, when partial erosion occurs, the device is expelled from the bladder. The device is partially biodegradable so that it breaks down into small enough non-degradable parts. As used herein, the term "biodegradable" refers to a device or part thereof. The portion is in-vivo absorbed by dissolution, enzymatic hydrolysis, erosion, absorption, or a combination thereof. In one embodiment, this degradation refers to the degradation of the intended device. For example, substantial erosion of the device occurs at a time that does not interfere with the drug release kinetics from the formulation. In another embodiment, this cannot occur until the device is substantially or completely released. The device is erodible and the release of the formulation depends on the degradation characteristics or erosion of the erodible device body. The devices described herein are controlled at least in part by the properties of the No. 2012 / 0089122 (TB117), which is incorporated herein by reference. ) can be designed to conform to the characteristics of those described in

[0078] The drug delivery device may be sterilized before being inserted into a patient. The device is sterilized using a suitable process such as gamma irradiation or ethylene oxide sterilization. however, other sterilization processes may be used.

[0079] Retention of the device within the body cavity

[0080] The devices described herein provide a means for delivering a fluid into the patient's bladder (or external body cavity) through a lumen. A relatively straight or non-coiled shape is suitable for insertion and for preventing device insertion into the bladder (or other body cavity). The coil shape is elastically deformable between a holding shape suitable for holding a vice and a coil shape. In some embodiments, the drug delivery device may be naturally repositioned to a retained shape and may be manually repositioned. be transformed manually or with the assistance of an external device into a relatively straight shape for insertion into the body. Once deployed, the device may spontaneously or naturally initiate for retention in the body. It can be restored to its original shape.

[0081] For purposes of this disclosure, the term "retention configuration" generally refers to a configuration that is designed to be in the intended implantation position. This refers to any shape suitable for holding a device in the bladder. , including, but not limited to, a coil shape or a "pretzel" shape as shown in FIG. 1A. Similarly, the term "relatively linear shape" generally refers to a drug delivery device in the body. refers to any shape suitable for placement in a device, such as a catheter positioned in a body lumen, such as the urethra. Suitable for placing the device through the working channel of a bladder, cystoscope, or other placement instrument , including but not limited to, linear or elongated shapes as shown in Figures 7A, 8A, and 10A. It will not be done.

[0082] In some embodiments, the ion exchange membrane shown in FIGS. Thus, the device includes retaining frame lumens 734, 834, 1034 and a retaining frame and a retaining frame (not shown) positioned within the lumen. The frame lumen and the retaining frame are described in U.S. Patent Application Publication No. 2010 / 0331770 ( TB101), U.S. Patent Application Publication No. 2010 / 0060309 (TB108), U.S. Patent U.S. Patent Application Publication No. 2011 / 0202036 (TB107) and U.S. Patent Application Publication No. 20 The composition may be as described in US Pat. No. 11 / 0152839 (TB112).

[0083] In another embodiment, the device may include a protective The retaining frame does not include any lumen or retaining frame or wires. Instead, the housing material but elastically deforms between a straight and a retained shape in the absence of a retaining frame or wire. In such an embodiment, the design and manufacture of the device may It is simplified to minimize the overall size of the device (or the size of the device remains constant) (If the drug load remains the same, the drug load can be increased). Advantageously, the embodiment without a holding frame In this state, the tubular housing material (i) forms a drug storage lumen, (ii) controls drug release, and and (iii) to retain the device within the bladder once placed.

[0084] For example, the tubular housing may be thermally configured to have a retaining shape. Thus, the housing may comprise one or more thermoplastic materials that are suitable for being thermoformed into a holding shape. In certain embodiments, the drug delivery device may comprise at least one thermoplastic a tubular housing having an enclosed drug storage lumen surrounded by a wall structure comprising a material; (i) at least a portion of the wall structure is water permeable and at least a portion of the wall structure is drug permeable. (ii) the tubular housing has a retention shape suitable for retaining the device in the bladder; Elastically deformable to a relatively straight shape suitable for insertion of the device through the lumen into the bladder and (iii) the tubular wall is thermoformed to have the retained shape.

[0085] In certain embodiments, the wall structure comprises first and second wall structures or first and second annular segments. In an embodiment, the first and second wall structures / segments are each made of thermoplastic polyurethane. In one embodiment, the tubular housing is thermoformed to have the retaining shape. prevents the device from assuming a relatively straight shape once implanted in the bladder. The tubular wall properties therefore allow the device to withstand pressure loads. A spring that deforms in response to load but spontaneously returns to its original shape once the load is removed. It can be made to function as such.

[0086] In certain embodiments, the device may naturally assume a retained shape and may be relatively straight. It can be deformed into a mold shape and can naturally return to a retained shape after insertion into the body. The tubular wall structure may be shaped for retention within a body cavity and may have a relatively straight shape. The tubular wall structure is inserted into the body through the working channel of a placement device such as a catheter or cystoscope. To achieve such a result, the tubular wall structure may be shaped to accommodate the The elastic limit, elasticity, was chosen to prevent the vise from becoming relatively thin once implanted. Such a configuration may have a stiffness and / or spring constant that is suitable for withstanding anticipated forces. This may limit or prevent the device from being accidentally expelled from the body. may be retained in the bladder during micturition or detrusor contraction.

[0087] In a preferred embodiment, the device comprises a catheter extending through the patient's urethra. A relatively straight shape that is suitable for insertion through a catheter or cystoscope, and a After releasing the device from the end, it is used to retain the device in the bladder (i.e., during urination). A curved or coiled shape suitable for preventing the device from being expelled from the bladder It is elastically deformable between these.

[0088] As shown in FIG. 1A, the retention shape includes a coil or "pretzel" shape. The pretzel shapes are essentially individual smaller arcs, each with its own unique shape. It comprises at least two partial circular structures sharing a common larger arcuate portion. When the well shape is first compressed, the larger arcuate sections absorb most of the compressive force and begin to deform. However, as compression continues, the smaller arcuate segments overlap, and then all three arcuate segments are compressed. When two partial circles overlap, the overall resistance of the device to compression increases. This prevents the device from collapsing and emptying when the bladder contracts during urination.

[0089] The wall structure of the holding shape can be a two-dimensional structure limited to a plane, or a structure occupying the interior of a spheroid. The holding shape may be a linear or two-dimensional structure, or some combination thereof. connected either radially or radially, bent in the same or alternating directions, overlapping The loop may include one or more overlapping or non-overlapping loops, spirals, or partial circles. The shape may include one or more circles or ellipses that are two-dimensional or three-dimensional in configuration, or the ellipses may be either closed or open, and may have the same or different sizes; They may or may not overlap and are joined at one or more connection points. , a spherical space, a space with a proportional spheroidal shape, or a space with an oblate spheroidal shape Three-dimensional shaped to occupy or wrap around a spheroidal shaped space, such as a space The wall structure of the retaining shape may be configured to occupy or wrap around a spherical space. The wall structure of the retaining shape generally consists of two intersecting walls that lie in different planes. a circle that intersects with another circle, two intersecting circles that lie in different planes with inwardly rounded edges, two intersecting circles that lie in different planes It can take the form of three intersecting circles lying in a plane, or a spherical spiral. Each of these examples In the embodiment, the wall structure can be extended into a linear configuration for deployment by a deployment device. In various other ways, around or through spherical space, or other spheroidal shaped spaces, Examples of alternative configurations are found in U.S. patent applications which are incorporated herein by reference. It is written.

[0090] Advantageously, a thermoformed co-extruded tube having a drug-permeable portion and a drug-impermeable portion is used. The drug delivery device consists of three functional components: drug reservoir / housing, drug permeation pathway, and retention The device design and drug delivery system are integrated into a single thermoformed co-extruded tubing component. As described herein, such devices simplify the ability to control the release rate. In this case, the drug release rate is determined by the angle and thickness of the drug-permeable portion (e.g., strip). This control allows for relatively easy adjustment without changing the entire tube housing material. obtain.

[0091] A thermoformed co-extruded tubular housing may contain a pharmaceutical tablet and has both ends thermally and Adhesive (Tecoflex 1-MP TPU Adhesive, Lubrizol In the event of localized pipe cross-sectional deformation or pipe kinking, Therefore, when thermoforming a tube, the tube dimensions should be adjusted to prevent kinks. Under pure bending conditions, the critical bending of the elastic tube Radius of curvature (R * ) can be approximated using the following formula:

number

[0092] Formulations and solid drug tablets

[0093] The drug storage lumen can store drugs in various forms, including solid, semi-solid, liquid, suspension, gel, etc. In a preferred embodiment, the formulation may contain a dextromethorphan-type steroid, as shown in Figures 1A and 1B. The drug is formed into a solid drug unit 108 that is placed in the drug storage lumen 106 of the device 100 . Each solid drug unit (delivery device typically requires assembly, storage, and handling prior to implantation) and substantially retaining the shape selectively imparted thereto (under the temperature and pressure conditions to which it will be exposed during application). A drug unit is a tablet, capsule, pellet, or bead. The configuration may be in the form of a sphere, but other configurations are possible.

[0094] The solid drug unit can be formed using a stable, scalable manufacturing process. The drug tablet is delivered to the patient's bladder or another cavity, cavity, or tissue site in a minimally invasive manner. The size and shape of the drug delivery device housing that can be placed in the device are suitable for storing and efficiently storing tablets. It has a shape.

[0095] Solid drug units can be produced by direct powder compression or tableting, molding, or other methods known in the pharmaceutical industry. It may be made by other processes known in the art. Suitable methods for forming pharmaceutical tablets are described in detail in the appended claims. U.S. Patent Application Publication No. 2010 / 0330149 (TB102), which is incorporated herein by reference. The formulation may also be placed in a device housing in a processable form, For example, in embodiments where the formulation is configured to melt and solidify, The formulation can be melted, injected into the device housing in molten form, and then allowed to solidify. The formulation may also be extruded with the drug housing and allowed to harden within the housing, after which , at spaced positions along the length of the housing to form segments having an exposed surface area of ​​drug. It may be cut at the position.

[0096] The solid drug unit comprises a formulation, which comprises a drug content and may comprise an excipient content. In a preferred embodiment, the drug content is one or more drugs or active pharmaceutical ingredients (APs). I), while the excipient content includes one or more pharmaceutically acceptable excipients. and are useful for localized delivery to or around a body cavity or lumen. The formulation may include essentially any therapeutic, prophylactic, or diagnostic agent, such as: It may consist solely of the API or may include one or more excipients.

[0097] As used herein, the term "drug" in reference to any particular drug described herein. The term "" refers to its alternative forms, such as salt forms, free acid forms, free base forms, and hydrated forms. The term "excipient" is known in the art and is used in the formulation of the present invention. Representative examples of useful excipients include binders, lubricants, glidants, disintegrants, colorants, fillers, Ingredients such as diluents, coatings, or preservatives, as well as manufacturing, stability, dispersibility, wettability, and and / or other inactive ingredients to enhance release kinetics. The active ingredient may be a small molecule, a macromolecule, a biologic, or a metabolite, among others.

[0098] It is stored in and released from a given drug delivery device of a selected (small) size. To maximize the amount of drug that can be dispensed, the drug unit preferably contains a high weight fraction of drug or or API, and considerations for manufacturing solid drug units and for device assembly and use For purposes of this disclosure, the weight fraction of excipients required is reduced or low. For this purpose, the terms "weight fraction," "weight percent," and "weight percentage" are used in relation to a drug or API. The terms "amount" and "amount" refer to the salt, free acid, free base, or hydrate form of the compound used. For example, a solid drug product with 90% by weight of the drug in salt form. The unit may contain less than 90% by weight of the drug in its organic base form.

[0099] In one embodiment, the solid drug unit is greater than 50% drug by weight. In this case, 75% or more of the weight of the solid drug unit is the drug, and the remaining weight is the composition of the solid drug unit. For the purposes of this disclosure, the term "drug or The term "high weight fraction" in reference to an API means that an excipient constitutes less than 25% by weight of the solid drug unit. less than 20% by weight, more preferably less than 15% by weight, even more preferably In some cases, the drug content may be less than 10% by weight of the solid drug alone. More specifically, the drug content accounts for about 8% or more of the weight of the drug tablet. For example, the drug content may comprise from about 85% to about 99% of the weight of the solid drug unit. In some embodiments, the excipient content may be omitted entirely. Good too.

[0100] In one embodiment, the solid drug unit is solubilized when the device is located in the bladder. The drug and excipients are selected to release solubilized drug, and the solid drug unit is water soluble. It is formulated as follows:

[0101] The individual solid drug units may be of any selected shape that fits within the devices described herein. In one embodiment, the solid drug unit is located within a drug storage lumen within the housing. is of a size and shape such that it is substantially filled with a selected number of solid drug units. Each solid drug unit has a cross-sectional shape that substantially corresponds to the cross-sectional shape of the drug storage lumen of a particular housing. For example, the drug unit may be located within a substantially cylindrical drug storage lumen. Once placed, the solid drug unit may be substantially cylindrical in shape. In some embodiments, the drug storage lumen can be substantially filled, and the drug Forms the housing part.

[0102] In one embodiment, the solid drug units are aligned when the device is in its deployed configuration. For example, each solid drug unit is shaped to fit within the cross section of the drug storage lumen within the housing. and each solid drug unit may have a cross-sectional shape corresponding to the shape of an adjacent solid drug unit. The gaps or crevices between the solid drug units may have an edge shape corresponding to the edge of the solid drug units. The individual drug units can accommodate deformation or movement of the device during placement, while retaining their solid state. The shape is maintained so that each drug unit can be moved relative to adjacent drug units. Therefore, the drug delivery device is relatively flexible or flexible, even though it contains a solid drug. It may be deformable.

[0103] A solid drug unit is delivered to a body lumen or cavity (e.g., the bladder) via a drug delivery device. In embodiments designed for insertion or implantation, the drug unit may be inserted into a natural urethra of the body, such as the urethra. It may also be a "mini-tablet" of a size and shape suitable for insertion through a lumen. Therefore, the term "minitablet" generally refers to a tablet having ends and sides that are substantially cylindrical. Mini-tablets refer to solid drug units that are substantially cylindrical in shape and have a diameter of about 1.0 to about 3.2 mm. The diameter extending along the end surface is, for example, in the range of about 1.5 to about 3.1 mm. The tablets have a diameter ranging from about 1.7 mm to about 4.8 mm, for example, from about 2.0 mm to about 4.5 mm. , and has a length extending along the side. The tablet friability may be less than about 2%. Embodiments of the product units and systems and methods for making same are incorporated herein by reference. Further description is provided below with reference to the incorporated U.S. patents and patent applications.

[0104] In one embodiment, the formulation is in solid form. In another embodiment, the formulation is in emulsion form. The formulation may be in a semi-solid form such as a liquid or suspension, a gel, or a paste. As used herein, solid form may be a highly soluble emulsion or suspension. In one embodiment, the formulation is in liquid form. be.

[0105] The drug may be a low solubility drug. As used herein, "low solubility drug" refers to a drug that is " has a water solubility of about 0.01 mg / mL to about 10 mg / mL at 37°C. In other embodiments, the drug is a highly soluble drug. When used, the term "highly soluble" refers to a compound having an aqueous solubility of greater than about 10 mg / mL at 37°C. For example, the approximate solubility of a particular formulation is: Lidocaine: 500 mg / mL; Lidocaine HCl: 680 mg / mL; Lidocaine base: 8 mg / mL, gemcitabine HCl: 80 mg / mL; gemcitabine base: 15 mg / mL Oxybutynin HCl: 50 mg / mL; Oxybutynin base: 0.012 mg / mL ;and tolterodine tartrate: 12 mg / mL.

[0106] In one embodiment, the drug delivery device is used to treat urinary tract cancers, such as bladder cancer and prostate cancer. Drugs that can be used include antiproliferative agents, cytotoxic agents, chemotherapeutic agents, or other agents. Representative examples of drugs that may be suitable for treating urinary tract cancer include Calmette-Guérin Bacillus Calmette-Guerin (BCG) vaccine, docetaxel, cisplatin, doxorubicin, valrubicin Synth, gemcitabine, mycobacterial cell wall-DNA complex (MCC), methotrexate acetaminophen, vinblastine, thiotepa, mitomycin (e.g., mitomycin C), flucloxacin, Olouracil, leuprolide, diethylstilbestrol, estramustine, methyl acetate Gestrol, cyproterone, flutamide, selective estrogen receptor modulators (i.e. Drugs include steroids (SERMs such as tamoxifen), botulinum toxin, and cyclophosphamide. The drugs may include monoclonal antibodies, TNF inhibitors, antileukins, etc. or an immunomodulatory agent such as a TLR agonist, including imiquimod or another TLR7 agonist. The drug also acts, inter alia, as a fibroblast growth factor receptor-3 (FGFR3)-selective tyrosine kinase inhibitor. kinase inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, or mitogen-activated protein kinase (MAPK) inhibitors, or a combination thereof, etc. Other examples include celecoxib, erolotinib, and the like. ib), gefitinib, paclitaxel, Polyphenon E, valrubicin, neocarcinoma Statins, apaziquone, belinostat, ingenol mebutate, urocidin (MCC ), Proxinium (VB4845), BC819 (BioCa ncell Therapeutics), keyhole limpet hemocyanin, LOR 2040 (Lorus Therapeutics), urocanic acid, OGX427 (O ncoGenex) and SCH721015 (Schering-Plough) Drug treatment may also be combined with traditional radiation or surgical treatments to target cancerous tissue. good.

[0107] In one embodiment, the devices described herein contain anesthetics, analgesics, and The anesthetic agent may be an aminoamide, an aminoester, or a combination thereof. Representative examples of aminoamide or amide type anesthetics include Artica In, bupivacaine, carticaine, cinchocaine, etidocaine, levobupivacaine, Includes lidocaine, mepivacaine, prilocaine, ropivacaine, and trimecaine. Representative examples of aminoester or ester-type anesthetics are amylocaine, benzocaine, Takane, chloroprocaine, cocaine, cyclomethicaine, dimethicane, hexylcaine In, larocaine, meprylcaine, metabutoxycaine, orthocaine, piperocaine , procaine, proparacaine, propoxycaine, proxymetacaine, lysocane, These anesthetics are generally weak bases and are diluted with hydrochloric acid to make them water soluble. Anesthetics may also be used in free base or hydrate form, although they may be formulated as salts such as salts. Other anesthetics, such as lontocaine, may also be used. Also, antimuscarinic compounds that exhibit anesthetic effects, such as oxybutynin or propiverine, Drugs may also be used alone or in combination with local anesthetic agents, such as those described herein. It may also contain a drug.

[0108] In certain embodiments, the analgesic agent comprises an opioid. Representative opioid agonists include: Examples include alfentanil, allylprozine, alphaprozine, anileridine, and benzyl Ibuprofen, bezitramide, buprenorphine, butorphanol, clonitazene, codeine In, desomorphine, dextromoramide, dezocine, diampromide, diamorphone (diamorphone), dihydrocodeine, dihydromorphine, dimenoxadol , Dimepheptanol, Dimethylthiambutene, Dioxaphetyl butyrate, Dipipano thiamin, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etho Etonitazene fentanyl, heroin, hijab Locodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levo Irfanol, levophenacylmorphan, lofentanil, meperidine, meptazinol methadone, methapon, morphine, myrophine, na Lubuphine, Narceine, Nicomorphine, Norlevorphanol, Normethadone, Nalor Fin, normorphine, norpipanone, opium, oxycodone, oxymorphone, papavere Tam, pentazocine, phenadoxone, fenomorphan, phenazocine, fenoperizine phenytoin, piminodine, piritramide, proheptadine, promedol, properidine, propionate ram, propoxyphene, sufentanil, tilidine, tramadol, these pharmaceutical Including acceptable salts and mixtures thereof. μ, κ, δ, and pain opioid receptor activity Other opioid drugs, such as drugs, are contemplated.

[0109] Representative examples of other suitable analgesics include salicylic alcohol, phenazopyridine hydrochloride, acetaminophen, Toxaminophen, acetylsalicylic acid, flufenisal, ibuprofen, indoprofen These include agents such as phenytoin, indomethacin, and naproxen.

[0110] In certain embodiments, the drug delivery device is used to treat interstitial cystitis (IC), radiation cystitis, Treating inflammatory conditions such as cystitis, bladder pain syndrome, prostatitis, urethritis, post-operative pain, and kidney stones Non-limiting examples of specific drugs for these conditions include lidocaine, Glycosaminoglycans (e.g., chondroitin sulfate, sulodexide), pentosan polysaccharides Sodium sulfate (PPS), dimethyl sulfoxide (DMSO), oxybutynin, mycophenolate tomycin C, heparin, flavoxate, ketorolac, cyclosporine or any of their For kidney stones, the drug(s) may be used to treat pain. and / or may be selected to promote the dissolution of kidney stones.

[0111] Other non-limiting examples of drugs that may be used to treat IC include nerve growth factor monoclonal antibody (NGFA) and steroid drug (SEQ ID NO: 1). antibody (MAB) antagonists, such as tanezumab, and calcium channel alpha-2-delta modulators; Examples include PD-299685 or gaben- tin. NGF delivered intravesically to the bladder caused bladder hyperactivity and increased the activity of dissociated bladder afferents. It increases excitability (Nature Rev Neurosci 2008;9 :453-66), evidence suggests that the bladder locally expresses nerve growth factor (NGF). Therefore, the delivery device described can be used to deliver MAB, or N Local delivery of other agents against GFs significantly reduces the total dose required for therapeutic effect. Evidence also supports the α-2-δ unit of voltage-sensitive calcium channels. The combination of acetaminophen with, for example, gabapentin, has been shown to be useful in the treatment of neuropathic pain disorders such as fibromyalgia. It is possible that IC may be effective and that there may be common mechanisms between IC and neuropathic pain disorders. (Tech Urol. 2001 Mar, 7(1):47-49) Therefore, the delivery devices described may be used to administer PD-299685 or Local administration of calcium channel α-2-δ modulators such as gaben- tin Localized delivery of steroids is advantageous in treating IC by minimizing dose-related systemic toxicity. It is possible.

[0112] Other intravesical cancer treatments include apaziquone, adriamycin, AD-32, doxorubicin, Doxetaxel, epirubicin, gemcitabine, HTI-286 (Hemiastrin analogue), idarubicin, gamma-linolenic acid, mitoxantrone, meglum small molecules such as thiamin and thiotepa, EGF-dextran, HPC-doxorubicin, IL-1 2, IFN-α2b, IFN-γ, α-lactalbumin, p53 adenovector, TN Large molecules such as Fα, epirubicin + BCG, IFN + farmarubicin (farmarub icin), doxorubicin + 5-FU (oral), BCG + IFN, and pertussis toxin + bladder Combination of cystectomy, activated cells such as macrophages and T cells, IL-2 and doxycycline Intravesical instillation of sorbicin, BCG + antifibrinolytics olytics) (paramethylbenzoic acid or aminocaproic acid) and doxorubicin + chemotherapy sensitizers such as verapimil, hexylaminolevulinic acid, 5 -Aminolevulinic acid, Iododexyuridine, HM Diagnostic / imaging agents such as FG1Mab+Tc99m, and local toxicity (exposure) of formalin, etc. Includes medications for the management of hemorrhagic cystitis.

[0113] The drug delivery device may be used to treat urinary incontinence, incontinence, or other conditions, including, for example, urge incontinence and neurogenic incontinence. It can be used to treat urinary urgency and trigonitis. Cholinergic agents, antispasmodics, antimuscarinics, beta-2 agonists, alpha-adrenergic agents, anticonvulsants, norepinephrine Pinephrine absorption inhibitors, serotonin absorption inhibitors, calcium channel blockers, potassium channel blockers Representative examples of drugs suitable for treating incontinence include oxybutyric acid, channel openers, and muscle relaxants. Chlamydin, S-oxybutytin, emepronium, verapamil imipramine, flavoxate, atropine, propantheline, tolterodine, Verine, Clenbuterol, Darifenacin, Terodiline, Trospium, Hyoscyamus Hyoscyamin, propiverine, desmopressin, vamicamide, clizimidazole bromide Sodium, Dicyclomine HCl, Glycopyrrolate Amino Alcohol Ester, Ipomoea Bromide Latropium, mepenzolate bromide, methscopolamine bromide, scopolamine hydrobromide, Iotropium bromide, fesoterodine fumarate Salt, YM-46303 (Yamanouchi Co., Japan), lanperisone ( Nippon Kayaku Co., Japan), Inaperisone, NS-21 (Ni ppon Shinyaku Orion, Formenti, Japan / Italy ), NC-1800 (Nippon Chemiphar Co., Japan), ZD -6169 (Zeneca Co., United Kingdom), and styrene iodide Contains stilonium iodide.

[0114] In yet another embodiment, the intravesical drug delivery device of the present invention is Used to treat infections involving the liver, kidneys, and urinary tract. Antibiotic, antibacterial, antifungal Antimicrobials, antiprotozoal agents, antiseptics, antiviral agents and other anti-infective agents are available for the treatment of such infections. Representative examples of drugs for treating infections include mitomycin, ciprofloxacin, and the like. Sacin, norfloxacin, ofloxacin, methanamine, nitrofurantoin, Picillin, amoxicillin, nafcillin, trimethoprim, sulfonamide trimethoprim Musulfamethoxazole, erythromycin, doxycycline, metronidazole, Tetracyclines, kanamycin, penicillins, cephalosporins, and aminoglycosides Includes do.

[0115] In other embodiments, the drug delivery device is administered to a urogenital site such as the bladder or uterus. A representative example of a drug for the treatment of fibrosis is pentoxufulin (p entoxphylline) (xanthine analogue), anti-TNF, anti-TGF, GnRH Analogs, exogenous progestins, antiprogestins, selective estrogen receptor modulators, Dana These include benzodiazepines, benzodiazepines, and NSAIDs.

[0116] Implantable drug delivery devices are also used to treat spastic or flaccid neurogenic bladders. Representative examples of drugs for the treatment of neurogenic bladder include lidocaine, bupivaca pain relievers such as thiamin, mepivacaine, prilocaine, articaine, and ropivacaine; Anesthetics, anticholinergics, antimuscarinics such as oxybutynin or propiverine, capsaicin vanilloids such as acetaminophen or resiniferatoxin, M3 muscarinic acetylcholine receptors Antimuscarinic drugs such as those acting on mAChR, and GABAB agonists such as baclofen Antispasmodics, including botulinum toxin, capsaicin, alpha adrenergic antagonists, anticonvulsants, amitriptyline These include serotonin uptake inhibitors such as liptiline, as well as nerve growth factor antagonists. In the form, the drug is 67-72 (2004), those acting on bladder afferent nerves or efferent nerves. The compound may also have an effect on cholinergic transmission.

[0117] In one embodiment, the drug is used to treat neurological detrusor overactivity and / or detrusor hypotension. These types of urinary incontinence are selected from those known for treating urinary incontinence due to soft tissue. Examples of drugs include bladder relaxants (e.g., oxybutynin (which has significant muscle relaxant and local anesthetic activity) antimuscarinic agents with steroids), propiverine, impratropium, tiotropium, Rospium, terodiline, tolterodine, propantheline, oxyphencyclamine, flavoxate and tricyclic antidepressants, drugs that block the nerves that control the bladder and urethra (e.g. vanilloids (capsaicin, resiniferatoxin), botulinum toxin A), or Medications that modulate detrusor contraction strength, micturition reflex, and detrusor-sphincter dyssynergia (e.g., GABAb In another embodiment, the drug comprises: Selected from those known for the treatment of urinary incontinence due to neurological sphincter deficiency. Examples of these drugs are alpha adrenergic agonists, estrogens, and beta adrenergic agonists. , tricyclic antidepressants (imipramine, amitriptyline). In this case, the drug is selected from those known to promote urination (e.g., alpha-adrenergic receptor antagonist). In yet another embodiment, a renal antagonist (phentolamine) or a cholinergic agonist. , medications include anticholinergics (e.g., dicyclomine), calcium channel blockers (e.g., verapamil), tropane alkaloids (e.g., atropine, scopolamine), Siseptin / orphanin FQ and bethanechol (e.g., m3 muscarinic agonists, The compound is selected from the group consisting of phenyl esters.

[0118] In certain embodiments, the drug is triamcinolone, budesonide, or prednisone. In certain embodiments, the drug is a steroid such as lidocaine, gemcitabine, or the like. docetaxel, carboplatin, cisplatin, oxaliplatin, trospium, Tolterodine, oxybutynin, or mitomycin C.

[0119] Other device features

[0120] The devices described herein may be administered to a healthcare professional as part of a transplant or retrieval procedure. Facilitate detection or visualization of the device by personnel (e.g., X-ray imaging or fluoroscopy) In one embodiment, the device may include at least one radiopaque portion or structure to provide a radiopaque effect. In the present invention, the housing is filled with a radiopaque filler material such as barium sulfate or other fillers known in the art. Some housings are constructed of materials including other radiopaque materials known in the art. During processing of the material from which the housing is made, a radiopaque material such as barium sulfate or another suitable material may be added. It can be made radiopaque by blending transparent fillers. The material may be associated with a retaining frame in embodiments that include a retaining frame. Ultrasound imaging or fluoroscopy is used to image the device in vivo. That's fine.

[0121] The drug delivery device may be, for example, a non-absorbable device after release of the formulation from the solid drug unit. For removal from the body, use a string, loop, or other device to facilitate removal of the device from the body cavity. In some cases, the device may further include retrieval features such as stripping or other structures. The device may be removed from the bladder by having a catheter pull the device through the urethra. The device is located within the lumen of a catheter or cystoscope or within the urethra, depending on the retrieval characteristics. The slit may be configured to assume a relatively narrow or linear shape when pulled.

[0122] Methods of Drug Delivery

[0123] The devices and methods disclosed herein may be used by men or women, adults or children. Regardless of whether it is for use in humans or in animals, such as for veterinary or livestock use, Thus, the term "patient" refers to a human or other mammal. It can refer to the object of something.

[0124] In certain embodiments, a method of administering a drug to a patient includes inserting a drug delivery device into the patient. For example, the device may be a device comprising: In one embodiment, the drug may include any feature or combination of features described above. from the drug storage lumen by diffusion through the second material of the second annular segment of the wall structure. In embodiments where the wall structure comprises a first and a second wall structure, the method further comprises: This involves releasing the drug from the drug reservoir lumen by diffusion through the wall structure.

[0125] In certain embodiments, releasing the drug from the device may be achieved by providing a water-permeable wall portion or This is achieved by absorbing water through the segment (e.g., the second wall structure / second material only). solubilizing the drug through, or through both the first and second wall structures / materials), the second and releasing the solubilized drug from the device by diffusion through the wall structure / material. That is, in certain embodiments, the elution of the drug from the device is determined by the elution of the drug within the device. This occurs after dissolution. Body fluids enter the device, contact the drug, solubilize it, and then dissolve it. The solubilized drug diffuses out of the device. For example, if the device is implanted in the bladder, the drug The drug may be solubilized upon contact with urine. In one embodiment, the drug may be released from the device. is absorbed through the second wall structure / material, or through both the first and second wall structures / materials This involves solubilizing the drug in water.

[0126] In certain embodiments, inserting comprises inserting a catheter through the patient's urethra and into the patient's bladder. The device may be implanted non-surgically, and the implantation procedure may include placing the device in a It can deliver drugs for days, weeks, months, or longer after the drug is stopped. In one embodiment, placing the drug delivery device in the patient is performed through a placement instrument. For example, the device may be inserted into a body cavity or lumen of a patient via a catheter, such as the urethra. a catheter or cystoscope positioned within a natural lumen of the body or a body cavity such as the bladder The deployment device may be removed from the body lumen and The drug delivery device remains within the bladder or other body cavity for a predetermined treatment period.

[0127] The device may, in some embodiments, be used as a standalone procedure or in conjunction with another urological procedure. or in conjunction with other procedures or surgeries, placed into the patient's bladder before, during, or after the other procedure. The device may be used for therapeutic or prophylactic purposes during surgery, after surgery, or both. The pharmaceutical composition may release one or more drugs that are delivered to local and / or regional tissues for therapeutic purposes.

[0128] In one example, the device includes a drug delivery device that is passed through a placement instrument and then delivered from the placement instrument into the body. The device is deployed by releasing the device. When the device is deployed in a body cavity such as the bladder Once the device exits the deployment instrument into the cavity, the device assumes an expanded or bulkier shape. The placement device may be any suitable device, such as a catheter, e.g., a urinary catheter, or a cystoscope. These terms are used throughout this specification unless expressly indicated otherwise. The terms "placement equipment" and "placement device" are used interchangeably in the specification. The placement equipment may be a commercially available device or may be Alternatively, it may be a device specially adapted for use with the drug delivery device of the present invention. In this state, placing a drug delivery device within a patient involves (i) keeping the device relatively straight; (ii) inserting the device through the patient's urethra; and (iii) releasing the device into the patient's bladder so that the device assumes a coiled retention configuration. This includes:

[0129] The drug delivery device may, for example, extend the lumen of the device as the drug delivery device enters the bladder. The catheter may be placed in a position driven by a stylet or a flow of lubricant or other fluid until it emerges. The device may then be passed through the patient's body. The bladder of a male or female human patient in need thereof may be implanted into the bladder of the patient.

[0130] Once placed in vivo, the device may then be used to treat one or more conditions. One or more drugs are delivered locally to one or more tissues at the deployment site and / or The release may be controlled and may be administered in effective amounts over an extended period of time. The device may then be removed, absorbed, or excreted. or some combination thereof. The device is in the bladder for a predetermined period of time, such as 2 weeks, 3 weeks, 4 weeks, 1 month, or more. The drug is released over a period of time.

[0131] Once implanted, the device provides long-term delivery of the desired amount of drug for a desired, predetermined period of time. In embodiments, the device may provide continuous, intermittent, or periodic release. Duration, e.g. 12 hours, 24 hours, 5 days, 7 days, 10 days, 14 days, or 20, The desired dosage for 25, 30, 45, 60, or 90 days or more The rate and dose of drug delivery may vary depending on the drug being delivered and the patient being treated. In one embodiment, the drug delivery device may be selected depending on the disease or condition being treated. In one embodiment, the release rate of the drug is zero order for at least 36 hours. The release rate of the drug from the drug delivery device is essentially zero order over a period of at least 7 days. be.

[0132] The device is used for interstitial cystitis, radiation cystitis, pelvic pain, cystitis, overactive bladder syndrome, bladder Cancer, neurogenic bladder, neuropathic or non-neuropathic bladder sphincter dysfunction, infection, surgery To treat post-natal pain or other diseases, disorders and conditions treated with drugs delivered to the bladder The device can be used to deliver medication locally to the bladder and to other sites near the bladder. The device may release substances that affect the bladder, such as bladder capacity, compliance, and / or frequency of uninhibited contractions. Drugs that improve bladder function, reduce pain and discomfort in the bladder or other nearby areas The drug may deliver a drug that has a specific effect, or a drug that has some other effect, or a combination thereof. The bladder-deployed device also delivers, among other things, a therapeutically effective amount of one or more drugs. , kidneys, urethra, ureters, penis, testes, seminal vesicles, vas deferens, ejaculatory ducts, prostate, vagina, uterus, ovaries, eggs other locations within the body, such as the urinary or reproductive systems, including ducts, or combinations thereof For example, the drug delivery device may be used to treat a number of other diseases, disorders, , and may be used to treat kidney stones or fibrosis, erectile dysfunction, among other conditions.

[0133] In one embodiment, the device contains two drug loads that are released at different times. The first drug load may be adapted for relatively rapid release, while the second drug load may be adapted for relatively rapid release. The loading may be adapted for a more continuous release.

[0134] Later, if the device is non-absorbable or otherwise needs to be removed, etc. The device can be retrieved from the body. Retrieval devices for this purpose are known in the art. The device may also be used to remove urine from the bladder, for example, during urination. Will the entire device be absorbed or will the device degrade sufficiently to be extruded? They are either fully or partially biodegradable, absorbable, or biodegradable so that they do not need to be collected. The device may be absorbent or biodegradable. The drug cannot be recovered or absorbed until most or all of the drug has been released. If so, a new drug-loaded device may be subsequently implanted during or after the same procedure. Good too.

[0135] Device fabrication method

[0136] The devices described herein generally comprise a coaxial cable for forming an elongated, resilient housing for the device. It is formed by using an extrusion process: filling the drug storage lumen with a suitable amount of drug. and sealing the ends of the tubular housing. .

[0137] In embodiments where the drug-permeable portion does not extend along the entire length of the elongate housing, the device The method of making includes extruding a first material by an extrusion process including introducing the first material into an extrusion channel. forming an annular segment integrally connected to one or more second annular segments; in a manner effective to form a tubular structure comprising one or more first annular segments, intermittently introducing a second material into an extrusion channel containing a first material at preselected locations; Specifically, in the second annular segment, the first material is a first arcuate portion. a first material forming a second arcuate portion, a second material forming a second arcuate portion, and the first and second arcuate portions being integral and the first and second annular segments are connected to each other so as to together define an annulus of a second annular segment. The second material is located within the extrusion channel. The method includes cutting the tubular structure at one or more locations to form thin films. forming a long elastic housing; placing a drug in a drug storage lumen; and sealing the first and second ends of the member. The device may have a tubular wall structure as shown in Figures 8A-8D and 9A-9B.

[0138] In another embodiment, a method of making a device includes introducing a first material into an extrusion channel. forming a first annular segment by an extrusion process including: A tubular structure having two or more first annular segments integrally connected to a second annular segment. Interchanging the first material along a selected length of the extrusion flow path in a manner effective to form a structure. To convert the second material into the extrusion channel, a second annular segment is formed by intermittently introducing the second material into the extrusion channel. Specifically, the first annular segment is impermeable to the drug. The annular segment is formed entirely of a first material that is permeable to the drug, and the second annular segment is permeable to the drug. and configured to release the drug in vivo by diffusion through the second material. The term "predominantly" means that any transition region is formed primarily of the second material of the present invention. For purposes of this specification, the second annular segment is meant to be included in the method. cutting the structure at one or more locations to form an elongated elastic housing; and dispensing the drug into the drug storage lumen. and sealing the first and second ends of the housing. With this, the resulting device has a tubular wall structure as shown in Figures 10A-10D. obtain.

[0139] In some embodiments, the tubular wall structure has a retention lumen extending therethrough. The retaining lumen may optionally contain a nitinol wire or other superelastic wire. An elastic retaining frame, such as a suction cup, is then inserted into the lumen. may be sealed and / or optionally filled with a gas (e.g., air), and then The device may be sealed at its ends before or after loading the device with the drug. In this embodiment, the retention lumen is filled with high durometer silicone prior to loading the device with the drug. which may then be effective to bias the tubular wall structure into a coiled bladder-retaining shape. The mixture is hardened to a solid elastic form.

[0140] In another embodiment, the method includes providing a coiled retaining shape that is resiliently deformable to a non-coiled shape. In such an embodiment, the retaining loop includes a thermal configuration that configures the tubular structure to The members and frame may advantageously not be necessary.

[0141] Some steps or sub-steps of the method for making a drug delivery device may be performed in other order. It may be done sequentially or simultaneously.

[0142] The present disclosure may be further understood with reference to the following non-limiting examples.

[0143] Example

[0144] The drug container is thermoformed to have a suitable retention shape for retaining the drug container in the bladder, and Relatively straight, suitable for insertion through the lumen into the bladder without a support frame or wires A thermoplastic material may be used to form the tubular drug housing that is elastically deformable into the shape of Tests were conducted to determine whether aliphatic polyethers in an amount of 50 weight percent Tecoflex™ (EG-80A) (Lubrizol Corp.), and an aliphatic hydrophilic polymer-based thermoplastic polyurethane in an amount of 50 weight percent. Rethan Tecophilic (trademark) (HP-93A-100) (Lubrizol C orp.) was mixed with a 1 / 4" diameter tube having an inner diameter of about 2.16 mm and an inner diameter of about 0. It was formed into a tube with a wall thickness of 81 mm.

[0145] Essentially, each has its own smaller arc and a common larger arc. It has a coil or pretzel-like shape consisting of two partially circular structures sharing a common Bend a tube approximately 15 cm long using a heat plate, heat gun, and wire fixture. Then, a lactose tablet (diameter: about 2.16 mm) was inserted into the mold, which was about 13 cm long. The end was secured by a 2.77 mm (outside diameter) silicone spacer mechanically inserted into the end of the tube. The part was enclosed.

[0146] Degassed deionized water (300 g) was poured into a beaker, the tubing was placed in the beaker, and then Then, the plate was covered with paraffin and placed in a chamber at 37°C.

[0147] In this way, the thermoplastic material (e.g., polyurethane blend) is or to form a tubular drug housing that is thermoformed to have a retaining shape in the absence of a wire. It was concluded that this could be used for

[0148] Separate lengths of tubing were formed according to the method described above, but essentially each was its own smaller It has an arcuate portion and shares a larger arcuate portion in common with adjacent subcircular structures. The hot plate, the heat gun, and the wire were arranged so as to have a multi-coil shape consisting of four partial circular structures. Fixtures were used to bend and thermoform.

[0149] Many variations and other implementations of the disclosure described herein are possible in light of the above teachings and related aspects. It will be apparent that the present disclosure will be of benefit to those skilled in the art having the benefit of the teachings presented in the accompanying drawings. The present invention is not limited to the specific implementations described, and modifications and other implementations are set forth in the appended claims. It is to be understood that all such terms are intended to be within the scope of the present invention. Although they are used in general and descriptive sense only, they are not intended to be restrictive. It is not for the purpose of

Claims

1. An elongated housing comprising a first wall structure and a second wall structure adjacent to each other and together forming a tube that defines a drug storage lumen, A plurality of tablets housed in the drug storage lumen, each containing a drug comprising a kinase inhibitor, The second wall structure, or both the first and second wall structures, are permeable to water. The first wall structure is impermeable to the drug, and the second wall structure is permeable to the drug; therefore, the drug can be released by diffusion through the second wall structure. The second wall structure has an arc angle of 10 to 170 degrees on the outer circumference of the cross-section of the pipe, The first wall structure is formed of a first thermoplastic polyurethane composition, which includes a polycarbonate-based thermoplastic polyurethane. An intravesical drug delivery device wherein the second wall structure is formed of a second thermoplastic polyurethane composition different from the first thermoplastic polyurethane composition.

2. The intravesical drug delivery device according to claim 1, wherein the first thermoplastic polyurethane composition has a Shore durometer value of less than 90 A, and the second thermoplastic polyurethane composition has a Shore durometer value of more than 70 A.

3. The intravesical drug delivery device according to claim 1, wherein the polycarbonate-based thermoplastic polyurethane is Carbothane® AC-4075A.

4. The intravesical drug delivery device according to claim 1, configured to be elastically deformable from a coiled retaining shape suitable for holding the device in the patient's bladder to a non-coiled shape suitable for insertion through the patient's urethra and into the bladder.

5. The coil-type holding shape has at least one with a radius of curvature of at least 0.5 cm The intravesical drug delivery device according to claim 4, comprising a loop.

6. The intravesical drug delivery device according to claim 1, further comprising a retaining frame lumen and an elastic retaining frame positioned within the retaining frame lumen.

7. The intrabladder drug delivery device according to claim 6, wherein the elastic retaining frame includes a nitinol wire.

8. The intravesical drug delivery device according to any one of claims 1 to 7, wherein the kinase inhibitor comprises a fibroblast growth factor receptor-3 (FGFR3)-selective tyrosine kinase inhibitor.

Images