RU2809797C2 - Method of treating a patient with idiopathic overactive bladder and urinary incontinence (options) - Google Patents

Abstract

FIELD: medicine; urology.

SUBSTANCE: group of inventions can be used to treat idiopathic overactive bladder (iOAB) and urinary incontinence. The methods of the invention involve local administration of 5 to 24 mg/day of trospium into the patient's bladder continuously over a treatment period of 30 to 84 days via a drug delivery device placed in the patient's bladder.

EFFECT: use of inventions makes it possible to achieve improvements in drug delivery systems for the treatment of patients with iOAB and urinary incontinence.

10 cl, 4 tbl, 31 dwg, 5 ex

Description

Cross references to related applications

[1] This application claims benefit to U.S. Provisional Patent Applications No. 62/453,333, filed February 1, 2017, and No. 62/480,744, filed April 3, 2017, the contents of which are incorporated herein by reference in their entirety.

State of the art

[2] This description of the invention relates generally to medical devices that are used in vivo for the controlled delivery of a drug, and also, in particular, to such devices that include a section with a permeable wall, as well as one or more mechanisms for ensuring a controlled rate of release of drugs from such a device.

[3] Many currently available drug delivery devices operate by employing one or more diaphragms in the side wall or end of the device to release the drug therefrom. However, these types of diaphragms, especially those located in the side wall of the device, may be susceptible to buildup and occlusion after insertion of the drug delivery device into the patient's body. Having a blocked diaphragm is undesirable because it often results in less reproducible drug release or may prevent drug release altogether. In addition, diaphragms located at the ends of the device ensure that drug is released only through the end section of the device, which may not be desirable for all device configurations and dosage forms.

[4] In other cases, the drug delivery device may not have a special diaphragm for releasing drugs and their release is controlled by diffusion from a particular matrix material (binder) and/or through the wall delimiting the drug reservoir. However, such configurations that rely on diffusion may limit the drug release kinetics that can be achieved and/or may limit the range of materials suitable for creating such devices to materials that do not have the desired parameters of biocompatibility, stability, sterilability and mechanical properties, including manufacturability, creation of the desired wall thickness, flexibility, etc.

[5] Thus, there is a need to provide a drug delivery device that does not have one or more of these disadvantages. In addition, there is a need to develop more advanced drug delivery methods and systems for the treatment of patients with idiopathic overactive bladder and urinary incontinence, as well as patients with neurogenic overactivity of the detrusor muscle due to spinal cord injury. Disclosure of the Invention

[6] In one aspect, a method is provided for treating a patient who is in need of treatment for idiopathic overactive bladder (iOAB) and urinary incontinence, the method comprising locally administering 2 to 30 mg/day of trospium into the patient's bladder continuously for a period of treatment. lasting from 30 to 84 days by means of a drug delivery device located in the patient's bladder and including a housing that has a wall defining a reservoir that is located inside the housing, this wall having at least one pre-formed through hole, and also a water-permeable section, wherein the body includes an elastic section; a dosage form that includes trospium and is located inside the reservoir; and at least one limiting plug that covers the housing opening and contacts the resilient housing section, the opening providing a fluid communication path with the reservoir, in which the water-permeable wall section is configured to allow water to enter the drug delivery device and contact with dosage form located in a reservoir in which the release of trospium from this device is controlled by (i) the release of trospium through at least one pre-made through hole in the wall, and also (ii) the release of trospium through a transition system of one or more microchannels between the elastic section of the housing and at least one restriction plug extending into said opening until the reservoir reaches hydrostatic pressure sufficient to form one or more microchannels.

[7] In another aspect, a method is provided for treating a patient who is in need of treatment for idiopathic overactive bladder (iOAB) and urinary incontinence, the method comprising locally administering 2 to 30 mg/day of trospium into the patient's bladder continuously for a period of treatment. lasting from 30 to 84 days by means of a drug delivery device placed in the patient's bladder and including a tubular-shaped body that has a wall defining a reservoir that is located inside the body, a wall having a water-permeable section, and an elastic section having at least one pre-formed drug release channel located within this section; a dosage form that includes trospium and is placed within the reservoir, within which a water-permeable wall section allows water to pass into the drug delivery device and contact the dosage form contained in the reservoir; and at least one restriction plug mounted within the reservoir in contact with the elastic section of the housing and in proximity to at least one preformed drug release channel such that the at least one restriction plug controls the release of trospium from such device through at least one one preformed drug release channel by a transition system of one or more microchannels between the elastic section of the housing and at least one limiting plug included in at least one preformed drug release channel, until the reservoir reaches a hydrostatic pressure sufficient to form one or more microchannels.

[8] Methods of administering a drug to a patient using one of the above-described devices are also described, including by introducing a drug delivery device into a passageway or body cavity of the patient; and by causing the flow of water into the reservoir to raise the pressure in the reservoir to a level sufficient to cause the medicinal product to flow from the reservoir and the device and introduce it into the passageway or body cavity of the patient.

[9] Also described is a method of treating a patient who requires treatment for neurogenic detrusor overactivity (NDO) resulting from spinal cord injury (SCI), including by locally administering an effective amount of trospium into the patient's bladder continuously throughout the treatment period ( lasting from 30 to 60 days).

[10] In addition, a method is described for treating a patient who requires relief from idiopathic overactive bladder (iOAB) and urinary incontinence by locally administering an effective amount of trospium into the patient's bladder continuously over a treatment period of 30 to 60 days.

Brief description of graphic materials

[11] Let us now turn to graphic materials, which should be taken as illustrative, not restrictive, and in which the same components have the same numbering. The following is a detailed description, together with references to illustrative examples of the accompanying graphics, in which the use of the same reference symbols indicates similar or identical components. Some embodiments of the present invention may include elements, components and/or configurations different from those shown in the drawings, with some of those elements, components and/or configurations shown in the drawings in some embodiments may be missing.

[12] FIG. 1A is a cross-sectional side view of one embodiment of a resilient section of the device including a restrictive end plug.

[13] FIG. 1B is a cross-sectional end view of an embodiment of the device in accordance with FIG. 1A.

[14] FIG. 1C is a cross-sectional side view of the device according to FIG. 1A, in which the reservoir is not under osmotic pressure.

[15] FIG. 1D is a cross-sectional side view of the device according to FIG. 1A, in which the reservoir is under osmotic pressure.

[16] FIG. 2 is a cross-sectional side view of one embodiment of the device having a preformed diaphragm in the side wall and two limiting end plugs.

[17] FIG. 3A is a top view of one embodiment of the device having a preformed diaphragm in the side wall and two limiting end plugs.

[18] FIG. 3B is an enlarged cross-sectional view of one of the end plugs in accordance with FIG. 3A.

[19] FIG. 3C is an expanded perspective view of the end plug according to FIG. ZV.

[20] FIG. 4 is a cross-sectional end view of one embodiment of a drug delivery device.

[21] FIG. 5 illustrates various embodiments of restriction plugs in accordance with this specification.

[22] FIG. 6 is a cross-sectional view illustrating the restriction plugs according to FIG. 5 in the case of their use as end plugs of a drug delivery device.

[23] FIG. 7 illustrates the procedure for using a device to deliver a drug from a special device for deploying the device.

[24] FIG. 8 illustrates the use of the device for delivering a drug to a patient's body.

[25] FIG. 9A is a top view of one embodiment of a drug delivery device having restriction plugs and a preformed drug release channel.

[26] FIG. 9B is an enlarged cross-sectional view of the device in accordance with FIG. 9A.

[27] FIG. 10A is a plan view of one embodiment of a drug delivery device having restriction plugs and a preformed drug release channel.

[28] FIG. 10B is an enlarged cross-sectional view of the device in accordance with FIG. 10A.

[29] FIG. 11 is a graph showing the drug release rate from the drug delivery device that was tested in the Examples described below.

[30] FIG. 12 is a graph showing the drug release rate from the drug delivery device that was tested in the Examples.

[31] FIG. 13 is a graph showing the drug release rate from the drug delivery device that was tested in the Examples.

[32] FIG. 14 is a graph showing the drug release rate from various drug delivery devices that were tested in the Examples.

[33] FIG. 15 is a graph showing the cumulative drug release rate from various drug delivery devices that were tested in the Examples.

[34] FIG. 16 is a graph showing the drug release rate from various drug delivery devices that were tested in the Examples.

[35] FIG. 17 is a graph showing the cumulative drug release rate from various drug delivery devices that were tested in the Examples.

[36] FIG. 18 is a graph showing the drug release rate from various drug delivery devices that were tested in the Examples.

[37] FIG. 19 is a graph showing the drug release rate from various drug delivery devices that were tested in the Examples.

[38] FIG. 20 is a graph showing the drug release rate from various drug delivery devices that were tested in the Examples.

[39] FIG. 21 is a graph showing the drug release rate from various drug delivery devices that were tested in the Examples.

[40] FIG. 22 is a graph showing the cumulative drug release rate from various drug delivery devices that were tested in the Examples.

[41] FIG. 23 is a graph showing the relative percent drug release rate from various drug delivery devices that were tested in the Examples.

[42] FIG. 24 is a graph showing the drug release rate from various drug delivery devices that were tested in the Examples.

Detailed Description of the Invention

[43] This disclosure provides drug delivery devices 50 having a section with a water-permeable wall 64 defining a reservoir 60 (also referred to herein as a "reservoir channel" or a "drug reservoir channel") containing the beneficial agent. a payload 58, such as a dosage form, as well as methods for delivering that payload 58 from the device 50. As shown in FIG. 2, the permeable wall section 64 may generally be configured to allow water to pass into the device and contact the dosage form (i.e., payload) 58 contained in the reservoir 60 to promote release of the drug. means 58 from the device. For example, the influx of water into reservoir 60 under osmotic pressure may create a pressure within reservoir 60 that causes drug 58 to be released from reservoir 60 through one or more mechanisms. For example, in those embodiments described in this section, release of drug 58 from the device may occur through one or more diaphragms 66 preformed in the side wall (see FIG. 2) and/or through a transition system that consists of one or more microchannels 62 leading into a preformed drug release channel 68 or other opening (see FIG. 9). In some embodiments described herein, various combinations of these release mechanisms are used to provide the desired parameters of the drug release process, as well as to overcome the disadvantages that have been found in those devices that provide drug release solely through one or more pre-made diaphragms.

[44] In particular, implantable intravesical drug delivery devices that have pre-formed diaphragms in the side or end walls of the device used to release drugs from the device have been found to be susceptible to layering and clogging of the diaphragms following intravesical use or implantation. As a result, in some embodiments of the invention, as shown in FIG. 2, drug delivery devices 50 of the present invention include one or more preformed diaphragms 66 in the side wall or end of the device in combination with a one-way valve design including a transition system consisting of one or more microchannels 62 that connected to a preformed drug release channel or other opening until a hydrostatic pressure is achieved sufficient to form one or more microchannels in the reservoir 60. For example, the creation of a hydrostatic pressure in the reservoir 60 that exceeds the critical pressure for the transition microchannel system 62 can occur when the preformed diaphragm(s) 66 is partially or completely occluded or when release through the diaphragm(s) 66 does not occur quickly enough to relieve hydrostatic pressure within the reservoir 60. In some embodiments, such as this is shown in FIG. 9 and 10, a preformed drug release channel 68 is provided in the side wall or end of the device in combination with a restriction plug 56 that blocks access to the drug release channel 68, thereby preventing the creation of hydrostatic pressure in the reservoir sufficient to form one or more microchannels 62 that connect to the drug release channel 68.

[45] It has been found that controlled release of drugs can be achieved using devices having improved one-way valve release mechanisms, used alone or in combination with other release mechanisms. For example, controlled release of drugs can be achieved using a transition system of microchannels through which liquid drug can be withdrawn from the drug delivery device. Microchannels are formed in the contact area of the device components due to the increase in hydrostatic pressure that is created in the reservoir with the drug. Drug delivery devices have been developed that are configured to form and utilize microchannels (i.e., channels other than those pre-formed in the walls of diaphragms) that prevent or mitigate potential problems associated with conventional mechanisms for drug release, including , with precision miniature diaphragms, which can increase the cost of the component and the risk of clogging (or with conventional mechanisms, which are limited in the case of diffusion through or from another material).

[46] In embodiments of the invention, drug delivery device 50 includes a device body 52 that has at least one section with a permeable wall 64 defining a drug reservoir 60 that is located within the body 52. Dosage form 58. which includes the drug, is loaded into the drug reservoir 60. The housing 52 includes a resilient section 54 that is connected by a fluid transfer channel to the drug reservoir 60. Device 50 further includes a restriction plug 56 that contacts resilient section 54 of housing 52 and controls release of drug 58 from device 50 through a transition system consisting of one or more microchannels 62 between resilient section 54 of housing 52 and at least one limiting plug 56.

[47] The term "microchannels" as used herein refers to a passageway or system of passageways through which drugs can exit the device described herein. In embodiments of the invention, the microchannels are formed as a result of an increase in hydrostatic pressure in the water-permeable body due to the influx of water under the influence of osmotic pressure; moreover, in the case when the hydrostatic pressure begins to exceed a certain critical value, microchannels are formed, thereby ensuring the forced withdrawal of at least part of the drug from the device and releasing the accumulated hydrostatic pressure into the reservoir with the drug. As hydrostatic pressure is released, the microchannel may be at least partially compressed. This process is repeated until all or a significant portion of the drug is released from the device, or until the influx of water under osmotic pressure is insufficient to continue this process.

[48] Microchannels can form anywhere on the inner surface of the elastic section of the permeable body, thereby significantly reducing the likelihood of complete occlusion (even in cases where insoluble excipients are present in the dosage form). This has the advantage that microchannels (as opposed to a diaphragm) can reduce or eliminate the possible risk of sudden release of drug if the device is compressed or deformed. For example, in cases where drug delivery devices are surrounded by body fluid and are located in an environment that exposes the devices to moderate external mechanical stress (for example, during urination, when such a device is used as a drug delivery device to the bladder) , drugs are much less likely to be released through microchannels.

[49] FIG. 1A-1D show one embodiment of microchannels in a drug delivery device. The device 50 includes a housing or outer shell 52 having a resilient section 54 with a restriction plug 56 inserted into an opening in the housing 52 such that the elastic section 54 is located opposite (around) the outer surface of the restrictive plug 56. As indicated by the dotted line arrows. , water diffuses through the permeable wall 64 of the housing 52 and enters the drug reservoir 60 to form a liquid drug 58, which, for example, may be an aqueous solution containing the drug 58 that was originally loaded into the reservoir 60. Hydrostatic pressure in the reservoir 60 forces the liquid drug 58 from the reservoir 60 between the elastic section 54 and the restriction plug 56 through microchannels 62 that are formed between them, for example, due to elastic deformation of one or both of the mating surfaces. FIG. 1C shows such a device in a state in which the hydrostatic pressure in the reservoir has not reached a critical value such that no microchannels are formed between the elastic section 54 and the restriction plug 56. In the embodiment of the invention shown in FIG. 1A, 1B and 1D, a microchannel 62 is shown that is formed between the reservoir 60 and the terminal (prefabricated) opening 72 of the device 50; however, as described below, in some embodiments, the device 50 is configured such that a microchannel 62 is formed between the reservoir 60 and the drug release channel 68 in the side wall or closed end wall of the device.

[50] The devices, systems and methods described herein are based on certain features and variations of those devices, systems and methods described in the following published patent applications: US 2016/0199544 (authors: Lee et al. / Lee et al. ); USA 2012/0089122 (authors: Lee et al.); USA 2012/0089121 (authors: Lee et al.); USA 2011/0152839 (authors: Cima et al.); USA 2010/0331770 (authors: Lee et al.); USA 2010/0330149 (authors: Daniel et al.); USA 2009/0149833 (authors: Cima et al.); and US 2007/0202151 (authors: Lee et al.), which are incorporated herein by reference where appropriate.

[51] Drug delivery device

[52] An embodiment of a drug delivery device is shown in FIG. 3 and 4. The device includes a water-permeable housing 52 having a medicament reservoir section 78 and a holding frame section 76. As used herein, the term “drug reservoir section” refers to that section of the device that defines the “drug reservoir” or “drug reservoir channel.” These terms are used to refer to the same or similar and overlapping features of devices. In FIG. 3A, device 50 is shown in a relatively expanded form that is suitable for retention in a patient's body, such as the bladder. As shown in FIG. 7, device 700 may also be shaped with a relatively lower profile for use through a channel of a special device 702, such as a cystoscope or other catheter. Once inserted into the body, the device may assume a relatively expanded shape to support the drug delivery device in the bladder or other cavity or passageway of the body.

[53] In some embodiments, the intravesical device includes a mold for deploying the device and a mold for holding the device. For example, as shown in FIG. 7, the device 700 can be elastically deformed from a relatively straight or untwisted shape that is designed to be inserted through a passageway into the patient's bladder (an deployment shape) to a retention shape that is designed to retain the device within the bladder. As used herein, the term "retention mold" generally refers to any shape that is designed to retain a device in the bladder, including but not limited to, the term refers to a coiled or "ring" shape. curl." The curl shape is shown in FIG. 3A. The retention form enables the device to resist entrainment in the flow of urine and its removal from the body when the patient empties the bladder. The terms "relatively extended form" and "relatively tall form" can be used interchangeably with the term "holding form". Likewise, the term “relatively lower profile mold” can be used interchangeably with the term “device deployment mold,” and generally these terms refer to any mold that is designed to accommodate a drug delivery device in the body of a patient, including including the linear or elongated shape shown in FIG. 7, that is, a form that is intended to accommodate the device in the body through the working channel of a catheter, cystoscope or other device for deploying the device, which is located in a particular passageway in the patient's body, for example, in the urethra. In other embodiments, the drug delivery device may naturally assume a relatively expanded shape and may be elastically deformed (either manually or by some external device) into a relatively lower profile shape for insertion into the body. Once deployed into its operative form, the device may spontaneously or naturally (eg, elastically) return to its original shape, a relatively expanded form to support the device in the body. In some embodiments, the device behaves like a spring that has been deformed by the application of a compressive load (eg, by deforming the device to force it into shape for deployment) but that spontaneously returns to shape to hold the device when the load is removed. In some embodiments, it is proposed that this form may modify the functionality of the intravesical device, including by using it in the form of a holding frame (ie, simply a "holding frame") in the device, as described below.

[54] In the embodiment of the invention which is shown in FIG. 4, the drug reservoir section 78 and the drug delivery device frame holding section 76 are longitudinally oriented and connected to each other (or integrally formed) along their entire length, although other configurations are possible. For example, the drug reservoir section 7-8 may be attached to the frame holding section 76 at separate points, but in other embodiments the reservoir section may be separated from or spaced apart from the frame holding section 76.

[55] As shown in FIG. 4, the drug delivery device includes a resilient or flexible device body 52, which thereby defines a drug reservoir channel 60 and a frame holding passage channel 80. The drug reservoir channel 60 is configured to accommodate a dosage form, such as a quantity of drug solid tablets 158, and to create a drug reservoir section 78. The frame holding passageway 80 is designed to accommodate the holding frame 74 and to create a frame holding section 7 6 . The passage openings of the sections 78, 76 shown in the respective figures are separated from each other, although other configurations are possible.

[56] As shown in the cross-sectional view of FIG. 4, the device body 52 includes a tube or wall 82 that defines a channel of the drug reservoir 60 and a tube or wall 84 that defines a passageway 80 supporting the frame. The tubes 82, 84 and passageways 60, 80 may have a substantially cylindrical shape that mates with the bore of the drug reservoir 60, these tubes and openings having a relatively larger diameter than the frame supporting passageway 80, although other options may also be selected. other configurations based on, for example, the amount of drug to be delivered, the diameter of the holding frame, and also based on the conditions of practical use, for example, the inner diameter of the device for deploying the device. The body of the device 52 can be structurally constructed as a single unit, for example, by pressing or extrusion, although a separate design of the tubes 82, 8 4 and their separate installation is also possible. The wall 84 that defines the frame holding passageway 80 may extend the entire length of the wall 82 that defines the medicament reservoir channel 60 such that the frame holding passageway 80 is the same length as the reservoir channel 60. drug, as shown in the corresponding figures, although in other embodiments of the invention one wall may be shorter than the other wall. In addition, two walls 82, 84 are fixed along the entire length of the device, as shown in the embodiment of the invention shown in this figure, although intermittent fastening may be used. In one embodiment, the channel wall 82 of the drug reservoir 60 has an internal diameter of approximately 1.5 mm and an external diameter of approximately 1.9 mm, and the wall 84 of the frame holding passageway 80 has an internal diameter of approximately 0 .5 mm and an outer diameter of approximately 0.9 mm. In another embodiment, the channel wall 82 of the drug reservoir 60 has an internal diameter of approximately 2.16 mm and an external diameter of approximately 2.56 mm. However, the inner and outer diameters of the wall 82 of the drug reservoir channel 60 and the wall 84 of the frame holding passageway 80 may be any value suitable for the respective configuration. The cross-sectional area of the entire body of device 52 may be approximately 0.035 cm ² or less. However, the cross-sectional area of the entire body of device 52 may be any suitable value.

[57] As shown in FIG. 3A, the drug reservoir channel may be filled with a number of individual drug fragments 158 in a sequential arrangement. The drug fragments can be in the form of tablets, for example, in the form of mini-tablets. For example, it is possible to load from about 10 to about 100 drug fragments, for example from about 30 to about 70 drug fragments, or more specifically from about 50 to 60 drug fragments. However, virtually any number of individual drug fragments can be used depending on the size of the reservoir and the size of the drug fragments. The drug reservoir channel includes openings, which may be relatively circular holes, at opposite ends of the drug reservoir channel. These openings provide access for those drug fragments that must be placed in the channel of the drug reservoir during loading and assembly of the device.

[58] Restriction plugs, as defined herein, may be installed into the reservoir through the end openings of the device. The restriction plug and elastic section can be installed in any appropriate position along the entire length of the drug delivery device. In some embodiments, as defined herein, the restriction plug may be located at or near the end of the device. In other embodiments, the restriction plug may be located in or adjacent to the central section of the device. In one embodiment of the invention, one of the end openings of the device has a limiting plug, and the opposite opening is sealed with a plug or other material that does not allow the formation of microchannels.

[59] In some examples, as shown in FIG. 1C and 1D, each of the restriction plugs 56 may, as defined herein, have an outer diameter that is greater than the inner diameter of the bore of the drug reservoir 60. In some embodiments of the invention as shown in FIG. 9A and 10A, restriction plugs 56 may be secured within the channel of the drug reservoir 60 at the ends of the device 50 such that the ends or openings of the device 50 are sealed, for example, with an adhesive 70 or other suitable fastening device. In other embodiments of the invention, as shown in FIG. 1C-1D, the restriction plugs 56 may be secured within the channel of the drug reservoir 60 by the adhesive 70, but not provide a seal to the passage opening. In other embodiments, the restriction plugs may be secured within the drug reservoir channel by some external clamping device located adjacent to the drug reservoir channel. The restriction plugs may be secured within the drug reservoir channel using any of the devices described herein, or a combination of such devices, as long as they provide the desired microchannel formation.

[60] In some embodiments, each of the containment plugs may include a cavity for receiving an end portion of the containment frame. In other cases, a number of limiting plugs may be installed in holes or other positions along the length of the device. Restriction plugs can be made in the form of silicone plugs, ethylene vinyl acetate plugs, or a combination of such devices. In those embodiments in which one of the restriction plugs is missing, the hole without the restriction plug is closed using any other suitable biocompatible material. In one embodiment of the invention, such material is an adhesive substance, which is placed in the channel of the reservoir with the medicinal product in an usable form and which hardens therein. In some embodiments, the restriction plug is inserted into the opening of the drug reservoir channel and the second opening of the drug reservoir channel is sealed with an adhesive. In other embodiments, both ends of the drug reservoir may be sealed, and one or more restriction plugs may be positioned within the device adjacent to or away from the sealed ends.

[61] As shown in FIG. 4, the passage channel 80 holding the frame is filled with material using the holding frame 74, which can be made in the form of an elastic wire. The holding frame 74 may be configured to spontaneously return to its original form for holding the device, such as the exemplary "swirl" shape shown in the respective figures, or any other swirling shape, such as those described in those above published patent applications and which are incorporated herein by reference. In particular, the holding frame 74 may support the device in a body, such as the bladder. For example, the holding frame 74 may have an elastic limit and elastic modulus that allow the device 50 to be inserted into the body in a relatively lower profile shape, allow the device to return to a relatively expanded shape once inserted into the body, and prevent the device from adopting a relatively lower profile shape. within the body in response to the perceived impact of various forces, for example, hydrodynamic forces associated with detrusor contraction and urination. As a result, once the device is deployed, it can be retained in the body, limiting or preventing the possibility of it being accidentally pushed out of the body.

[62] The material that is used to create the body of the device 52 may be an elastic or flexible material (at least in part) that allows the device to transform from a form for deploying the device to a form for holding the device in the body. When the device is in the holding form, the holding frame section 76 may tend to be stacked on the inside of the medicament reservoir section 78, although in other cases the holding frame section 76 may be mounted inside, outside, above, or below the medicinal reservoir section 78. drug reservoir. In addition, at least a portion of the material used to construct the body of the device 52 is a permeable material such that a solubilizing fluid (e.g., urine or other bodily fluid) can penetrate into the drug reservoir 60 to to dissolve drug fragments 158 after deployment of the device. For example, silicone and ethylene vinyl acetate (EVA) materials, thermoplastic polyurethanes, or other biocompatible elastomeric material can be used to create the body of the device.

[63] In one embodiment of the invention, wherein the drug delivery device is intended for insertion into the bladder, the device being designed to be inserted into (and, if necessary, removed from) the bladder through urethra cystoscopically. As a result, the device may be sized and shaped such that it can pass through a narrow tubular channel of some special deployment device, such as a catheter or cystoscope.

[64] The exact configuration and shape of the drug delivery device may be selected depending on a number of factors, including the specific point of deployment and use of the device, the route of administration of the device, the drug and its dosage regimen, and use of the device for therapeutic purposes. The device design can minimize patient pain and discomfort by providing precise local delivery of a therapeutically effective dose of drug to a specific tissue point (eg, urothelial tissue) in the patient's body.

[65] Device body/medicine reservoir section

[66] As shown in FIG. 1-3, 9, and 10, the drug delivery device 50 has a housing 52, such as an outer shell, which contains a drug reservoir 60 having a water-permeable wall 64, and which also includes an elastic section 54 for mounting one or more limiting plugs 56. The drug reservoir 60 is at least partially defined by a water-permeable wall 64. That is, such a device includes a "water-permeable body", which (as the phrase is sometimes used herein) includes any structure , at least part of which is permeable to water. In other embodiments, the water-permeable body is made entirely of water-permeable material. In other embodiments, the water-permeable body is made of a water-permeable material as well as a water-impermeable material. In other embodiments, the water-permeable body is made of a material that has at least one water-permeable section as well as at least one water-impermeable section. As used herein, a wall or material is “permeable” when it allows liquid to enter the drug delivery device, for example, by diffusion through the wall and its subsequent contact with the dosage form, which is located in a reservoir within the body of the device.

[67] In addition, the body 52 of the drug delivery device 50 that is described herein includes at least one resilient section 54. The resilient section 54 of the device body 52 may be the same as the water-permeable body section 64 of the device 52 , which is described in the previous paragraph, or it may differ from it. In some embodiments of the invention, as shown in FIG. 1A, the restriction plugs 5-6 engage at least one resilient section 54 of the body of the device 52 to tightly close the housing opening, which opening defines a channel for moving liquid into the drug reservoir 60 within the device, thereby closing the drug agent 58 inside drug reservoir 60.

[68] In some embodiments, all of the resilient sections of the device body are in contact with restrictive plugs that release the drug in a manner as defined herein. In other embodiments, one or more resilient sections of the device body are in contact with restrictive plugs that release the drug in a manner as defined herein, and the remaining resilient sections of the device body are sealed by other suitable means, e.g. cap, adhesive, insulating tape, soldering, solvent welding, or a combination of such devices or methods.

[69] In most cases, the length of the elastic section should be equal to or greater than the length of the restriction plug section that contacts the elastic section of the device body, such that the formation/use of microchannels is not prevented, for example, by the inelastic section of the device body.

[70] In other embodiments, the resilient section 54 of the housing 52 is constructed from a material that allows for the formation of microchannels 62 or micropassages between the interior surface of the resilient section 54 and the restriction plug 56 when hydrostatic pressure increases in the drug reservoir 60. As detailed herein, the micropassages may extend along the surface of the restriction plug/elastic section from the drug reservoir to the unsealed distal opening of the device body, as shown in FIG. 1-3, or to a pre-formed drug release channel in the vicinity of the restriction plug, as shown in FIG. 9-10. The resilient section may include materials that are permeable, waterproof, or a combination of such materials.

[71] In the first embodiment of the invention, as shown in FIG. 1A-1D, drug delivery devices 50 as described herein include one or more restriction plugs 56 in contact with resilient body section(s) 54 of device 52 to permit release of drug through distal ( s) the opening(s) of the device housing as described in US Patent Application Pub. No. 2016/0008271 (Author: Lee), which is incorporated herein by reference in its respective embodiments. However, in some embodiments of the invention, as shown in FIG. 2 and 3A, as opposed to the situation where no aperture is used (i.e., unlike the situation where a pre-arranged system of different apertures is provided) according to US Patent Application Published No. 2016/0008271 (by Lee) , respective devices include at least one preformed through hole (i.e., diaphragm) 66, which is located in the wall of the device housing 52.

[72] As a result, in some embodiments of the invention, as shown in FIG. 1-4, the drug delivery device 50 includes a housing 52 that has a wall defining a reservoir 60 located within the housing 52, a wall having at least one preformed through hole 66 (which is located in this wall), and including including a water-permeable section 64, a housing 52, which includes a resilient section 54; a dosage form 58 that contains a drug, the dosage form 58 being contained within a reservoir 60; and at least one restriction plug 56 that tightly seals the opening of the housing 52, as well as the elastic section 54 of the housing 52 in contact therewith, this opening being a conduit for the movement of liquid into the reservoir 60. The water-permeable wall section 64 is configured such that which will allow water to pass into the drug delivery device 50, as well as its contact with the dosage form 58 located in the reservoir 60, the release of the drug 58 from the device 50 being controlled by at least one of (i) drug release devices means 58 through at least one preformed through hole 66 (i.e., through an aperture or diaphragm) in the wall, and (ii) means for releasing the drug through a transition system that consists of one or more microchannels 62 between the elastic section 54 body 52 and at least one restriction plug 56 extending into that opening until sufficient hydrostatic pressure is reached to form one or more microchannels 62. In these embodiments, restriction plugs 56 may be partially or completely unsealed at the distal end openings of the device 50. Such systems have been found to provide consistent and repeatable drug release and also provide pressure relief valve actuation, which provides the preferred drug release option in cases where the through-hole is partially or completely occluded. As a result, the device can operate to cause release of the drug through the preformed diaphragm until the hydrostatic pressure within the drug reservoir reaches the critical pressure of the restriction plug(s) at which release through the restriction plug(s) begins. For example, release of the drug through at least one pre-formed through-hole may be effected by osmotic pressure.

[73] A preferred embodiment of the invention is that such a device design allows drug release from the sides and/or center of the device, which provides increased flexibility of the device, and also allows for improvements in manufacturability compared to those devices. in which drug release occurs only through the distal openings of the device.

[74] In a second embodiment of the invention, as shown in FIG. 9-10, drug delivery devices 50 as described herein include sealed distal ends (shown sealed with adhesive 70) with a single limiting plug or a plurality of stoppers 56 that are in contact with the elastic(s). ) section(s) 54 of the body of the device 52, in order to provide release of the drug through preformed drug release channel(s) 68 in the body of the device 52 (for example, in the side walls) in the vicinity of the restriction plug 56. Elastic sections 54 may be located at or near the ends of device 50, as shown in FIG. 9-10, or they can be located along the length of the device, for example, in the central part of the device or near it. Restriction plug(s) 56 may be positioned proximate to one or more of the preformed drug release channels 68 in device body 52 such that restriction plug(s) 56 covers the and effectively closes the preformed drug release channel(s) 68 in cases where the critical hydrostatic pressure within the drug reservoir 60 is not achieved. In such embodiments, the restriction plugs 56 and elastic sections 54 of the device could be similar to those described above, as well as those plugs and sections described in US Patent Application Published No. 2016/0008271 (by Lee), except those situations where one or more microchannels 62 that are accidentally formed in the drug reservoir 60 will reach a critical hydrostatic pressure and extend from the drug reservoir 60 to the preformed release channel(s) 68 medicine.

[75] As a result, in some embodiments of the invention, as shown in FIG. 9-10, the drug delivery device 50 includes a tubular-shaped housing 52 that includes a wall defining a reservoir 60 located within the housing, a wall having a water-permeable section 64, and a resilient section 54 that has at least one a formed release channel 68 (eg, a through hole, an aperture, a diaphragm, a slit) located inside it; a dosage form 58 that contains a drug, wherein the dosage form 58 is located within a reservoir 60, within which a permeable wall section 64 allows water to pass into the drug delivery device and contacts the dosage form 58 contained in the reservoir 60; and at least one restriction plug 56 secured within the reservoir 60, which is in contact with the elastic section 54 of the housing 52 and adjacent to at least one preformed release channel 68, whereby the at least one restriction plug 56 controls the release of the drug means from the device through at least one preformed release channel 68 using a transition system consisting of one or more microchannels 62 between the elastic body section 54 and at least one restrictive plug 56 included in at least one preformed release channel 68 , until a hydrostatic pressure within the reservoir 60 is sufficient to form one or more microchannels 62. In some such embodiments, at least one preformed release channel 68 is a through hole or slot located in the wall of the housing 52.

[76] To achieve the desired drug release parameters, any suitable number of restriction plugs 5-6 and any locations thereof, as well as pre-formed release channels 68, can be used. For example, as shown in FIG. 9B, device 50 may include two preformed passages 68, shown here as apertures directly opposite each other (180 degrees) in the tubular body of device 52 such that a single restriction plug 56 is located proximate to both apertures. As shown in FIG. 9B, two apertures 68 and a corresponding restriction plug 56 may be provided at or near each distal end of the device. For example, as shown in FIG. 10B, a single preformed port 68, shown here as a slot, may be located proximate to each restriction plug 56. As shown in FIG. 10B, it may be proposed to locate a preformed port 68 and a corresponding restriction plug 56 at or near each distal end of the device.

[77] In such embodiments, a suitable adhesive 70 or other sealing means as described herein may be used to seal the ends of the device body. In some embodiments, the restriction plug 56 is sealed in place using an adhesive 70 or other means that seals the end(s) of the device body, or other adhesive. These types of device designs can reduce the complexity of manufacturing and installing a tapered end plug that is used in applications where release is accomplished from an at least partially unsealed end opening of the device. As a result, such release channels provide stop valves on the side and/or middle of the device, allowing drug to be released from any point along the length of the device, thereby reducing design limitations. Additionally, locating the drug release point away from the ends of the device is advantageous and allows the use of a device with a rounded end (i.e., not a cut-off beveled end), such as a spherical or spherical end design, which reduces the amount of configuration variation that can become centers for the formation of layers. In addition, such device designs provide the advantage of increasing the overall flexibility and bendability of the ends of the device.

[78] In some embodiments, the device also includes at least one preformed through hole located in the wall of the housing, as described above, in combination with a preformed release channel adjacent to the restriction plug, thereby releasing the drug from The device is further controlled by releasing the drug through at least one pre-formed through hole in the wall.

[79] In those embodiments where the dosage form is a solid or semi-solid, as described in detail below, the device may be configured to allow in vivo diffusion of water through the permeable wall section and entry into the reservoir for dissolution of the dosage form.

[80] Those devices as described herein have been designed to provide controlled release of drugs through these advanced one-way valve release mechanisms, used alone or in combination with other release mechanisms, such as preformed diaphragms in the side walls, which are susceptible to clogging. As a result, those devices described herein provide a longer and more reliable drug delivery procedure than those devices that use only sidewall diaphragms, as they are susceptible to buildup.

[81] More specifically, controlled release of drugs can be achieved using a transition system of microchannels through which liquid drug can be discharged from the drug delivery device (either through the distal end opening of the device or through one or more pre-formed channels release close to the restricting plug). Microchannels are formed at the contact area of the device components in response to increased hydrostatic pressure that is created in the drug reservoir, as a result of which the parameters of the device can be adjusted to ensure the release of the drug only when a certain critical value is reached within the drug reservoir hydrostatic pressure value.

[82] In order to facilitate the formation of microchannels, the elastic section 54 of the body of the device 52 and the restriction plugs 56 can be made of materials that have a certain elasticity or hardness. In some embodiments, the Shore hardness of the resilient body section is lower than the Shore hardness of the confining plug. In one embodiment of the invention, the Shore hardness of the resilient body section is from about 40A to about 60A, and the Shore hardness of the restriction plug is from about 70A to about 100A. In another embodiment of the invention, the Shore hardness of the resilient body section is from about 45A to about 55A, and the Shore hardness of the restriction plug is from about 75A to about 85A. In yet another embodiment, the hardness of the resilient body section is approximately 50A Shore A and the hardness of the restriction plug is approximately 80A. In yet another embodiment of the invention, the Shore hardness of the resilient body section is from about 40A to about 60A, and the Shore hardness of the restriction plug is about 97A. In some embodiments, when the restriction plug is located at or near the ends of the device, and a preformed drug release channel in the device body is located in the vicinity of the restriction plug, the hardness of the restriction plug may be even lower in order to reduce the stiffness of the device end. .

[83] In other embodiments, the device body 52 may include two or more elastic sections 54 with different elasticity values that are in contact with two (or more) restriction plugs 56 with different elasticity values. Such a configuration may be useful to control drug release from two (or more) different drug reservoirs of different solubilities, different desired release rates, etc. For example, the water-permeable body may have first and second resilient sections that are made of two different materials having hardness values of 45A and 55A Shore, respectively, wherein the first and second resilient sections may be inserted into first and second containment plugs that are made of two different materials having Shore hardness values of 75A and 85A, respectively.

[84] In one embodiment of the invention, the body of the device is made entirely of elastic material. In other embodiments, the body is made of at least one elastic material and at least one non-elastic material. In other embodiments, the body is made of a material that has at least one elastic section and at least one non-elastic section.

[85] The elastic section 54 of the body of the device 52 can have any shape that allows the installation of a restrictive plug 5 6 and the creation of an interference fit between the elastic section 54 and the plug 56. If you analyze the cross section, it is clear that the passage channel of the elastic section may be slightly angular . For example, the cross-section may be round, nearly round or oval. In some embodiments, the shape of the bore of the elastic section substantially matches the shape of the restrictive plug.

[86] The body of the device 52 can generally be made of any biocompatible material, as long as at least a portion of the body 64 is a permeable material. The resilient section 54 of the body 52, which is in contact with the restriction plug 56, can be made of any biocompatible material that provides the formation of one or more microchannels 62 through which the drug can exit the device 50.

[87] In one embodiment of the invention, the body of the device 52 is an elongated tube. Within this tube may be one or more drug reservoirs 60, and the dosage form 58 may be placed within such reservoir(s) 60. For example, such an elongated tube may be annular in shape and have an annular gap, that is, the passageway of the tube, which is used as a reservoir with the drug. In other embodiments, the drug reservoir section is not tubular in shape. The rate of drug release from the drug reservoir section is generally controlled by a certain combination of device design parameters, including, but not limited to, material characteristics, dimensions of various components, working surface area, pre-formed release channels/through holes, limiting plugs, as well as a specific dosage form and (including) the total mass of the loaded drug.

[88] In FIG. 4 shows an example of a medicament reservoir section 78, that is, the body of the device. As shown, the drug reservoir section 78 may include a housing in the form of an elastomeric tube 82. The tube 82 defines a reservoir 60 that contains a number of individual drug fragments 158. Restriction plugs are inserted into the holes at the ends of the tube 82.

[89] In other embodiments, the drug reservoir section 78 and the drug reservoir 60 function together as an osmotic pump. In such embodiments, the drug reservoir section is constructed (at least in part) from a permeable material. In the most preferred embodiment of the invention, silicone is used as the permeable material. After the device is inserted/implanted into the patient's body, water or urine leaks through the wall of the drug reservoir section. Water enters the reservoir, comes into contact with the dosage form and forms a liquid drug (eg, a drug solution) which can then be withdrawn at a controlled rate from the reservoir through microchannels that are formed between the restriction plugs and the elastic section of the drug reservoir. The delivery rate and overall performance of such an osmotic pump are influenced by device parameters, such as the surface area of the drug reservoir; the filtration coefficient into the liquid of the material that is used to create the section with the drug reservoir; the relative sizes, shapes, and locations of pre-formed release channels/through holes in the device body; the relative sizes, shapes, elasticity or hardness of the restricting plugs and the elastic section of the channel of the drug reservoir; and (among other factors) the solubility characteristics of the dosage form. In some embodiments, the device may initially exhibit a zero order release rate and may subsequently exhibit a reduced non-zero order release rate, in which case the overall drug release characteristics may be determined from the initial zero order release rate as well as the overall payload. Representative examples of osmotic pump designs, as well as equations for selecting such designs, are described in US Patent Application Published No. 2009/0149833 (Cima et al.).

[90] The drug reservoir section may be made at least in part from some elastomeric material that can elastically deform the device during insertion into the patient's body, for example, during deployment by a deployment tool, e.g. using a cystoscope or catheter. For example, the tube may be elastically deformed along with the holding frame during insertion of the device into the bladder, as described in detail below.

[91] In one embodiment of the invention, the drug reservoir section is constructed from a material that is both elastomeric and water permeable. Examples of materials that are both elastomeric and water-permeable include silicones and thermoplastic polyurethanes, which are known in the art today. Other suitable and biocompatible materials may also be used, including non-elastic biocompatible materials.

[92] The length, diameter, and thickness of the drug reservoir section may be selected based on the volume of the dosage form to be contained in the reservoir, the desired rate of drug delivery, the intended deployment point of the device within the body, the desired structural integrity of the device, the desired release rate, or filtration rate into water and urine, the desired length of time until the initial release of drug from the device occurs, and (among others) the desired method or route of introduction of the device into the body. Tube wall thickness can be determined based on the mechanical properties and water permeability of the tube material, since a tube wall that is too thin may not have sufficient structural integrity, and a tube wall that is too thick may cause an undesirably long time lag before initial release occurs. medicine from the device.

[93] In one embodiment of the invention, the body of the device is made of a material that is incapable of complete absorption in the human body. Such a housing can be made in the form of a tube of silicone intended for medical use, which is known in the current state of the art. Other suitable materials that are not capable of complete absorption in the human body can be used. In other embodiments, the device body is made at least in part from a biodegradable material. In one embodiment of the biodegradable device, the drug reservoir section is constructed from a material that is susceptible to microbiological degradation or a bioresorbable polymer. Any suitable and biocompatible polymers may be used.

[94] In those embodiments where the drug reservoir section is in the form of a tube, the tube may be substantially linear, and in some cases it may be substantially cylindrical with a circular or oval cross-section, although it may also other things, use tubes with square, triangular, hexagonal and other polygonal cross sections.

[95] In one embodiment of the invention, the drug reservoir section 78 has multiple reservoirs. Each reservoir may be defined by a portion of the inner surface of the drug reservoir and at least one partition. In those embodiments of the invention where the drug reservoir section is in the form of a tube, such a partition can be configured as (including) a separating structure or as a plug inserted into the tube (for example, in the form of a cylinder, sphere or disk), and in In this case, such a separation structure may have a larger cross-section than a tube that locks the separation structure directly into place and separates adjacent tanks. Such a septum may be non-porous or semi-porous, non-absorbable or fully absorbable in the human body, and may be made from the materials described herein and referenced to the restrictive plugs. Such a partition can also be produced in a pipe, for example by pressing. For example, one or more bridges may extend along the length of the tube to separate axial reservoirs that extend along the length of the tube. Such a partition can also be made in the form of a structure that connects two different tubes that are used as separate reservoirs.

[96] A large number of reservoirs makes it possible to distribute two or more different dosage forms into different reservoirs, deliver the same drug from different reservoirs at different rates or at different times after deployment of the device (or various combinations of the above situations are possible). For example, two different reservoirs may be connected by two different restriction plugs having different configurations (as described herein) that deliver drugs into two different reservoirs from which they must be released at different rates. In addition, the two different reservoirs may contain the same dosage form or different dosage forms in the same state or in different states, such as liquid, semi-solid or solid (or various combinations of the above situations are possible). It is also possible to propose the use of different coatings or casings on different sections of a single drug reservoir or on different drug reservoirs that contain the same dosage form or different dosage forms. Such coatings or shells can be used to modify the filtration coefficient of a permeable body. To achieve the desired release parameters of the desired drug, various embodiments of the invention can be combined together and modified.

[97] For example, by determining the appropriate configuration of the device, it is possible to stagger the timing of the release of two doses of drug in different reservoirs, for example, by using different materials (for example, materials with different filtration coefficients) for those sections of the tube that define different reservoirs, by housing drugs with different solubility rates in reservoirs or by housing drugs in different physical states in reservoirs, for example, a liquid state for immediate release and a drug in a solid state that must first be dissolved in vivo to allow its release from the device. As a result, the device can release a drug relatively quickly after deployment of the device, and another drug will be released after the induction time has elapsed.

[98] Pre-prepared apertures/ports

[99] In some embodiments, the device includes one or more channels (e.g., apertures, diaphragms, slits, and the like) for releasing drug from the device, for example, by creating an osmotic pressure within the drug reservoir, such as described in this specification. Such apertures can be located along the length of the tube and thus create a channel for the release of the drug. These types of apertures or diaphragms may be located on the side wall of the tube. The apertures may be connected by a fluid path to a single reservoir or to a plurality of reservoirs (as illustrated by orifice 66 in FIGS. 2 and 3A), or they may be located adjacent to a restriction plug (as illustrated by passages 68 in FIG. 9 and 10, as well as as described in this description).

[100] An embodiment of aperture 66 is shown in the example of the drug reservoir section 7-8 in FIG. 3A. The aperture 66 may be located approximately in the middle of the drug reservoir section 78 or near the end of the drug reservoir 60, which may affect the ease of loading solid drug fragments 158 into the drug reservoir section 78, as described below. These types of apertures may be located away from the section of tubing that will flex during insertion into the body in order to limit wear of the biodegradable membranes on the apertures.

[101] To ensure a controlled rate of drug release, aperture sizes, numbers, and locations can be selected. The device, which functions primarily as an osmotic pump, may have one or more apertures that are small enough to reduce the diffusion of drug through such aperture(s), but large enough to to reduce the build-up of hydrostatic pressure in the pipe (provided that these apertures are suitably spaced along the length of the pipe). To achieve the selected drug release rate, the size and number of apertures for a single device (or reservoir) can be modified in accordance with the above restrictions. In exemplary embodiments, the aperture diameter is from about 20 μm to about 500 μm, such as from about 25 μm to about 300 μm, and more particularly from about 30 μm to about 200 μm. In one specific example, the aperture has a diameter of from about 100 μm to about 200 μm, such as about 150 μm. In another specific example, the aperture has a diameter of from about 25 μm to about 100 μm, such as about 75 μm. One single device may have apertures of two or more different sizes. The aperture may be circular, although apertures with other shapes are possible and designed, usually depending on manufacturing conditions. Examples of manufacturing processes for creating apertures include mechanical punching, laser drilling, laser ablation, and pressing. The aperture may taper slightly from the outer surface to the inner surface of the tube, and the aperture may be created before or after loading the drug into the tube.

[102] In some embodiments of the invention, as shown in FIG. 10, the preformed release channel 68 is a slit in the body of the device 52, which is configured to provide a channel for the release of drug 58 after applying sufficient pressure to deploy the elastic section 54 of the body 52, in which a port 68 is created to open the slit. and thus create a through hole for the passage of the drug solution. This slot may be configured to function as a one-way valve allowing release of medication from the device when it is opened by internal pressure, but otherwise remains closed so that no external fluids are released. penetrate the device.

[103] Restriction plugs

[104] The restriction plugs 5 - 6 may be of any shape that is suitable for being located in a single resilient section or in a plurality of resilient sections 54 of the housing 52 that provide microchannels 62 as defined herein. In other embodiments, the restriction plugs 56 are cylindrical or substantially cylindrical in shape. As used herein, the term "substantially cylindrical shape" refers to any shape that is not polygonal in cross section. In other embodiments, the restriction plugs are partially cylindrical or substantially cylindrical and have at least one section that is tapered, tapered, angular, or rounded in shape. In other embodiments of the invention, the limiting plugs are made solid and have no internal cavities.

[105] In FIG. 6 shows several restriction plugs 502, 503, 504, 505 and 506, which have different shapes. In FIG. 7 shows restriction plugs 502, 503, 504, 505 and 506 that are inserted into the tubular resilient section 501 of the device body. If the restriction plug has a wedge-shaped, tapered, angular or rounded surface, then such surfaces facilitate the formation of microchannels as described herein. The authors do not wish to be bound by a particular theory, but have reason to believe that wedge-shaped, tapered, angular or rounded surfaces may provide a more favorable path for osmotic flow along or near such surfaces. As a result, not very high hydrostatic pressure may be required to create one or more microchannels between the restriction plug and the elastic section of the permeable body. In most cases, the restriction plugs may have one or more wedge-shaped, tapered, angular or rounded surfaces on one or both sides with respect to the longitudinal axis of the restriction plugs. In other embodiments, the angle between the longitudinal surface of the restriction plug and the surface of the wedge-shaped, tapered, angular or rounded section may be from about 30° to about 60°.

[106] As shown in FIG. 7, the wedge-shaped, tapered, angular or rounded surfaces of the restriction plugs 502, 503, 504, 505, 506 may be inserted into the end of the tubular resilient section 501 such that the wedge-shaped, tapered, angular or rounded surfaces of the restriction plugs are in contact with the internal volume (reservoir with a medicinal product) of the drug delivery device. In FIG. 7, the opposite base of the restriction plugs faces outward from the device as it forms the outer surface of the drug delivery device. In other situations and in other embodiments of the invention, this position may be reversed, whereby the wedge-shaped, tapered, angular or rounded surfaces of the restriction plug will face outward from the device as they form the outer surface of the devices that are intended to be delivered drug, and the base of the restriction plug will be in contact with the internal volume (drug reservoir) of the drug delivery device. In this position, the wedge-shaped, tapered, angular or rounded surfaces of the limiting plugs can create an unfilled space at or near the end of the elastic section. This void space, or a portion thereof, may contain an adhesive, a clamping device, a plug, or other known device to secure the restriction plug in place, as shown in FIG. 3A-3C.

[107] In some embodiments, the resilient housing section and restriction plug may be located at a location other than the end within the device.

[108] The restriction plugs 56 must be in contact with the elastic sections 54 of the permeable body 52 in such a way as to prevent the restriction plug 56 from being pushed out of the elastic section 54 in cases where the device 50 is in a compressed state in the patient's body after deployment. and/or in cases where the limiting plug 5 6 is subject to hydrostatic force. In other embodiments, the restriction plug 56 and the elastic section 54 are secured together by an interference fit, for example by frictionally engaging the plug and the elastic section, which may be an interference fit only or alternatively may be accompanied by the addition of an adhesive. substances. The restriction plug 56 must remain in the elastic section 54 of the permeable body 52 in cases where the device 50 experiences elastic deformation during the transition from the form for holding the device in the body to a relatively straightened form.

[109] In the most preferred embodiment of the invention, the restriction plugs 56 do not move within the elastic sections 54 of the device body 52 after deployment of the device and during drug release. In other embodiments, the restriction plugs 56 move within the resilient sections 54 of the permeable body 52 after deployment of the device and during drug release. Movement of the limiting plugs 5 6 can be allowed provided that it is undesirable to affect the drug release process.

[110] In other embodiments, the cross-sectional shape of the restriction plugs 5 6 substantially matches the internal dimensions of the elastic section 54 of the device body 52. In other embodiments, the outer diameter of the restriction plugs 56 is greater than the internal diameter of the elastic section 54 of the device body 52. The phrase " "inner diameter" as used herein does not mean that the cross-section of the elastic section is always circular in shape; in fact, the term refers to the largest diameter or major axis of the bore of the resilient section of the permeable body. Likewise, the phrase "outer diameter" as used herein does not mean that the cross-section of the restriction plug is always circular in shape; in fact, the term refers to the largest diameter or major cross-sectional axis of the confining plug or its base.

[111] In one embodiment, the outer diameter of the restriction plug exceeds the inner diameter of the elastic section of the device body by at least 3 percent. In another embodiment of the invention, the outer diameter of the restriction plug exceeds the inner diameter of the elastic section of the device body by at least 5 percent. In yet another embodiment of the invention, the outer diameter of the restriction plug exceeds the inner diameter of the elastic section of the device body by at least 10 percent. In yet another embodiment, the outer diameter of the restriction plug exceeds the inner diameter of the elastic section of the device body by at least 15 percent. In yet another embodiment of the invention, the outer diameter of the restriction plug exceeds the inner diameter of the elastic section of the device body by at least 20 percent. In one of the detailed embodiments of the invention, the outer diameter of the restriction plug exceeds the inner diameter of the elastic section of the body by at least 25 percent.

[112] In one embodiment, the outer diameter of the restriction plug exceeds the inner diameter of the elastic section of the device body by approximately 5 percent, and the inner diameter of the elastic section of the device body is in the range of 2.1 to 2.2 mm, (for example, 2. 16 mm), and the outer diameter of the restriction plug is in the range of 2.2 to 2.3 mm (for example, 2.27 mm). In this embodiment, the restriction plug has a length of from about 2.5 mm to about 5 mm.

[113] In another embodiment of the invention, the outer diameter of the restriction plug exceeds the inner diameter of the elastic section of the permeable body by approximately 28 percent. For example, in one embodiment, the internal diameter of the elastic section of the water-permeable body is in the range of 2.1 and 2.2 mm (for example, 2.16 mm), and the external diameter of the restriction plug is in the range of 2.7 and 2. 8 mm (for example 2.77 mm). In this embodiment, the restriction plug has a length of approximately 2.5 mm (or, more specifically, its length is 5 mm).

[114] The restriction plugs can be of any length that is suitable for forming microchannels between the restriction plug and the elastic body section of the device. The outer surface of the limiting plug may be in contact with the inner surface of the elastic section of the device body along the entire length of the limiting plug, or only with a portion of the surface along the length of the limiting plug. For example, the outer surface of the confining plug, which is made in the form of a cylinder, may be in contact with the inner surface of the hole in the elastic section of the water-permeable body along the entire length of the confining plug. However, the outer surface of the confinement plug, which has only one or more wedge-shaped, angular or tapered surfaces, may be in contact only with the inner surface of the elastic section of the permeable body along a portion of the confinement plug (overall length), as shown, for example, in FIG. . 3 and 6.

[115] In other embodiments, the length of the restriction plug may be from about 2 mm to about 10 mm, from about 2 mm to about 8 mm, from about 2 mm to about 6 mm, or from about 2.5 mm to about 5 mm.

[116] In most cases, the inner surface of the resilient water-permeable body section and the confining plug may be shaped such that the confinement plug and the resilient water-permeable body section will remain in contact with each other during deployment of the device. In some embodiments of the invention, as shown in FIG. 3, an adhesive 70 may be used to secure the resilient section 54 of the permeable body 52 and the restriction plug 56 together. One or more individual portions of the adhesive may be applied as long as the amount of adhesive and the application points do not have an undesirable effect on the drug release process ( as described herein). In other embodiments, the restriction plug may be secured by mechanical means. For example, an external clamping device may be used to secure the resilient section of the permeable body and the restriction plug together. Any suitable clamping device may be used as long as it does not have an undesirable effect on the patient's acceptability of the device or on the drug release process (as defined herein). If the confinement plug is secured by mechanical devices, an adhesive, or both, it may be necessary to make the elastic section or the confinement plug, or both, from a softer material in order to allow microchannels to form.

[117] Restriction plugs can be made from any biocompatible material or combination of biocompatible materials that enable the release of drugs from the device in a manner as defined herein. For example, the restriction plugs may be made from some kind of polymeric material (eg, silicone or ethylene vinyl acetate), a ceramic material, an adhesive, or a combination of these materials.

[118] In some embodiments, the restriction plugs are coated with some material that prevents unwanted mechanical contact between the inner surface of the elastic section and the restrictive plug, which can occur with some polymeric materials in cases where the entire assembled device is subjected to sterilization, for example, using gamma ray irradiation. For example, restriction plugs may be made of silicone and coated with a parylene material, such as Parylene C.

[119] Frame holding section

[120] In the most preferred embodiment of the invention (as shown in FIGS. 3 and 4), the drug delivery device 50 includes a holding frame section 76. The frame holding section 76 is coupled to the medicament reservoir section 78 and ensures that the medicament reservoir section 78 is retained in the patient's body, such as the bladder. The device frame holding section 76 may include a holding frame 74 that deforms from a relatively more extended shape to a relatively lower profile shape. For example, the holding frame 74 may naturally assume a relatively more expanded shape, it may be manually converted to a relatively lower profile shape that is intended to be inserted into the body, and it may spontaneously return to a relatively expanded shape after insertion into the body. The holding frame 74 in a relatively more developed form may be shaped to be retained in a body cavity, and the holding frame 74 in a relatively lower profile form may be shaped to be inserted into the body through the working channel of a special device deployment device, such as a catheter or cystoscope. To achieve this result, the holding frame 74 may have an elastic limit, elastic modulus, and/or spring constant that is selected to prevent the device from returning to a relatively lower profile shape after deployment. Such a configuration may limit or prevent the possibility of the device being accidentally extruded from the body by anticipated forces. For example, the device can be held in the bladder during urination or during detrusor contraction.

[121] In the most preferred embodiment of the invention, the holding frame 74 includes or consists of an elastic wire. For example, in the embodiment of the invention shown in FIG. 3 and 4, the retaining frame 74 is an elastic wire of some superelastic alloy (for example, nickel-titanium alloy "nitinol"), which is surrounded by the wall 84 of the frame retaining passage channel 80, forming a protective sheath around the retaining frame 74. The wall 84 can made from any polymer material, for example, silicone. In some other embodiments, the holding frame may be constructed using an elastic wire of some superelastic alloy (eg, nitinol), which is coated with a polymer (eg, silicone sheath) and secured to the drug reservoir section. In other embodiments, such elastic wire may be made from some elastomeric material with a relatively low modulus of elasticity.

[122] In some embodiments, the frame holding passageway 80 may include a holding frame 74 as well as a fill material, such as a polymer-based fill material. An example of such a filler material is silicone adhesive, such as MED3-4213 from Nusil Technology LLC, although other filler materials can be used. Such fill material may completely or partially fill a cavity in the frame retaining passage 80 proximate the retaining frame 74. For example, the fill material may be inserted into the frame retaining passage 80 proximate the retaining frame 74 and may solidify therein. Such fill material may reduce the tendency for the drug reservoir channel 60 to unfold, twist, or wrap around the holding frame 74. In doing so, the material may hold the drug reservoir channel 60 in a selected orientation relative to the holding frame 74. However, such filling material is not absolutely necessary, so you can do without it.

[123] When the holding frame 74 is in a relatively more expanded form, such as the twisted form shown in FIG. 3A, the device 50 may occupy a space that is sized to prevent the device from being pushed out of the bladder. When the holding frame is in a relatively lower profile form, such as an elongated form as shown in FIG. 8, the device 700 may occupy a space suitable for insertion into the body, for example, through the working channel of a special device deployment device, 702. The properties of the elastic wire allow the device to function as a spring that has been deformed by the application of a compressive load, but which spontaneously returns to its original shape after the load is removed.

[124] The support frame, which may take a "curly" shape, may be relatively resistant to compressive forces. Essentially, the curl shape consists of two unfinished circles, each with its own small arc, as well as part of a larger arc. When a compressive force is applied to the curl shape, the large arc absorbs most of the compressive force and begins to deform, but with further application of compressive force, both small arcs overlap, resulting in all three arcs resisting the compressive force. The resistance of the entire device to the compressive force increases after the two incomplete circles overlap, thereby preventing the device from compressing and releasing the drug when the bladder contracts during urination.

[125] In those embodiments where the holding frame includes a shape memory material, such material, which is used to make the frame and body of the device, can “memorize” and spontaneously assume a relatively expanded shape when thermal energy is applied to the device, e.g. in cases where the housing is exposed to body temperature after its insertion into the bladder.

[126] The holding frame may be shaped such that it has a high spring rate that is sufficient to support the device in a body cavity, such as the bladder. Materials with high or low modulus of elasticity can be used. Particularly in cases where a low modulus material is used, the retaining frame may have a specific diameter and/or shape that will provide the proper spring rate, without which the frame may experience significant deformation under voiding forces. For example, the retaining frame may include one or more coils, coils, spirals, or various combinations of the foregoing components that are specifically designed to provide a desired spring constant, as described in US Patent Application Published No. 2009/0149833 (authors: Sima et al.).

[127] The support frame may have a two-dimensional structure that is largely confined to a plane, as well as a spatial structure, such as a structure that occupies the interior volume of a spheroid (or the frame may have a combination of such components).

[128] Dosage forms

[129] The term "drug" as used herein includes any corresponding pharmaceutically active ingredients. The drug may be in the form of a small molecule, macromolecule, biologic, or metabolite, as well as other forms/types of active ingredients. Those drugs described herein include their alternative forms, such as salts, free acids, free bases and hydroxides. The drug formulation may be formulated in the form of one or more pharmaceutically acceptable excipients that are known in the art. Non-limiting examples of the drug include: gemcitabine, oxaliplatin and/or other chemotherapeutic agent; trospium and/or other antimuscarinic agent; and/or lidocaine and/or other pain reliever. In one embodiment, tablets of two or more types of drugs (eg, different drugs) can be loaded into the first compartment of the device, thereby allowing delivery of a combination of drugs.

[130] In other embodiments, the drug is used to relieve pain. Many different painkillers, painkillers, and various combinations of these can be used. In one embodiment of the invention, the drug is an analgesic. Such an anesthetic could be an analogue of cocaine. The anesthetic may be an aminoamide, an aminoester, or various combinations of these drugs. Representative examples of aminoamides or amide class anesthetics include: articaine, bupivacaine, sarticaine, cinchocaine, etidocaine, levobupivacaine, lidocaine, mepivacaine, prilocaine, ropivacaine, and trimecaine. Representative examples of amino esters or ester class anesthetics include: amylocaine, benzocaine, butacaine, chloroprocaine, cocaine, cyclomethicaine, dimethocaine, hexylcaine, larocaine, meprilcaine, metabutoxyaine, orthocaine, piperocaine, procaine, proparacaine, propoxycaine, proximethacaine, rizocaine, and tetracaine. In addition, an antimuscarinic compound that has an anesthetic effect, such as oxybutynin or propiverine, can be used as a drug. In other embodiments, the anesthetic is an opium drug. Representative examples of opioid agonists include alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphine, dihydrocodeine, dihydromorphine, dimenoxadol, dimefeptanol, dimethylthiambutene, di oxafetyl butyrate, dipipanone, eptazocine, etoheptacin, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypetidine, isomethadone, ketobemidone, levorphanol, levofenacilmorphan, lofentanil, meperidine, meptazinol, metazocin, methadone, metopone, morphine, mirofin, nal bufine, narcein, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, pantopon, pentazocine, phenadoxone, phenomorphan, phenazocine, fenoperedine, piminodine, piitramide, proheptazine, promedol, propedine, propyram, propoxyphene, sufentanil, tilidine, tramadol, pharmaceutically acceptable salts of the above agents, as well as mixtures of the above agents. The use of other drugs based on opium preparations is suggested, for example, nociceptive opioid receptor agonists (mu, kappa, delta). Representative examples of other suitable analgesics include: salicylic alcohol, phenazopyridine hydrochloride, acetaminophen, acetylsalicylic acid, flufenisal, ibuprofen, indoprofen; indomethacin, naproxen.

[131] In some embodiments, the drug is used to treat the following inflammatory conditions: interstitial cystitis, radiation cystitis, painful bladder syndrome, prostatitis, urethral inflammation, post-operative pain, and urolithiasis. Non-limiting examples of drugs for the treatment of these diseases include: lidocaine, glycosaminoglycans (eg, chondroitin sulfate, sulodexide), sodium pentosan polysulfate (PPS), dimethyl sulfoxide (DMSO), oxybutynin, mitomycin C, heparin, flavoxate, ketorolac, or any combination of these funds. Other non-limiting examples of drugs that can be used in the treatment of inflammatory processes (IP) include neurotrophic growth factor monoclonal antibody (MAT) antagonists, such as tanezumab, and alpha-2 delta calcium channel modulators, such as PD-299685 or gabapentin.

[132] In some embodiments, the drug is used to treat urinary incontinence (urinary frequency or urgency), including the treatment of urge and nervous urinary incontinence, and the treatment of trigonitis. Drugs that may be used include anticholinergics, antispasmodics, antimuscarinics, alpha-2 agonists, alpha-adrenergic agents, anticonvulsants, norepinephrine uptake inhibitors, serotonin uptake inhibitors, calcium channel blockers, potassium channel openers, and also muscle relaxants. Representative examples of relevant drugs for the treatment of urinary incontinence include: oxybutynin, S-oxybutynin, emepronium, verapamil, imipramine, flavoxate, atropine, propantheline, tolterodine, rociverine, clenbuterol, darifenacin, terodyline, trospium, hyoscyamine, propiverine, desmopressin, vamicamide , clidinium bromide, dicyclomine HCl, glycopyrrolate aminoalcohol ester, ipratropium bromide, mepenzolate bromide, methscopolamine bromide, scopolamine hydrobromide, iotropium bromide, fesoterodine fumarate, YM-4 6303 (Yamanouchi Co., Japan), lanperisone (Company Nippon Kayaku Co., Japan), inaperizone, NS-21 (Nippon Shinyaku Orion Co., Formenti, Japan/Italy), NC-1800 (Company Nippon Chemiphar Co., Japan), Z D-6169 (Zeneca Co., United Kingdom), and stylonium iodide.

[133] In some embodiments, the drug is used to treat urinary tract cancer, such as bladder cancer and prostate cancer. Drugs that can be used include antiproliferative agents, cytotoxic agents, chemotherapeutic agents, or combinations of these agents. Representative examples of drugs that may be useful in the treatment of urinary tract cancer include: Bacillus Calmette-Guérin (BCG) vaccine, cisplatin, doxorubicin, valrubicin, gemcitabine, mycobacterial cell wall complex (MCW) DNA, methotrexate, vinblastine , thiotepa, mitomycin, fluorouracil, leuprolide, diethylstilbestrol, estramustine, megestrol acetate, cyproterone, flutamide, selective estrogen receptor modulators (i.e., SERMs, such as tamoxifen), botulinum toxins, and cyclophosphamide. The drug may be a biological agent, which may include a monoclonal antibody, a tumor necrosis factor (TNF) inhibitor, an anti-leukin, or the like. In addition, the drug may be an immunomodulator, such as a Toll-like receptor (TLR) agonist, including imiquimod or another TLR7 agonist. The drug may also be a kinase inhibitor, such as a fibroblast growth factor receptor 3 (FGFR)-selective tyrosine kinase inhibitor, a phosphatidylinositol kinase 3 inhibitor (IPKI), or a mitogen-activated protein kinase (MAPK) inhibitor, among others, or various combinations of these drugs. funds. Other examples include celecoxib, erlotinib, gefitinib, paclitaxel, polyphenon E, valrubicin, neocarcinostatin, apaziquone, belinostat, ingenol mebutate, urocidin (MCC test), Proxinium (VB 4845 test), BC 819 test ( BioCancell Therapeutics), cochlear hemocyanin, LOR 2040 test (Lorus Therapeutics), urocanic acid, OGX 427 test (OncoGenex), as well as the test "SCH 721015" (Schering-Plough Company). Other intravesical anticancer drugs include small molecules, for example, apaziquone, adriamycin, AD-32 test, doxorubicin, docetaxel, epirubicin, gemcitabine, HTI-286 test (hemiasterlin analogue), idarubicin, γ-linolenic acid, mitoxantrone, meglumine, and thiotepa; large molecules, e.g. activated macrophages, activated T cells, epidermal growth factor (EGF) dextran, HPC-doxorubicin, IL-12 test, interferon-a2b test, interferon-γ test, α-lactalbumin , p53 adenovector, "TNFα" test; combinations of these drugs, for example, epirubicin + BCG, interferon + pharmacorubicin, doxorubicin + 5-fluorouracil (oral), BCG + interferon, as well as pertussis toxin + cystectomy; activated cells, such as macrophages and T cells; intravesical infusion solutions, such as IL-2 and doxorubicin; chemosensitizers, for example, BCG + antifibrinolytic substances (paramethylbenzoic acid or aminocaproic acid), as well as doxorubicin + verapamil; diagnostic/imaging agents, eg hexylaminolevulinate, 5-aminolevulinic acid, iododeoxyuridine, HMFG1 Mab+Tc99m test; and agents to control local toxicity, such as formalin (hemorrhagic cystitis).

[134] In some embodiments, the drug is used to treat infectious diseases that affect the bladder, prostate and urethra. To treat such infectious diseases, antibiotics, antibacterial, antifungal, antiprotozoal, antiseptic, antiviral and other anti-infective agents can be used. Representative examples of drugs for the treatment of infectious diseases include mitomycin, ciprofloxacin, norfloxacin, ofloxacin, methanamine, nitrofurantoin, ampicillin, amoxicillin, nafcillin, trimethoprim, trimethoprimsulfamethoxazole sulfonamides, erythromycin, doxycycline, metronidazole, tetracycline, kanamycin, pen cillins, cephalosporins, and also aminoglycosides.

[135] In some embodiments, the drug is used to treat fibrosis of the genitourinary organs, such as the bladder or uterus. Representative examples of drugs for the treatment of fibroid tumors include: pentoxifylline (xanthine analogue), anti-tumor necrosis factor alpha (TNF) agents, anti-platelet-derived growth factor (TCGF) agents, gonadotropin-releasing hormone (GnRH) analogues, exogenous progestins, antiprogestins , selective estrogen receptor modulators, danazol, and non-steroidal anti-inflammatory drugs (NSAIDs).

[136] In some embodiments, the drug is used to treat neurogenic bladder. Representative examples of such drugs include pain relievers or anesthetics, for example, lidocaine, bupivacaine, mepivacaine, prilocaine, articaine, and ropivacaine; anticholinergic drugs; antimuscarinics, such as oxybutynin or propiverine; vanilloid receptors, such as capsaicin or resiniferatoxin; antimuscarinics, for example, those drugs that act on the M3 acetylcholine muscarinic receptor (mAChRs); antispasmodics, including GABAB agonists (agonists of ionotropic receptors (type B) of gamma-aminobutyric acid), for example, baclofen; botulism bacillus toxins; capsaicins; α-adrenergic receptor antagonists; anticonvulsants; serotonin reuptake inhibitors, such as amitriptyline; as well as neural growth factor antagonists. In various embodiments, the drug may be an agent that affects afferents (nerve fibers entering the bladder) or an agent that affects cholinergic transmission through efferents (nerve fibers leaving the bladder), as described in Literature: Reitz et al., Spinal Cord 42:267-72 (2004)

[137] In some embodiments, the drug is used to treat urinary incontinence due to neurogenic detrusor overactivity and/or detrusor laxity. Examples of drugs of this type include: bladder laxatives (eg, oxybutynin (an antimuscarinic with distinct muscle relaxant activity and local analgesic effects), propiverine, ipratropium, tiotropium, trospium, terodiline, tolterodine, propantheline, oxyphencyclimine, flavoxate as well as tricyclic antidepressants; drugs to block nerve fibers that irritate the bladder and urethra (eg, vanilloid receptors (capsaicin, resiniferatoxin), botulinum toxin type A); or drugs that regulate the intensity of detrusor contraction, micturition reflex, detrusor-sphincter dyssynergia (eg, GABAb agonists (baclofen), benzodiazepines) In another embodiment, the drug is selected from those known to treat urinary incontinence due to neurological sphincter dysfunction. Examples of these drugs include: α-adrenergic agonists, estrogens, β-adrenergic agonists, tricyclic antidepressants (imipramine, amitriptyline). In yet another embodiment, the drug is selected from those known to promote bladder emptying (eg, α-adrenergic receptor antagonists (phentolamine) or cholinergics). In yet another embodiment, the drug is selected from among anticholinergic drugs (eg, dicyclomine), calcium channel blockers (eg, verapamil), tropane alkaloids (eg, atropine, scopolamine), nociceptin/FQ-orphanine, and bethanechol (eg , M3 muscarinic receptor agonist, choline ester).

[138] In some embodiments, the agent that increases osmotic pressure may be contained in a water-permeable housing, contained in a dosage form, or (in some embodiments) the drug itself may act as an osmotic agent. For example, the drug and the osmotic agent can be mixed together to form a homogeneous system or made into tablets by compression. In another embodiment of the invention, the drug tablet may be located adjacent to the restriction plug, and the osmotic agent may be located adjacent to the drug tablet. Non-limiting examples of osmotic agents are: urea, citric acid, L-tartaric acid, lactose-fructose, dextrose-fructose, sucrose-fructose, mannitol-fructose, sodium chloride, fructose, lactose-sucrose, potassium chloride, lactose-dextrose, mannitol-fructose. dextrose, dextrose-sucrose, mannitol-sucrose, sucrose, mannitol-lactose, dextrose, potassium sulfate, mannitol, sodium phosphate tribasic⋅12 H ₂ O, sodium phosphate dibasic⋅7 H ₂ O, sodium phosphate dibasic anhydrous, as well as sodium phosphate monobasic⋅H ₂ O.

[139] Operation and practical applications of the device

[140] This device can be installed in a particular body cavity or passageway, and can subsequently release one or more drugs to treat one or more diseases within one or more body tissues locally at a specific point of application of the device and/ or within other body tissues over longer areas that are distant from the specific point of application of the device. Drug release can be controlled over extended periods of time. The device can then be removed from the body, refilled with medication, injected into the patient's body, or some other combination of these steps.

[141] In one embodiment of the invention, the device is installed into the body through a special device and then deployed into the body from this special device. When the device is installed in a body cavity, such as the bladder, it is shaped to support the device in the body, such as an expanded or higher profile shape, and then the device is removed from the device and inserted into the body cavity. According to the example shown in FIG. 7, the device 700 is shaped to retain the device in the body after it is removed from the special device 702. Such special device 702 can be configured as any suitable device with a passageway, for example, the device can be a catheter, a ureteral catheter, or a cystoscope. The custom device 7 02 may be a device that is commercially available, or it may be a device that is specifically adapted to these drug delivery devices, such as those described in US Patent Application Published No. 2011/0202036. : Boyko et al.

[142] Once the device is inserted into the body, the device releases the drug in a controlled manner. The device can provide continuous, continuous, intermittent or intermittent release of the desired amount of drugs over a desired and predetermined period of time. In various embodiments, the device can release the desired dose of drug over an extended period of time, for example, 12 hours, 24 hours, 5 days, 7 days, 10 days, 14 days or 20, 25, 30, 45, 60, 90 or more days. In the most preferred embodiment of the invention, the corresponding device is a bladder drug delivery device that provides continuous release of an amount of drug into urine in the bladder over a predetermined treatment period of 7 days to 60 days, for example 14 days to 30 days. The rate of delivery and dosage of the drug can be selected depending on the specific drug to be delivered to the patient's body, as well as the specific disease or conditions for its treatment.

[143] In those embodiments where the device includes a drug in a solid state, the release of the drug from the device occurs after it has dissolved within the device. Bodily fluid enters the device, comes into contact with the drug and dissolves it, after which the dissolved drug exits the device through the microchannels that are described here. For example, in cases where the device is placed in the bladder, the drug may dissolve as long as it is in contact with urine.

[144] The device may then be removed from the body, for example in cases where the device fails to fully dissolve within the human body, fails to fold back into its original shape, or in other cases where the device needs to be removed.

[145] In addition, the device may be configured to be fully or partially biodegradable within the human body, thereby eliminating the need for removal from the body. In one case, the device dissolves completely or is sufficiently destroyed that it can be removed from the bladder during urination. In some embodiments, the material of the device includes chemical components that cause microbiological degradation of the device so that the device can be passed through the urethra during urination, as described in U.S. Patent No. 8,690,840, which is issued to to Lee et al. and which is incorporated herein by reference. The device may not be removed from the patient's body, or may not have to wait for it to degrade in the body until it releases some of the drug, or preferably most or all of the drug.

[146] In FIG. 8 shows the procedure for deploying the device 800 into the bladder (the anatomy of an adult male is shown as an example). The special device 802 can be inserted into the bladder through the urethra, and the device 8 00 can be passed through the special device 8 02, which is driven by a thin probe and/or a flow of lubricant or other liquid, for example, until until the device 800 enters the bladder. As a result, the device will be inserted and deployed into the bladder of the man or woman who needs treatment.

[147] The device may be inserted and deployed into the patient's bladder during a single procedure or in combination with another urologic or other procedure, or in combination with a surgical procedure before, during, or after any other procedure or operation. The device may release one or more drugs that will be released at a specific point and/or area of body tissue for therapeutic or prophylactic purposes before or after surgery (or both before and after such surgery).

[148] In one embodiment of the invention, the drug delivery device, which initially contains a drug payload, is fully deployed within the bladder to provide sustained delivery of at least one drug to the bladder in an amount that will be therapeutically effective. effective for those body tissues that need treatment (this may be the bladder itself or other tissue areas near the bladder). Such delivery of the drug to tissue sites may provide an alternative to systemic drug administration, which may entail undesirable side effects or lead to insufficient bioavailability of the drug. Following the in vivo deployment procedure of the device, at least a portion of the drug payload is released from the device substantially continuously over an extended period of time into the urothelium and (possibly) nearby body tissues in an amount that is effective to provide treatment or improve urinary function. patient's bladder. In the most preferred embodiment of the invention, the device remains in the bladder, releasing the drug over a predetermined period of time (eg, two weeks, three weeks, four weeks, a month, or a longer period of time).

[149] In such cases, the device can be used to treat the following diseases and disorders: interstitial cystitis, radiation cystitis, pelvic pain, overactive bladder syndrome, bladder cancer, neurogenic bladder syndrome, neuropathic or non-neuropathic bladder sphincter dysfunction, infectious diseases, postoperative pain or other diseases, disorders, as well as pathological conditions treated with those drugs that are released into the bladder. The device may release drugs that improve bladder function (such as bladder capacity and compliance and/or the frequency of uninhibited bladder contractions), which reduce pain and discomfort in the bladder or other organs in the vicinity of the bladder, or which have other effects. or a combination of the various effects indicated above. In addition, a device that is positioned and deployed in the bladder may release a therapeutically effective amount of one or more drugs to other genitourinary organs within the body, such as other sites within the body's urological or reproductive system, including one or more both kidneys, into the urethra, into one or both ureters, into the penis, into the testicles, into one or both seminal glands, into one or both vas deferens, into one or both ejaculatory ducts, into the prostate gland, into the vagina, into the uterus, into one or both ovaries, or into one or both fallopian tubes, among others (or simultaneously into various combinations of the above organs of the male or female body). For example, a device for delivering a drug to the bladder can be used in the treatment of urolithiasis or fibrosis, erectile dysfunction, as well as other diseases, disorders and pathological conditions.

[150] In one embodiment, a bladder drug delivery device is inserted into the bladder to release lidocaine or other analgesic locally (at a specific point) to control pain occurring in any organ of the body (eg, as a result of any disease or disorder in the tissues of the genitourinary system), or to control pain resulting from any bladder procedure, such as surgery, catheter insertion, ablation, medical device implantation or (including) removal of stones or foreign bodies, among other things.

[151] In other embodiments, the drug delivery device is sterilized, for example, after fabrication/installation of the device and before insertion of the device into the patient's body. In some cases, the device may be sterilized after the finished device is packaged, for example, in such cases, the package containing the device will be subjected to gamma irradiation, electron beam irradiation, or ethylene oxide gas. Although exposure to gamma rays may affect certain characteristics of devices that are intended to deliver a drug, as explained herein, device materials and configuration can be selected to eliminate or substantially neutralize any adverse effects. .

[152] In one embodiment, a method of administering a medicament to a patient comprises introducing any of the medicament delivery devices described herein into a passageway or body cavity of the patient; and also creating conditions for the influx of water into the reservoir in order to raise the pressure in the reservoir to a value sufficient to force the medicinal product to flow out of the reservoir through any pre-made through holes in the body of the device, as well as through one or more microchannels formed between limiting plug and elastic section of the device body, from (i) the drug reservoir and at least one pre-formed drug release channel or (ii) from the drug reservoir and from an opening in the end of the device and subsequent introduction of the drug into passageway or into the patient's body cavity. In some embodiments, the body cavity is the patient's bladder.

[153] In certain specific embodiments, trospium is administered locally to a patient's bladder to treat neurogenic detrusor overactivity (NDO) resulting from spinal cord injury (SCI). In some embodiments, the patient is assessed for more than 6 months to identify traumatic or non-traumatic damage to the suprasacral segments in SCI and to create a documented medical history for the treatment of SSD. In this case, it may also be necessary to use an intravesical catheter (temporarily) to empty the bladder of such a patient. In some such embodiments, trospium is administered locally to the patient's bladder using one of the drug delivery systems described herein. In some specific embodiments of the invention, the device (with a payload of trospium, such as tablets containing trospium chloride) is placed in the bladder using a special insertion tool, and the device is then removed after a period of 30 to 60 days. for example, after 42 days. This device provides gradual and continuous release of trospium over an extended period of time. In certain such embodiments, the device releases trospium at an average daily rate of about 2 mg/day to about 30 mg/day, such as about 5 mg/day to about 25 mg/day, such as about 5 mg /day up to approximately 15 mg/day, or at a level of approximately 10 mg/day throughout the treatment period, for example, over a continuous 42-day period. In some other embodiments, trospium may be locally administered to the bladder using other delivery systems known in the art, such as those described in US Patent Application Published No. 2015/0182516 (by Giesing). which is incorporated herein by reference.

[154] In certain specific embodiments, trospium is administered locally to a patient's bladder to treat idiopathic overactive bladder (iOAB) and urinary incontinence. In some embodiments, the patient is assessed for at least 6 months to identify symptoms of overactive bladder (OAB; urinary frequency/urgency) combined with urge incontinence or mixed urinary incontinence (with a predominant urge component). incontinence). In some such embodiments, local administration of trospium to the patient's bladder is accomplished using one of the drug delivery systems described herein. In some specific embodiments of the invention, the device (with a payload of trospium, such as tablets containing trospium chloride) is placed in the bladder using a special insertion tool, and the device is then removed after a period of 30 to 60 days. for example, after 42 days. The device provides gradual and continuous release of trospium over an extended period of time. In certain such embodiments, the device releases trospium at an average daily rate of about 2 mg/day to about 30 mg/day, such as about 5 mg/day to about 25 mg/day, such as about 5 mg/day. day to approximately 15 mg/day or at a level of approximately 10 mg/day throughout the treatment period, for example, over a continuous 42-day period. In some other embodiments, trospium may be locally administered to the bladder using other delivery systems known in the art, such as those described in US Patent Application Published No. 2015/0182516 (author: Giesing), which is incorporated herein by reference.

[155] After reviewing the following non-limiting examples, a greater understanding of the present invention may be provided.

[156] Example 1

[157] Prototypes of the devices were made, with a central diaphragm drilled by a laser beam, and these prototypes were loaded with trospium chloride tablets. The first set of devices had two diaphragms with spacer sleeves (that is, plugs with longitudinal diaphragms drilled into them) at each end of the device, and the second set of devices had two limiting plugs at the ends of each device. These prototypes are shown in FIG. 11 and 12. The device in accordance with FIG. 11 has three drug release apertures: two at opposite ends of the device and one aperture in the side wall. The device had a drug reservoir channel with an internal diameter of 2.64 mm and a wall thickness of 0.2 mm. Shore wall hardness: 50A. The device according to FIG. 12 has one drug release aperture plus two apertures at opposite ends of the device to release the drug once sufficient osmotic pressure is reached to create the microchannels. The device had a drug reservoir channel with an internal diameter of 2.64 mm and a wall thickness of 0.2 mm. Shore wall hardness: 50A.

[158] These devices were installed in containers of deionized water and the amount of trospium chloride released over a period of time was measured. The in vitro test results (five tests for each prototype design) are shown in the graphs in FIG. 11 and 12. As can be seen, the restriction plugs provide appropriate and highly reproducible drug release parameters compared to less reproducible release parameters when a diaphragm with a spacer sleeve is installed in the device. The differences observed in practice between the two systems were unpredictable.

[159] Example 2

[160] The device which is shown in FIG. 3 was manufactured as follows. The device was a double-lumen silicone tube with a laser-drilled diaphragm, with parylene C-coated silicone elastomer plugs that defined the drug cavity and also formed one-way valves at both ends of the cavity. These plugs were held in place using white silicone adhesive in a large bore, and preformed super-elastic nitinol wire was placed in the bore holding the frame, with the ends of the bore being sealed with clear silicone adhesive. The drug was a tablet that included trospium chloride (pharmaceutical active ingredient), povidone (polyvinylpyrrolidone (PVP)) K29/32 (binder excipient), and polyethylene glycol 8000 (lubricant excipient). Each device contained 850 mg of trospium chloride. These devices were small in size (less than 5 cm along the long axis), they were flexible and had certain complex shapes in order to minimize possible irritation and inflammation. The device had a drug reservoir channel with an internal diameter of 2.64 mm and a wall thickness of 0.41 mm. The nitinol wire had a thickness of 0.279 mm.

[161] The body of the device acts as an osmotic pump and provides passive control of drug release once it is loaded into the device, while the nitinol wire ensures that the system is retained in the bladder throughout the treatment period, and the system remains able to move freely in the bladder. This device, acting as an osmotic pump, releases the drug at a controlled rate through osmosis. The wall of the silicone tube that contains the trospium mini-tablets acts as a semi-permeable membrane, and the thickness of the wall can regulate the flow of water into the system, and ultimately controls the rate of drug release. The system has many channels for drug release: one channel is located in the middle part of the system, and other channels are located at the ends of each device. The rate of drug delivery is controlled by the filtration coefficient of the semipermeable membrane, as well as the osmotic properties of the drug and osmotic agent in the passage channel. Trospium chloride has a high water filtration coefficient and is itself an osmotic agent; therefore, no additional osmotic agents are included in it. This particular device was designed to release trospium chloride at a rate of approximately 10 mg/day.

[162] This system was installed in a container of deionized water at 37°C and the rate of trospium release was measured. The results of in vitro measurements (with standard deviation, number of measurements - 3) are shown in FIG. 13. As can be seen, the average daily release rate was approximately 10 mg/ml. As a result, it was found that this system can be adjusted to provide the desired daily trospium chloride release parameters.

[163] Example 3

[164] Devices designed to deliver trospium into the bladder were fabricated to determine in vitro release parameters according to the parameters in Table 1. These devices were fabricated using one of two types of silicone outer shells. The first type of shell ("RW" - "regular wall silicone tube") included an annular tube with a wall thickness of 0.2 mm, defining the channel of the drug reservoir and having a hardness of 50 Shore A. The second type of sheath ("TW" - "thick wall silicone tube") included an annular tube with a wall thickness of 0.4 mm, defining the channel of the drug reservoir and having a hardness of 35 Shore A. Both types of these silicone shells included a drug reservoir channel with an internal diameter of 2.64 mm. All devices included a 150 µm diameter diaphragm, which was drilled by a laser beam and located approximately in the central part of the side wall of the silicone shell. These systems were installed using plugs of different lengths. Such systems included either two plugs at each end, or one plug complete with a spacer sleeve at the second end of the system. These plugs seal the ends of the tank, as a result of which microchannels cannot form on them. Approximately 996 mg of trospium chloride tablets were loaded into the drug reservoir channel of each system. Tablet composition: 95 percent trospium chloride-polyvinylpyrrolidone (PVP) granules with a ratio of these components of 97:3 percent by weight, as well as 5 percent polyglycol 8000 PF (PEG 8k / PEG 8k) by weight. Trospium chloride acts on both the active agent and the osmotic agent in order to stimulate the osmotic mechanism of drug release. To determine the stability parameters of these systems in vitro, a total of 42 such devices were tested. All systems were irradiated for sterilization purposes.

[165] For RW systems, first order trospium release kinetics were observed after initial peak drug release rates of approximately 18 to 24 mg/day were achieved on day 7. TW type systems had an initial maximum release rate of 10 to 15 mg/day with a constant release rate of 10 to 14 mg/day over the subsequent 35 days. RW type systems exhibited higher cumulative release compared to TW systems, but the number of plugs that are present in these systems, as well as the length of these plugs, have no effect on drug release rates from these systems.

[166] All equipment components that were sterilized by irradiation were used to perform in vitro drug release tests. Each component was placed in a laboratory glass beaker containing 300.00+/- 0.05 grams of degassed deionized water and placed in a simulated operating environment chamber where the beaker was maintained at 37°C at predetermined times. (T=1, 2, 4, 7, 10, 14, 21, 28, 35 and 42 days) samples were taken from each beaker. At each specific time point, these glasses were turned up and down 15 times in a row, a 1 ml sample was taken, and 1 ml of fresh release medium was filled in instead. At the onset of days 14 and 28, the release medium was completely replaced. Trospium samples collected at appropriate time points were analyzed using a high performance liquid chromatography (HPLC) system running the MassLynx application software.

[167] The release rate of trospium chloride (mg/day) at a given time T(i) was estimated using the inverse difference method according to Equation 1:

where the values M(i) and M(i-1) are the total volumes of the released medium at the current time T(i) and at the previous time T(i-1), respectively. Shown in FIG. 22, the cumulative amount of trospium released was used to provide the trospium chloride release rates shown in FIG. 18-21. The initial drug loading value was used to estimate the percentage of trospium released, which is shown in FIG. 23. The average values for the cumulative percentage of trospium released for each configuration are given below in

[168] RW and TW systems with two plugs (see FIG. 18). The first order kinetic parameters of trospium release were recorded after reaching an initial release rate of approximately 18 to 20 mg/day approximately 7 days after the start of the drug release experiment, in which RW systems were run with plugs of different lengths (5, 8 and 16 mm). After 7 days, a gradual decrease in release rates from the RW system was observed. After completion of the 42-day experiment, the release rate averaged 5 to 6 mg/day. It has been determined that the initial release rate for the TW system should be approximately 12 to 13 mg/day. After the first 10 days, release rates remained essentially constant at approximately 11 to 13 mg/day for the first 35 days. After the first 35 days, first-order kinetic parameters for trospium release were observed. After completion of the 42-day experiment, release rates averaged 8 to 9 mg/day. There was no change in release rate when the length of the plug was changed. All RW systems with 5, 8, or 16 mm long plugs exhibited the same performance during media release, and all TW systems with 5, 8, or 16 mm long plugs also exhibited identical performance during media release.

[169] System with one plug and one spacer sleeve (see FIG. 19). First-order trospium release kinetics were recorded after reaching an initial release rate of approximately 20 to 23 mg/day approximately 7 days after the start of a drug release experiment in which RW systems were run with plugs of varying lengths (5, 8 and 16 mm). After 7 days, a gradual decrease in the release rate from the RW system was observed. After completion of the 42-day experiment, the release rate averaged 5 to 6 mg/day. It has been determined that the initial release rate for TW systems should be approximately 13 to 15 mg/day. After the first 10 days, release rates remained essentially constant at approximately 10 to 13 mg/day for the first 35 days. After the first 35 days, first-order kinetic parameters for trospium release were observed. After completion of the 42-day experiment, release rates averaged 8 to 9 mg/day. No change in media release rate was observed when the plug length was varied. All RW systems with 5, 8, or 16 mm long plugs exhibited the same performance during media release, and all TW systems with 5, 8, or 16 mm long plugs also exhibited identical performance during media release.

[170] Single-plug, single-spacer system versus dual-plug system (see FIG. 20). All RW systems with 5, 8, or 16 mm long plugs exhibited the same performance during media release, and all TW systems with 5, 8, or 16 mm long plugs also exhibited identical performance during media release. Additionally, the RW and TW systems showed no change in release rate when comparing the single plug systems and the dual 8mm plug systems from the batch of mini plug systems tested. Changes in the length of the plugs and the number of plugs present did not change the rate of trospium chloride release from these systems.

[171] Systems with 8 mm plugs (see FIG. 21). First-order trospium release kinetics were recorded after reaching an initial release rate of approximately 19 to 24 mg/day approximately 7 days after the start of a drug release experiment in which RW systems were run with varying amounts of plugs. 8 mm long. After 7 days, a gradual decrease in release rates from RW systems was observed. After completion of the 42-day experiment, the release rate averaged 5 to 6 mg/day. It has been found that the initial release rate for TW systems should be approximately 10 to 13 mg/day. After the first 10 days, release rates remained essentially constant at approximately 10 to 14 mg/day for the first 35 days. After the first 35 days, first-order kinetic parameters for trospium release were observed. After completion of the 42-day experiment, release rates averaged 8 to 10 mg/day. There was no change in release rate when varying the number of 8 mm plugs included in each of these systems. All RW systems with 8mm plugs exhibited the same media release performance when one or two plugs were present in the system, and all TW systems with 8mm plugs exhibited the same media release performance when there were one or two plugs present in the system.

[172] In conclusion, it should be noted that osmotic trospium release devices with a wall thickness of 0.2 mm (RW) and a wall thickness of 0.4 mm (TW) were manufactured, into which approximately 917 mg of trospium chloride was loaded, after which An in vitro release experiment was performed at 37°C with deionized water as the release medium. For RW systems, first order trospium release kinetics were recorded after reaching an initial release rate of approximately 18 to 24 mg/day at approximately day 7 after the start of the media release experiment. The initial release rate for TW systems was approximately 10 to 15 mg/day. For TW systems, the release rate remained essentially constant at approximately 10 to 14 mg/day for the first 2 to 8 days. After the first 35 days, the first order kinetic parameters of trospium release were recorded. Thus, at the end of this experiment, the RW systems had a high initial maximum release rate and a higher cumulative release of the total drug overall. TW systems had a more consistent release rate over the first 35 days and a lower cumulative release of total drug overall. There were no changes in release rate parameters when changing the number of plugs present or the length of those plugs. All RW type systems exhibited approximately the same release rate, cumulative release, and relative (percentage) release. All TW systems also exhibited approximately the same release rate, cumulative release, and relative release.

[173] Example 4

[174] Bladder trospium release devices with drug release port(s) were fabricated for in vitro drug release testing. For the manufacture of such systems, double-lumen silicone tubes with two passage channels were used. A double-oval wire was installed in the small passage channel, and trospium mini-tablets were loaded into the large passage channel, which contained (percentage by weight) 92 percent trospium chloride, 3 percent PVP and 5 percent PEG 8K. The amount of trospium chloride that was loaded into each system was approximately 910 to 920 mg.

[175] Configuration with four holes formed by stamping. In FIG. 9A-9B show a four-hole stamping configuration: two holes in the side wall of the outer shell near each end of the drug reservoir. These holes are located over parylene C coated silicone restriction plugs that are 5 mm long and 2.77 mm outer diameter (OD). Silicone adhesive behind the restriction plugs is used to hold the restriction plugs in place, and this adhesive seals the ends of the passageway. A double-oval wire was installed in the smaller bore of the tube, and silicone adhesive was injected into this bore to hold the wire in place, allowing it to harden for approximately 24 hours, after which the ends of the wire were cut so that they protruded 5 mm from the ends of the limiting plugs. These silicone restriction plugs were oversized; the internal diameter of the silicone tube was 2.64 mm, and the external diameter of the silicone restriction plugs was 2.77 mm. Parylene coating on the limiting plugs was used to inhibit adhesion after gamma irradiation on the contact surface of two silicone components after gamma irradiation was used to sterilize the product. The holes formed by stamping were located at a distance of 2 to 3 mm from each end of the drug reservoir. The punched holes over the oversized restriction plugs were designed to be used as drug release outlets once the osmotic pressure within the drug reservoir had built up.

[176] The locations and number of holes may vary depending on the number and locations of restriction plugs along the length of the tube. For example, if there is only one restriction plug and two stamping holes in the middle portion of the tube, then two drug release holes will be located in the middle portion of the tube.

[177] Double slotted hole configuration. In FIG. 10A-10B show a device configuration with two slot openings: these slots are provided in the side walls of the outer shell near each end of the drug reservoir. Parylene C coated silicone restriction plugs (length 5 mm and outer diameter 2.77 mm) are installed in the tube and slits are then created in the plugs using a razor blade. The razor blade is passed through the wall of the tube and partially penetrates the limiting plug, as a result of which the silicone material is not removed from the wall (unlike stamped holes, which remove the wall material when creating them). Silicone adhesive behind the restriction plugs is used to hold the restriction plugs in place, and this adhesive seals the ends of the passageway. These slits are located at a distance of 2 to 3 mm from each end of the drug reservoir. A double-oval wire was installed in the smaller bore of the tube, and silicone adhesive was injected into this bore to hold the wire in place, allowing it to harden for approximately 24 hours, after which the ends of the wire were cut so that they protruded 5 mm from the ends of the limiting plugs. These silicone restriction plugs were oversized; the internal diameter of the silicone tube was 2.64 mm, and the external diameter of the silicone restriction plugs was 2.7 7 mm. Parylene coating on the limiting plugs was used to inhibit adhesion after gamma irradiation on the contact surface of two silicone components after gamma irradiation was used to sterilize the product. A small piece of paper was placed in each slot in order to prevent possible adhesion and closure of the walls during radiation treatment, and after radiation treatment this piece of paper was removed. Slots over oversized restriction plugs were designed to be used as drug release outlets once osmotic pressure within the drug reservoir had built up.

[178] The locations and number of slots may vary depending on the number and locations of restrictive plugs along the length of the tube. For example, if only one restriction plug is present in the middle portion of the tube, then one slot may be provided in the middle portion of the tube.

[179] Three-hole system (one laser-drilled diaphragm and two plugs). In FIG. 2 and 3A show a three-hole system in which the middle portion of the tube has a laser-drilled aperture with a diameter of 150 microns and two plugs (see FIGS. 3B and 3C) that have an outer diameter of 2.77 mm and a length of 8 mm. These plugs are made of silicone and have a Parylene C coating, with each plug having a bevel on one end (see FIGS. 3A-3C). Silicone adhesive is applied to the beveled end and large bore area to hold the plugs in place, but this adhesive does not seal the bore ends. In FIG. 3B and 3C show one end of the system with three holes and a plug. FIG. 1C and 1D show a diagram of such a one-way valve; each plug exceeding the size of the large passage channel, after increasing the osmotic pressure in the large passage channel, forms a one-way valve.

[180] In contrast to the holes that were formed by stamping, over the limit plugs (FIGS. 9A-9B), which are oversized, the slots over the limit plugs, which are oversized, (FIGS. 10A-10B) and the plugs (FIG. 1C, 1D, 3B, 3C), the hole drilled by the laser beam is an aperture, the dimensions of which are predetermined and which is already in the design, regardless of the presence of osmotic pressure in the drug reservoir (i.e., in the large passage channel or in the cavity of the passage channel, which is intended for the drug).

[181] In vitro drug release tests. Six types of in vitro drug release systems were tested according to the parameters shown in Table 3. The shapes of all types of systems were double-oval. However, the number and configuration of drug release holes, the wall thickness of the silicone tube (RW or TW), and the hardness of the silicone tube (50A and 35A) were different depending on the type of system. All of these systems were irradiated with gamma rays (intensity: 25 to 40 kilogray) and were then considered to be adequately tested in vitro for drug release.

[182] In vitro drug release from 0.20 mm wall thickness (RW) tube. Such systems were installed in beakers containing 300 grams of deionized water at 37°C and sampled at predetermined time points to plot in vitro release characteristics. FIG. 14 and 15 show the trospium chloride release rates and cumulative amounts released over time for Types 1, 2, and 3 systems, which are characterized in Table 3. No noticeable differences in drug release characteristics were observed between the two-hole (slit) systems. and four-hole systems (with holes formed by stamping), which provide an osmotically controlled rate of drug release. However, the three-hole system, which has a laser-drilled aperture with predetermined dimensions and two plugs, demonstrated a higher overall cumulative release rate compared to the two-hole systems and the four-hole systems.

[183] In vitro drug release from a 0.41 mm wall thickness (TW) tube. Such systems were installed in beakers containing 300 grams of deionized water at 37°C and sampled at predetermined time points to plot in vitro release characteristics. FIG. 16 and 17 show the trospium chloride release rates and cumulative amounts released over time for Types 4, 5, and 6 systems, which are characterized in Table 3. No noticeable differences in drug release characteristics were observed between the two-hole (slit) systems. and four-hole systems (with punched holes) that provide osmotically controlled drug release rates. However, the three-hole system, which has a laser-drilled aperture with predetermined dimensions and two plugs, demonstrated a higher overall cumulative release rate compared to the two-hole systems and the four-hole systems.

[184] Example 5

[185] Devices have been manufactured to compare a system that has two restriction plugs at the ends of the device and no diaphragm on the side wall (for example, as described in US Patent Application Published 2016/0008271 by Lee) with a system , in which there are pre-formed channels in the side wall near the limiting plugs, and there is no diaphragm on the side wall (for example, as shown in FIG. 9). The parameters of such a device are shown below in Table 4.

[186] These devices were immersed in deionized water, after which the drug release rate was measured over a sufficiently long period of time. These results are shown in FIG. 24 and they show that the system, which has punched holes close to the restricting plugs to create microchannels between them, provides similar release performance over the course of an 84-day in vitro test compared to the performance of the previous system, which only has plugs. Indeed, a system that included stamped holes and restrictive plugs exhibited smoother release characteristics compared to a system that had only plugs.

[187] The publications cited herein, as well as other materials to which these publications refer, are expressly incorporated herein by reference. Modifications and variations to the methods and apparatus described herein will be apparent to those skilled in the art upon reading the foregoing detailed description. Such modifications and changes are intended to fall within the scope of the appended claims.

Claims (18)

1. A method of treating a patient who needs treatment for idiopathic overactive bladder (iOAB) and urinary incontinence, the method comprising locally administering 5 to 24 mg/day of trospium into the patient's bladder continuously over a treatment period of 30 to 84 days. by means of a drug delivery device placed in the patient's bladder and including: a housing that has a wall defining a reservoir located inside the housing, this wall having at least one pre-made through hole, as well as a water-permeable section, the housing including an elastic section; a dosage form that includes trospium and is located inside the reservoir; And at least one limiting plug that covers an opening of the housing and contacts the elastic section of the housing, this opening providing a fluid communication path with the reservoir, the water-permeable wall section is configured to allow water to enter the drug delivery device and contact the dosage form contained in the reservoir, and the release of trospium from this device is controlled by (i) release of trospium through said at least one pre-formed through hole in the wall, and (ii) release of trospium through a transition system of one or more microchannels between the elastic section of the housing and at least one limiting plug covering this is an opening until the reservoir reaches hydrostatic pressure sufficient to form one or more microchannels. 2. Method according to claim 1, characterized in that the duration of the treatment period is from 30 to 60 days, in particular 42 days. 3. The method according to claim 1, characterized in that trospium is released into the bladder at an average daily rate of 5 to 20 mg/day during the treatment period. 4. The method according to claim 1, characterized in that trospium is released into the bladder at an average daily rate of 5 to 15 mg/day during the treatment period. 5. The method according to claim 1, characterized in that trospium is released into the bladder at an average daily rate of 10 mg/day during the treatment period. 6. A method of treating a patient who needs treatment for idiopathic overactive bladder (iOAB) and urinary incontinence, the method comprising locally administering 5 to 24 mg/day of trospium into the patient's bladder continuously over a treatment period of 30 to 84 days. by means of a drug delivery device placed in the patient's bladder and including: a tubular-shaped body that has a wall defining a reservoir located inside the body, this wall comprising a water-permeable section and an elastic section having at least one drug release channel pre-formed therein; a dosage form that includes trospium and is placed within said reservoir, a water-permeable section of the wall of which allows water to pass into the drug delivery device and contact the dosage form located in the reservoir; And at least one restriction plug secured within the reservoir in contact with the elastic section of the housing and in proximity to at least one preformed drug release channel, such that the at least one restriction plug controls the release of trospium from said device through at least one a pre-formed drug release channel through a transition system of one or more microchannels between the elastic section of the housing and at least one limiting plug included in at least one pre-formed drug release channel, until the reservoir reaches a hydrostatic pressure sufficient to form one or more microchannels. 7. Method according to claim 6, characterized in that the duration of the treatment period is from 30 to 60 days, in particular 42 days. 8. The method according to claim 6, characterized in that trospium is released into the bladder at an average daily rate of 5 to 20 mg/day during the treatment period. 9. The method according to claim 6, characterized in that trospium is released into the bladder at an average daily rate of 5 to 15 mg/day during the treatment period. 10. The method according to claim 6, characterized in that trospium is released into the bladder at an average daily rate of 10 mg/day during the treatment period.