Drug therapy delivery system and method

Abstract

A drug delivery device is provided for metering delivery of a drug to ocular tissue over a period of time. The device (100) includes a tube (104), a microporous core (106), and a body portion (102) having an exterior surface (108) defining an interior reservoir (110). The outer surface defines a port (112) of the body portion, the port being arranged to facilitate a first passage of the medicament from the reservoir. The tubular length defines a second passage of the medicament from the first end to the second end of the tubular. The first end is coupled to the port to receive a first passage of medicament from the reservoir. The second end is disposed at a distance from the first end to deliver a drug to ocular tissue. A microporous core is disposed in the lumen along at least a portion of the length of the tube and has a porosity to meter a second passage of the medicament.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 395,501, filed on August 5, 2022, which is incorporated herein by reference in its entirety for all purposes. Technical Field

[0002] The present disclosure relates generally to devices and methods for delivering drugs to a tissue region of the body. More specifically, the present disclosure relates to devices and methods for delivering therapeutic drugs to tissue associated with the eye. Background Art

[0003] Aqueous humor is a fluid that fills the anterior chamber of the eye and contributes to the intraocular pressure, or fluid pressure within the eye. Ocular hypertension is a condition in which the intraocular pressure, or fluid pressure inside the eye, is elevated. Untreated ocular hypertension can lead to diseases including glaucoma, which can cause gradual and sometimes permanent loss of vision in the affected eye.

[0004] Many attempts have been made to treat ocular hypertension, particularly glaucoma. These attempts have included surgical procedures involving the implantation of drainage devices designed to reduce intraocular pressure in the affected eye, as well as the administration of medications. The goal of these treatments is to improve quality of life and preserve visual function by reducing intraocular pressure.

[0005] Although eye drops are typically administered to patients who must self-administer the drug, implantable extended drug delivery devices may be used in some cases. Implantable extended drug delivery devices are typically located outside the eye (e.g., an extraocular approach), or alternatively implanted within the anterior chamber of the eye (an intracameral approach).

[0006] Extraocular methods of drug delivery present various challenges. To be effective, extraocular methods require that sufficient amounts of drug be delivered through the conjunctival layer of the eye and into the anterior chamber of the eye via the biological processes of the eye. Apparent natural mechanisms, such as the continuous flushing mechanism of the human tear film, and the natural barrier of the interior of the eye formed by the conjunctiva, complicate the effectiveness of extraocular methods, resulting in suboptimal dose delivery over time. Therefore, extraocular methods sometimes involve administering an excess of drug to prolong the duration of efficacy.

[0007] On the other hand, the intracameral approach is a more invasive approach that requires puncturing through various tissue layers of the eye to gain access to the device and to place the device in the anterior chamber of the eye. In the case of administering drugs in conjunction with absorbable (bioabsorbable) devices, the intracameral approach is further complicated because the degradable nature of the device may cause the device to shift and float in the anterior chamber. In addition, removal and repeated replacement of the device requires trauma to the eye tissue. Summary of the invention

[0008] Disclosed herein are drug delivery or metering devices and methods for metering drug delivery to ocular tissue over a period of time. Advantages of such devices and methods include controlling the rate at which a drug is delivered or dispensed to a target location (e.g., a target tissue) for therapeutic treatment, and facilitating the transition of a drug from its first state to its second state as the drug travels along a delivery pathway to be delivered to the target location.

[0009] According to one example ("Example 1"), a drug delivery device is disclosed for metering the delivery of a drug to an ocular tissue over a period of time, wherein the device includes: a main body portion having an outer surface defining an internal storage portion, the outer surface defining a port of the main body portion, the port being configured to facilitate a first passage of a drug from the storage portion; a tubing having a first end, a second end opposite the first end, and an inner cavity extending therebetween along the length of the tubing, the length of the tubing defining a second passage of the drug from the first end to the second end, the first end being connected to the port to receive the first passage of the drug from the storage portion, the second end being disposed at a distance from the first end to deliver the drug to the ocular tissue; and a microporous core disposed in the inner cavity along at least a portion of the length of the tubing, the microporous core having a porosity for metering the second passage of the drug.

[0010] According to another example ("Example 2") further than Example 1, the drug has a first state when it is disposed at the first end of the tubular object, and has a second state when it is disposed at the second end of the tubular object. When the drug travels through the microporous core along the second path, the drug changes from the first state to the second state.

[0011] According to another example ("Example 3") further than Example 2, the first state is a delivery state of the drug, and the second state is a treatment state of the drug.

[0012] According to another example ("Example 4") further than Example 2, the first state is a non-therapeutic state of the drug, and the second state is a therapeutic state of the drug.

[0013] According to another example ("Example 5") further relative to Example 2, the first state is a high concentration state of the drug, and the second state is a low concentration state of the drug. The low concentration state has a lower concentration than the high concentration state.

[0014] According to another example ("Example 6") further than any one of Examples 1 to 5, the microporous core includes a plurality of nodes and fibrils configured to meter a second passage of the drug.

[0015] According to another example ("Example 7") further to Example 6, the second pass of the drug is configured to be metered by the surface roughness and surface energy of the plurality of nodes and fibrils of the microporous core.

[0016] According to another example ("Example 8") further than Example 6 or 7, the microporous core includes ePTFE fibers.

[0017] According to another example ("Example 9") further relative to Example 8, the ePTFE fiber includes a uniaxial expansion structure.

[0018] According to another example (“Example 10”) further to Example 8, the ePTFE fiber includes a spiral geometry or a helicoidal geometry.

[0019] According to another example ("Example 11") further than Example 6 or 7, the microporous core includes an ePTFE strip including a biaxially expanded structure.

[0020] According to another example (“Example 12”) further than any of Examples 1 to 11, the tubular object includes a thermoplastic compound.

[0021] According to another example further than Example 12 (“Example 13”), the thermoplastic compound includes one or more of the following: FEP, EFEP, ETFE, or PATT.

[0022] According to another example (“Example 14”) further than any one of Examples 1 to 11, the tubular object includes an elastomeric compound.

[0023] According to another example (“Example 15”) further than Example 14, the elastomeric compound includes silicone (silicone resin).

[0024] According to another example ("Example 16") further to any one of Examples 1 to 15, the tubular is a coating disposed on an outer surface of the microporous core.

[0025] According to another example ("Example 17") further to any of Examples 1 to 15, the tubular is a tape wrapped around the outer surface of the microporous core.

[0026] According to another example ("Example 18") further to any one of Examples 1 to 17, the porosity of the microporous core is preselected to allow passage of a drug compound having a predetermined molecular shape.

[0027] According to another example ("Example 19") further to any one of Examples 1 to 17, the porosity of the microporous core is preselected to allow a drug compound having a predetermined molecular weight to pass therethrough.

[0028] According to another example ("Example 20") further to any one of Examples 1 to 17, the porosity of the microporous core is preselected to allow a drug compound having a predetermined molecular polarity to pass therethrough.

[0029] According to another example (“Example 21”) further relative to any one of Examples 1 to 20, the outer surface of the main body portion includes a first surface and a second surface opposite to the first surface, and the port is arranged between the first surface and the second surface.

[0030] According to another example (“Example 22”) further relative to any one of Examples 1 to 20, the outer surface of the main body portion includes a first surface and a second surface opposite to the first surface, and the port is provided in the first surface.

[0031] According to another example ("Example 23") further relative to Example 22, the first end of the tubular object is disposed in the storage portion, so that most of the length of the tubular object is disposed in the storage portion.

[0032] According to another example ("Example 24") further than Example 23, a majority of the tubular object disposed within the reservoir is configured to partially cover the microporous core to provide a plurality of density-distributed openings.

[0033] According to another example ("Example 25") further than Example 23 or 24, between 10% and 40% (or 10% to 40%) of the length of the tubular object, inclusive of the endpoint, is located outside the storage portion.

[0034] According to another example ("Example 26") further relative to Examples 1 to 25, the main body portion includes a resealable opening, and the reservoir is configured to be refilled with the drug to be delivered through the opening.

[0035] According to one example ("Example 27"), a drug metering device is disclosed for metering the delivery of a drug to an eye tissue over a period of time, wherein the drug metering device includes: a tubular having a first end, a second end opposite the first end, and an inner cavity extending therebetween along the length of the tubular; and a microporous core disposed in the inner cavity along at least a portion of the length of the tubular, the microporous core having a porosity that facilitates a metered passage of the drug through the microporous core from the first end of the tubular toward the second end of the tubular. The drug has a first state when disposed at the first end of the tubular and a second state when disposed at the second end of the tubular, and the drug changes from the first state to the second state as the drug travels along the metered passage. The first end of the tubular includes a drug receiving portion, the drug receiving portion being sized to receive the drug in the first state and positioned to direct the drug in the first state to the microporous core.

[0036] According to another example ("Example 28") further relative to Example 27, the first state is a delivery state of the drug, and the second state is a treatment state of the drug.

[0037] According to another example ("Example 29") further relative to Example 27, the first state is a non-therapeutic state of the drug, and the second state is a therapeutic state of the drug.

[0038] According to another example ("Example 30") further relative to Example 27, the first state is a high concentration state of the drug, and the second state is a low concentration state of the drug, and the concentration of the low concentration state is lower than that of the high concentration state.

[0039] According to another example ("Example 31") further to any one of Examples 27 to 30, the drug receiving portion includes a microporous drug receiving component having a porosity different from the porosity of the microporous core.

[0040] According to another example ("Example 32") further relative to any one of Examples 27 to 30, the first end is substantially closed, and the drug receiving portion is a drug receiving space within the inner cavity, and the drug is temporarily stored in the inner cavity for delivery.

[0041] According to another example ("Example 33") further relative to any one of Examples 27 to 31, the first end is substantially open, and the drug receiving portion is configured to receive the drug from the surrounding environment outside the tubular object.

[0042] According to another example ("Example 34") further relative to Example 33, the device also includes a filter membrane disposed at the first end and configured to filter the drug received from the surrounding environment.

[0043] According to another example ("Example 35") further than Example 33, the first end is angled relative to the length of the tubular object.

[0044] According to another example ("Example 36") further than Example 33 or 35, a portion of the microporous core proximate to the first end of the tubular is angled relative to the length of the tubular.

[0045] According to another example ("Example 37") further relative to any one of Examples 33 to 36, the device also includes a main body portion having an exterior surface that defines an interior reservoir. The exterior surface defines a port of the main body portion that is coupled to the first end of the tubular article and configured to deliver the drug from the reservoir to the tubular article. The surrounding environment is the reservoir of the main body portion.

[0046] According to another example ("Example 38") further than any one of Examples 27 to 37, the microporous core includes a plurality of nodes and fibrils configured to control the passage of a dosed amount of a drug.

[0047] According to another example ("Example 39") further than Example 38, the second pass of the drug is configured to be metered by the surface roughness and surface energy of the plurality of nodes and fibrils of the microporous core.

[0048] According to another example ("Example 40") further than Example 38 or 39, the microporous core includes ePTFE fibers.

[0049] According to another example ("Example 41") further relative to Example 40, the ePTFE fiber includes a uniaxial expansion structure.

[0050] According to another example ("Example 42") further relative to Example 40, the ePTFE fiber includes a helical geometry or a spiral-like geometry.

[0051] According to another example ("Example 43") further than Example 38 or 39, the microporous core includes an ePTFE strip including a biaxially expanded structure.

[0052] According to another example (“Example 44”) further than any of Examples 27 to 43, the tubular includes a thermoplastic compound.

[0053] According to another example further to Example 44 (“Example 45”), the thermoplastic compound includes one or more of: FEP, EFEP, ETFE, or PATT.

[0054] According to another example (“Example 46”) further than any one of Examples 27 to 43, the tubular object includes an elastomeric compound.

[0055] According to another example (“Example 47”) further than Example 46, the elastomeric compound includes silicone.

[0056] According to another example ("Example 48") further than any of Examples 27 to 47, the tubular is a coating disposed on an outer surface of the microporous core.

[0057] According to another example ("Example 49") further than any of Examples 27 to 47, the tubular is a tape wrapped around an outer surface of the microporous core.

[0058] According to another example ("Example 50") further to any one of Examples 27 to 49, the porosity of the microporous core is preselected to allow a drug compound having a predetermined molecular shape to pass therethrough.

[0059] According to another example ("Example 51") further to any one of Examples 27 to 49, the porosity of the microporous core is preselected to allow a drug compound having a predetermined molecular weight to pass therethrough.

[0060] According to another example ("Example 52") further to any one of Examples 27 to 49, the porosity of the microporous core is preselected to allow a drug compound having a predetermined molecular polarity to pass therethrough.

[0061] According to one example ("Example 53"), a method for delivering a metered drug to eye tissue is disclosed, wherein the method includes: positioning a drug delivery device near the eye tissue, the drug delivery device including an outer surface defining an internal storage portion and a port configured to facilitate a first passage of the drug from the storage portion to the port; positioning a drug delivery tubing extending from the port at a first end of the tubing to position a second end of the tubing opposite to the first end in contact with the eye tissue fluid, thereby facilitating a second passage of the drug from the port to the second end of the tubing; and delivering the drug from the second end of the tubing via a microporous core disposed in the tubing, the microporous core having a porosity for the second passage of the metered drug.

[0062] According to another example ("Example 54"), a method for metering drug delivery to eye tissue is disclosed, wherein the method includes: disposing a first end of a drug delivery tubing near the eye tissue; disposing a second end of the drug delivery tubing opposite to the first end of the drug delivery tubing to establish fluid contact with the eye tissue; and delivering the drug from the second end of the tubing via a microporous core disposed in the tubing, the microporous core having a porosity that meters the passage of the drug from the first end to the second end of the tubing.

[0063] According to another example ("Example 55") further than Example 53 or 54, the second end of the drug delivery tubing is disposed in the anterior chamber of the eye.

[0064] According to another example ("Example 56") further relative to Example 53 or 54, the second end of the drug delivery tubing is disposed in the posterior chamber of the eye.

[0065] According to another example ("Example 57") further than Example 53 or 54, the second end of the drug delivery tubing is disposed within the vitreous body of the eye.

[0066] According to another example ("Example 58") further than Example 53 or 54, the second end of the drug delivery tubing is disposed between the scleral tissue and the choroid tissue of the eye.

[0067] The foregoing examples are merely examples and should not be construed as limiting or otherwise narrowing the scope of any inventive concept otherwise provided in the present disclosure. Although the present disclosure discloses a number of examples, still other examples will become apparent to those skilled in the art from the following detailed description, which shows and describes illustrative examples. Therefore, the drawings and detailed description should be considered illustrative in nature and not restrictive in nature. BRIEF DESCRIPTION OF THE DRAWINGS

[0068] The accompanying drawings are included to provide a further understanding of embodiments of the present disclosure and are incorporated in and constitute a part of this specification, illustrate examples, and together with the description serve to explain the principles of the present disclosure.

[0069] Figure 1 is a line drawing of a drug delivery device according to an embodiment disclosed herein;

[0070] FIG. 2A to FIG. 2F is a cross-sectional view of an eye in which a drug delivery device is implanted according to various embodiments disclosed herein to facilitate drug delivery to various locations in the eye;

[0071] Figure 3A is a schematic diagram of a drug delivery device according to an embodiment disclosed herein viewed from the top;

[0072] Figure 3B yes Figure 3A A cross-sectional view of the drug delivery device taken along line BB;

[0073] Figure 3C yes Figure 3B A cross-sectional view of a tubular object of a drug delivery device taken along line CC;

[0074] Figure 3D yes Figure 3CAnother cross-sectional view of the tube in FIG. 1 , showing its microstructure including nodes and fibrils for illustration purposes;

[0075] FIG. 4A to FIG. 4G is a schematic cross-sectional view of different drug delivery tubulars used in drug delivery devices according to embodiments disclosed herein;

[0076] FIG. 5A to FIG. 5C is a SEM image of a cross-sectional view of a microporous core implemented in a drug delivery device according to an embodiment disclosed herein (the image is to scale as shown in the figure);

[0077] Figure 5D is observed from one end along the diffusion direction Figure 5A SEM image of the microporous core (the image is to scale as shown in the figure);

[0078] FIG. 6A to FIG. 6C is a schematic diagram of different drug delivery routes according to embodiments disclosed herein;

[0079] Fig. 7A is a line drawing of a drug delivery device according to an embodiment disclosed herein;

[0080] FIG. 7B to FIG. 7D According to the embodiments disclosed in this article Fig. 7A A schematic cross-sectional view of a drug delivery device;

[0081] Fig. 8A and Figure 8B is a schematic cross-sectional view of an implanted drug delivery device according to an embodiment disclosed herein;

[0082] Fig.9A and Fig. 9B is a schematic cross-sectional view of an implanted drug delivery device according to an embodiment disclosed herein;

[0083] Fig. 10A and Fig. 10B is a schematic cross-sectional view of an implanted drug delivery tubing according to embodiments disclosed herein;

[0084] FIG. 11A to FIG. 11D are schematic cross-sectional views showing different stages of drug transport and delivery according to embodiments disclosed herein;

[0085] FIG. 12A to FIG. 12D are schematic cross-sectional views showing different stages of drug transport and delivery according to embodiments disclosed herein;

[0086] Fig.13 is a schematic cross-sectional view illustrating drug transport and delivery via concentration difference diffusion according to an embodiment disclosed herein; and

[0087] Fig.14 is a SEM image of a cross-sectional view of a main body portion of a drug delivery device according to an embodiment disclosed herein (the image is to scale as shown in the figure).

[0088] It should be understood that the drawings and photographs are not necessarily reproduced to scale unless otherwise indicated. In some cases, details that are not necessary for understanding the present disclosure or details that make other details difficult to perceive may be omitted. Of course, it should be understood that the present disclosure is not necessarily limited to the specific examples or embodiments described or depicted herein. DETAILED DESCRIPTION Definitions and terminology

[0089] The present disclosure is not intended to be read in a restrictive manner. For example, the terms used in the present application should be read broadly in the context of the meaning of such terms that will be attributed to those skilled in the art. It will be readily understood by those skilled in the art that the various embodiments of the inventive concepts provided in the present disclosure may be implemented by any number of devices and methods configured to perform the intended functions. It should also be noted that the drawings referenced in the text are not all drawn to scale (unless otherwise indicated), but may be expanded to illustrate various aspects of the present disclosure, and the drawings should not be interpreted as being restrictive in this regard. However, some figures do represent anatomical structures and the positioning of embodiments relative to the anatomical structures, and such representations should be understood to be accurately scaled and positioned, allowing some deviations, because the anatomical structures depicted will vary from person to person in size and position.

[0090] Regarding imprecise terms, the terms "about" and "approximately" are used interchangeably to refer to measurements including the measured value and also any measurements that are reasonably (fairly) close to the measured value. As understood and easily determined by a person of ordinary skill in the relevant art, a measurement that is reasonably (fairly) close to the measured value deviates from the measured value by a reasonably small amount. Such deviations may be attributed to, for example, measurement errors, differences in calibration of the measured values ​​and / or manufacturing equipment, human errors in reading and / or setting the measured values, fine-tuning to optimize performance and / or structural parameters in view of differences in the measured values ​​associated with other components, specific implementation scenarios, imprecise adjustments and / or manipulations of objects by humans or machines, and / or the like. In the case where it is determined that a person of ordinary skill in the relevant art will not easily determine a value for such a reasonably small difference, the terms "about" and "approximately" may be understood as the value plus or minus 10%.

[0091] The phrases "at least one", "one or more", and "and / or" are open-ended expressions that can be either conjunctive (combined) or disjunctive when the expressions are effective. For example, each of the expressions "at least one of A, B, and C", "at least one of A, B, or C", "one or more of A, B, and C", "one or more of A, B, or C", and "A, B, and / or C" refers to A alone; B alone; C alone; A and B together; A and C together; B and C together; or A, B, and C together. When each of A, B, and C in the above expressions refers to an element, such as X, Y, and Z, or a class of elements, such as X1-X n 、Y1-Y m and Z1-Z o When the phrase is used, it means a single element selected from X, Y and Z, a combination of elements selected from the same category (e.g., X1 and X2), and a combination of elements selected from two or more categories (e.g., Y1 and Z o ).

[0092] It should be understood that each maximum numerical limitation given throughout this disclosure is considered to include each lower numerical limitation as an alternative, just as these lower numerical limitations are clearly written in this article. Each minimum numerical limitation given throughout this disclosure is considered to include each higher numerical limitation as an alternative, just as these higher numerical limitations are clearly written in this article. Each numerical range given throughout this disclosure is considered to include each narrower numerical range that falls within such a wider numerical range, just as these narrower numerical ranges are clearly written in this article.

[0093] Before any embodiment of the present disclosure is described in detail, it should be understood that the present disclosure is not limited to the application thereof to the details of the construction and the arrangement of the parts described in the following description or shown in the accompanying drawings. The present disclosure can have other embodiments and can be practiced or implemented in various ways. Moreover, it should be understood that the words and terms used herein are for descriptive purposes and should not be considered as limiting. As used herein, "including", "comprising" or "having" and variations thereof are intended to include the items listed thereafter and their equivalents and additional items.

[0094] As used herein, the term "fibril" refers to an elongated piece of material, such as a polymer, whose length and width are substantially different from each other. For example, a fibril may resemble a string or fiber, wherein the width (or thickness) is much shorter or smaller than the length. In some examples, the width or thickness of a fibril may be smaller (microscopic) than a fiber.

[0095] The term "node" as used herein describes the point of connection of at least two fibrils, wherein a connection can be defined as a location where two fibrils permanently or temporarily contact each other. In some examples, a node can also be used to describe a volume of polymer that is larger than a fibril, as well as a location where a fibril originates or terminates without a clear continuation of the same fibril through the node. In some examples, a node is wider than a fibril but shorter than a fibril.

[0096] As used herein, "node" and "fibril" may be used to describe objects that are typically, but not necessarily, connected or interconnected and, for example, of microscopic size. A "microscopic" object may be defined as an object having at least one dimension (width, length, or height) that is substantially small, such that the object or details of the object cannot be seen by the naked eye, or are difficult or even impossible to observe without the aid of a microscope (e.g., including but not limited to a scanning electron microscope or SEM) or any appropriate type of magnification device. Description of various embodiments

[0097] The present disclosure relates to systems, devices and methods for delivering drugs to the patient's eyes. In various embodiments, the drug is an ocular drug configured to treat, for example, ocular hypertension and / or glaucoma by reducing intraocular pressure from an undesirably high level, which may cause gradual and sometimes permanent vision loss in the diseased eye. In various embodiments, a drug delivery device according to the present disclosure is configured to measure the drug release rate of one or more different drugs, and therefore can be configured to provide a variety of different release rates, including a variety of different release rates for a variety of drugs. Some examples of suitable ophthalmic drugs include therapeutic agents such as prostaglandin analogs (PGA) (e.g., latanoprost), or therapeutic agents from other drug classes, including, for example, beta-blockers such as timolol, alpha-2-agonists such as brimonidine tartrate, or carbonic anhydrase inhibitors such as dorzolamide, compounds of carbonic anhydrase inhibitors and beta-blockers, and compounds of alpha-agonists and beta-blockers that can be administered in combination with PGA.

[0098] In some embodiments, such a drug delivery device is configured to be implanted and can be refilled once or multiple times in situ minimally invasively without removing the device from the implantation site. In the case of a given size and subconjunctival target (target) implantation position, the implantation procedure can be performed outside the operating room, where needle puncture and small incisions are usually performed. In addition, some examples include features for helping to reduce micro-motion between the device and the tissue in which they are implanted. Micro-motion can be defined as small motion between the device and the tissue, wherein the motion can be micron or millimeter, and microsecond or millisecond scale. Micro-motion sometimes leads to stimulation of surrounding tissues, which is known to cause foreign body tissue reaction, final erosion and / or site infection of the implanted device, and foreign body tissue reaction can cause excessive scar formation. In some examples, the target implantation position can include the subconjunctival and / or sub-Tenon position of the eye.

[0099] Figure 1 (Photo) and Figure 3A and Figure 3B (Schematic) shows a drug delivery device 100 for metered delivery of a drug to an ocular tissue over a period of time according to some embodiments. The device 100 includes a body portion 102, a tubing 104, and a microporous core 106. The body portion 102 has an exterior surface 108 defining an interior reservoir 110. The exterior surface 108 defines a port 112 of the body portion 102, which is configured to facilitate a first passage "P1" of the drug from the reservoir 110. The tubing 104 has a first end 114, a second end 116 opposite the first end 114, and an inner cavity 118 extending between the two ends. The inner cavity 118 extends along a tubing length "L" defined by the distance between the first end 114 and the second end 116.

[0100] In some examples, the main body portion 102 may include flaps 120 to which the tubing 104 may be attached or adhered, and suture tabs 122 that may be used to attach sutures to the main body portion 102 without interfering with or affecting the reservoir 110 .

[0101] The length L of the tubing 104 defines a second passage "P2" of the drug through the lumen 118, or more specifically, through the microporous core 106 within the lumen 118. The second passage P2 extends from the first end 114 to the second end 116, from which the drug exits the lumen 118 via a third passage "P3" that allows the drug to be delivered to tissue at a target location. Thus, the first end 114 is coupled to the port 112 to receive the first passage P1 of the drug from the reservoir 110, and the second end 116 is disposed at a distance from the first end 114 (where the distance is the tubing length L) to deliver the drug to the target eye tissue.

[0102] The microporous core 106 is disposed in the lumen 118 along at least a portion of the tubing length L, and the core 106 has a porosity for a second pass P2 that meters the drug as it passes through the core 106. In some examples, the core 106 may extend the entire length L, while in other examples, the core 106 may extend a portion of the tubing length L (depending on the requirements of how much drug must be metered as further explained herein, e.g., less than about 95%, less than about 90%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, or any other suitable range or value therebetween).

[0103] In some examples, the drug may have a first state when disposed at the first end 114 of the tubular 104, and may also have a second state when disposed at the second end 116 of the tubular 104. The drug may transition from the first state to the second state as the drug passes through the core 106 along the second pass P2.

[0104] In some examples, the first state is a delivery state of the drug, which enables the drug to be delivered from the storage portion 110 to the core 106, and the second state is a therapeutic state that enables the drug to provide treatment to the target tissue. In some examples, the first state is a non-therapeutic state of the drug, and the second state is a therapeutic state. In some examples, the drug can be transformed from the first state to the second state in the storage portion 110 before passing through the first pass and passing through the core 106 along the second pass. In some examples, the first state is a high concentration state (or initial state) of the drug, and the second state is a low concentration state of the drug (or a subsequent state of the drug, whose concentration is lower than the initial state). The low concentration state has a lower concentration than the high concentration state.

[0105] In some examples, the exterior surface 108 of the device 100 may include a resealable opening 301 through which the drug in the reservoir 110 may be filled or refilled. In some examples, the exterior surface 108 of the device 100 may include a first surface 300 and a second surface 302 opposite the first surface 300. In some examples, the port 112 may be disposed between the first surface 300 and the second surface 302, such as Figure 3B In some examples, the first surface 300 and the second surface 302 are two components or material layers attached at the periphery 304 to form a single body portion 102 defining the reservoir 110 therein. In some examples, after implantation of the device 100, the first surface 300 is the surface proximal to the eye or the surface facing the eye, and the second surface 302 is the surface distal to the eye or the surface facing away from the eye.

[0106] In some embodiments, one or more of the first surface 300 and the second surface 302 may include a microporous microstructure. For example, one or more of the first surface 300 and the second surface 302 may include a biocompatible material, such as expanded polytetrafluoroethylene (ePTFE). In addition, one or more of the first surface 300 and the second surface 302 may be formed of other biocompatible materials, including biocompatible polymers, which may or may not be microporous, including but not limited to polyurethane, silicone, polysulfone, polyvinylidene fluoride (PVDF), polyhexafluoropropylene (PHFP), perfluoroalkoxy polymer (PFA), polyolefin, fluorinated ethylene propylene (FEP), acrylic copolymers, and polytetrafluoroethylene (PTFE).

[0107] The first surface 300 and / or the second surface 302 can be in the form of one or more sheets or films, and they can include knitting, weaving and / or nonwoven forms, which include separate strands or multi-fiber strands. In some embodiments, the first surface 300 and / or the second surface 302 can be formed by a plurality of polymer material sheets or films. In some embodiments, the sheet or film can be laminated or otherwise mechanically coupled together to form the first surface 300 and / or the second surface 302 and to form the main body 102. The coupling of the sheet or film can be achieved by various mechanisms, including heat treatment, high pressure compression, bonding agents such as one or more adhesives, lamination or other suitable methods known to those skilled in the art.

[0108] In some embodiments, adjacently positioned surfaces 300 and 302 and / or the material layers forming these surfaces 300 and 302 may be partially or completely combined via thermal methods, wherein each polymer forming the material is brought to or above their melting temperature. In some embodiments, such thermal processes are conducive to forming a viscous bond or cohesive (cohesive) bond between each material or each material layer. In some embodiments, adjacently positioned surfaces 300 and 302 and / or the material layers forming such surfaces 300 and 302 may be partially combined via thermal methods, wherein at least one material is brought to or above its melting temperature. Such thermal processes may contribute to forming a viscous bond or cohesive (cohesive) bond between each material or each material layer. In some embodiments, one or more suitable adhesives are utilized and a fully combined interface is provided. Adjacently positioned surfaces 300 and 302 and / or the material layers forming such surfaces 300 and 302 may be coupled together at one or more discrete locations (such as periphery 304) to form a stabilization structure extending through the resulting structure.

[0109] In some examples, the tubing 104 and the core 106 may be formed of one or more materials, including but not limited to, inter alia, PTFE, ePTFE, urethanes, polyurethanes, silicones (organopolysiloxanes), polysulfones, PVDF, PHFP, PFA, polyolefins, FEP, ethylene fluorinated ethylene-propylene (EFEP), ethylene-tetrafluoroethylene (ETFE), 3′-(2-aminopyrimidinyl)-2,2′:5′,2″-terthiophene (PATT), and acrylic copolymers. In some embodiments, the material may include other biocompatible polymers suitable for forming any one or more of the tubing 104 and the core 106, including but not limited to silicon-urethane copolymers, styrene / isobutylene copolymers, polyisobutylene, polyethylene-co-poly(vinyl acetate), polyester copolymers, nylon copolymers, fluorinated hydrocarbon polymers, and copolymers or mixtures of any of the foregoing may be used. In various embodiments, the elastomer or elastomeric material may include perfluoromethyl vinyl ether and tetrafluoroethylene, (per)fluoroalkyl vinyl ether (PAVE), copolymers of tetrafluoroethylene and perfluoromethyl vinyl ether, silicone, fluoroelastomer, urethane, butyl rubber, styrene-butadiene, isobutylene-isoprene or TFE / PMVE copolymers.

[0110] In some examples, the core 106 is made of ePTFE fibers, which are uniaxially stretched or expanded to form a structure with nodes and fibrils disclosed herein. In some examples, the core 106 can be stretched or expanded in a spiral geometry or a spiral geometry to form such a structure. In some examples, the core 106 can be made of an ePTFE tape, which is biaxially stretched or expanded to form a structure with nodes and fibrils as disclosed herein. For example, the size of the tape can be larger than the fiber (e.g., a larger width or thickness). The tubular object 104 can be formed by an elastomeric compound including but not limited to silicone resin (silicone). In some examples, the elastomeric compound can be coated on the outer surface of the core 106 to form a coating disposed on the outer surface. In some examples, the elastomeric compound can be a band wrapped around the outer surface of the core 106 to form a tubular object 104 around the core 106. Any other suitable method for manufacturing or producing the tubular object 104 and the core 106 can also be implemented.

[0111] In some examples, the device 100 may include one or more parts that are configured to promote or allow cell infiltration and / or tissue attachment. The drug may include a single therapeutic agent (e.g., medication), or may include multiple therapeutic agents. The drug may include additional materials (e.g., bioabsorbable polymers, pharmaceutically acceptable carriers) to affect the elution of the therapeutic agent (e.g., bioabsorbable polymer) from the delivery device. Throughout the description herein, the drug may also be referred to as a drug or pharmaceutical composition or combination, which may consist of both a therapeutic agent and / or additional materials for effectively eluting the therapeutic agent. For example, the drug may include bioabsorbable particles having a size range of about 0.1 microns to 50 microns, or from about 1 micron to 50 microns, or from about 5 microns to 50 microns, or from about 15 microns to 50 microns, or from about 10 microns to 40 microns, or from about 15 microns to 25 microns, or from about 18 microns to 23 microns. In some embodiments, the bioabsorbable particles have an average size of about 20 microns. In other embodiments, the therapeutic agent retained in the bioabsorbable particles may be latanoprost. During use, the bioresorbable microparticles may remain within the device 100, while the drug may be released from the bioresorbable microparticles and, therefore, from the device 100. As described herein, the device 100 may be configured to meter drug release rates for a plurality of different drugs at a plurality of different release rates.

[0112] As previously mentioned, medicine can be a pharmaceutical composition composed of at least one therapeutic agent and at least one additional material, such as but not limited to bioabsorbable microparticles. The pharmaceutical composition can adopt a first state and adopt a second state, and can be converted (transitioned) between the first state and the second state. For example, when exposed to a fluid, the pharmaceutical composition can be converted from the first state to the second state. In certain embodiments, the presence of a fluid can cause the conversion of the composition from the first state to the second state. In certain embodiments, the first state corresponds to a non-therapeutic state and the second state corresponds to a therapeutic state, so that in the absence of a sufficient amount of fluid, the therapeutic agent may not be released from the composition (and therefore not administered to a patient in need thereof). In the therapeutic state, the amount of the therapeutic agent released from the additional material can be increased relative to the amount released in the non-therapeutic state. In the therapeutic state, the therapeutic agent can be released in a pharmaceutically effective amount sufficient to treat a patient in need thereof. In certain embodiments, the first state is substantially free of fluid.

[0113] In certain embodiments, fluid comprises water. However, in other embodiments, various other fluids may also be present. In certain embodiments, the composition provided is transformed into the required time of the second state and can change in a manner suitable for application, and can be relatively short. For example, in some embodiments, the pharmaceutical composition is transformed into the second state after being exposed to the fluid in the time period between 10 seconds to 1 week (for example, 30 seconds to 6 days, 1 minute to 5 days, 1 minute to 4 days, 1 minute to 3 days, 1 minute to 2 days or 1 minute to 1 day).

[0114] Similarly, the time that the composition provided remains in the second state can change in a manner suitable for application, and can be relatively long. For example, in some embodiments, the pharmaceutical composition can remain in the second state after being exposed to fluid for a period of time between 1 minute and 1 year and any time range included therein, such as 1 hour, 1 day, 1 week, 1 month, 2 months, 3 months, 4 months, 5 months, 8 months or 11 months. In other words, the amount of medicine flowing into the patient's eyes from the storage unit every day is consistent and controllable in this time period. In the case of not wishing to be bound by any particular theory, this can be achieved by using pharmaceutically acceptable carrier particles with various sizes and geometric complexity, wherein, based on the degradation rate of additional bioabsorbable material, the conversion of the pharmaceutical composition is carried out at different time points during several months.

[0115] FIG. 2A to FIG. 2F Several different examples of how the device 100 is implanted in the eye are shown, such as between the conjunctiva and sclera of the eye. The anterior chamber (AC), posterior chamber (PC), choroid, retina, lens, and vitreous body (VB) associated with the implant are also shown.

[0116] exist Figure 2A In the embodiment, the tube 104 of the device 100 extends through the sclera into the AC, and the second end 116 is disposed within the AC so that the tube 104 can deliver the drug into the AC. Figure 2B In the embodiment of the present invention, the tube 104 of the device 100 extends through the sclera into the PC, and the second end 116 is disposed within the PC so that the tube 104 can deliver the drug into the PC.

[0117] exist FIG. 2C to FIG. 2E In the embodiment, the tube 104 of the device 100 extends through the sclera and the choroid into the VB, and the second end 116 is disposed in the VB so that the tube 104 can deliver the drug into the VB. Figure 2C In FIG. 1 , the tube 104 is slightly bent to direct the second end 118 of the tube 104 toward the center of the eye. Figure 2D In the embodiment, the tubular object 104 is Figure 2CThe tube 104 in is more angled (more angular) or more bent, and the second end 116 is directed toward the front portion of the eye, such as toward the lens. Figure 2E In the embodiment, the tubular object 104 is Figure 2C The angle of the tube 104 in FIG. 1 is smaller or straighter, and the second end 116 is directed toward the back of the eye, such as toward the retina.

[0118] exist Figure 2F In the embodiment, the tube 104 is arranged so that the second end 116 is located between the choroid tissue and the scleral tissue so that the drug can be specifically delivered to the area or region therebetween.

[0119] In an example embodiment, the drug delivery device 100 can be used to treat glaucoma. Glaucoma is a progressive vision loss associated with high intraocular pressure. To treat glaucoma, the drug delivery device 100 can be at least partially implanted under the conjunctiva (e.g., at or around a location between the corneal limbus of the eye to the (ciliary body) pars plana). The main advantages are, for example, reduced wear of tissue and refillable elements of the drug delivery system, and the use of the drug delivery system described herein for treating glaucoma can overcome the common problem of patient compliance when using previously established treatment methods. For example, the use of an implantable medical delivery system reduces the possibility that a patient may forget to apply daily medications, such as by using eye drops.

[0120] In some examples, example embodiments of the drug delivery device 100 can be used to treat macular degeneration of the retina. Wet macular degeneration is a chronic eye disease that involves the growth of abnormal blood vessels beneath the macula, which is responsible for the central vision of the eye. In previously established treatments for macular degeneration, a needle is inserted into the eye and breaks through the blood-aqueous barrier. Among other advantages, one of the main advantages of the presently presented embodiments is the ability to eliminate such invasive techniques and the ability to deliver treatment minimally invasively. To treat macular degeneration, the drug delivery device 100 can be at least partially implanted subconjunctivally, and at least partially implanted suprachoroidally (e.g., posterior to the pars plana of the eye).

[0121] Example embodiments of the drug delivery device 100 may be used to treat other retinal diseases such as macular edema of the retina. Macular edema is a chronic eye disease that involves distorted vision caused by swelling of the macula, which is responsible for the central vision of the eye. To treat macular edema, the drug delivery device 100 may be implanted at least partially subconjunctivally, and at least partially suprachoroidally (e.g., posterior to the pars plana of the eye). The drug delivery device 100 may be implanted and positioned at one or more implantation locations or sites to deliver a drug for treating macular edema.

[0122] Another retinal disease that can be treated using example embodiments of the drug delivery device 100 is retinitis. Retinitis is an eye disease involving inflammation of the retina. To treat retinitis, the drug delivery device 100 can be implanted at least partially subconjunctivally and at least partially suprachoroidally (e.g., posterior to the pars plana of the eye). In an example, the drug delivery device 100 can be implanted and positioned at one or more implantation locations or sites to deliver a drug for treating retinitis.

[0123] Yet another retinal disease that can be treated using example embodiments of the drug delivery device 100 is retinoblastoma, which is a form of eye cancer. To treat retinoblastoma, the drug delivery device 100 can be implanted at least partially subconjunctivally, and at least partially suprachoroidally (e.g., posterior to the pars plana of the eye). In an example, the drug delivery device 100 can be implanted and positioned at one or more implantation locations or sites to deliver a drug for treating retinoblastoma.

[0124] Retinal vein occlusion is a retinal disease that can be treated using example embodiments of the drug delivery device 100. Retinal vein occlusions, such as CRVO and BRVO, are blockages of one or more retinal veins. These blockages can result in excess blood and fluid in the retina. To treat retinal vein occlusion, the drug delivery system can be implanted at least partially subconjunctivally, and at least partially suprachoroidally (e.g., posterior to the pars plana of the eye). In examples, the drug delivery device 100 can be implanted and positioned at one or more implantation locations or sites to deliver drugs for treating retinal vein occlusion.

[0125] The present disclosure includes devices and methods suitable for treating corneal diseases. Some such corneal diseases include keratitis and dry eyes. In some examples, the reservoir 110 or the tubing 104 can dispense the drug from opposite sides of the reservoir 110 or the tubing 104 so that the drug is released in a direction toward the eye and into the eye, and in a direction away from the eye and into the conjunctiva.

[0126] Example embodiments of the drug delivery device 100 may be used to treat keratitis. Keratitis is an inflammation of the cornea. To treat keratitis, the drug delivery device 100 may be implanted subconjunctivally (eg, near the limbus of the eye).

[0127] Dry eye is another corneal disease that can be treated using example embodiments of the drug delivery device 100. Dry eye is insufficient lubrication of the tear film of the eye. To treat dry eye, the drug delivery device 100 can be implanted under the conjunctiva. In an example, the drug delivery device 100 can be implanted and arranged at one or more implantation locations or sites to deliver drugs for treating dry eye.

[0128] Yet another disease that can be treated using example embodiments of the drug delivery device 100 is presbyopia, which is a hardening of the lens of the eye. To treat presbyopia, a drug delivery system can be implanted under the conjunctiva. In an example, the drug delivery device 100 can be implanted and arranged at one or more implantation locations or sites to deliver a drug for treating presbyopia.

[0129] In some examples, the device 100 can be used when gene therapy is used to prevent glaucomatous neurodegeneration, to treat age-related macular degeneration, retinitis pigmentosa, geographic atrophy, diametric (diabetic) macular edema, and diabetic retinopathy. In some examples, gene therapy is achieved by sustained administration of viral transduction vectors, adeno-associated viral (AAV) vectors, polymer-based nanoparticles, liposomes, or compressed nucleic acid nanoparticles.

[0130] In view of the above, the drug delivery device 100 can be implanted in any suitable position of the eye according to the disease to be treated with the drug, so that the drug to be administered can be effectively metered to the appropriate eye tissue. For example, the drug delivery device 100 can be set near the eye tissue. The tubular 104, which can be a drug delivery tubular, can extend from the port 112 of the main body 102 (which facilitates the first passage P1 of the drug from the storage portion 110 to the port 112) at the first end 114 of the tubular 104 to position the second end 116 of the tubular 104 in contact with the eye tissue fluid, thereby facilitating the second passage P2 of the drug from the port 112 to the second end 116 of the tubular 104. The drug is delivered from the second end 116 via the microporous core 106 set in the tubular 104, and the tubular 104 has a porosity of the second passage P2 for metering the drug.

[0131] In some examples, the tubing 104 of the drug delivery device 100 can be disposed adjacent to the ocular tissue. The second end 116 of the tubing 104 can be disposed to establish fluid contact with the ocular tissue. The drug can be delivered from the second end 116 via a core 106 disposed in the tubing 104, the core 106 having a porosity for metering (dosing) the passage P2 of the drug from the first end 114 to the second end 116 of the tubing 104.

[0132] like Figure 3C and Figure 3DAs shown, the core 106 can be disposed within the tubular 104 so that the core 106 substantially fills the inside of the tubular 104 or the lumen 118 of the tubular 104, as shown, the lumen 118 has an inner radius "r". The core 106 can include a plurality of nodes 306 and fibrils 308, which can be interconnected with each other and with the surrounding tubular 104. In different examples, the nodes 306 and fibrils 308 can be positioned and interconnected in different ways to control the flow of the second passage P2 of the drug in different ways, such as allowing faster flow or slower flow, as further explained herein. In some examples, the passage P2 of the drug is controlled or metered by the surface roughness and surface energy of the nodes 306 and fibrils 308 of the core 106. The surface roughness of the nodes 306 and fibrils 308 can cause frictional forces that control or restrict the flow of the drug (fluid and particles) passing through the core 106. The surface energy of the nodes 306 and fibrils 308 may cause the intermolecular bonds of the drug to be disrupted, thereby controlling or limiting the flow of the drug through the core 106 .

[0133] FIG. 4A to FIG. 4G Different examples of embodiments disclosed herein are shown, wherein the drug delivery device 100 includes a tubing 104 and a microporous core 106, but may or may not include a body portion 102 as previously described. In the absence of the body portion 102, the device may alternatively be referred to as a "drug metering device" because the tubing 104 and the core 106 facilitate metering of the drug delivered therethrough. The tubing 104 has a first end 114, a second end 116 opposite the first end 114, and an inner cavity 118 extending along the length L of the tubing. The microporous core 106 is disposed in the inner cavity 118 along at least a portion (partially or entirely) of the tubing length L. The core 106 has a porosity that facilitates metered passage of the drug from the first end 114 toward the second end 116 through the core 106, shown as P2 in the figure. When the drug is disposed at the first end 114, it may have a first state, and when the drug is disposed at the second end 116, it may have a second state, and it transitions from the first state to the second state while traveling along the metered path (P2).

[0134] The first end 114 of the tubular article 104 includes a drug receiving portion 400 sized to receive the drug in the first state. The drug receiving portion 400 is positioned to direct the drug in the first state to the core 106. As shown, the drug is directed from the drug receiving portion 400 to the core 106 via a first pass P1.

[0135] exist Figure 4A, the drug receiving portion 400 includes a microporous drug receiving component 402 having a porosity different from that of the core 106. For example, the component 402 may be made of the same or different material as the core 106, and is constructed or manufactured to gradually release the drug stored in the component 402 into the core 106 via a first pass P1, after which the drug travels through the core 106 via a second / metered pass P2, and is finally released from the second end 116 of the tubular 104 via a third pass P3.

[0136] It should be understood that the first end 114 can be substantially closed or substantially open. If substantially closed, the drug stored in the component 402 is prevented from being released into the environment via the first end 114. If substantially open (open), the component 402 can be formed as a seal to prevent the drug from being released via the substantially open first end 114. In some examples, such a seal can be formed by attaching or fusing the end of the component 402 that is not in contact with the core 106 to another component having a zero or very low porosity compared to the porosity of the component 402 (for example, the very low porosity is almost negligible compared to the porosity of the core 106 and the component 402). In some examples, the seal is formed by applying some treatment to the end of the component 402, such as melting, collapsing, bundling, or any other suitable means that can be applied, so that the porosity of the treated end of the component 402 (not in direct contact with the core 106) can be sufficiently reduced to help reduce the drug released via the substantially open first end 114.

[0137] exist Figure 4B 114 is substantially closed, the drug receiving portion 400 includes a drug receiving space 404 defined as a portion of the inner cavity 118 that is surrounded on one side by the closed first end 114 of the tubular 104 and on the other side by an end portion of the core 106 near the first end 114. The space 404 can initially or temporarily store the drug inside, so that the drug gradually travels into the core 106 via the first pass P1, and then the drug passes through the core 106 via the second / metered pass P2, and then is released from the inner cavity 118 of the tubular 104 via the third pass P3.

[0138] exist FIG. 4C to FIG. 4F In the embodiment of the present invention, the first end 114 is substantially open, and the drug receiving portion 400 (which may be shown in some figures as including a drug receiving space 404, but may also alternatively or additionally include a microporous drug receiving component 402, as appropriate) receives the drug from an ambient environment 406 outside the tubular object 104. The environment 406 may be an area of ​​the body different from the target area to which the drug is to be delivered. For example, the environment 406 in which the drug is initially and temporarily stored may be the subconjunctival space in which the first end 114 is disposed, and the second end 116 may be disposed at a different location, such as at the AC ( Figure 2A )、PC( Figure 2B )、VB( FIG. 2C to FIG. 2E ) or between the sclera and choroid ( Figure 2F ), and any other suitable location. Thus, in these examples, a starting pass "P0" is defined, showing the pass (path) through which the drug travels from the environment 406 to the drug receiving portion 40 before the drug enters the core 106 from the drug receiving portion 400 via the first pass P1.

[0139] exist Figure 4C In , since the drug does not change state or property from pass P0 to pass P1, the initial pass P0 and the first pass P1 can be regarded as substantially the same pass. Figure 4D In the embodiment of the present invention, the drug is filtered as it travels through the filtering portion or membrane 408 disposed at the first end 114 of the tubular article 104 via the initial pass P0. When the portion or membrane 408 receives the drug from the environment 406, the portion or membrane 408 filters the drug, thereby filtering out unwanted tissue or foreign particles to reduce the amount of undesirable material allowed to enter the core 106.

[0140] exist Figure 4E and Figure 4F In one embodiment, the first end 114 or the core 106 may have an angled (angled) cross-section that is cut or truncated in a substantially angled (substantially inclined) configuration relative to the longitudinal axis of the tubular 104. Figure 4E In, the first end 114 is angled to form an angled first end 410. Figure 4F , the end of the core 106 near the first end 114 is angled to form an angled section 412. The purpose of the angle is to increase the cross-sectional area of ​​the angled end portion so that more drugs can be allowed to pass through than before the angle (i.e., when the end portion is substantially perpendicular to the longitudinal axis of the tubular object 104). Specifically, the angled first end 410 helps increase the flow rate through P0, while the angled section 412 of the core 106 helps increase the flow rate through P1.

[0141] exist Figure 4G In the embodiment, the first end 114 and the core 106 are both angled so that the angled first end 410 of the tubular 104 and the angled section 412 of the core 106 are flush with each other. This can be achieved by cutting or truncating both the first end 114 and the core 106 at an angle at the same time.

[0142] FIG. 5A to FIG. 5D 1 shows different configurations of nodes 306 and fibrils 308 forming core 106 according to various embodiments disclosed herein, wherein the diffusion direction is FIG. 5A to FIG. 5C In Figure 5AAt the bottom of the display is displayed: "5.0kV 13.1mmx1.00k LA1(UL)2 / 15 / 2017", and the distance between two consecutive lines shown in the lower right corner represents 5.0μm. Figure 5B At the bottom of the graph, it is shown: "10.0kV 9.0mm x500 SE 7 / 6 / 2022", and the distance between two consecutive lines shown in the lower right corner represents 10μm. Figure 5C The bottom of the graph shows: “10.0 kV 4.0 mm x500 SE 7 / 7 / 2022”, and the distance between two consecutive lines shown in the lower right corner represents 10 μm.

[0143] Figure 5D Shown with Figure 3D A similar cross-sectional view of the core 106 is shown. Figure 5D At the bottom of the diagram is shown: "5.0 kV 15.8 mm x 1.00 k SE (UL) 2 / 16 / 2017", and the distance between the two consecutive lines shown in the lower right corner represents 5.0 μm. As shown, nodes 306 can be formed by fusing together or clumping multiple fibrils 308 to reduce the diffusion rate through the core 106 as the drug travels through the core 106 along the diffusion direction. In some examples, the diffusion direction defines the general direction in which the drug is configured to travel via the passage P2.

[0144] FIG. 6A to FIG. 6C Different examples of how nodes 306 and fibrils 308 can meter drug flux are shown by affecting the delivery rate of the passage P2 taken by the drug as it travels along the diffusion direction shown through the core 106. The number of nodes 306 and fibrils 308 and their positioning relative to each other can greatly affect the rate at which drug delivery occurs (e.g., the rate at which the drug travels from the first end 114 to the second end 116 of the tubular 104).

[0145] According to Fick's first law, the flux, or the amount of drug traveling per unit area per unit time, can be expressed by the following equation: It can be written as the following equation: Where J is the flux, A is the inner area of ​​the tube (i.e., the cross-sectional area of ​​the lumen of the tube in which the core is placed for filling), D is the diffusion rate of the substance (i.e., drug), dC is the concentration gradient, and dx is the length of the tube (i.e., the tube length L). The inner area of ​​the tube, A, can be calculated using Figure 3C It is calculated using the radius r shown in .

[0146] Therefore, based on the above equation, as the porosity of the core 106 decreases, the amount of material in the core 106 increases, which acts to reduce the effective area for elution from the tubing 104. In addition, the length of the tubing (dx) is inversely proportional to the drug delivery rate, so increasing the tubing length L also helps to reduce the drug delivery rate. Figure 7C This lengthening can be observed in the example shown and is explained further in this article.

[0147] Furthermore, the rate is proportional to the diffusion rate D, which is affected by the tortuosity within the microstructure of core 106, which can be controlled by changing the microstructure of core 106, such as the positioning and interconnection between nodes 306 and fibrils 308 that make up the structure of core 106.

[0148] exist Fig. 6A , each dashed arrow represents a possible path P2 through a node 306 and a fibril 308 of the core 106, according to an example of the microstructure of the core 106. These lines pass through the fibrils 308, but cannot pass through the nodes 306, and therefore avoid them when passing around them. Figure 6B In the process, the microstructure is changed so that Fig. 6A Compared with the example in FIG. 1 , there are more nodes 306 in the core 106, thereby forcing the passage P2 to travel along the set general diffusion direction to bypass each node 306, resulting in a drug delivery rate of Fig. 6A Compared with the previous period, Figure 6C In the process, the microstructure is changed so that Fig. 6A Compared to the example in FIG. 1 , there are fewer nodes 306 in the core 106, thereby Fig. 6A By contrast, allowing pass P2 to travel along a relatively straight line increases the drug delivery rate through the microstructure because pass P2 requires fewer reroutings around nodes 306. Thus, node porosity can define drug delivery rates as well as node density. As the traveled pass P2 becomes more tortuous due to the denser clustering of nodes 306, the drug delivery rate will become increasingly lower.

[0149] In some examples, the composition ratio of nodes to fibrils and / or the porosity or density of the microstructure may affect the drug delivery rate. For example, when there are fewer nodes and more fibrils, the delivery rate increases. For example, when the microstructure has a more open structure (greater porosity, lower density), the delivery rate also increases.

[0150] 7A to 7D An example of a drug delivery device 100 according to an embodiment disclosed herein is shown. For example, the device 100 includes a port 112 disposed in one of the first surface 300 or the second surface 302, rather than, for example, Figure 3BThe figures show the port 112 disposed in the first surface 300 so that the tube 104 extends from a surface proximal to or facing the eye after implantation, but it should be understood that in some examples, the port 112 can be disposed in the second surface 302 so that the tube 104 can extend around the body portion 102 before reaching the target tissue of the eye into which the second end 116 is configured to be inserted, as appropriate.

[0151] exist Figure 7B In the embodiment, the majority (i.e., multiple portions) of the tubular object 104 (or the length of the tubular object) is disposed outside the reservoir 110. Figure 7B For example, greater than 50% and less than about 90%, less than about 80%, less than about 70%, less than about 60%, or any other suitable range or value including endpoints therebetween, of tubular 104 may be located outside of the reservoir. Figure 7C In the embodiment, the majority of the tubular article 104 is disposed inside the reservoir 110 (referred to as the inner portion 700). The majority may be defined as greater than about 50%, greater than about 60%, greater than about 70%, greater than about 80%, greater than about 90% of the total length L of the tubular article 104, or any other suitable range or value including endpoints therebetween. Figure 7C For example, less than about 40%, less than about 30%, less than about 20%, or any other suitable range or value including endpoints therebetween of the tubular 104 may be located outside the reservoir. In some examples, 10% to 40% (including endpoints) of the tubular 104 may be located outside the reservoir, i.e., the inner portion 700 is between 60% and 90% (including endpoints) of the total length L of the tubular 104. Thus, the tubular 104 may be arranged within the reservoir 110 so as to appropriately increase the length L of the tubular 104 to control the drug delivery rate through the core 106, which may extend through a portion or all of the lumen 118 of the tubular 104, because as explained above with respect to Equation 2, increasing the tubular length L helps to reduce the drug delivery rate therein.

[0152] exist Fig.7D 1 , the interior portion 700 of the tube 104 has a plurality of density-distributed openings 702 in which the core 106 is exposed to the reservoir 110. Thus, the openings 702 in the tube 104 form a plurality of locations through which the drug can enter the core 106 via the first pass P1 by density distribution, so as to provide additional means to, for example, control the metering of the drug passing through the core 106.

[0153] Fig. 8A and Figure 8B , Fig.9A and Fig. 9B as well as Fig. 10A and Fig. 10B It is shown how the device 100 can be positioned within different layers of the eye from outside the eye to facilitate intraocular drug delivery according to embodiments disclosed herein.

[0154] exist Fig. 8A and Fig.9A In the embodiment, the main body 102 is disposed under the conjunctiva so that the reservoir 110 rests between the conjunctiva and the sclera, and the tubular 104 extends through the sclera, choroid and retina so that the second end 116 is disposed in the VB (vitreous body) for intraocular drug delivery. FIG. 2C to FIG. 2E corresponds to the example shown in . Figure 8B and Fig. 9B In the embodiment, the tube 104 extends only through the sclera, with a portion of it resting between the sclera and the choroid, allowing the second end 116 to be positioned to facilitate intraocular drug delivery to the target space defined between the sclera and the choroid. Figure 2F corresponds to the example shown in .

[0155] exist Fig. 10A In the embodiment, the first end 114 of the tubular article 104 is disposed under the conjunctiva so that the microporous drug receiving part 402 is placed between the conjunctiva and the sclera, and the tubular article 104 extends through the sclera, choroid and retina so that the second end 116 is disposed in the VB for intraocular drug delivery. Fig. 10B In the embodiment of the present invention, the tube 104 extends only through the sclera, with a portion of it resting between the sclera and the choroid, allowing the second end 116 to be positioned to facilitate intraocular drug delivery to the target space defined between the sclera and the choroid.

[0156] It should be understood that although the tubular article shows a component 402 for illustrative purposes, any suitable drug receiving portion 400, such as a drug receiving space 404, may be implemented. For example, the drug may be disposed in an area between the conjunctiva and the sclera, and the first end 114 of the tubular article 104 may receive the drug from the area, which will be defined as the surrounding environment 406. It should be understood that in this case, the surrounding environment 406 in which the drug may be initially and temporarily stored is different from the target space to which the drug is to be delivered. The target space may be any suitable area within the eye, including but not limited to the VB ( Fig. 10A ) and the area between the sclera and choroid ( Fig. 10B ), as shown in the figure.

[0157] FIG. 11A to FIG. 11D and FIG. 12A to FIG. 12DIt is shown that different ways of metering (dosing) of drug delivery can be achieved using different types of drug carrier polymers according to the embodiments disclosed herein. Any suitable material for drug carrier polymers and delivery processes can be implemented as known in the art, such as Sun T, Zhang YS, Pang B, Hyun DC, Yang M, Xia Y. "Engineered nanoparticles for drug delivery in cancer therapy." Angew Chem Int Ed Engl. 2014 November 10; 10; 53 (46): 12320-64. doi: 10.1002 / anie.201403036 Electronic publication October 7, 2014. PMID 25294565, the entire contents of which are incorporated herein by reference.

[0158] exist Fig.11A In the present invention, a non-biodegradable drug carrier polymer 1100 (or an insoluble polymer film) is provided, in which drug molecules 1102 pre-loaded for delivery are stored. In some examples, the polymer 1100 may also include an aqueous solution 1104 to facilitate controlled delivery of the drug molecules 1102 from the polymer 1100 via diffusion. In some examples, instead of the aqueous solution 1104, the polymer 1100 may be provided with an internal polymer matrix to prevent the drug molecules 1102 from being released prematurely, as is known in the art.

[0159] exist Fig. 11B In the embodiment, the polymer 1100 gradually releases the drug molecules 1102 via controlled diffusion, so that the drug molecules 1102 are released and are no longer confined within the polymer 1100. Fig. 11C In the process, the released drug molecules 1102 are released via Fig. 11B The passage P1 shown in FIG. 1 travels from the first end 114 to the microporous core 106 within the tubing 104, and the drug molecules 1102 travel from the first end 114 to the second end 116 via the passage P2 using diffusion. Fig.11D In the embodiment of the present invention, the drug molecules 1102 are delivered to the target area via passage P3, while the non-biodegradable drug carrier polymer 1100 remains on the other side of the tube 104 near the first end 114 .

[0160] Due to the internal microstructure of the core 106 (e.g., the nodes 306 and the fibrils 308), the drug molecules 1102 selectively permeate through the core 106 while limiting the entry of the polymer 1100. Specifically, the internal microstructure is formed to pre-select the porosity of the core 106 to accommodate the molecular shape, molecular weight, and / or molecular polarity of the drug molecules 1102. For example, the internal microstructure can be pre-selected to allow the passage of drug molecules 1102 having a predetermined molecular shape, a predetermined molecular weight, and / or a predetermined molecular polarity. That is, for each type of drug, the microstructure of the core 106 can be appropriately changed to prevent any molecule or compound having a molecular shape or mass larger than the selected drug, or a molecular polarity different from the selected drug from entering the core 106 or completely passing through the core 106 from the first end 114 to the second end 116. Therefore, in some examples, the nodes 306 and the fibrils 308 are able to capture molecules of any larger foreign particles located therein, as further explained herein. FIG. 12A to FIG. 12D As shown in .

[0161] exist Fig. 12A In the present invention, drug molecules 1102 are preloaded and initially stored in an erodible or biodegradable drug carrier polymer 1200. The polymer 1200 can be tailored to control the erosion kinetics so that the polymer 1200 degrades at a predetermined rate to release the drug molecules 1102. Fig. 12B In the process, polymer 1200 gradually erodes or degrades into smaller degraded polymer particles 1202 while leaving undegraded polymer 1204 behind.

[0162] Once released, Fig. 12C As shown, drug molecules 1102 enter the core 106 from the first end 114 via passage P1 and travel toward the second end 116 via passage P2. During this process, some degraded polymer particles 1202 may also enter the microstructure of the core 106, while undegraded polymer 1204 remains outside the core 106, near the first end 114, until all undegraded polymer 1204 is finally eroded into smaller particles 1202, at which time the particles 1202 can enter the core 106.

[0163] exist Fig.12D In the embodiment of the present invention, drug molecules 1102 are delivered to the target area from the second end 116 via passage P3. In some examples, the microstructure of the core 106 captures polymer particles 1202 therein to prevent the particles 1202 from entering the target area. This can be beneficial in reducing the amount of carrier polymer that enters the target area, or preventing the carrier polymer from entering the target area until they are eroded to become small enough to pass through the microstructure. Either way, the microstructure of the core 106 can reduce any large foreign particles that are delivered to the target area, thereby improving the safety of the device 100 for its user.

[0164] In some examples, such as Fig.13 As shown, drug molecules 1102 can be delivered from the first end 114 to the second end 116 according to the concentration difference (concentration gradient) of drug molecules 1102 between the two ends 114 and 116. Concentration gradients are widely used in the medical field to transport fluids and drugs, as explained in Sulaiman, D & Suhaimi, H & Shamsuddin, Norazanita. (2020). "Estimating glucose diffusion coefficient of membranes for tissue engineering applications using Fick's First Law." IOP Conference Series: Materials Science and Engineering. 991.012103.10.1088 / 1757-899X / 991 / 1 / 012103, the entire contents of which are incorporated herein by reference. Thus, a concentration gradient indicating that the concentration of drug molecules 1102 at the first end 114 (or the higher concentration region 1300 around the first end 114) is greater than at the second end 116 (or the lower concentration region 1302 around the second end 116) causes drug molecules 1102 to be transported by diffusion through passage P2 through the core 106. Thus, drug delivery continues until the concentration gradient no longer exists, i.e., when the concentrations of drug molecules 1102 in regions 1300 and 1302 are the same.

[0165] Fig.14 A microscopic view of the microporous material of the exterior surface 108 of the body portion 102 of the drug delivery device 100 is shown according to some embodiments. Fig.14 The bottom of the diagram shows: "5.00kV4.2mm x500 SE 1 / 23 / 2018", and the distance between the two consecutive lines shown in the lower right corner represents 10μm. For example, a medical implant device or system may always be referred to. Fig.14 Microporous materials. As those skilled in the art refer to Fig.14It will be appreciated that the microporous aspects and parameters of a microporous material can be defined in a variety of ways. In the application of a microporous material in an ocular device, such as the drug delivery device 100 described herein, which is configured to be placed in situ in the tissue of an eye to facilitate the delivery of a drug to the eye to treat a disease, the microporous properties of such a microporous material can generally be characterized by a volume porosity value, which can be defined as the ratio of the volume of air or fluid defined by and contained in the microporous material to the entire volume (or total volume) of the microporous material.

[0166] In another definition, volume porosity can be defined as the percentage of the volume of a microporous material that is occupied by nonstructural or transient elements such as air or other fluids. For example, a total volume of 100 mm 3 And the total volume of 30mm 3 A microporous material that includes chambers that hold air or fluid would have a volume porosity value of 0.3 because 30% of the volume of the microporous material is transient space that is filled with air or other fluid or is empty.

[0167] As can be appreciated, two microporous materials can have the same volume porosity but differ in the pore size (pore size) presented to air or fluid entering or leaving. For example, a first material can have a small number of large pores distributed over a fixed total volume, while a second material can have a relatively large number of relatively smaller pores distributed over the same fixed volume, and if the air / fluid volume of the two materials is the same, then the two microporous materials can have the same volume porosity.

[0168] As can be further appreciated, the properties of the microporous material used in the device can also be defined by the size of the channels through the microporous material, or similarly defined as the pore size measured at the surface where the channel terminates at the microporous material or the pore size measured along the length of the channel within the material. Microporous materials with small pores or channels can hinder flow through the material, while relatively larger pores or channels can provide increased throughput of air or fluid into, out of, or within the microporous material.

[0169] As still further understood, the properties of microporous materials can also be defined by the tortuosity of the channels into and through the material, where relatively small or large channels present obstructed fluid paths due to the frequency of turns in the channels or due to the placement of obstacles in the fluid path. The air / fluid permeation rate (penetration rate) of the microporous material can be controlled or defined by any of the above characteristics of the material to provide a suitable material for facilitating the delivery of drugs to the eye to treat disease.

[0170] For simplicity, the aforementioned characteristics and variables of the microporous materials used in the various embodiments and examples described herein may be presented simply as porosity, which may be based on volume porosity, pore or channel size, or (metric) tortuosity. Fig.14 The interior portion of the microporous material may have varying porosity (or volume porosity, or pore size, or tortuosity). The interior portion may extend between the inner surface 1400 and the outer surface 108 .

[0171] At any of these parts of the main body portion 102, the porosity can be relatively ranged by degree into smaller pore size (SP), medium and small pore size (MSP), medium pore size (MP), medium and large pore size (MLP), and large pore size (LP). For the purposes of discussion here, it is assumed that delivery travels along a relatively straight path through the microporous material to sequentially join the porosity of the inner surface 1400, the uniform inner portion, and the outer surface 108, and the combined flow resistance can be represented by connecting their respective porosities in the same manner. For example, the inner surface 1400 generally has an overall low porosity (e.g., to resist tissue ingrowth into the reservoir 110), while the inner portion and the outer surface 108 may have any of the aforementioned degrees of porosity. In these cases, when the inner portion has a medium porosity and, for example, the inner portion has a medium porosity and the outer surface 108 has a high porosity, the drug delivery from the reservoir 110 to the tissue surrounding the device through the microporous material can be represented as SP-MP-LP. More examples are discussed below.

[0172] Various delivery paths may exist within the microporous material. Relatively linear flow paths may include regions SP1-SP4-SP5, for example, or SP3-MLP1-MP1-MSP1. While some flow paths may be relatively straight, non-linear flow paths also exist. For example, under certain conditions, at least some flow may continue to flow through regions of gradually decreasing resistance, such as SP1-LP1-LP2 or SP3-MLP1-LP1-LP2. As will be appreciated, the microstructure of the microporous material may undergo modification processes to obtain certain types of flows through the microstructure. For example, the microstructure may have multiple layers that are relatively uniform across the stratification within the microstructure, or, as shown here, the microstructure may have a variable portion across the thickness of the microporous material.

[0173] In some examples, the body portion 102 defines a wall portion thickness extending between the inner surface 1400 and the outer surface 108. The wall portion thickness can define an interior region of the body portion 102 having a transition porosity between the porosity of the low porosity surface of the inner surface 1400 (e.g., having a smaller pore size) to the porosity of the high porosity surface of the outer surface 108 (e.g., having a larger pore size). Additionally or alternatively, the interior region can have an interior region porosity that is equal to the porosity of the low porosity surfaces of the inner surface 1400 and the outer surface 108. Additionally or alternatively, the interior region can have an interior region porosity that is equal to the porosity of the low porosity surface of the inner surface 1400. Additionally or alternatively, the interior region can have an interior region porosity that is equal to the porosity of the high porosity surface of the outer surface 108.

[0174] Still reference Fig.14 , the fluid path may also be affected by the concentration gradient between a fluid such as water and the drug in the reservoir 110. More specifically, during the drug delivery process, the drug is first contained in the reservoir 110. The fluid can then be delivered through the microporous material and enter the reservoir 110, causing the drug to filter out of the microporous material and reach the targeted delivery site. Although described herein as having multiple layers or strata, the microporous material can lack separate and different layers and instead include different regions with varying porosity for fluids and drugs to travel through, as previously described. The drug delivery device 100, and more specifically, the microporous material of the drug delivery device 100, can also be optimized for targeted delivery. In other words, the area incorporating the microporous material can be selected to allow drug delivery only in the target position around the device 100.

[0175] Various modifications and additions may be made to the exemplary embodiments discussed without departing from the scope of the present disclosure. For example, although the embodiments described above relate to specific features, the scope of the present disclosure also includes embodiments having different combinations of features and embodiments that do not include all of the described features. Therefore, the scope of the present disclosure is intended to cover all such alternatives, modifications and variations that fall within the scope of the claims, and all their equivalents.

Claims

1. A drug delivery device for metering the delivery of a drug to an ocular tissue over a period of time, the device comprising: a body portion having an exterior surface defining an interior reservoir, the exterior surface defining a port of the body portion, the port being configured to facilitate a first passage of a medicament from the reservoir; a tubing having a first end, a second end opposite the first end, and a lumen extending therebetween along the length of the tubing, the length of the tubing defining a second passage of medication from the first end to the second end, the first end coupled to the port to receive the first passage of medication from the reservoir, the second end disposed a distance from the first end to deliver the medication to the ocular tissue; as well as A microporous core is disposed in the lumen along at least a portion of the length of the tubing, the microporous core having a porosity that meters a second passage of the drug.

2. The device according to claim 1, characterized in that The drug has a first state when disposed at the first end of the tubing and a second state when disposed at the second end of the tubing, the drug transitioning from the first state to the second state as the drug travels along the second passage through the microporous core.

3. The device according to claim 2, characterized in that The first state is a delivery state of the drug, and the second state is a treatment state of the drug.

4. The device according to claim 2, characterized in that The first state is a non-therapeutic state of the drug, and the second state is a therapeutic state of the drug.

5. The device according to claim 2, characterized in that The first state is a high concentration state of the drug, and the second state is a low concentration state of the drug, the concentration of the low concentration state being lower than that of the high concentration state.

6. The device according to any one of claims 1 to 5, characterized in that The microporous core includes a plurality of nodes and fibrils configured to meter a second passage of the drug.

7. The device according to claim 6, characterized in that The second pass of the drug is configured to be metered through the surface roughness and surface energy of the plurality of nodes and fibrils of the microporous core.

8. The device according to any one of claims 1 to 7, characterized in that The tubing is a coating disposed on the exterior surface of the microporous core.

9. The device according to any one of claims 1 to 7, characterized in that The tubing is a tape wrapped around the outer surface of the microporous core.

10. The device according to any one of claims 1 to 9, characterized in that The porosity of the microporous core is preselected to allow passage of a drug compound having a predetermined molecular shape.

11. The device according to any one of claims 1 to 9, characterized in that The porosity of the microporous core is preselected to allow passage of a pharmaceutical compound having a predetermined molecular weight.

12. The device according to any one of claims 1 to 9, characterized in that The porosity of the microporous core is preselected to allow passage of a pharmaceutical compound having a predetermined molecular polarity.

13. The device according to any one of claims 1 to 12, characterized in that The exterior surface of the body portion includes a first surface and a second surface opposite to the first surface, and the port is disposed between the first surface and the second surface.

14. The device according to any one of claims 1 to 12, characterized in that The exterior surface of the body portion includes a first surface and a second surface opposite to the first surface, and the port is disposed in the first surface.

15. The device according to claim 14, characterized in that The first end of the tubular object is disposed within the reservoir such that a majority of the length of the tubular object is disposed within the reservoir.

16. The device according to claim 15, characterized in that The majority of the tubular member disposed within the reservoir is configured to partially cover the microporous core to provide a plurality of density-distributed openings.

17. The device according to claim 15 or 16, characterized in that Between 10% and 40% of the length of the tube is located outside the reservoir.

18. The device according to any one of claims 1 to 17, characterized in that The body portion includes a resealable opening, and the reservoir is configured to be refilled with a drug to be delivered through the opening.

19. A drug metering device for metering the delivery of a drug to an ocular tissue over a period of time, the drug metering device comprising: a tube having a first end, a second end opposite the first end, and a lumen extending therebetween along the length of the tube; as well as a microporous core disposed in the lumen along at least a portion of the length of the tubing, the microporous core having a porosity that facilitates the passage of a measured amount of a drug through the microporous core from the first end of the tubing toward the second end of the tubing, wherein the drug has a first state when disposed at the first end of the tubular object and has a second state when disposed at the second end of the tubular object, and when the drug travels along the measured passage, the drug changes from the first state to the second state, and Wherein, the first end of the tubular article includes a drug receiving portion, the drug receiving portion being sized to receive a drug in a first state and positioned to direct the drug in the first state to the microporous core.

20. The device according to claim 19, characterized in that The first state is a delivery state of the drug, and the second state is a treatment state of the drug.

21. The device according to claim 19, characterized in that The first state is a non-therapeutic state of the drug, and the second state is a therapeutic state of the drug.

22. The device according to claim 19, characterized in that The first state is a high concentration state of the drug, and the second state is a low concentration state of the drug, the concentration of the low concentration state being lower than that of the high concentration state.

23. The device according to any one of claims 19 to 22, characterized in that The drug receiving portion includes a microporous drug receiving component having a porosity different from the porosity of the microporous core.

24. The device according to any one of claims 19 to 22, characterized in that The first end is substantially closed, and the drug receiving portion is a drug receiving space within the lumen where the drug is temporarily stored for delivery.

25. The device according to any one of claims 19 to 23, characterized in that The first end is substantially open, and the drug receiving portion is configured to receive the drug from an ambient environment external to the barrel.

26. The device according to claim 25, characterized in that Also included is a filter membrane disposed at the first end and configured to filter a drug received from the surrounding environment.

27. The device according to claim 25, characterized in that The first end is angled relative to the tube length.

28. The device according to claim 25 or 27, characterized in that A cross section of the microporous core proximate the first end of the tubing is angled relative to the length of the tubing.

29. The device according to any one of claims 25 to 28, characterized in that Also includes: a body portion having an exterior surface defining an interior reservoir, the exterior surface defining a port of the body portion, the port coupled to the first end of the tubing and configured to deliver the drug from the reservoir to the tubing, wherein the surrounding environment is the reservoir of the body portion.

30. The device according to any one of claims 19 to 29, characterized in that The microporous core includes a plurality of nodes and fibrils configured to control the passage of the dosed amount of the drug.

31. The device according to claim 30, characterized in that The second pass of the drug is configured to be metered through the surface roughness and surface energy of the plurality of nodes and fibrils of the microporous core.

32. The device according to any one of claims 19 to 31, characterized in that The tubing is a coating disposed on the exterior surface of the microporous core.

33. The device according to any one of claims 19 to 31, characterized in that The tubing is a tape wrapped around the outer surface of the microporous core.

34. The device according to any one of claims 19 to 33, characterized in that The porosity of the microporous core is preselected to allow passage of a drug compound having a predetermined molecular shape.

35. The device according to any one of claims 19 to 33, characterized in that The porosity of the microporous core is preselected to allow passage of a pharmaceutical compound having a predetermined molecular weight.

36. The device according to any one of claims 19 to 33, characterized in that The porosity of the microporous core is preselected to allow passage of a pharmaceutical compound having a predetermined molecular polarity.

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