Intraocular implants for drug delivery

Abstract

A medical implant is disclosed. The medical implant has a body having a first end having a first cross-sectional dimension, a second end having a second cross-sectional dimension, and a tapered portion extending between the first and second ends. The first cross-sectional dimension is greater than the second cross-sectional dimension. In some embodiments, the body comprises multiple layers.

Description

[Technical Field]

[0001] This application claims priority to U.S. Patent Application No. 17 / 518,281, filed November 3, 2021, U.S. Provisional Application No. 63 / 241,395, filed September 7, 2021, and U.S. Provisional Application No. 63 / 109,615, filed November 4, 2020, the contents of which are incorporated herein by reference in their entireties.

[0002] The present disclosure relates generally to medical implants and methods of manufacturing those implants. More particularly, the present disclosure is directed to geometric configurations and methods of retaining a medical implant within a needle of an implant delivery device. [Background technology]

[0003] When a solution is delivered directly to the eye, injected, or otherwise administered, the drug is quickly washed out or depleted from the eye into the systemic circulation. This can be as useless from a therapeutic standpoint as not providing any drug at all. As a result, solid pharmaceutically active implants have been developed that provide sustained release of active ingredients, providing a relatively uniform concentration of the active ingredient delivered to the eye. The implants are particularly useful for providing high local concentrations at specific target sites over extended periods of time. These sustained-release implants reduce the number of drug doses administered and avoid the peaks and troughs in drug concentrations found with conventional drug treatments. The use of a biodegradable drug delivery system that degrades over time has the added advantage of eliminating the need to remove used implants from the target site.

[0004] An intraocular implant is a drug delivery system configured to deliver a pharmaceutical agent to ocular tissue once injected into the eye. Intraocular implants are typically inserted using a 22-gauge to 27-gauge needle in an implant delivery device. The implant is typically retained within the delivery device using retention features built into the design of the delivery device, as opposed to the implant itself. Such systems can result in poor retention, where the implant falls out of the delivery device before the implantation procedure is complete.

[0005] Prior art implant retention designs and delivery device features can also often malfunction, resulting in the delivery of unwanted particles from the delivery device to the desired delivery site. Summary of the Invention

[0006] It is therefore desirable to provide an implant with improved retention within the needle of a delivery device that reduces the risk of delivery device-based retention failure to ensure that the implant is securely secured until deployment and reduces the risk of introducing undesirable particulate matter into the patient.

[0007] The following embodiments and aspects thereof are described and illustrated in conjunction with systems, tools and methods that are meant to be exemplary and illustrative, not limiting in scope.

[0008] In one aspect, a medical implant is described. The medical implant has a body having a first end having a first cross-sectional dimension, a second end having a second cross-sectional dimension, and a tapered portion extending between the first and second ends. The first cross-sectional dimension is larger than the second cross-sectional dimension.

[0009] In another embodiment, the tapered portion extends only partially between the first end and the second end.

[0010] In another embodiment, the length from the first end of the body to the first end of the tapered portion ranges from about 5% to about 50% of the total length of the implant.

[0011] In another embodiment, the length from the first end of the tapered portion to the second end of the body is in the range of about 950 μm to about 4750 μm.

[0012] In another aspect, the body of the medical implant comprises a single layer.

[0013] In another embodiment, the body of the medical implant is made from a mixture of a therapeutic or diagnostic agent and a biocompatible polymer. The number and type of biocompatible polymers used, as well as their relative concentrations, can vary depending on the characteristics of the therapeutic or diagnostic agent contained in the medical implant, the location and environment in which the implant is to be inserted, and the desired duration for which the therapeutic or diagnostic agent elutes from the implant. Optionally, a combination of one, two, three, or more biocompatible polymers can be used in the implants described herein. Specific examples of biocompatible polymers having application herein are discussed below. The duration for which the therapeutic or diagnostic agent elutes from the implant can be 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, or 1 year or more. Optionally, the biocompatible polymer(s) of the implants described herein can have a terminal ester or acid.

[0014] In another aspect, the body of the medical implant comprises multiple layers.

[0015] In another embodiment, at least one of the layers is made of a biocompatible polymer and at least one other of the layers is made of a mixture of a therapeutic or diagnostic agent and a biocompatible polymer.

[0016] In another aspect, medical implants are formed or manufactured using a particle replication in non-wet templates (PRINT) method to form medical implants.

[0017] In yet another aspect, a medical implant includes a body having a first layer, a second layer, and a third layer. The body has a first end having a first cross-sectional dimension and a second end having a second cross-sectional dimension. The first cross-sectional dimension is larger than the second cross-sectional dimension. The body further includes a tapered portion extending between the first and second ends. Furthermore, the first and third layers include a first material, and the second layer includes a second material.

[0018] In addition to the exemplary aspects and embodiments described above, further aspects and embodiments will become apparent by reference to the drawings and by study of the following detailed descriptions.

[0019] Exemplary embodiments are illustrated in the drawings: It is intended that the embodiments and figures disclosed herein be considered illustrative rather than restrictive. [Brief explanation of the drawings]

[0020] [Figure 1A] FIG. 1A is a top view of the medical implant of the present application. [Figure 1B] FIG. 1B is a cross-sectional view of a medical implant prior to insertion into a medical delivery device. [Figure 1C] FIG. 1C is a cross-sectional view of a medical implant inserted into the needle lumen of a medical delivery device. [Figure 2A] FIG. 2A is a perspective view of one embodiment of the medical implant shown in FIG. 1A. [Figure 2B] FIG. 2B is a perspective view of another embodiment of the medical implant shown in FIG. 1A. [Figure 3A] FIG. 3A shows a diagram of the medical implant of FIG. 1A positioned within a drug delivery device. [Figure 3B] FIG. 3B shows a top cross-sectional view of the device shown in FIG. 3A. [Figure 3C] FIG. 3C shows another view of the medical implant of FIG. 1A positioned within a drug delivery device. [Figure 4] FIG. 4 shows single and multiple medical implants positioned within the needle of a drug delivery device. [Figure 5] FIG. 5 shows how the implant is held within a needle-based delivery device and delivered using a wire pusher wire that, when actuated, delivers the implant over the frictional forces between the implant and the needle lumen. [Figure 6] FIG. 6 is an illustration summarizing one possible method used to fabricate PRINT (Particle Replication in Non-Wet Templates) molds with customizable feature shapes and dimensions for implant fabrication. [Figure 7] FIG. 7 is a photomicrograph showing a top view of a laser-etched silicon master, illustrating the geometric features used to fabricate the mold for manufacturing the PRINT implant. [Figure 8] FIG. 8 is an illustration summarizing the PRINT molding process used to fabricate implants with customizable geometries and dimensions. [Figure 9] Figure 9 shows the device used to measure implant retention force. [Figure 10] FIG. 10 is a graph showing the retention force of a number of differently shaped medical implants in a 27 gauge needle. [Figure 11] FIG. 11 shows a single mold configuration that can be used to fabricate the implants of the present disclosure. [Figure 12] FIG. 12 illustrates a multiplexed mold configuration that can be used to fabricate an implant of the present disclosure. [Figure 13] FIG. 13 shows one possible filament type configuration that can be used to fabricate an implant of the present disclosure, compared to a cannula cross section. [Figure 14] FIG. 14 shows a cross section of an implant made using a filament mold. [Figure 15] FIG. 15 shows one possible end mold design that can be used in an injection molding process to fabricate the implants of the present disclosure. [Figure 16] FIG. 16 shows a cross-sectional view of an implant of the present disclosure having an interfering feature. [Figure 17] FIG. 17 shows one possible compression-type construction design that can be used to fabricate an implant of the present disclosure. [Figure 18] FIG. 18 shows a cross-sectional view of an implant of the present disclosure. [Figure 19] FIG. 19 is a perspective view of one possible design of a delivery device that can be used to insert an implant of the present disclosure into a patient's tissue. [Figure 20] FIG. 20 shows a cross-sectional view of the delivery device of FIG. [Figure 21] FIG. 21 is a perspective view of a medical implant having a surface modification. DETAILED DESCRIPTION OF THE INVENTION

[0021] A medical implant for use with a needle-based implant delivery device is disclosed. The medical implant is characterized by a geometry having a profile designed to create an interference fit between an inner diameter of a needle or cannula positioned adjacent the needle or cannula and an outer surface region of the implant, such that the implant is retained within the needle from the time of manufacture until the implant is inserted and administered to the patient's tissue. Retention within the needle is maintained during packaging, shipping, and storage of the loaded implant delivery device.

[0022] 1A shows an exemplary medical implant 100 for use with a needle-based delivery device to deliver a medical implant into a patient's body. In one possible embodiment, the medical implant is a drug-containing intraocular implant, i.e., an active pharmaceutical ingredient (API). The medical implant 100 has a shape or geometry that is large enough to retain the implant within the drug delivery device during manufacturing, packaging, shipping, and storage of the device, yet creates a frictional force upon administration that allows the implant to be released, delivered, inserted, or embedded during administration from the delivery device into the patient's tissue upon actuation of the delivery device.

[0023] As shown in FIG. 1A , the medical implant 100 has a body 102 having a first end 104 and a second end 106. In one embodiment, the first end 104 has a cross-sectional dimension W1 that is greater than or equal to the cross-sectional dimension W2 of the second end 106, such that the first end 104 is retained within the drug delivery device by frictional interference with the inner surface of the needle. As shown in FIG. 1A , the first end 104 and the second end 106 can have rounded contours 104A, 106A. In other embodiments, the contours of the first end 104 and the second end 106 can take other geometric forms, such as a rectangular prism.

[0024] 1B shows a cross section of region L1 of medical implant 100 before loading into a medical device, having a maximum diagonal length D1, which is related to W1 and H1 by the following equation:

number

[0025] D1 is preferably predetermined and configured to be larger than the nominal inner diameter (ID) of the needle into which it will be inserted and retained (see FIG. 1C). In some embodiments, D1 has a length that is 104% of the nominal inner diameter (ID) of the needle into which it will be retained, and can range from about 105% to about 102.5% of the needle's nominal ID. In some embodiments, D1 has a length that is 102.5% of the nominal inner diameter (ID) of the needle into which it will be retained, and can range from about 104% to about 100.5% of the needle's nominal ID. For a 27-gauge needle, the ID can range from about 292.1 μm to about 330.15 μm. For a 25-gauge needle, the ID can range from about 393.7 μm to about 431.8 μm. Implants of the present disclosure can be configured to retain needle sizes ranging from 21-gauge to 30-gauge.

[0026] 1A , in some embodiments, the length L of the body 102 can be in the range of about 1000 μm to about 5000 μm. In some embodiments, the body 102 has a tapered portion 108 extending between the first end 104 and the second end 106. In some embodiments, the tapered portion 108 extends only partially between the first end 104 and the second end 106. For example, the tapered portion 108 begins at a midpoint M110 between the first end 104 and the second end 106. In one embodiment, the length L1 of the first end 104 of the body extends to the midpoint 110, which is also the beginning of the tapered portion 108, and can be in the range of about 5% to about 50% of the total implant length L. Similarly, the length L2 of the second end 106 of the tapered portion 108, which begins at the midpoint 110 and ends at the second end 112 of the tapered portion 108, ranges from about 10% to about 90% of the total implant length L. In some embodiments, the tapered portion 108 can define the entire second end 106 of the body 102.

[0027] In one embodiment, the medical implant 100 is monolithic or has a single layer, as shown in FIG. 2A. In this embodiment, the medical implant 100 can be comprised of a therapeutic agent, such as dexamethasone, and, for example, poly(D,L-lactic-co-glycolic acid) (PLGA). In other embodiments, the medical implant can have a blend of a therapeutic agent, such as monotosylate ((S)-4-(3-amino-1-(isoquinolin-6-yl-amino)-1-oxopropan-2-yl)benzyl alcohol monotoluenesulfonate; (S)-3-amino-2-(4-(hydroxymethyl)phenyl)-N-(isoquinolin-6-yl)propanamide monotosylate), and a polyesteramide (PEA) polymer or any other suitable material.

[0028] Proteglandins and analogs or derivatives thereof that find use as therapeutic agents in the pharmaceutical implant compositions of the present disclosure include latanoprost, bimatoprost, travoprost, 3-hydroxy-2,2-bis(hydroxymethyl)propyl 7-((lr,2r,3r,5s)-2-(r-(benzo[b]thiophen-2-yl)-3-hydroxypropyl)-3,5 dihydroxycyclopentanoate (chemical structure (II)), cloprostenol isopropyl ester, 13,14-dihydrochlorostenol isopropyl ester, latanoprost, unoprostone, PGF 1α Lysopropyl ester, PGF 2α Isopropyl ester, PGF 3α In some embodiments, proteglandins and analogs or derivatives thereof having therapeutic use include dukeprot, tiaprost, or both. In some embodiments, proteglandins and analogs or derivatives thereof having therapeutic use include the free acid of proteglandins, and pharmaceutically acceptable salts thereof, and analogs or derivatives thereof.

[0029] Other therapeutic agents that have use in the pharmaceutical implant compositions of the present disclosure for treating ocular diseases or disorders, such as glaucoma, include, but are not limited to, beta-blockers, myotics, alpha-adrenergic agonists, or carbonic anhydride inhibitors, and antimetabolites such as 5-fluorouracil or mitomycin C.

[0030] It should be understood that the pharmaceutical compositions of the present disclosure can comprise a therapeutic agent or a combination of two or more therapeutic agents, examples of which are described above. Additionally, analogs or derivatives, pharmaceutically acceptable salts, zwitterions, solvates, esters, and polymorphs of the therapeutic agents discussed herein have application in the pharmaceutical compositions of the present invention. As used herein, an "analog" is a compound that has a similar structure to another compound (its "parent" compound), but differs from it with respect to certain components. An analog can differ from its parent compound in one or more atoms, functional groups, or substructures, which are replaced with other atoms, groups, or substructures. Similarly, an analog of a parent compound can also be formed by substituting specific atoms of the parent compound with radioactive isotopes of those specific atoms. A "derivative" is a compound that results from, or can actually be synthesized from, a parent compound by substituting one atom for another atom or group of atoms.

[0031] In the pharmaceutical compositions of the present disclosure, a therapeutic agent is mixed with a biodegradable polymer matrix to form the pharmaceutical composition. The amount of therapeutic agent used in the pharmaceutical composition depends on several factors, such as the biodegradable polymer matrix selection, the therapeutic agent selection, the desired release rate in a substantially linear manner, the duration of the desired release rate, the composition of the pharmaceutical composition, and ocular PK, to name a few.

[0032] For example, the total therapeutic agent content of pharmaceutical compositions of the present disclosure may comprise from about 0.1% to about 60.0% by weight of the total pharmaceutical composition. In some embodiments, the therapeutic agent comprises from about 1% to about 90%, or from about 1% to about 80%, or from about 1% to about 1% to about 70%, or from about 1% to about 1% to about 1% to about 60%, or from about 1% to about 1% to about 1% to about 40%, or from about 1% to about 10% to about 10%, or from about 10% to about 10% to about 40%, or from about 10% to about 10% to about 30%, or from about 10% to about 10% to about 25%, or from about 10% to about 10% to about 10% to about 23%, or from about 10% to about 15% to about 25%. All of these percentages are by weight. In certain embodiments, dexamethasone comprises about 20.0% by weight of the pharmaceutical composition.

[0033] The pharmaceutical compositions of the present disclosure are prepared by dissolving the polymer matrix and the therapeutic agent in a suitable solvent to create a homogeneous solution. For example, acetone, alcohol (e.g., methyl alcohol or ethyl alcohol), acetonitrile, tetrahydrofuran, chloroform, and ethyl acetate can be used as solvents. Other solvents known in the art are also contemplated. The solvent is then evaporated, leaving a homogeneous film. The solution can be sterile filtered before evaporating the solvent.

[0034] Further exemplary implant formulations are described in US Pat. No. 10,624,904, the entirety of which is hereby fully incorporated by reference.

[0035] In another embodiment, medical implant 100 can be comprised of multiple layers. In one example, as shown in FIG. 2B , medical implant 100 has first layer 110, second layer 120, and third layer 130. Second layer 120 is disposed between first layer 110 and third layer 130. In some embodiments, first layer 110 and third layer 130 are made of the same material. In some embodiments, first layer 110 and third layer 130 are comprised of a mixture of PLGA with each other, and second layer 120 can be comprised of a mixture of dexamethasone or other therapeutic agent with PLGA, for example. In other embodiments, first layer 110, second layer 120, and third layer 130 can be comprised of any other suitable material.

[0036] Although medical implant 100 is shown as having three layers, it should be understood that in other embodiments, the implant may include any number of layers.

[0037] 3A, 3B, and 3C show a medical implant 100 positioned within a needle of a needle-based drug delivery device 200, which can range in size from 21 gauge to 30 gauge. As shown in FIGS. 1B, 3B, and 4, the geometry of the medical implant 100, i.e., its exterior geometry, creates an interference fit with the inner diameter 202 of the needle 200, retaining the implant 100 within the needle.

[0038] In another embodiment, multiple medical implants 100 can be inserted into a single delivery device DD, as shown in FIG. 4, to deliver increased amounts of pharmaceutical agent, to deliver more than one pharmaceutical agent, or to deliver implants designed and configured with more than one drug delivery profile.

[0039] 5 shows an example of how an implant may be held within a needle-based delivery device and delivered using a pusher wire that, upon actuation, overcomes the frictional forces between the implant and the needle lumen to deliver the implant. The pusher wire may be propelled or actuated using features of a spring-based, electromechanical-based, or pneumatic-based device.

[0040] Numerous possible devices can be constructed and used to deliver the present implants. For example, FIGS. 19 and 20 show one possible embodiment delivery device 100 having an elongated, substantially cylindrical body or housing 1 defining a longitudinal flow channel or longitudinal axis 105, the delivery device having a distal end 110 and a proximal end 120. The housing 1 can be formed from portions, such as two halves 1a and 1c, that are permanently connected to each other during assembly of the device. When assembled, the housing 1 can have a generally tapered end 8, which provides ergonomic benefits when holding and using the device to deliver an implant into tissue. The tapered proximal end can also provide a user with convenient guidance on where on the housing to grip or hold the delivery device. To further indicate where a user should grip or hold the delivery device during use, the outer surface of the distal end of the housing 1 can have a gripping surface 6. The gripping surface can be comprised of multiple surfaces in the form of raised or ridged surfaces or ribs, knurled or roughened surfaces, tactile / soft-touch material inlays or overlays, stippling features, dimples, or any other feature that indicates to the user where to grip or hold the device during use. Another feature of the gripping surface 6 is that it can provide a pushing or bearing surface that the user can use to axially deploy the device distally while inserting the needle into the desired implant insertion location site. Another device feature that can assist the user in moving or pushing the needle into the target tissue location is the raised surface of the actuation member 5. In certain cases, it may be desirable to have a pushing surface 9 that provides tactile and / or leverage functions for the user during operation of the implant delivery device 100.

[0041] The housing 1 can also have a cutout located at its distal end that slidably receives the lock 3 having an anvil stop surface and a retention detent that can be configured to engage a portion of the housing 1 to prevent premature or unintentional disengagement from the locked position. The lock 3 is configured to have two positions: a locked position and an unlocked position. FIGS. 19 and 20 show the lock 3 in a first or locked position, in which the anvil stop surface contacts and prevents movement of the actuation member 5, thereby preventing actuation of the implant delivery device. The second or unlocked position is a position in which a user removes and physically separates the lock 3 from the housing 1, for example, by pulling the lock laterally relative to the longitudinal axis 105 to overcome the reversible retention detent. Once the lock 3 is removed from the delivery device 100, the actuation member 5 is no longer inhibited from moving relative to both the housing and the shuttle assembly 14, and more specifically, the shuttle 18. When in the first or locked position, the lock 3 can function as an anti-roll feature. That is, the protruding structure of the lock prevents the delivery device from rolling uncontrollably on a flat surface, such as accidentally rolling across a table surface. A gripping tab may be provided extending radially from the lock beyond the outer surface of the housing and shaped to allow a user to grip and remove the lock 3 from the housing 1.

[0042] Other examples of delivery devices include, but are not limited to, the devices shown and described in U.S. Patent Application Publication No. 2019 / 0374380, U.S. Patent No. 592,746, U.S. Patent No. 9,039,761, and U.S. Patent No. 10,258,503.

[0043] One possible method of manufacturing or forming the medical implant 100 is particle replication in non-wet templates (PRINT) methods and techniques to obtain the molded medical implant 100 of the present disclosure. The geometry of the medical implant 100 can be easily changed during the manufacturing process by changing the geometry of the mold tooling features used to form the implant using PRINT techniques.

[0044] Figure 6 shows a top view of a PRINT mold feature whose geometry can be altered to produce implants of different geometries, as further described in U.S. Patent No. 10,624,904, the teachings of which are fully incorporated herein by reference. Figures 7 and 8 show the step-by-step process used to manufacture implants with customizable geometries for the fabrication of micron-sized medical implants. In the PRINT manufacturing process, a flexible elastomeric mold is designed to have cavities that match the two-dimensional planar projection of the implant. The rigid material is etched or machined to produce a series of features whose depths match a repeating, planar X-axis and Y-axis design, with one end of a diagonal prism larger than the inner diameter of the delivery needle and one end of a diagonally tapered prism smaller than the inner diameter of the delivery needle. The rigid mold is replicated to create a flexible template consisting of inverted features that can be described as pillars. The flexible template is replicated to create a flexible mold or tooling consisting of cavities. The flexible template and flexible mold are designed to facilitate material release from their surfaces. To fabricate an implant using the PRINT manufacturing technique, the matrix material is heated and pressure is applied to the laminate of the flexible mold, matrix material film, and flexible substrate. The matrix material fills the flexible mold cavities as the laminate is heated and compressed. The flexible mold presents a series of tapered prismatic features that are released from the matrix material and bonded to the flexible substrate.

[0045] Details of the PRINT method and technology are described in detail in U.S. Pat. Nos. 7,976,759, 8,439,666, 8,662,878, 8,944,804, 8,945,441, 9,314,548, 9,340,001, 9,545,737, and 9,662,809, all of which are hereby incorporated by reference.

[0046] Additional methods for fabricating the tapered, trapezoidal, or wedge-shaped implants of the present disclosure include mold extrusion, filament extrusion, injection molding, compression molding, and stamp molding. These methods can produce implants with a portion of the prism length having a diagonal dimension greater than the inner diameter (ID) of the delivery needle and a portion having a diagonal dimension smaller than the ID of the delivery needle. Two-dimensional (2-D) feature designs can serve as one possible starting point for different manufacturing techniques. The 2-D feature defines the perimeter of the target shape, and then a separate processing step can be used to control the undefined third dimension, which may be referred to as the z-dimension or z-axis. Still other manufacturing techniques can utilize three-dimensional design, such as three-dimensional printing, layer-by-layer manufacturing, or additive manufacturing. Even more manufacturing techniques can combine coating or additive manufacturing processes with 2-D foam manufacturing techniques to create implants with a portion of the feature length having a diagonal or diameter greater than the ID of the delivery needle and a portion having a diagonal or diameter smaller than the ID of the delivery needle.

[0047] The first step in creating the two-dimensional shape is to fabricate a mold, or tool, into which the implant matrix material will be formed. This can be accomplished by machining or etching metal, ceramic, silicon, or other known tool-making materials that are capable of retaining their shape during processing.

[0048] For die extrusion, a two-dimensional projection of the X and Y planar design would be etched to create the die opening shape, as illustrated in Figure 11. The matrix material would be extruded through the die shape using a combination of heat and pressure. The pressure could be pneumatically actuated or mechanically driven using interlocking screws. An electric heating element would be used to achieve appropriate control of the heat applied to the matrix material. The matrix material could be fed into a die with a single opening. The die could be constructed with multiple openings of the same planar design to increase throughput, similar to Figure 12. Each opening would be fed by the same matrix material. Alternatively, multiple formulations could be co-extruded into a single extrusion geometry using a split matrix feed path. This co-extrusion could be used to create a wedge-shaped form of one of the matrix components, which would then be expanded after the die to generate a three-dimensional section larger than the inner diameter of the injecting needle cannula.

[0049] For filament extrusion, the matrix material can be mixed using an extruder, as described above for die extrusion. A filament die with a diameter larger than the inner diameter of the target needle cannula would be attached to the end of the extruder barrel. Figure 13 shows an exemplary comparison between the cross-section of the larger filament die and the cross-section of the target needle. The circular extrudate from the extruder would be drawn using variable elongational stress to achieve a tapered filament section along the length of the extrudate. See Figure 14 for an example depiction of the side profile of the filament extrudate. A cutting mechanism would be used to cut the filament extrudate into sections to produce implants of controlled length. The filament extrudate would have a diameter narrower than the target needle cannula to provide sufficient entry into the target delivery needle during loading of the implant into the needle cannula. The filament extrudate would become increasingly thicker in diameter as it moved from the narrow or tapered end of the cut section to the interfering end of the cut section.

[0050] For the injection molding process to form the implants of the present disclosure, a rigid mold will have cavity features that project a two-dimensional plan view of the intended implant geometry. The mold and individual cavities can be machined or three-dimensionally printed to produce the final shape. The cavities will have a tapered exterior to create a cylindrical or prismatic shape with one end that is smaller than the inner diameter of the delivery needle and another end that is larger than the inner diameter of the delivery needle. Figure 15 shows one possible design for an injection molding mold.

[0051] When injection molding is used to fabricate the implants of the present disclosure, the number of cavities per injection mold is optional. The sprue and runner configuration of the injection mold will be designed to have a reduction in channel diameter based on proximity to the end cavity. End connections can be positioned so that flash resulting from removal of individual parts does not change the side profile of the implant. An example of a connection arrangement that does not change the side profile would be the top or bottom end of the implant (see FIG. 15). The injection mold design also allows for the introduction of interference features, such as flange designs, along the side profile of the implant cavity. The interference features can be designed to provide a controlled amount of resistance for retention and a controlled amount of resistance for ejection rate. The interference features will cause the diameter or diagonal profile of the implant to be larger than the inner diameter of the delivery needle. An interferometric feature can be a continuous feature around the circumference or periphery of the implant, or it can be a discrete feature around the circumference or periphery of the implant, for example, a feature on one face of a prism or a single point along the circumference of a cylinder. Figure 16 shows examples of continuous and discrete interferometric features.

[0052] For compression or stamp molding, a rigid mold or die is designed with a cavity that matches the two-dimensional planar projection of the desired implant. The rigid material is etched or machined to create a series of features with depths that match a repeating, planar X- and Y-axis design, with one end of a diagonal prism larger than the inner diameter of the delivery needle and one end of a diagonal tapered prism smaller than the inner diameter of the delivery needle (see FIG. 17). The matrix material is heated using a temperature-controlled heating element and compressed using a pressure-controlled press, which can use air or hydraulic pressure. Compression or stamp molding involves using two rigid platens together to fill the mold cavities with matrix material. The mold design can be a flat surface that mates with a patterned mold platen. Alternatively, the mold design can include a patterned series of cavities on both mold platens, with the combined depth of the cavities on each mold surface equal to the target implant thickness in the z-axis. After the platens achieve full compression, the matrix is ​​cooled and released from the mold cavity.

[0053] In the case of three-dimensional printing or layer-by-layer manufacturing, the construction of the implant utilizes precise spatial deposition of matrix material. Precise spatial deposition of matrix material is typically achieved through robotics, automation, and computer-aided drawing. The computer-aided drawing will be generated from the implant. The implant design will incorporate one end of the implant having a maximum diagonal or diameter greater than the inner diameter of the delivery needle and another end of the implant having a maximum diagonal or diameter smaller than the inner diameter of the delivery needle. Manufacturing techniques that create implants using a filament-fed stylus involve a feed tip with a diameter smaller than the smallest implant design feature. For techniques similar to layer-by-layer manufacturing, the z-dimension resolution of layer features must be smaller than the target thickness of the implant. This minimum resolution criterion allows for the creation of interference and non-interference zones along the length of the implant.

[0054] Regardless of the method used to fabricate the implants of the present disclosure, there are post-processing modifications possible using the aforementioned manufacturing procedures to create sections of the implant with one or more interference features. The initial size of the implant produced by the initial fabrication procedure will be smaller than the inner diameter of the target cannula. A material capable of increasing in size in the presence of a specific medium (e.g., a hydrogel that increases in volume in the presence of water) is applied to the end of the implant loaded into the needle cannula. The selective addition of a second material will create two separate sections of the implant design, with a portion of the prismatic length having a diagonal larger than the inner diameter of the delivery needle. Manufacturers will fabricate implants with sub-needle ID diameters or diagonals using any of the techniques described above. A portion of the implant length will be coated with a swelling medium via various techniques, such as dipping, spray drying, slot-die coating, or vapor deposition. The swelling medium can be applied as a liquid and dried or crosslinked to form a solid coating.

[0055] Implant shape can be described using six parameters: total length, thickness, interference width, slip width, interference length, and slip length. These six implant design parameters affect pharmaceutical performance through three primary responses. Four of these parameters are shown in FIG. 18; total length is not shown but would be the implant length from end to end, with rounded ends. Thickness would be captured by projection onto the z-axis. The three primary responses are (1) resistance during loading of the implant into the delivery needle, (2) resistance to retention of the implant in the delivery needle or movement of the implant while it is being loaded into the delivery needle, and (3) resistance to ejection as the implant is removed from the needle and delivered.

[0056] The total length and thickness parameters are positively correlated with the three responses above. As the total length or thickness increases, the amount of implant surface that can contact the delivery needle wall or inner surface also increases. The interference width parameter is positively correlated with resistance to loading. As the interference width increases, the implant's diagonal increases, resulting in increased resistance during loading. The implant's resistance to movement within the delivery needle and its resistance to ejection increases with the interference width until the implant's diagonal matches the inner diameter of the delivery needle. An interference width where the implant's diagonal is above the inner diameter of the delivery needle makes no practical difference in implant retention or resistance to ejection. The implant's diagonal does not change once it enters the delivery needle because material is sheared from the edges of the implant as it is loaded into the delivery needle. Once inside the delivery needle, the implant's resistance to movement and its resistance to ejection do not change because the implant's diagonal has been reduced to match the inner diameter of the delivery needle.

[0057] The interference length parameter is positively correlated for all three responses. A larger interference length increases resistance to loading, retention, and ejection, based on the same rationale as total length and thickness. The slip width parameter influences loading resistance. The incorporation of a slip section or tapered design creates a lead-in to facilitate implant loading. The slip width should not be so small that mechanical strength is compromised during routine manufacturing processes, including loading and ejection. The implant is preferably designed to withstand being pushed by another implant within a delivery needle or by a pusher wire for loading or ejection. However, if the slip width is too large or too similar to the inner diameter of the delivery needle, it increases resistance to loading and may result in mechanical failure of the implant during loading. The slip width cannot exceed the inner diameter of the delivery needle. In other words, the slip length parameter influences the resistance to loading of the implant and is negatively correlated. A properly predetermined slip width parameter should make the process of loading the implant into the needle cannula easier, since resistance to loading decreases as the slip length increases. As the implant is loaded, the tapered prism's sloped surface orients the implant parallel to the delivery needle cannula and forces it to move further into the delivery needle, so the slip section of the implant centers the implant relative to the delivery needle opening. Smaller slip lengths and larger interference lengths have the same effect on the three responses. A smaller slip length increases resistance to loading, movement within the delivery needle, and ejection from the delivery needle.

[0058] Determination of the implant retention force within the needle cannula can be obtained by measuring the force required to expel the implant from the lumen of a delivery needle, e.g., a 27-gauge needle. Using a Mark-10 Model M5-10 force gauge, or a similar force gauge, a narrow-gauge stainless steel pusher rod operatively associated with the force gauge and a load cell provides an indication of the pusher wire force required to expel the implant from inside the needle cannula. Figure 9 shows an example of an apparatus used to measure implant retention force. A steel pusher wire is inserted into the needle containing the implant and advanced until the implant is released from the needle. The force required to release the implant is measured by the load cell as the retention force.

[0059] 10 is a graph showing retention force measurements for a number of differently shaped medical implants on a 27 gauge needle. The numerical results and information for the implants tested are summarized below in Table 1 for implants on a 27 gauge needle. [Table 1]

[0060] The test results show that the present implant 100 (wedge-shaped) had the best retention force (greater than 0.350 lbs) of the seven different designs tested. The retention forces of the uniform diameter designs were either too low (cylinder) and easily dislodged, or too high (rectangular prism) and did not fit within the needle lumen.

[0061] In operation, medical implant 100 is used in conjunction with a drug delivery device, such as needle 200, to inject (insert) medical implant 100 into a patient's tissue. In one embodiment, medical implant 100 is an intraocular lens implant configured to be injected into the posterior chamber of a patient's eye. First, the needle of the delivery device is inserted through the sclera of the posterior chamber. The implant is then mechanically delivered into the posterior chamber by forward movement of a pusher wire within the lumen of the needle, as shown in FIG. 5. Movement of the pusher wire can be driven by various delivery device features, including a metal or plastic spring or air pressure. Actuation of the delivery mechanism can be achieved by coupling the delivery mechanism to a push button or slide on a device handle that is operated by the physician performing the procedure.

[0062] Another embodiment of the implant of the present disclosure has the ability to impart surface modifications (see reference numbers 200 and 210 in FIG. 21 ) to create an interference surface for the medical implant 100. Such surface modifications can enhance and optimize retention when the implant is loaded onto a needle cannula. Examples of surface modifications can include coatings, films, biomatrices, nanostructures (nanotubes and nanopores), roughened, sputtered, and sprayed surfaces, both at the macro- and nanoscale. Rugosity or roughness of the implant surface can also be achieved by including these textural features in the mold tool used to form the implant. Coatings and films can use layering techniques applied to the implant surface, possibly involving the use of combinations of different polymers or other coating materials with different surface energies relative to the lumen of the contacting delivery device surface. Combinations of different surface modifications can be used, for example, one type of surface modification 200 on one portion of the implant 100 and another surface modification 210 used on a different portion of the implant.

[0063] While a number of exemplary aspects and embodiments have been described above, those skilled in the art will recognize that further modifications, substitutions, additions, and sub-combinations of features of the disclosed embodiments are still possible. The present disclosure also includes the following inventions. The first aspect is In medical implants, The medical implant comprises: a body having a first end having a first cross-sectional dimension, a second end having a second cross-sectional dimension, and a tapered portion extending between the first end and the second end; The first cross-sectional dimension is greater than the second cross-sectional dimension of the medical implant. The second aspect is The medical implant in a first aspect, wherein the tapered portion extends only partially between the first end and the second end. The third aspect is The medical implant according to the first aspect, wherein the first end and the second end each have a rounded profile. The fourth aspect is The medical implant according to the first aspect, wherein the length from the first end of the main body to the first end of the tapered portion is within a range of about 5% to about 50% of the total length of the implant. The fifth aspect is The medical implant according to the first aspect, wherein the length from the first end of the tapered portion to the second end of the main body is in the range of about 950 μm to about 4750 μm. The sixth aspect is The medical implant of the first aspect, wherein the body of the medical implant comprises a single layer. A seventh aspect is The medical implant of the first embodiment, wherein the body of the medical implant is made from a mixture of a therapeutic or diagnostic agent and a biocompatible polymer. The eighth aspect is The medical implant of a seventh embodiment, wherein the biocompatible polymer comprises a terminal ester or acid. A ninth aspect is The medical implant of the first aspect, wherein the body of the medical implant comprises multiple layers. A tenth aspect is A medical implant according to a ninth aspect, characterized in that at least one of the plurality of layers is made of a biocompatible polymer, and at least one other of the plurality of layers is made of a mixture of a therapeutic agent or diagnostic agent and a biocompatible polymer. An eleventh aspect is The medical implant of the first aspect, wherein the medical implant is formed or manufactured using a particle replication in non-wet templates (PRINT) method to form the medical implant. A twelfth aspect is The medical implant of the first embodiment is inserted using a drug delivery device. A thirteenth aspect is The medical implant of the first aspect, wherein the body of the medical implant has a surface modification. A fourteenth aspect is In medical implants, The medical implant comprises: a body having a first layer, a second layer, and a third layer, the body further having a first end having a first cross-sectional dimension and a second end having a second cross-sectional dimension; the body further includes a tapered portion extending between the first end and the second end; the first layer and the third layer comprise a first material, and the second layer comprises a second material; The medical implant has a first cross-sectional dimension greater than the second cross-sectional dimension. A fifteenth aspect is A fourteenth aspect is a medical implant according to a fourteenth aspect, wherein the tapered portion extends only partially between the first end and the second end. A sixteenth aspect is The medical implant according to the fourteenth aspect, wherein the length from the first end of the main body to the first end of the tapered portion is within a range of about 5% to about 50% of the total length of the implant. A seventeenth aspect is The medical implant of embodiment 14, wherein the first material comprises a mixture of PLGA and the second material comprises a mixture of a therapeutic agent and PLGA. An eighteenth aspect is 14. A drug delivery device configured to insert one or more of the medical implants into a patient's eye, comprising: The drug delivery device is a drug delivery device that includes a needle configured to hold the medical implant from the time of manufacture until the medical implant is inserted into the patient's eye. A nineteenth aspect is The drug delivery device of an eighteenth aspect, wherein the medical implant is retained within the needle via a friction fit. The twentieth aspect is 1. A method for manufacturing a medical implant, comprising: The method comprises: forming a medical implant using a particle replication in non-wet templates (PRINT) method for molding medical implants, the medical implant comprising a medical implant body having a first end having a first cross-sectional dimension, a second end having a second cross-sectional dimension, and a tapered portion extending between the first end and the second end, the first cross-sectional dimension being greater than the second cross-sectional dimension; a shape of the medical implant that allows the medical implant to be retained within a needle of a medication delivery device via a friction fit; The medical implant is configured to be inserted into an eye using the drug delivery device and a method for manufacturing the medical implant.

Claims

1. In medical implants, The medical implant comprises: a substantially wedge-shaped body having a height and a width; the body has a first end having a first cross-sectional area with a first cross-sectional dimension in the width direction, a second end having a second cross-sectional area with a second cross-sectional dimension in the width direction, and a tapered portion extending at least partially in the width direction between the first end and the second end; the first end of the body is configured to be initially inserted into a cannula and the second end of the body is configured to be inserted into an eye; the first cross-sectional dimension is greater than the second cross-sectional dimension; a length of the body from the first end to the tapered portion is less than 50% of a total length of the medical implant; The medical implant, wherein the height is substantially constant between the first end and the second end.

2. The medical implant of claim 1 , wherein the tapered portion extends from the first end and the second end.

3. The medical implant of claim 1 , wherein the first end and the second end each have a rounded profile.

4. 10. The medical implant of claim 1, wherein the length from the first end of the body to the first end of the tapered portion is within the range of about 5% to about 50% of the overall length of the medical implant.

5. 10. The medical implant of claim 1, wherein the length from the first end of the tapered portion to the second end of the body ranges from about 950 μm to about 4750 μm.

6. The medical implant of claim 1 , wherein the body of the medical implant comprises a single layer.

7. 10. The medical implant of claim 1, wherein the body of the medical implant is made from a mixture of a therapeutic or diagnostic agent and a biocompatible polymer.

8. 8. The medical implant of claim 7, wherein the biocompatible polymer comprises a terminal ester or acid.

9. The medical implant of claim 1 , wherein the body of the medical implant comprises multiple layers.

10. 10. The medical implant of claim 9, wherein at least one of said plurality of layers comprises a biocompatible polymer and at least one other of said plurality of layers comprises a mixture of a therapeutic or diagnostic agent and a biocompatible polymer.

11. 10. The medical implant of claim 1, wherein said medical implant is inserted using a drug delivery device.

12. The medical implant of claim 1 , wherein the body of the medical implant has a surface modification.

13. In medical implants, The medical implant comprises: a substantially wedge-shaped body having a height and a width; the body having a first layer, a second layer, and a third layer; the body further has a first end having a first cross-sectional area with a first cross-sectional dimension in the width direction, and a second end having a second cross-sectional area with a second cross-sectional dimension in the width direction; the body further includes a tapered portion extending at least partially in the width direction between the first end and the second end; the first end of the body is configured to be initially inserted into a cannula and the second end of the body is configured to be inserted into an eye; a length of the body from the first end to the tapered portion is less than 50% of a total length of the medical implant; the first layer and the third layer comprise a first material, and the second layer comprises a second material; The medical implant, wherein the first cross-sectional dimension is greater than the second cross-sectional dimension.

14. 14. The medical implant of claim 13, wherein said tapered portion extends from said first end and said second end.

15. 14. The medical implant of claim 13, wherein the length from the first end of the body to the first end of the tapered portion is within the range of about 5% to about 50% of the overall length of the medical implant.

16. 14. The medical implant of claim 13, wherein the first material comprises a mixture of PLGA and the second material comprises a mixture of PLGA and a therapeutic agent.

17. 14. A drug delivery device configured for inserting one or more of the medical implants of claim 13 into a patient's eye, comprising: The drug delivery device comprises the cannula and a needle configured to hold the medical implant from the time of manufacture until the medical implant is inserted into the patient's eye.

18. 18. The medication delivery device of claim 17, wherein the medical implant is retained within the needle via a friction fit.

19. 1. A method for manufacturing a medical implant, comprising: The method comprises: forming a medical implant using a particle replication in non-wet template (PRINT) method for molding medical implants, the medical implant having a substantially wedge-shaped body having a height and a width, the body further having a first end having a first cross-sectional area with a first cross-sectional dimension in the width direction, a second end having a second cross-sectional area with a second cross-sectional dimension in the width direction, and a tapered portion extending at least partially in the width direction between the first end and the second end, the first cross-sectional dimension being greater than the second cross-sectional dimension; a length of the body from the first end to the tapered portion is less than 50% of a total length of the medical implant; a shape of the medical implant that allows the medical implant to be retained within a needle of a medication delivery device via a friction fit; A method for manufacturing a medical implant, wherein the medical implant is configured to be inserted into an eye using the drug delivery device.

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