Intraocular implants for drug delivery

Abstract

To ensure that the implant is securely fixed until deployment and to reduce the risk of introducing undesirable particulate matter into the patient, we provide an implant with improved retention within the needle of the delivery device, which reduces the risk of retention failure based on the delivery device. [Solution] 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 larger 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 these applications are hereby incorporated by reference in their entirety.

[0002] This disclosure generally relates to medical implants and methods of manufacturing those implants. More particularly, this disclosure is directed to geometric configurations and methods for holding a medical implant within a needle of an implant delivery device.

Background Art

[0003] When a solution is delivered directly to, injected into, or otherwise administered to the eye, the drug is either rapidly washed out or consumed from the eye into systemic circulation. This can be of little benefit from a therapeutic perspective, as it may as well not deliver any drug at all. As a result, solid pharmaceutically active implants have been developed that provide sustained release of the active ingredient, which provides delivery of a relatively uniform concentration of the active ingredient into the eye. Implants are particularly useful for providing a high local concentration over a long period of time at a specific target site. These sustained release implants reduce the number of doses of the drug administered and avoid the peaks and troughs in drug concentration found in conventional drug therapies. By using biodegradable drug delivery systems that degrade over time, there is an additional advantage that it is not necessary to remove the used implant from the target site.

[0004] An intraocular implant is a drug delivery system configured to deliver medication to ocular tissue once injected into the eye. Intraocular implants are typically inserted using a 22-gauge to 27-gauge needle in the implant delivery device. The implant is typically held within the delivery device by retention features incorporated into the device's design, as opposed to the implant itself. Such systems can lead to poor retention, potentially causing the implant to detach from the delivery device before the implantation procedure is complete.

[0005] The features of conventional implant retention designs and delivery devices can also frequently malfunction, resulting in the delivery of undesirable particles from the delivery device to the desired delivery site. [Overview of the project]

[0006] Therefore, it is desirable to provide implants with improved retention within the needle of the delivery device, which reduces the risk of retention failure based on the delivery device, in order to ensure that the implant is securely fixed until deployment and to reduce the risk of introducing undesirable particulate matter into the patient.

[0007] The following embodiments and aspects thereof are described and illustrated in relation to systems, tools, and methods, meaning that they are illustrative and illustrative, and not limiting in scope.

[0008] In one embodiment, 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 greater than the second cross-sectional dimension.

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

[0010] In another embodiment, the length from the first end of the main body to the first end of the tapered portion is in the range of approximately 5% to 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 main body is in the range of approximately 950 μm to approximately 4750 μm.

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

[0013] In another embodiment, the body of the medical implant is made of a mixture of a therapeutic or diagnostic agent and a biocompatible polymer. The number and types of biocompatible polymers used, as well as their relative concentrations, may vary depending on the properties 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. Selectively, combinations of one, two, three, or more biocompatible polymers may be used in the implants described herein. Specific examples of biocompatible polymers having applications herein are discussed below. The duration of elution of the therapeutic or diagnostic agent from the implant may be one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, or more than one year. Selectively, the biocompatible polymers of the implants described herein may have terminal esters or acids.

[0014] In another embodiment, 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 of the other layers is made of a mixture of a therapeutic or diagnostic agent and a biocompatible polymer.

[0016] In another embodiment, a medical implant is formed or manufactured using particle replication in a non-wet template (PRINT) method to shape the medical implant.

[0017] In yet another embodiment, the medical implant has 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 greater than the second cross-sectional dimension. The body further has a tapered portion extending between the first end and the second end. Furthermore, the first and third layers have a first material, and the second layer has a second material.

[0018] In addition to the exemplary embodiments and embodiments described above, further embodiments and embodiments will become apparent by referring to the drawings and considering the following detailed description.

[0019] Exemplary embodiments are shown in the drawings. The embodiments and drawings disclosed herein are intended to be illustrative rather than restrictive. [Brief explanation of the drawing]

[0020] [Figure 1A] Figure 1A is a top view of the medical implant of the present invention. [Figure 1B] Figure 1B is a cross-sectional view of a medical implant before insertion into a medical delivery device. [Figure 1C] Figure 1C is a cross-sectional view of a medical implant inserted into the lumen of a needle in a medical delivery device. [Figure 2A] Figure 2A is a perspective view of a medical implant according to one embodiment shown in Figure 1A. [Figure 2B] Figure 2B is a perspective view of a medical implant of another embodiment shown in Figure 1A. [Figure 3A] Figure 3A shows the medical implant from Figure 1A positioned within the drug delivery device. [Figure 3B] Figure 3B shows a top cross-sectional view of the apparatus shown in Figure 3A. [Figure 3C] Figure 3C shows another diagram of the medical implant from Figure 1A positioned within the drug delivery device. [Figure 4] Figure 4 shows single and multiple medical implants positioned within the needle of a drug delivery device. [Figure 5] Figure 5 shows how the implant is held within a needle-based delivery device and how it is delivered using a wire pusher wire that delivers the implant beyond the frictional force between the implant and the needle lumen during operation. [Figure 6] Figure 6 is an explanatory diagram summarizing one possible method used to fabricate a PRINT (Particle Replication in Non-wet Templates) mold having customizable feature shapes and dimensions for fabricating an implant. [Figure 7] Figure 7 is a micrograph showing a top view of a laser-etched silicon master, showing the geometric features used to fabricate a mold for manufacturing a PRINT implant. [Figure 8] Figure 8 is an explanatory diagram summarizing the PRINT molding process used to fabricate an implant having customizable geometric shapes and dimensions. [Figure 9] Figure 9 shows an apparatus used to measure implant retention force. [Figure 10] Figure 10 is a graph showing the retention forces of a number of different shaped medical implants in a 27-gauge needle. [Figure 11] Figure 11 shows the configuration of a single mold that can be used to fabricate the implant of the present disclosure. [Figure 12] Figure 12 shows the configuration of a multiplexed mold that can be used to fabricate the implant of the present disclosure. [Figure 13] Figure 13 shows one possible filament mold configuration that can be used to fabricate the implant of the present disclosure as compared to a cannula cross-section. [Figure 14] Figure 14 shows a cross-sectional view of an implant made using a filament mold. [Figure 15] Figure 15 shows one possible end mold design that can be used in an injection molding process for fabricating the implant of the present disclosure. [Figure 16] Figure 16 shows a cross-sectional view of an implant of the present disclosure having interference features. [Figure 17] Figure 17 shows one possible compression-type configuration design that may be used to fabricate the implant of this disclosure. [Figure 18] Figure 18 shows a cross-sectional view of the implant described herein. [Figure 19] Figure 19 is a perspective view of one possible design of a delivery device that can be used to insert the implant of this disclosure into a patient's tissue. [Figure 20] Figure 20 shows a cross-sectional view of the delivery device shown in Figure 19. [Figure 21] Figure 21 is a perspective view of a medical implant with surface modification. [Modes for carrying out the invention]

[0021] A medical implant for use with a needle-based implant delivery device is disclosed. The medical implant features a geometric shape having an external form designed to create a tight fit between the inner diameter of the needle or cannula positioned adjacent to the needle or cannula and the outer surface area of ​​the implant, so 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] Figure 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 an intraocular implant containing a drug, i.e., a drug active ingredient (API). The medical implant 100 is large enough to hold the implant within the drug delivery device during the manufacture, packaging, shipping, and storage of the device, but has an external or geometric shape that creates a frictional force that allows for the release, delivery, insertion, or implantation of the implant during administration, during the operation of the delivery device, and during administration from the delivery device to the patient's tissue.

[0023] As shown in Figure 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 larger than or greater than the cross-sectional dimension W2 of the second end 106, and as a result, the first end 104 is held in the drug delivery device by frictional interference with the inner surface of the needle. As shown in Figure 1A, the first end 104 and the second end 106 may have rounded outer shapes 104A, 106A. In other embodiments, the outer shapes of the first end 104 and the second end 106 may take other geometric forms, such as rectangular prisms.

[0024] Figure 1B shows a cross-section of region L1 of the medical implant 100 before it is loaded into the medical device, with a maximum diagonal length D1. D1 is related to W1 and H1 by the following formula.

number

[0025] D1 is preferably predetermined and configured to be larger than the nominal inner diameter (ID) of the needle it is inserted into and held therein (see Figure 1C). In some embodiments, D1 has a length of 104% of the nominal inner diameter (ID) of the needle it holds and can range from about 105% to about 102.5% of the nominal ID of the needle. In some embodiments, D1 has a length of 102.5% of the nominal inner diameter (ID) of the needle it holds and can range from about 104% to about 100.5% of the nominal ID of the needle. 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. The implants of this disclosure can be configured to hold needle sizes in the range of 21 gauge to 30 gauge.

[0026] Referring again to Figure 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 a first end 104 and a 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 starts at an intermediate point 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 intermediate point 110, which is also the starting point 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, starting from the midpoint 110 and ending at the second end 112 of the tapered portion 108, is in the range of approximately 10% to approximately 90% of the total implant length L. In some embodiments, the tapered portion 108 may define the entire second end 106 of the main body 102.

[0027] In one embodiment, the medical implant 100 is monolithic or has a single layer, as shown in Figure 2A. In this embodiment, the medical implant 100 may consist of a therapeutic agent, e.g., dexamethasone, and, e.g., poly(D,L-lactic acid-glycolic acid copolymer) (PLGA). In other embodiments, the medical implant may have a mixture of a therapeutic agent, e.g., monotosilate ((S)-4-(3-amino-1-(isoquinoline-6-yl-amino)-1-oxopropan-2-yl)benzyl alcohol monotoluene sulfonate; (S)-3-amino-2-(4-(hydroxymethyl)phenyl group)-N-(isoquinoline-6-yl)propanamide monotosilate) and a polyesteramide (PEA) polymer or any other suitable material.

[0028] The protegrandins and their analogs or derivatives that have therapeutic use in the pharmaceutical implant compositions of this disclosure include latanoprost, bimatoprost, travoprost, 3-hydroxy-2,2-bis(hydroxymethyl)propyl7-((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, latanobunode, unoprostone, and PGF. 1α Lysopropyl ester, PGF 2α Isopropyl ester, PGF 3α Examples include isopropyl esters, fluprotenol, or any combination thereof. In some embodiments, protegrandins and their analogues or derivatives that have therapeutic applications include Dukekeprost, thiaprost, or both. In some embodiments, protegrandins and their analogues or derivatives that have therapeutic applications include free acids of protegrandins, pharmaceutically acceptable salts thereof, and their analogues or derivatives.

[0029] Other therapeutic agents having use in the pharmaceutical implant compositions of this disclosure for treating eye diseases or disorders, such as glaucoma, include, but are not limited to, beta-blockers, myotics, alpha-adrenergic agonists, or anhydrous carbonate inhibitors, and anti-metabolites such as 5-fluorouracil or mitomycin C.

[0030] Naturally, the pharmaceutical compositions of this disclosure may comprise a therapeutic agent or a combination of two or more therapeutic agents, examples of which are given above. Furthermore, analogues or derivatives of therapeutic agents, pharmaceutically acceptable salts, zwitterions, solvates, esters, and polymorphs, as discussed herein, have applicability in the pharmaceutical compositions of the present invention. As used herein, “analog” is a compound that has a similar structure to another compound (its “parent” compound), but with respect to some component, it has a different structure. An analogue may differ from its parent compound in one or more atoms, functional groups, or basic structures, which can be substituted with other atoms, groups, or basic structures. Similarly, analogues of parent compounds can also be formed by substituting specific atoms of the parent compound with radioisotopes of those specific atoms. A “derivative” is a compound that can be derived from or actually synthesized from a parent compound by substituting one atom with another atom or group of atoms.

[0031] In the pharmaceutical compositions of this disclosure, the 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, for example, the selection of the biodegradable polymer matrix, the selection of the therapeutic agent, the desired release rate in a substantially linear manner, the duration of the desired release rate, the composition of the pharmaceutical composition, and the ocular pharmacokinetics (PK).

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

[0033] The pharmaceutical compositions of this disclosure are prepared by dissolving a polymer matrix and a therapeutic agent in a suitable solvent to produce 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 possible. The solvent is then evaporated, leaving a homogeneous film. The solution can be aseptically filtered before the solvent is evaporated.

[0034] Further examples of implant manufacturing methods (formulations) are described in U.S. Patent No. 10,624,904, which is incorporated in its entirety by reference.

[0035] In another embodiment, the medical implant 100 may consist of multiple layers. In one example, as shown in Figure 2B, the medical implant 100 has a first layer 110, a second layer 120, and a third layer 130. The second layer 120 is positioned between the first layer 110 and the third layer 130. In some embodiments, the first layer 110 and the third layer 130 are made of the same material. In some embodiments, the first layer 110 and the third layer 130 are composed of a mixture of PLGAs, and the second layer 120 may be composed of a mixture of dexamethasone or other therapeutic agents and, for example, PLGA. In other embodiments, the first layer 110, the second layer 120, and the third layer 130 may be made of any other suitable material.

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

[0037] Figures 3A, 3B, and 3C show a medical implant 100 positioned within the needle of a needle-based drug delivery device 200, the needle of which can be in the size range of 21 gauge to 30 gauge. As shown in Figures 1B, 3B, and 4, the geometric shape of the medical implant 100, i.e., its external geometric shape, creates an interlocking fit with the inner diameter 202 of the needle 200, holding the implant 100 inside the needle.

[0038] In another embodiment, multiple medical implants 100 can be inserted into a single delivery device DD, as shown in Figure 4, to increase the amount of pharmaceutical product delivered, deliver one or more pharmaceutical products, or deliver implants designed and configured to have one or more drug delivery shapes.

[0039] Figure 5 illustrates an example of how an implant is held within a needle-based delivery device and how it is delivered using a pusher wire that overcomes the frictional force between the implant and the needle lumen during operation. The pusher wire may be propelled or actuated using features of a spring-based, electromechanical, or pneumatic device.

[0040] Numerous possible devices can be configured and used to deliver the implant of the present invention. For example, Figures 19 and 20 show a possible embodiment of a delivery device 100 having an elongated, substantially cylindrical body or housing 1 defining a longitudinal 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 parts that are permanently connected to each other during the assembly of the device, for example, two halves 1a and 1c. When assembled, the housing 1 may have a generally tapered end 8 that provides an ergonomic benefit when holding and using the device to deliver the implant into tissue. The tapered proximal end may also provide a user-friendly facilitator of where on the housing the delivery device should be grasped or held. To further indicate the position where the user should grasp or hold the delivery device during use, the outer surface of the distal end of the housing 1 may have a gripping surface 6. The gripping surface may consist of multiple surfaces in the form of a raised surface or raised surface or rib, a notched surface or rough surface, a tactile / soft-touch material inlay or overlay, a stepping feature, a dimple, 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 may provide a pushing surface or support surface that the user can use to deploy the device distally and axially while inserting the needle into the desired implant insertion site. Another feature of the device that can assist the user in moving or pushing the needle to the target tissue site is a raised surface of the actuarial member 5. In certain cases, it is desirable to have a pushing surface 9 that provides the user with tactile and / or levering functions during the operation of the implant delivery device 100.

[0041] Furthermore, the housing 1 may have a cutout located at its distal end that slidably receives the lock 3 having an anvil stop surface, and a retaining stopper that can be configured to engage with a portion of the housing 1 to prevent premature or unintended disengagement from the locked position. The lock 3 is configured to have two positions: a locked position and an unlocked position. Figures 19 and 20 show the lock 3 in the first or locked position, where the anvil stop surface contacts to prevent movement of the actuator 5 and, consequently, to prevent operation of the implant delivery device. The second or unlocked position is the position in which the lock 3 is removed and physically separated from the housing 1 by the user, for example, by pulling the lock laterally relative to the longitudinal axis 105 and overcoming the reversible retaining stopper. Once the lock 3 is removed from the delivery device 100, the actuator 5 is no longer prevented from moving relative to both the housing and the shuttle assembly 14, more specifically the shuttle 18. When in the first or locked position, the lock 3 can function as an anti-rolling function. In other words, the protruding structure of the lock prevents the delivery device from rolling uncontrollably on a flat surface, such as accidentally rolling over the table surface. A gripping tab can be provided, which extends radially from the lock beyond the outer surface of the housing and is shaped to allow the user to grasp the lock 3 and remove it from the housing 1.

[0042] Other examples of delivery devices include, but are not limited to, those described in U.S. Patent 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 for manufacturing or forming a medical implant 100 is particle replication in a non-wet template (PRINT) method and technique for obtaining the molded medical implant 100 of the present disclosure. The geometric shape of the medical implant 100 can be readily modified during the manufacturing process by changing the geometric shape of the mold tooling features used to form the implant using the PRINT technique.

[0044] Figure 6 shows a top view of a PRINT mold feature section, which can be modified to produce implants with different geometric shapes, as further described in U.S. Patent No. 10,624,904, the teaching of which is fully incorporated herein by reference. Figures 7 and 8 show the stepwise process used to manufacture implants with customizable geometric shapes for the production of micron-sized medical implants. In the PRINT manufacturing process, a flexible elastomer mold is designed to have a cavity that matches a two-dimensional planar projection of the implant. The rigid material is etched or machined to produce a series of feature sections with depths that match a repeating planar X-axis and Y-axis design, having one end of a diagonal prism larger than the inner diameter of the delivery needle and the other 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 feature sections that can be described as prisms. The flexible template is replicated to create a flexible mold or tooling consisting of a cavity. Flexible templates and molds are designed to allow for easy release of material from their surfaces. To manufacture implants using PRINT manufacturing technology, 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 cavity as this 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. Patent 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 incorporated herein by reference.

[0046] Further methods for fabricating tapered prism, trapezoidal prism, 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 having a portion of the prism length having a diagonal dimension greater than the inner diameter (ID) of the delivery needle and a portion of the prism length having a diagonal dimension smaller than the inner diameter of the delivery needle. Two-dimensional (2-D) morphological designs can serve as one possible starting point for different manufacturing techniques. A two-dimensional morphology defines the periphery of the target shape, and then, using another processing step, an undefined third dimension, which may be referred to as the z-dimension or z-axis, can be controlled. Further manufacturing techniques can utilize three-dimensional design, e.g., three-dimensional printing, layer-by-layer manufacturing, or additive (lamination) manufacturing. Even more manufacturing techniques can combine coating or additive manufacturing processes with two-dimensional form manufacturing techniques to produce implants having a portion of the shape length having a diagonal or diameter greater than the inner diameter of the delivery needle and a portion of the shape length having a diagonal or diameter smaller than the inner diameter of the delivery needle.

[0047] The first step in creating a two-dimensional shape is to fabricate a mold, or tool, to form the implant matrix material. This can be achieved by machining or etching metal, ceramic, silicon, or other known toolmaking materials. These materials can retain their shape during processing.

[0048] For mold extrusion, a two-dimensional projection of the X and Y plane design will be etched to create the mold opening shape, as illustrated in Figure 11. The matrix material will be extruded through the mold shape using a combination of heat and pressure. The pressure can be actuated by air or driven mechanically using a meshing screw. Electric heating elements will be used to achieve proper control of the heat applied to the matrix material. The matrix material may be supplied to a mold having a single opening. The mold may be constructed to have multiple openings of the same plane design to increase processing capacity, as shown in Figure 12. Each opening will be supplied by the same matrix material. Alternatively, multiple formulations may be co-extruded within a single extrusion geometry using divided matrix supply paths. This co-extrusion may be used to create a wedge-shaped form of one of the extended matrix components behind the mold to produce 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 mold extrusion. A filament mold with a diameter larger than the inner diameter of the target needle cannula will be mounted at the end of the extruder barrel. Figure 13 shows an exemplary comparison between a cross-section of a larger filament mold and a cross-section of the target needle. The circular extruder from the extruder will be drawn using variable tensile stress to achieve tapered filament sections along the length of the extruder. See Figure 14 for an example of a depiction of the lateral shape of the filament extruder. Using a cutting mechanism, the filament extruder will be cut into several sections to produce implants of controlled length. The filament extruder will have a narrower diameter than the target needle cannula to provide sufficient introduction into the target delivery needle during loading of the implant into the needle cannula. The diameter of the filament extruder will become increasingly thicker as it moves from the narrow or tapered end of the cut section to the interfering end of the cut section.

[0050] In the injection molding process for forming the implant of the present disclosure, the rigid mold will have cavity features onto which a two-dimensional plan view of the intended implant geometry is projected. The mold and individual cavities can be machined or three-dimensionally printed to produce the final shape. The cavities will have a tapered outer shape to produce a cylindrical or prismatic shape having one end smaller than the inner diameter of the delivery needle and the other end larger than the inner diameter of the delivery needle. Figure 15 shows one possible design of the injection molding mold.

[0051] When injection molding is used to fabricate the implants of this disclosure, the number of cavities per injection mold is arbitrary. 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 cavities. End connections can be positioned so that burrs generated from the removal of individual parts do not alter the lateral shape of the implant. Examples of connection positions that do not alter the lateral shape would be the apical or basal ends of the implant (see Figure 15). The design of the injection mold also allows for the introduction of interference features along the lateral shape of the implant cavity, such as a flange design. The interference features may be designed to provide a controlled amount of resistance for retention and a controlled amount of resistance for ejection speed. The interference features will make the diameter or diagonal shape of the implant larger than the inner diameter of the delivery needle. The interference feature can be a continuous feature around the circumference or periphery of the implant, or a discontinuous feature around the circumference or periphery of the implant, such as a feature on one face of a prism or a point along the circumference of a cylinder. Figure 16 shows examples of continuous and discontinuous interference features.

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

[0053] In the case of three-dimensional printing or layer-by-layer manufacturing, implant construction utilizes the precise spatial deposition of the matrix material. This precise spatial deposition is typically achieved through robotics, automation, and computer-aided drawings. The computer-aided drawings 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 the other end having a maximum diagonal or diameter smaller than the inner diameter of the delivery needle. Manufacturing techniques using a filament-feeding stylus to create the implant involve a feed tip with a diameter smaller than the smallest implant design feature. For techniques similar to those in layer-by-layer manufacturing, the z-dimensional resolution of the layer feature 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 this disclosure, there are post-processing modifications that can be performed using the aforementioned fabrication procedures to create sections of the implant having 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 having the ability to increase 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 the second material will create two distinct parts of the implant design in which a portion of the prismatic length has a diagonal larger than the inner diameter of the delivery needle. The fabricator will fabricate the implant having a sub-needle ID diameter or diagonal using any of the techniques described above. A portion of the implant length will be coated with a swelling medium via various techniques, e.g., immersion, 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] The implant shape can be described using six parameters: overall length, thickness, interference width, slip width, interference length, and slip length. These six implant design parameters influence the performance of the drug through three main responses. Figure 18 shows four of these parameters, although the overall length is not shown, which would be the end-to-end implant length with rounded ends. The thickness would be captured by projection onto the z-axis. The three main responses are: (1) resistance while the implant is loaded into the delivery needle; (2) resistance to the retention of the implant in the delivery needle or resistance to the movement of the implant while it is loaded into the delivery needle; and (3) resistance to ejection when the implant is removed from the needle and delivered.

[0056] The parameters of overall length and thickness are positively correlated with the three responses described above. As overall 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 diagonal length of the implant increases, resulting in increased resistance during loading. The resistance of the implant to movement within the delivery needle and the resistance to ejection increase with the interference width until the diagonal length of the implant matches the inner diameter of the delivery needle. At interference widths where the diagonal length of the implant is above the inner diameter of the delivery needle, there is no practical difference in the implant's retention performance or resistance to ejection. As the implant is loaded into the delivery needle, the material is sheared from the edges of the implant, so the diagonal length of the implant does not change once it enters the delivery needle. Once inside the delivery needle, the diagonal length of the implant is reduced to match the inner diameter of the delivery needle, so the resistance to movement and the resistance to ejection of the implant do not change.

[0057] The interference length parameter is positively correlated with all three responses. A larger interference length increases resistance to loading, holding, and ejection, based on the same rationale as overall length and thickness. The slip width parameter affects loading resistance. By incorporating a slip portion or tapered design, an introduction is created to facilitate implant loading. The slip width should not be so small that mechanical strength is compromised during the specified manufacturing process, including loading and ejection. The implant is preferably designed to withstand pushing another implant within the delivery needle or being pushed 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, resistance to loading increases, potentially leading to 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 affects the resistance of implant loading and is negatively correlated. As the slip length increases, the resistance to loading decreases, so a properly predetermined slip width parameter should make the process of loading the implant into the needle cannula easier. As the implant is loaded, the inclined surface of the tapered prism moves the implant in an orientation parallel to the delivery needle cannula, and further forces the implant to move into the delivery needle, so that the slip section of the implant aligns the implant with the opening of the delivery needle. A smaller slip length and a larger interference length have the same effect on the three responses. A smaller slip length increases the resistance to loading, movement within the delivery needle, and ejection from the delivery needle.

[0058] The 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 the delivery needle, for example, a 27-gauge needle. Using a Mark-10 Model M5-10 force gauge, or a similar force gauge, along with a narrow-gauge stainless steel pusher rod and load cell, an index of the force of the pusher wire required to expel the implant from inside the needle cannula can be obtained. Figure 9 shows an example of the apparatus used to measure the implant retention force. A steel pusher wire is inserted into the needle containing the implant and advanced until the implant is detached from the needle. The force required to detach the implant is measured as the retention force by the load cell.

[0059] Figure 10 is a graph showing the retention force measurements of numerous medical implants with different shapes using a 27-gauge needle. The numerical results and information regarding the tested implants are summarized in Table 1 below for the 27-gauge needle implants. [Table 1]

[0060] These test results indicate that the present implant 100 (wedge-shaped) had the best retention force (over 159g (0.350 lbs)) among the seven different designs tested. The retention force of the uniform diameter designs was either too low (cylindrical), easily dislodged, or too high (rectangular prism) and did not fit within the needle lumen.

[0061] During operation, the medical implant 100 is used in conjunction with a drug delivery device, such as a needle 200, to inject (insert) the medical implant 100 into the patient's tissue. In one embodiment, the medical implant 100 is an intraocular lens implant configured to be injected into the posterior chamber of the 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 the forward movement of a pusher wire within the lumen of the needle, as shown in Figure 5. The movement of the pusher wire can be driven by various delivery device features, including a metal or plastic spring or pneumatic mechanism. Operation of this delivery mechanism can be achieved by linking the delivery mechanism to a push button or slide on a device handle operated by the physician performing the procedure.

[0062] Another aspect of the present disclosure of implants has the ability to impart surface modifications (see reference numerals 200 and 210 in Figure 21) to produce interference surfaces on the medical implant 100. Such surface modifications can enhance and optimize retention when the implant is loaded into a needle cannula. Examples of surface modifications include coatings, films, biomatrixes, nanostructures (nanotubes and nanopores), roughening, sputtering, and sprayed surfaces, both at the macro and nanoscale. The rugosity or roughness of the implant surface can also be achieved by incorporating these textured features into the mold tools used to form the implant. Coatings and films may involve using layering techniques applied to the surface of the implant and possibly involve using combinations of different polymers or other coating materials having different surface energies relative to the lumen of the contacting delivery device surface. Different combinations of surface modifications can be used, for example, one type of surface modification 200 on one part of the implant 100 and another surface modification 210 used on different parts of the implant.

[0063] While numerous exemplary embodiments and models have been described above, those skilled in the art will recognize that further modifications, substitutions, additions, and sub-combinations thereof are still possible of the features of the disclosed embodiments. Furthermore, this disclosure includes the following inventions. The first aspect is, In medical implants, The aforementioned medical implant is It 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 end and the second end. The first cross-sectional dimension is larger than the second cross-sectional dimension of the medical implant. The second aspect is, The tapered portion is a medical implant in a first embodiment that extends only partially between the first end and the second end. The third aspect is, The first and second ends are each medical implants in the first embodiment, having a rounded outer shape. The fourth aspect is, A medical implant in a first embodiment, wherein the length from the first end of the main body to the first end of the tapered portion is within the range of approximately 5% to approximately 50% of the total length of the implant. The fifth aspect is, The first embodiment of the medical implant is characterized in that the length from the first end of the tapered portion to the second end of the main body is in the range of approximately 950 μm to approximately 4750 μm. The sixth aspect is, The medical implant in the first embodiment comprises a single layer. The seventh aspect is, The medical implant in the first embodiment is made of a mixture of a therapeutic agent or diagnostic agent and a biocompatible polymer. The eighth aspect is, The seventh embodiment is a medical implant in which the biocompatible polymer contains a terminal ester or an acid. The ninth aspect is, The main body of the medical implant is a medical implant according to a first embodiment, comprising multiple layers. The tenth aspect is, A medical implant according to a ninth embodiment, characterized in that at least one of the plurality of layers is made of a biocompatible polymer, and at least one other layer of the plurality of layers is made of a mixture of a therapeutic agent or diagnostic agent and a biocompatible polymer. The eleventh aspect is, This is a medical implant in a first embodiment, wherein the medical implant is formed or manufactured using particle replication in a non-wet template (PRINT) method in order to shape the medical implant. The twelfth aspect is, The medical implant is a medical implant in a first embodiment, which is inserted using a drug delivery device. The 13th aspect is, The main body of the medical implant is a medical implant according to the first embodiment, having surface modification. The 14th aspect is, In medical implants, The aforementioned medical implant is A body having a first layer, a second layer and a third layer, further having a first end having a first cross-sectional dimension and a second end having a second cross-sectional dimension, The main body further has a tapered portion extending between the first end and the second end, The first and third layers have a first material, and the second layer has a second material. The first cross-sectional dimension is larger than the second cross-sectional dimension of the medical implant. The 15th aspect is, The tapered portion is a medical implant in a 14th embodiment, extending only partially between the first end and the second end. The 16th aspect is, A medical implant in a 14th embodiment, wherein the length from the first end of the main body to the first end of the tapered portion is within the range of approximately 5% to approximately 50% of the total length of the implant. The 17th aspect is, A medical implant in a 14th embodiment, wherein the first material has a mixture of PLGAs, and the second material has a mixture of a therapeutic agent and PLGAs. The 18th aspect is, A drug delivery device configured to insert one or more of the medical implants in the 14th embodiment into the eye of a patient, 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. The 19th aspect is, The medical implant is a drug delivery device in 18th form, which is held within the needle via friction fitting. The 20th aspect is, In a method for manufacturing medical implants, The aforementioned method, The present invention relates to forming a medical implant using particle replication in a non-wet template (PRINT) method for shaping medical implants, wherein the medical implant comprises 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, wherein the first cross-sectional dimension is larger than the second cross-sectional dimension, The shape of the medical implant allows the medical implant to be held within the needle of the drug delivery device via friction fitting. The medical implant is a method for manufacturing a medical implant configured to be inserted into the eye using the drug delivery device.

Claims

1. In medical implants, The aforementioned medical implant is It has a substantially wedge-shaped body with height and width, The main body has a first end having a first cross-sectional area having a first cross-sectional dimension in the width direction, a second end having a second cross-sectional area having a second cross-sectional dimension in the width direction, and a tapered portion that extends at least partially in the width direction between the first end and the second end. The first end of the main body is configured to be initially inserted into the cannula, and the second end of the main body is configured to be inserted into the eye. The first cross-sectional dimension is larger than the second cross-sectional dimension. The length from the first end of the main body to the tapered portion is less than 50% of the total length of the medical implant. A medical implant in which the height is substantially constant between the first end and the second end.

2. The tapered portion extends from the first end and the second end, as described in claim 1.

3. The medical implant according to claim 1, wherein the first end and the second end each have a rounded outer shape.

4. The medical implant according to claim 1, wherein the length from the first end of the main body to the first end of the tapered portion is within the range of approximately 5% to approximately 50% of the total length of the medical implant.

5. The medical implant according to claim 1, wherein the length from the first end of the tapered portion to the second end of the main body is in the range of approximately 950 μm to approximately 4750 μm.

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

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

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

9. The medical implant according to claim 1, wherein the main body of the medical implant comprises a plurality of layers.

10. The medical implant according to claim 9, characterized in that at least one of the plurality of layers is made of a biocompatible polymer, and at least one other layer of the plurality of layers is made of a mixture of a therapeutic agent or diagnostic agent and a biocompatible polymer.

11. The medical implant according to claim 1, wherein the medical implant is inserted using a drug delivery device.

12. The medical implant according to claim 1, wherein the main body of the medical implant has surface modification.

13. In medical implants, The aforementioned medical implant is It has a substantially wedge-shaped body with height and width, The main body has a first layer, a second layer and a third layer, The main body further comprises a first end having a first cross-sectional area having a first cross-sectional dimension in the width direction, and a second end having a second cross-sectional area having a second cross-sectional dimension in the width direction, The main body further has a tapered portion that extends at least partially in the width direction between the first end and the second end, The first end of the main body is configured to be initially inserted into the cannula, and the second end of the main body is configured to be inserted into the eye. The length from the first end of the main body to the tapered portion is less than 50% of the total length of the medical implant. The first and third layers have a first material, and the second layer has a second material. A medical implant in which the first cross-sectional dimension is larger than the second cross-sectional dimension.

14. The tapered portion extends from the first end and the second end, as described in claim 13.

15. The medical implant according to claim 13, wherein the length from the first end of the main body to the first end of the tapered portion is within the range of approximately 5% to approximately 50% of the total length of the medical implant.

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

17. A drug delivery device configured to insert one or more of the medical implants described in claim 13 into the eye of a patient, The drug delivery device comprises a cannula and a needle configured to hold the medical implant from the time of manufacture until the medical implant is inserted into the eye of a patient.

18. The drug delivery device according to claim 17, wherein the medical implant is held within the needle via friction fitting.

19. In a method for manufacturing medical implants, The aforementioned method, A method for forming a medical implant using particle replication in a non-wet template (PRINT) method for shaping medical implants, wherein the medical implant has a substantially wedge-shaped body having height and width, the body further having a first end having a first cross-sectional area having a first cross-sectional dimension in the width direction, a second end having a second cross-sectional area having 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, wherein the first cross-sectional dimension is greater than the second cross-sectional dimension, The length from the first end of the main body to the tapered portion is less than 50% of the total length of the medical implant. The shape of the medical implant allows the medical implant to be held within the needle of the drug delivery device via friction fitting. A method for manufacturing a medical implant, wherein the medical implant is configured to be inserted into the eye using the drug delivery device.

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