Injection system and method of use

Abstract

An injection system and a method for using the same are provided. [Solution] An injection system comprising a syringe barrel; a first sealing element and a second sealing element movably disposed within the syringe barrel; an injection chamber between them; and a puncture element extending from the first sealing element for delivering an injectable agent from the injection chamber into a biological space, wherein one or more of the syringe barrel, the first sealing element, or the second sealing element are configured to prevent the proximal movement of the first sealing element beyond a pre-selected position, while allowing the second sealing element to come into contact with the first sealing element.

Description

Technical Field

[0004] , , , ,

[0003]

[0001] Related Applications This application claims the benefit and priority of U.S. Provisional Patent Application No. 63 / 052,518, filed Jul. 16, 2020, and U.S. Provisional Patent Application No. 62 / 903,406, filed Sep. 20, 2019. The entire contents of these applications are incorporated herein by reference.

[0002] Field The present disclosure relates to systems and methods that enable injection into a cavity or void, particularly injection through human body tissue into a cavity or void (e.g., the suprachoroidal space within eye tissue).

Background Art

[0003] Background Posterior segment eye diseases are a major cause of permanent vision impairment affecting millions of people and can lead to blindness if left untreated. Posterior segment eye diseases include a number of diseases such as age-related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema (DME), choroideremia (CHM), retinal vein occlusion (RVO), uveitis, and endophthalmitis. Although pharmaceuticals may be available to prevent disease progression in many cases, due to the blood-eye barrier, therapeutic concentrations cannot be achieved in the posterior segment of the eye by systemic delivery.

[0004] Local delivery via local, transscleral, and intravitreal routes may be effective, but higher concentrations at the delivery site are needed to maintain therapeutic concentrations in the affected retina after diffusion through the vitreous humor. While there are reports of intraocular lenses for continuous delivery, they can be considerably more invasive than intravitreal injections. Subretinal injections have also been used to increase concentrations in the affected retina. However, subretinal injections require demanding, inconsistent techniques that must be performed in the surgical setting, resulting in patchy, uneven coverage and a risk of retinal detachment. Furthermore, repeated subretinal injections may be impractical or undesirable, as additional injections can further damage the fragile affected retina. Further strategies to accelerate the movement of drug molecules into the retina, such as iontophoresis and magnetic fields, have been reported, but these add a new level of complexity to the overall drug delivery problem.

[0005] In recent years, the suprachoroidal space (SCS) has been investigated as a promising drug delivery route to the posterior part of the eye. The suprachoroidal space is the latent space between the sclera and the choroid. Drugs delivered into this space can travel around the eyeball and reach the posterior segment. This drug delivery route has been shown to be more effective for posterior segment treatment than intravitreal injection. However, the simplicity of intravitreal injection outweighs the surgical techniques traditionally required for suprachoroidal delivery. Historically, suprachoroidal delivery was performed by making a small incision with a scalpel and then delivering the drug using a puncture device or cannula. More recently, the suprachoroidal space has been targeted using short, predetermined-length micropuncture elements that can only penetrate to a certain depth. Since scleral thickness varies considerably within patient populations, when injecting with a hollow micropuncture element, it is necessary to map the geometric shape of the eye beforehand or to use trial and error. If the puncture element is too long, it can easily penetrate the thin suprachoroidal space and inject the drug into the vitreous humor; if it is too short, it can reach the sclera. Since the sclera is 10 times harder than the choroid and 200 times harder than the retina, penetrating the sclera without injecting into the vitreous humor is even more difficult. In some cases, it is necessary to inject a small amount (approximately 100 microliters) of the therapeutic agent into the suprachoroidal space, and in order to cover a wide area of ​​the posterior segment, the drug must be injected with enough force to counteract the positive resistance of intraocular pressure that is putting pressure on the choroid with the sclera behind it.

[0006] Therefore, there is a need for improved systems and methods for suprachoroidal drug delivery that can accurately and safely target the suprachoroidal space with minimal variation and broadly cover the posterior segment of the eye. [Overview of the project] [Means for solving the problem]

[0007] Abstract In some embodiments, the present disclosure provides an injection system comprising: a syringe barrel defining a lumen between a proximal and distal end; a first sealing element movably disposed within the lumen; a second sealing element movably disposed within the lumen proximal to the first sealing element, wherein the first and second sealing elements form a seal with the lumen and define an injection chamber between them; and a puncture element extending from the distal end of the first sealing element, the puncture element being in fluid communication with the injection chamber to deliver an injectable agent from the injection chamber into a space within the patient's tissue. The syringe barrel, one or more of the first and second sealing elements are configured to prevent the proximal movement of the first sealing element beyond a pre-selected position, while allowing the second sealing element to contact the first sealing element, and the system is configured such that, when a distal force is applied to the second sealing element, in response to a first reaction force, the first sealing element moves distally, advancing the puncture element distally without transporting the injectable drug through the puncture element, and in response to a second reaction force, the first sealing element remains stationary, allowing the injectable drug to be transported through the puncture element from the injection chamber. In some embodiments, the first reaction force is due to the back pressure exerted on the puncture element as it advances through the tissue; the second reaction force is due to the back pressure exerted on the puncture element as it enters a space within the tissue. In some embodiments, the force applied to the second sealing element is sufficient to advance the first sealing element but insufficient to deliver the injectable drug through the puncture element in response to the first reaction force; the force applied to the second sealing element is insufficient to advance the first sealing element but insufficient to deliver the injectable drug through the puncture element in response to the second reaction force.

[0008] In some embodiments, a unidirectional stop is positioned within the syringe barrel between a first sealing element and a second sealing element, configured to prevent the first sealing element from moving proximal to the unidirectional stop while allowing the second sealing element to pass through its mechanical stop and contact the first sealing element. The unidirectional stop may constitute a section of the syringe barrel having a reduced diameter, where the first sealing element has a diameter sufficiently larger than its reduced diameter, and the first sealing element cannot pass through the section, but the second sealing element is configured to pass through the section and contact the first sealing element. In some embodiments, the unidirectional stop constitutes a portion of the inner surface of the syringe barrel having a coefficient of friction sufficient to prevent the first sealing element from moving proximal to the unidirectional stop. In some embodiments, the unidirectional stop includes a mechanical stop. In some embodiments, the unidirectional stop constitutes a foldable stop positioned between a first sealing element and a second sealing element, the foldable stop being configured to prevent proximal movement of the first sealing element beyond the foldable stop, and to fold when a distal force is applied to the foldable stop, allowing the second sealing element to pass through the foldable stop and come into contact with the first sealing element. In some embodiments, the first sealing element is molded such that the proximal frictional or sliding force relative to the first sealing element is greater than the distal frictional or sliding force relative to the first sealing element and greater than the insertion force of the puncture element into the tissue.

[0009] In some embodiments, the first sealing element, in its relaxed state, is 1.01 to 2 times larger than the size of the lumen of the syringe barrel. In some embodiments, the first sealing element, in its relaxed state, is 1.01 to 1.10 times larger than the size of the lumen of the syringe barrel. In some embodiments, the first sealing element, in its relaxed state, is 1.01 to 1.4 times larger than the size of the lumen of the syringe barrel. The inner surface of the syringe barrel may be modified to increase friction between the inner surface of the syringe barrel and the first sealing element. In some embodiments, a lock is located distal to the first sealing element, and the lock is configured to selectively lock the first sealing element in a predetermined position. The lock may comprise a sealed compartment defined within the lumen of the syringe barrel distal to the first sealing element, an incompressible material inside the compartment, and a valve for releasing the incompressible material from the compartment, wherein when the valve is closed, distal movement of the first sealing element is prevented, and when the valve is open, distal movement of the first sealing element is permitted.

[0010] In some embodiments, a touch trigger mechanism is positioned between a first sealing element and a second sealing element, configured to deploy when the first sealing element comes into contact with the second sealing element to prevent distal movement of the first sealing element. In some embodiments, a filling port is positioned on the surface of the syringe barrel, and the filling port is in fluid communication with the injection chamber. In some embodiments, such a filling port may comprise a receiving portion positioned on the outer surface of the syringe barrel and configured to receive a vial; a flow path connecting the receiving portion and the injection chamber; a self-sealing member configured to seal the flow path; and a puncture element positioned within the receiving portion, the puncture element being configured to penetrate the self-sealing member and to fluidly connect the vial received in the receiving portion with the injection chamber. In some embodiments, the puncture element is movable relative to the receiving portion so that when a vial is received in the receiving portion, the puncture element moves toward the injection chamber, penetrates a self-sealing member, and the vial and injection chamber are fluidly connected; and when the drug container is removed from the receiving portion, the puncture element moves away from the injection chamber so that the self-sealing member can seal the flow path.

[0011] In some embodiments, a support element is positioned near the distal end of the puncture element, and the support element is movable in conjunction with the puncture element and the syringe barrel. The injection chamber may comprise a first chamber and a second chamber, where the chamber sealing portion of the second sealing element fluidly isolates the first chamber from the second chamber, and as the chamber sealing portion moves, the first and second chambers are fluidly connected. In some embodiments, the injection chamber comprises a first chamber and a second chamber, where the first and second chambers are fluidly isolated from each other when the second sealing element is in its initial position, and as the second sealing element moves, the first and second chambers are fluidly connected. In some embodiments, the second sealing element is configured to engage with the first sealing element and to withdraw the first sealing element and the puncture element into the syringe barrel.

[0012] In some embodiments, the present disclosure provides a method for treating an eye disease, the method comprising the step of pre-inserting a puncture element of an injection system into the sclera of a patient, the injection system comprising: a syringe barrel defining a lumen between its proximal and distal ends; a first sealing element movably disposed within the lumen; a second sealing element movably disposed within the lumen proximal to the first sealing element, wherein the first and second sealing elements form a seal with the lumen and define an injection chamber between them; and a puncture element extending from the distal end of the first sealing element, the puncture element being in fluid communication with the injection chamber to deliver an injectable agent from the injection chamber into a space within the patient's tissue, wherein the syringe barrel, the second The process includes: a step of: one or more of the first sealing element and the second sealing element being configured to prevent the first sealing element from moving proximal beyond a pre-selected position, while allowing the second sealing element to come into contact with the first sealing element; a step of advancing the puncture element through the sclera by applying force to the second sealing element, the force being sufficient to move the first sealing element distally and advance the puncture element distally without transporting the injectable agent through the puncture element; and a step of maintaining the force on the second sliding element so that, when the puncture element has passed through the sclera and entered the suprachoroidal space (SCS), the injectable agent is transported from the injection chamber through the puncture element to the SCS without further distal movement of the first sealing element. In some embodiments, the eye disease is age-related macular degeneration (AMD), diabetic macular edema (DME), glaucoma, retinal vein occlusion (RVO), uveitis, endophthalmitis, Stargardt disease, Leber congenital amaurosis (LCA), retinitis pigmentosa, or colloideremia. In some embodiments, the injection fluid comprises one or more injectable formulations comprising a viral delivery vector containing the gene of interest and a promoter selected to promote the gene of interest.The target gene may be an anti-VEGFR2 gene, the delivery vector may be an AAV vector, and the promoter for the anti-VEGFR2 gene may be a CAG promoter. In some embodiments, the injection fluid comprises one or more injectable formulations comprising: anti-VEGFR2 compounds selected from the group consisting of bevacizumab, ranibizumab, aflibercept, ramucirumab, disintegrin, anti-prostaglandins, tryptophanyl-tRNA synthetase-derived polypeptides, inosine monophosphate dehydrogenase (IMPDH) inhibitors and anti-PDGF for treating AMD; as well as corticosteroids for treating uveitis, chorioretinitis or other inflammatory eye diseases; botulinum toxin for use in various eyes; and tyrosine kinase inhibitors.

[0013] In some embodiments, the present disclosure provides a kit for injecting an injectable agent into tissue, the kit comprising: a syringe barrel defining a lumen between a proximal and distal end; a first sealing element movably disposed within the lumen; a second sealing element movably disposed within the lumen proximal to the first sealing element, wherein the first and second sealing elements form a seal with the lumen and define an injection chamber between them; and a puncture element extending from the distal end of the first sealing element, the puncture element being in fluid communication with the injection chamber to deliver the injectable agent from the injection chamber into a space within the patient's tissue, the injection system comprising the syringe barrel, An injection system comprising one or more of a first and second sealing element, configured to prevent the proximal movement of the first sealing element beyond a pre-selected position, while allowing the second sealing element to come into contact with the first sealing element, wherein the system is configured such that when a distal force is applied to the second sealing element, in response to a first reaction force, the first sealing element moves distally, advancing the puncture element distally without transporting the injectable agent through the puncture element, and in response to a second reaction force, the first sealing element remains stationary, allowing the injectable agent to be transported from the injection chamber through the puncture element; and an injection fluid comprising a predetermined volume of injection fluid containing one or more injectable formulations. In some embodiments, the eye disease is age-related macular degeneration (AMD), diabetic macular edema (DME), glaucoma, retinal vein occlusion (RVO), uveitis, endophthalmitis, Stargardt disease, Leber congenital amaurosis (LCA), retinitis pigmentosa, or colloideremia. In some embodiments, the injection fluid comprises one or more injectable formulations comprising a viral delivery vector containing the gene of interest and a promoter selected to promote the gene of interest. The gene of interest may be an anti-VEGFR2 gene, the delivery vector may be an AAV vector, and the promoter for the anti-VEGFR2 gene may be a CAG promoter.In some embodiments, the injection fluid comprises one or more injectable formulations comprising: bevacizumab, ranibizumab, aflibercept, ramucirumab, disintegrin, anti-VEGFR2 compounds selected from the group consisting of bevacizumab, ranibizumab, aflibercept, ramucirumab, disintegrin, anti-prostaglandins, tryptophanyl-tRNA synthetase-derived polypeptides, inosine monophosphate dehydrogenase (IMPDH) inhibitors and anti-PDGF for treating AMD; corticosteroids for treating uveitis, chorioretinitis or other inflammatory eye diseases; botulinum toxin for use in various eyes; and tyrosine kinase inhibitors.

[0014] This disclosure is further described in the following detailed description with reference to several drawings of interest as non-limiting examples of exemplary embodiments. Across some of those drawings, similar reference figures represent similar parts. [Brief explanation of the drawing]

[0015] [Figure 1A] Figure 1A shows an embodiment of the injection system of the present disclosure.

[0016] [Figure 1B] Figure 1B illustrates various embodiments of a puncture element suitable for use in connection with the injection system of this disclosure.

[0017] [Figure 2] Figure 2 illustrates an exemplary use of an embodiment of the injection system of this disclosure.

[0018] [Figure 3] Figure 3 shows an embodiment of the injection system of the present disclosure having a unidirectional stop.

[0019] [Figure 4] Figure 4 illustrates an exemplary use of an embodiment of the injection system of the present disclosure having a one-way stop.

[0020] [Figure 5] Figures 5A-5B show embodiments of the injection system of the present disclosure having a location where the diameter of the syringe barrel is reduced.

[0021] [Figure 6] Figures 6A-6B show embodiments of the injection system of the present disclosure where the sealing element is shaped to have an asymmetric frictional force.

[0022] [Figure 7A-C] Figures 7A-7C show embodiments of the injection system of the present disclosure having a foldable one-way stop.

[0023] [Figure 7D-E] Figures 7D-7E show various embodiments of a foldable one-way stop suitable for use in the injection system of the present disclosure.

[0024] [Figure 8] Figures 8A-8D illustrate an exemplary process for manufacturing an injection system having a foldable one-way stop.

[0025] [Figure 9] Figures 9A-9B show various embodiments of the distal end of the injection system of the present disclosure having a needle support.

[0026] [Figure 10] Figures 10A-10B show various embodiments of the distal end of the injection system of the present disclosure having a needle support.

[0027] [Figure 11] Figures 11A-11C show various embodiments of a safety cap suitable for use in the injection system of the present disclosure. <L

[0028] [Figure 12] Figures 12A-12E show embodiments of the injection system of the present disclosure pre-filled with a multi-component injection.

[0029] [Figure 13] Figure 13 shows a graph of the viscosity of the injection fluid according to the inner diameter of the puncture element in the injection system of this disclosure.

[0030] [Figure 14] Figure 14 shows an embodiment of the injection system of the present disclosure having an oversized sealing element.

[0031] [Figure 15] Figures 15A–15E show embodiments of the injection system of the present disclosure having a lock for a sealing element.

[0032] [Figure 16] Figure 16 shows an embodiment of the injection system of this disclosure having an access port at the distal end.

[0033] [Figure 17] Figures 17A to 17B show embodiments of the injection system of the present disclosure having a touch trigger mechanism between sealing elements.

[0034] [Figure 18] Figure 18 shows an embodiment of the injection system of the present disclosure having a rapid filling port.

[0035] [Figure 19A-B] Figures 19A–19D illustrate an exemplary process for filling the injection system of this disclosure through a rapid filling port. [Figure 19C-D] Figures 19A–19D illustrate an exemplary process for filling the injection system of this disclosure through a rapid filling port.

[0036] [Figure 20] Figures 20A–20C illustrate an exemplary process for rear-filling the injection system of this disclosure.

[0037] [Figure 21] Figures 21A–21B illustrate an exemplary process for filling the injection system of this disclosure through the proximal port.

[0038] [Figure 22] Figures 22A–22C illustrate an exemplary process for filling the injection system of this disclosure through a port sealed with a self-sealing polymer.

[0039] [Figure 23] Figures 23A to 23D show embodiments of the injection system of this disclosure having a port at the distal end.

[0040] [Figure 24] Figures 24A–24E show embodiments of the injection system of this disclosure configured for safe disposal. [Modes for carrying out the invention]

[0041] The drawings identified above illustrate embodiments of the present disclosure, but other embodiments are also conceived, as will be discussed. This disclosure provides illustrative embodiments as representative examples, not as an limitation. Numerous other modifications and embodiments that fall within the scope and spirit of the principles of the embodiments of this disclosure can be devised by those skilled in the art.

[0042] Detailed explanation Therefore, there is a need for improved systems and methods for injecting active agents into existing or potential biological spaces (e.g., the suprachoroidal space) that can be targeted accurately and safely with no variability, and that broadly cover adjacent structures or organs. For example, the injection system of the present disclosure may be used for drug delivery into the suprachoroidal space that broadly covers the posterior segment of the eye. The injection system of the present disclosure is configured such that the puncture element automatically stops at the interface of the target space, so that the depth to which the needle penetrates the cavity is limited. Therefore, the injection system of the present disclosure may be configured to self-adjust the depth of penetration of the puncture element into the target space. The injection system of the present disclosure can be used to penetrate tissue (e.g., the sclera) and deliver an injectable agent to a biological space (e.g., the suprachoroidal space), while self-controlling the depth of penetration into the biological space and injection site based on the resistance the system faces at various stages of the delivery cycle. In some embodiments, the refinement and miniaturization of the injection system of the present disclosure enable the puncture element to precisely target and stop at thin, potential cavities such as the suprachoroidal space, thereby enabling the precise delivery of a precise volume of injectable drug over a wide range of applications. In some embodiments, the volume may be less than a milliliter. In some embodiments, the injection system of the present disclosure is configured to deliver therapeutic drugs to target spaces with microliter precision.

[0043] The following descriptions of the injection systems and methods of use of the present disclosure are merely illustrative embodiments and are not intended to limit the scope, applicability, or arrangement of the present disclosure. Rather, the following descriptions of the exemplary embodiments provide a possible description for performing one or more exemplary embodiments for those skilled in the art. It will be understood that various modifications can be made to the function and arrangement of the elements without departing from the spirit and scope of the embodiments of the present disclosure.

[0044] The subject matter will be described more fully below with reference to the accompanying drawings, which form part of this specification and illustrate specific aspects and embodiments of the present disclosure. However, since the subject matter can be embodied in various different forms, it is intended to be interpreted that the subject matter covered or claimed is not limited to any of the embodiments shown herein; the embodiments are provided merely as illustrations. Therefore, the following detailed description is not intended to be interpreted as limiting.

[0045] Referring to Figure 1, the injection system of the present disclosure may comprise a syringe barrel 102 having a proximal end 104 and a distal end 106, with a lumen 108 defined between the proximal end 104 and the distal end 106. The injection system further comprises a first sealing element 110 and a second sealing element 112, both of which are slidably positioned within the lumen 108 of the syringe barrel 102. As shown in Figure 1, in the initial state, the first sealing element 110 and the second sealing element 112 are spaced apart from each other, and the space between the sealing elements in the syringe barrel defines an injection chamber 114 for holding a suitable volume of injectable agent therein. As used herein, “injectable agent” means a composition comprising a single substance or combination of substances that can be injected into a space or potential space within tissue. The injectable agent may be provided as a fluid, liquid, gas, suspension, solution, emulsion or other flowable composition. In some embodiments, the injectable preparation may comprise one or more therapeutic substances or formulations, including, but not limited to, small molecule compounds, antibodies, nucleic acid molecules, polypeptides, and compounds that help deliver the aforementioned to the patient, such as viruses or vectors for nucleic acid delivery. In some embodiments, a standard syringe barrel having a volume of 10 µl to 50 ml may be used. In some embodiments, the injection chamber may have a volume of about 0.025 ml to 20 ml, although larger or smaller syringe barrels may also be used. In some embodiments, the injection chamber may have a volume of about 0.025 ml, 0.05 ml, 0.1 ml, 0.5 ml, 1 ml, 3 ml, 5 ml, or 10 ml before dispensing the injectable preparation.

[0046] The sealing elements 110 and 112 can fit snugly into the syringe barrel 102, forming a seal with the wall of the syringe barrel 102 to prevent the injectable agent from leaking out of the injection chamber 114. In some embodiments, the second sealing element can slide or screw in so as to move relative to the syringe barrel. Thus, in some embodiments, the devices disclosed herein do not require operator feedback (e.g., touch, tactile sensation). In some embodiments, the sealing elements interact with the wall of the syringe barrel by friction as the sealing elements slide along the lumen of the syringe barrel. In some embodiments, the frictional force between the sealing element and the syringe barrel can be varied by changing the size and shape of the sealing agent. In some embodiments, the sealing element may be made from a natural or synthetic polymer, such as a natural or synthetic rubber or elastomer material.

[0047] In some embodiments, a puncture element 116 extends from the distal end of a first sealing element, and the lumen of the puncture element is in fluid communication with the injection chamber to deliver the injectable drug from the injection chamber to the target injection space. The puncture element may be protected by a safety cap 118 during storage, transport, and handling of the injection system. During operation, a force may be applied to the second sealing element distally or forward using a push rod 120, as described in detail below. This force causes the second sealing element to move forward, pressurizing the injectable drug and applying a forward force to the first sealing element. Depending on the proximal force (back pressure or reaction force) on the puncture element, the first sealing element moves distally, advancing the puncture element distally without carrying the injectable drug through the puncture element, or the first sealing element remains stationary, allowing the injectable drug to be carried through the puncture element from the injection chamber. Therefore, for the sake of simplicity, the first sealing element may be referred to as a floating sealing element, and the second sealing element may be referred to as a push sealing element.

[0048] The term “puncture element” refers to a device that can be used to penetrate tissue and deliver an injectable agent to a space or potential space within the tissue. In some embodiments, a puncture element may be a generally elongated device with a sharp end that can be used to puncture and penetrate tissue. The puncture member may have any number of preferred dimensions and / or geometric shapes. For example, a puncture element may have a circular or non-circular cross-section. In some embodiments, a puncture element may have one or more lumens for delivering an injectable agent to a target space or target potential space within the tissue, each of which has one or more openings at its end or along its side.

[0049] Figure 1B illustrates various embodiments of a puncture element that may be used in conjunction with the injection system of the present disclosure. In some embodiments, the puncture element has a non-uniform diameter to improve the delivery of a viscous active substance while keeping a portion of the puncture element inserted into a smaller diameter eye (e.g., 30G, 27G). In some embodiments, the geometric shape of the bevel at the tip of the puncture element is designed to minimize insertion force and bevel by modifying the bevel angle, the number of bevels, and the rake angle and insertion force. Examples of geometric shapes of the tip of the puncture element include, but are not limited to, bevel tips, lancet points, back bevel tips, and curved tips. Puncture elements with lower insertion forces are generally easier to guide and have less deflection.

[0050] In some embodiments, the puncture element is equipped with a standard 34G to 25G needle. In some embodiments, the puncture element may be a standard 30G needle. In some embodiments, the puncture element may be 25 gauge and above, 27 gauge and above, or 30 gauge and above. In some embodiments, the needle has a second bevel to reduce the cutting force. However, various sizes and shapes of puncture elements can be used in conjunction with the injection system of this disclosure. In some embodiments, a puncture element with a larger lumen can be used, particularly for high-viscosity formulations. It should be noted that various other sizes, shapes and geometric shapes may also be used depending on the desired results and operating parameters, e.g., viscosity of the injectable, density of the tissue into which the puncture element is inserted, desired flow rate of the injectable, and similar parameters.

[0051] The puncture element can be connected to the floating sealing element using several methods. In some embodiments, the puncture element is inserted into the floating sealing element and secured with a waterproof adhesive. In some embodiments, the floating sealing element can be molded around the puncture element. In some embodiments, a puncture element having threads on its outer surface can be screwed into the floating sealing element.

[0052] Referring to Figure 2, the injection system of this disclosure may be used to advance a puncture element through a first region 211 and inject an injectable agent into a second region 212 which provides a smaller reaction force to the injection than the first region. In some embodiments, injecting the agent into the second region may require less force than injecting the agent into the first region. In some embodiments, the density of the first region may be higher than that of the second region, making it easier to inject the agent into the second region than the first. In some embodiments, the first region exerts a higher back pressure on the puncture element than the second region, resulting in greater resistance or repulsion to the inflow of the agent into the first region compared to the second region.

[0053] Referring to Figure 2, step 201 illustrates an embodiment of the injection system in its initial position. This injection system contains the injectable agent in an injection chamber 114, with a puncture element exposed and extending slightly beyond the distal end 106 of the syringe barrel. In step 202, the puncture element is pre-inserted into a first region (e.g., tissue such as the sclera of the eye). During this pre-insertion, the tip of the puncture element is inserted into the first region of the tissue (e.g., the sclera), and at least the lumen of the puncture element is embedded or sealed by contact. In some embodiments, this step can be achieved manually by penetrating the sclera with the exposed length of the puncture element. In some embodiments, the need to be able to pre-insert the puncture element into the first region may limit the range of lumen diameter and bevel size of the puncture element that can be used to effectively target the SCS. For example, the density of the first region may be a factor in selecting an appropriate puncture element. In some embodiments, the puncture element may be inserted tangentially to the sclera with its tip facing the posterior segment of the eye. Once the puncture element is pre-inserted into the first region, the lumen of the puncture element is sealed so that the injectable agent can be delivered through it.

[0054] In some embodiments, when inserting a puncture element perpendicular to the scleral surface, keeping in mind the minimum human scleral thickness, optimal results can be obtained by limiting the pre-insertion depth to approximately 0.5 mm or less (e.g., about 0.05 mm to 0.5 mm). When pre-inserting a puncture element at angles other than perpendicular, puncture elements with longer bevels can be fully inserted without penetrating the sclera. In some embodiments, puncture elements may have bevel lengths of less than 2 mm, less than 1 mm, or less than 0.5 mm. The bevel angle may be greater than 15 degrees, greater than 30 degrees, or greater than 45 degrees. For example, based on geometric correlation, a 30-gauge puncture element with a standard bevel (angle: 12 degrees, length: 1.45 mm) inserted into the surface at an angle of approximately 20° or less typically reaches a depth of less than 0.5 mm when measured from the surface. Similarly, larger puncture elements with longer bevel lengths can also be used. Shorter bevels allow for a wider range of pre-insertion angles for a given puncture element size. Roughly speaking, puncture elements with an outer diameter smaller than the thickness of the sclera, approximately 0.5 millimeters, are readily usable for accessing the SCS, and the insertion angle of the puncture element is determined based on the length of the bevel tip.

[0055] In step 203, the press sealing element is advanced distally by applying a force distal to it. In some embodiments, the press sealing element advances by sliding or rotational motion (e.g., helical). The movement of the press sealing element applies a force to the injectable substance, thereby pressurizing the injectable substance and pressurizing the floating sealing element distally. In the first region, the frictional force between the floating sealing element and the syringe barrel is less than the force required to inject the injectable substance into the first region. Therefore, in the first region, the force applied to the press sealing element is sufficient to overcome the frictional force with the floating sealing element, but insufficient to inject the injectable substance into the first region. Thus, in step 203, the force applied to the press sealing element advances the floating sealing element and therefore the puncture element distally deeper into the first region without transporting the injectable substance from the injection chamber.

[0056] In step 204, the puncture element reaches the interface between the first and second regions, and the lumen of the puncture element partially or completely penetrates the second region, connecting the second region to the injection chamber with fluid. The force opposing the flow of the injectable drug into the second region is smaller than that in the first region. Therefore, the force required to inject the drug into the second region is smaller than the frictional force between the floating sealing element and the syringe barrel. Thus, when the lumen of the puncture element reaches the second region, the floating sealing element automatically stops, limiting the depth to which the puncture element penetrates the cavity.

[0057] In step 205, since the force required to inject the drug into the second region is less than the frictional force against the floating sealing element, the floating sealing element remains stationary, and the drug is injected into the second region by the force against the pressing sealing element. The puncture element does not penetrate further into the second region and essentially maintains its position at the interface between the first and second regions. In some embodiments, the fluid flow vector is parallel to the suprachoroidal space, thereby broadly covering the posterior segment of the eye rather than being used to move the choroidal and retinal tissue radially.

[0058] As a non-limiting example, the back pressure or reaction force experienced by the press-sealing element is a function of the velocity of the press-sealing element and the size of the puncture element. In some embodiments, such a force may be in the range of 2 to 100 N. In some embodiments, such a force may be in the range of 2 to 50 N. As a non-limiting example, for a 1 ml syringe with a 30 G puncture element, when the press-sealing element is pressed at 0.5 mm / s, the force experienced by the press-sealing element for injection into the sclera is approximately 5 to 20 N. Injection into the SCS is similar to injection in open air, and for the same parameter set, it is in the range of 0 to 2 N.

[0059] In some embodiments, the force acting on the first sealing element may be greater than 2N in the first region (depending on the syringe barrel ID / puncture element ID ratio) and less than 1N in the second region. Therefore, the maximum force that can be applied to move the puncture element distally without releasing the injection fluid is greater than 2N in the first region (e.g., the sclera) and less than 1N in the second region (e.g., the SCS). It should be noted that in the first region, the force acting on the second sealing element is less than the force required to inject the injection fluid into the first region. In some embodiments, when the injection agent exits the puncture element, a force is applied to the puncture element and the first sealing element, and this force increases as the flow velocity increases. When the flow velocity exceeds a threshold, the puncture element is pushed forward. To prevent the movement of the puncture element, the maximum threshold flow velocity can be increased by increasing the friction against the first sealing element. As described below, the disclosure also provides other means for stopping the distal movement of the first sealing element and puncture element once they reach the second region. Further non-limiting examples of permissible forces and flow velocities are disclosed in Nat Biomed Eng. 2019 Aug;3(8):621-631 (which is incorporated herein by reference in its entirety).

[0060] Referring again to Figure 2, once the puncture element reaches the interface between the first and second regions, the reaction force against the injectable drug decreases. As a result, when the operator continues to press the push-sealing element, the injectable drug in the injection chamber is delivered to the second region, but the puncture element maintains its position at the interface between the first and second regions. The floating sealing element can move along the entire length of the syringe (i.e., a distance of millimeters), but once the puncture element reaches the interface between those regions, it can stop with micron-level precision. This makes it possible to deliver therapeutic drugs primarily, and in some cases exclusively, to thin "cavity" compartments of anatomical structures, rather than "tissue" compartments of anatomical structures, as shown in Figure 2. In some embodiments, the injection system of the present disclosure is configured such that, when the lumen of the puncture element passes through a second region, the floating sealing element and the puncture element can be stopped within lengths of 250 microns, 200 microns, 150 microns, 100 microns, 50 microns, and 25 microns once they enter the second region.

[0061] In some embodiments, the puncture element can move through a first region at a constant speed, allowing for the assumption of quasi-static equilibrium where forward and reverse forces are balanced. Once the needle enters a second region (cavity / space), the reverse force immediately decreases. Therefore, the stopping distance can be directly related to the deceleration of the puncture element and its original moving speed. Typically, the moving speed can be low (0.1 mm / s to 10 mm / s, depending on the diameter of the puncture element). The deceleration is a function of the forward force (driving force or propulsive force) acting on the sealing element and the puncture element and the reverse force acting due to friction between the seal and the cylinder. In a given design, assuming that friction remains relatively constant, the deceleration depends on the driving force related to the geometric shape of the puncture element and the viscosity of the fluid. Upon completion of injection, the pressing sealing element comes into direct contact with the floating sealing element. This can cause the puncture element to move forward, which is a safety concern. This disclosure provides various safety features that ensure that the puncture element maintains its position even when the press sealing element comes into contact with the floating sealing element, provided that the puncture element is stopped as described above.

[0062] In some embodiments, the first region may correspond to patient tissue, and the second region may correspond to a space or latent space within the tissue or a space or latent space adjacent to the tissue. In other words, the injection system 100 of the present disclosure may be used to advance the puncture element 116 through patient tissue (e.g., the sclera of the eye) and inject an injectable agent into a space or latent space adjacent to that tissue (e.g., the suprachoroidal space or a space within the anterior chamber). The term “space” includes actual spaces, cavities, or latent spaces within tissue. Latent spaces refer to spaces that are collapsed under normal physiological conditions (e.g., multiple tissues in contact with each other) but may expand when opened (e.g., in response to the injection of a fluid). For example, the suprachoroidal space (SCS) is a latent space between the sclera and the choroid that traverses the periphery of the posterior segment of the eye. In some embodiments, the injection systems of this disclosure can deliver drugs and gene therapies that benefit from localization to the scleral cortex (SCS), including drugs and gene therapies that treat diseases and disorders of the choroid and retina. Disclosed herein are various embodiments of injection systems that enhance the ability of the injection system to target the SCS and deliver the desired injectable agent to posterior segment tissues (e.g., retina, retinal pigment epithelium, Bruch's membrane, choroid). Successful injections that accurately and consistently target the SCS by penetrating the sclera allow for the delivery of various classes of therapeutic agents to the choroid. Bruch's membrane lies between the SCS and the retinal pigment epithelium, acting as a diffusion barrier for injectable agents delivered via the SCS to reach the retina. Moore et al. (2001) reported that the permeability of Bruch's membrane isolated from donated human eyes decreased with age in ex vivo. Bruch's membranes from young donors showed permeability to proteins greater than 200 kDa, while those from older donors showed low permeability. The Bruch membranes of aged donors continued to exhibit permeability to proteins greater than 100 kDa. However, while this disclosure describes the injection system in relation to drug delivery to SCS cavities, it should be noted that the systems and methods of this disclosure may also be used to deliver injectable agents to other cavities or spaces in the human body, or for other applications outside the human body.For example, the injection system of this disclosure may be used for injections into the peripericardial cavity, pleural cavity (the latent space between the two pleura (visceral-parietal)), synovial spaces between joints, spaces between scar tissue and implants (e.g., scar tissue around breast implants for treating capsular contractures), airway access, vascular access, and similar biological or latent spaces.

[0063] In some embodiments, it may be desirable to prevent proximal movement of the floating sealing element when the puncture element is first inserted into the tissue. In particular, the syringe barrel, press sealing element, and floating sealing element of the injection system may be configured individually or in combination to prevent posterior (proximal) movement of the floating sealing element beyond a pre-selected position. In some embodiments, the injection system of the present disclosure may be used to deliver expensive injectable drugs that need to be administered in precise doses. In some embodiments, such doses may be within 10% of the indicated volume. Therefore, in some embodiments, the injection system may have one or more features that ensure that all or substantially all volume of the injectable drug is administered to the patient. In some embodiments, these two features are combined. In some embodiments, the syringe barrel, press sealing element, and floating sealing element of the injection system may be configured individually or in combination to prevent posterior (proximal) movement of the floating sealing element beyond a pre-selected position, while allowing the press sealing element to contact the floating sealing element to minimize or eliminate dead volume between the sealing elements. In some embodiments, such designs can ensure that all or substantially all of the therapeutic payload is delivered to the patient.

[0064] Referring to Figure 3, in some embodiments, the injection system of the present disclosure may include a one-way stop 210 configured to prevent backward movement of the floating sealing element, for example, when pre-inserting the puncture element into tissue. In some embodiments, the one-way stop 210 is installed and configured so that pre-insertion of the puncture element is achieved without the floating sealing element moving backward and without losing more than 10% of the injection volume of therapeutic agent.

[0065] In some embodiments, a one-way stop can prevent the press sealing element from moving beyond the stop. In some embodiments, the one-way stop may also be configured to allow the press sealing element to pass through unobstructed. Thus, at the end of injection, the gap between the press sealing element and the floating sealing element can be reduced or eliminated, thereby enabling the injection of the entire payload of therapeutic fluid into the cavity and reducing or eliminating dead volume. In some embodiments, the distal side of the press sealing element can be substantially in contact with or touching the proximal side of the floating sealing element, resulting in minimal dead volume between the sealing elements. In some embodiments, another one-way stop may also be provided proximal to the press sealing element to prevent the press sealing from moving proximal beyond a desired point.

[0066] In some embodiments, a one-way stop 210 may be provided immediately proximal to (i.e., immediately behind) the floating sealing element. Thus, after the initial placement, the floating sealing element is prevented from moving proximal to the one-way stop. In some embodiments, in the initial placement, the tip of the puncture element is sufficiently exposed to allow sealing of the lumen when the puncture element is pre-inserted into the tissue, and the amount of exposure depends on the bevel angle. This length may vary depending on the size of the puncture element and the bevel angle. In some embodiments, in the initial placement, the tip of the puncture element is exposed by 0.2 mm to 2 mm. In some embodiments, when the floating sealing element is in the initial placement state, about 0.5 mm of the puncture element is exposed. In some embodiments, the tip of the puncture element may be exposed longer than the length of the sclera, so the puncture element may be inserted into the sclera obliquely, rather than perpendicular to the curve.

[0067] The operation of an injection system having a one-way stop is shown in Figure 4. The injection system of this disclosure having a one-way stop 210 operates essentially the same as that described in relation to Figure 2. The one-way stop 210 can ensure that the floating sealing element 110 is not pushed backward when the puncture element is first inserted into the tissue. On the other hand, the one-way stop 210 is designed so that the press sealing element 112 passes through the one-way stop and comes into contact with the floating sealing element at the end of the injection. In this way, all or substantially all of the injectable agent can be delivered to the target space.

[0068] Referring to Figures 5A and 5B, in some embodiments, the injection system 100 of the present disclosure includes a location 310 where the diameter of the syringe barrel is reduced at one or more positions. In some embodiments, the location 310 may be provided proximal to the floating sealing element 110 as a unidirectional stop. In some embodiments, the inner diameter of the syringe barrel may be reduced so that a unidirectional stop is created at a pre-selected position between the press sealing element and the floating sealing element. In some embodiments, the reduced diameter provides sufficient resistance to back pressure to prevent backward movement by the floating sealing element when the puncture element is pre-inserted into the tissue (issue). Nevertheless, the reduced inner diameter is sufficiently large and / or the press sealing element is configured such that the press sealing element can move relatively easily over its area and strike the floating sealing element, so that the user can fully administer the therapeutic fluid and reduce variability in both dead volume and injection volume. For example, the compression sealing element may be made of a softer material than the floating sealing element in order to allow it to be compressed by a point where the diameter of the syringe barrel is smaller. In some embodiments, additionally or alternatively, a point where the diameter of the syringe barrel is smaller may be located proximal to the compression sealing element.

[0069] In some embodiments, the diameter of the syringe barrel can be reduced, for example, by creasing or crushing the syringe barrel at a desired position proximal to the floating sealing element. In some embodiments, the syringe may be molded to include a mechanical stop inside the lumen of the syringe barrel, thereby reducing the diameter at that position. In some embodiments, the inner diameter of the syringe barrel can be reduced by modifying the inner surface of the syringe barrel, for example, by including one or more protrusions, ridges or flanges on the inner surface of the syringe barrel. In some embodiments, the diameter of the syringe barrel may be variable along its length, with a larger diameter in the distal section to accommodate the floating sealing element and a smaller diameter proximal to the floating sealing element to prevent the floating sealing element from moving too far backward.

[0070] Referring to Figures 6A and 6B, in some embodiments of the injection system of this disclosure, a one-way stop may be provided by modifying the floating sealing element 110 to have a shape that gives rise to an asymmetric sliding force acting on the floating sealing element 110 as it moves. For example, as a result of such a modification of shape, the floating sealing element may experience considerably greater friction when moving proximal than when moving distally. Thus, the floating sealing element can easily move distally from its initial position but may be prevented from moving to its proximal position. On the other hand, the push sealing element can move freely toward and to the floating sealing element without any obstruction or hindrance. In some embodiments, the design of the floating sealing element is unique in that it allows only one-way movement, compared to the bidirectional movement of conventional syringe plungers. In some embodiments, as shown in Figure 6A, the floating sealing element includes a series of specialized ridges having an angle facing the rear of the floating sealing element that is steeper than the angle facing the front of the push sealing element. For example, a floating sealing element may have one or more frustocones or ribs facing distally. Such a design may promote forward movement of the floating sealing element rather than backward movement. In some embodiments, the interior of the syringe barrel has ribs angled proximal. In some embodiments, the interior of the syringe barrel may have ribs, protrusions, annularities, or similar shapes that are angled proximal or flat. In some embodiments, similar modifications may be made in the syringe barrel proximal to the press sealing element and / or the press floating element.

[0071] In some embodiments, the frictional force between the floating sealing element and the inner surface of the syringe barrel can be adjusted (increased or decreased) by the choice of material (e.g., polytetrafluoroethylene, polyethylene, polypropylene, thermoplastic elastomer, fluoroelastomer (all of which may or may not be silicone-treated)), the number of angled and directional ribs, or the thickness of the ribs, in order to address the viscosity of the formulation. In some embodiments, the frictional force against the floating sealing element can be reduced by using a polytetrafluoroethylene surface.

[0072] Referring to Figures 7A, 7B, and 7C, in some embodiments, the one-way stop may include a foldable one-way stop 410 located within the syringe barrel 102. Similar to the one-way stop described above, positioning the foldable stop on the inner surface of the syringe barrel provides a one-way stop that prevents the floating sealing element from moving backward during pre-insertion, while allowing the push sealing element to advance beyond the foldable stop by folding the foldable stop during administration of the injectable drug. In some embodiments, the foldable one-way stop may be provided as an insert for the syringe barrel. Referring to Figures 7D and 7E, such a foldable stop 410 may comprise a body 412 having one or more foldable gates 414 that can only be folded by a distal force. In some embodiments, the floating sealing element may be positioned opposite the foldable stop. While the puncture element is being inserted, the floating sealing element may be pushed proximal backward, but is held in place by a foldable stop. In some embodiments, the floating sealing element is firmly connected to the foldable stop, so compliance is minimal when the floating sealing element is pushed backward by the insertion force. However, when the injectable agent is administered, if the push sealing element reaches the foldable stop, the push sealing element applies a distal force relative to the gate, so that the gate folds, and the push sealing element can pass the foldable stop toward the floating sealing element. In some embodiments, an insert with a foldable stop may be provided within the syringe barrel.

[0073] Figures 8A–8D provide an exemplary process for manufacturing a syringe with a collapsible unidirectional stop. For example, Figure 8A shows a hollow tube sized to snuggly fit inside an optimal syringe. A strategic off-peripheral cut is made to create a collapsible gate, as shown in Figure 8B. These flaps are then shaped into the desired form, as illustrated in Figure 8C. This structure can then be inserted into the syringe barrel, as shown in Figure 8D. This structure can be bonded, welded, or mechanically fixed to the syringe barrel, if necessary.

[0074] In addition to, or instead of, unidirectional stopping and / or changes in frictional force between the floating sealing element and the syringe barrel, in some embodiments, the contents of the syringe barrel (e.g., the injectable drug in the injection chamber) may be pressurized before pre-inserting the puncture element into the tissue to prevent proximal movement of the floating sealing element during the pre-insertion process. In some embodiments, the user can apply pressure to the push sealing element, but preferably not so much pressure as to move the floating sealing element. In some embodiments, the push rod may be instantaneously locked in a suitable position (e.g., using a linear actuator) to fix the position of the push sealing element so as not to move the floating sealing element during the pre-insertion process. In some embodiments, a stopper may be provided on the puncture element to prevent leakage when the syringe barrel is pressurized. Such a stopper may allow movement of the puncture element when the push sealing element is pressed until the stopper contacts the tissue. In some embodiments, the plug may be configured to allow a puncture element to penetrate the plug for pre-insertion into the tissue, while the plug contacts the tissue with sufficient force to form a fluid-tight seal. In some embodiments, the plug is made from a material through which the puncture element can penetrate while creating a seal with the surrounding tissue at the pre-insertion site.

[0075] In some embodiments, the injection system of the present disclosure is designed such that the frictional resistance / frictional force between the syringe barrel and the press sealing element, the floating sealing element, or both may be greater than the insertion force required to penetrate the sclera. In some embodiments, the frictional resistance may be increased by modifying the inner surface of the syringe barrel or by modifying the size or shape of the sealing element, or by using a material with greater friction, as described elsewhere in the application, for example, in relation to the embodiment for a high-viscosity injectable drug shown in Figure 14. Thus, the puncture element can be pre-inserted into the tissue (sclera) without the floating sealing element moving backward. In some embodiments, the frictional resistance of the floating sealing element may be greater than the force required to inject into the cavity for a given formulation viscosity, syringe barrel inner diameter, and puncture element inner diameter, so that when the floating sealing element automatically stops in the cavity, pushing the press sealing element to squeeze out the injectable drug at the syringe tip does not cause the puncture element to advance further. In other words, depending on the viscosity of the formulation, the inner diameter of the syringe barrel, and the inner diameter of the puncture element, the frictional resistance of the floating sealing element may be higher than the force applied to the press sealing element to inject into the cavity. Thus, the floating sealing element can automatically stop in the cavity, and even if the press sealing element is pressed at the syringe tip to squeeze out the injectable drug, the puncture element will not advance further.

[0076] In such a design, the user may receive tactile feedback when the floating sealing element automatically stops and the injectable substance reaches the tip of the puncture element within the cavity. In some embodiments, the tactile feedback is based on the sensation of the resistance disappearing in the pressing sealing element. In some embodiments, the tactile feedback may be used in combination with visual feedback, such as the stopping of the floating sealing element, to determine when the delivery of the therapeutic fluid will begin. In some embodiments, with respect to visual feedback, for example, if the pressing sealing element continues to move but the floating sealing element does not move and no visible leakage is observed on the tissue surface, this is a strong indicator that the puncture element is delivering the injectable substance at the desired position.

[0077] In some embodiments, the injection system of this disclosure is miniaturized to deliver a volume of approximately 100–250 microliters with an accuracy of ±10%, using a long, thin gauge puncture element that penetrates rigid scleral tissue. In some embodiments, the accuracy can be increased to ±5%. The syringe size may be 10 µl–50 ml.

[0078] Figures 9A and 9B illustrate embodiments of the distal end 106 of the injection system. In some embodiments, a puncture element support 500 may be provided at the distal end of the syringe barrel to support the puncture element. Such a slidable support may be fixed to the syringe barrel or be slidable. In some embodiments, the slidable support 500 may comprise support flanges 510, 512 which may be located near the distal end of the syringe barrel. The support flanges 510, 512 are spaced apart from each other to provide an opening 514 that allows the puncture element 116 to slide between their support flanges. At the same time, the support flanges 510, 512 may provide support to the puncture element near the tip to reduce bending of the puncture element during scleral penetration and movement of the puncture element caused by changes in force against the floating sealing element. In some embodiments, the flanges 510, 512 may be integrated with the syringe barrel.

[0079] In some embodiments, the puncture element support contacts the sclera. In some embodiments, the puncture element support may be chamfered to allow injection at an oblique angle to the surface of the sclera. In some embodiments, the pre-insertion angle is 45 degrees or greater from the vertical plane. In some embodiments, the surface of the puncture element support that contacts the sclera may have notches along its edges to allow partial penetration into the sclera. In this way, the puncture element support can avoid unwanted scleral movement by firmly gripping the sclera. The opening of the sliding puncture element may be sized to correspond to the size and shape of the puncture element used.

[0080] In some embodiments of the injection system, the puncture element is exposed for only a short distance (100 μm to 5 mm) so as not to completely penetrate the sclera, but may extend further while SCS delivery is being performed while the floating sealing element is in operation. In some embodiments, the puncture element support may come into contact with the surface of the sclera before the puncture element, together with the puncture element, and slightly after the puncture element.

[0081] Referring to Figures 10A and 10B, the puncture element support may be slidably positioned within the syringe barrel, and the length of the exposed portion of the puncture element can be adjusted before SCS delivery. In some embodiments, the distal surface of the puncture element support may be perpendicular or oblique to the central axis of the syringe barrel. In some embodiments, the length of the pre-exposed portion of the puncture element can be adjusted before pre-insertion and may be independent of the floating sealing element. For example, Figure 10B shows that by moving the puncture support element proximal, the length of the exposed portion of the puncture element may be longer than when the puncture support element is positioned more distally within the syringe barrel, as shown in Figure 10A. However, even when the puncture element is pre-inserted into the patient's eye, the length of penetration of the puncture element can still be controlled by moving the floating sealing element. When pressing the push sealing element by hand, the operator may feel a difference in the force required to apply the push sealing element. The puncture element stops without requiring the user / physician to change their operation (for example, by continuing to press the pressure sealing element), and delivery of the injectable drug payload immediately begins.

[0082] Referring to Figures 11A–11C, various embodiments of the safety cap 118 are shown. The safety cap can protect the puncture element from mechanical damage before use. In some embodiments, the safety cap can also seal the puncture element to prevent leakage of the injectable agent during storage or injection from the injection chamber. The cap may be attached to the syringe using friction, an interlock, or a screw thread.

[0083] Referring to Figures 12A-12E, in some embodiments, the injectable drug may be provided as multiple components, which may be stored separately in an injection chamber and mixed immediately before use of the injection system to deliver the injectable drug to the target. In some embodiments, the injectable drug may be stored separately in an injection chamber separated from its diluent. When pressure is applied, the diluent is mixed with the therapeutic agent to produce a solution or suspension, which can then be injected into the SCS. In some embodiments, the therapeutic agent may be a lyophilized therapeutic agent.

[0084] In some embodiments, the injection system may have multiple chambers isolated from each other. In some embodiments, the injectable formulation may contain a dry component stored in one chamber and a diluent stored in another chamber. At the time of use, the diluent is pushed from its chamber into the chamber containing the dry component, thereby achieving in situ reconstitution of the two components of the injectable formulation.

[0085] As shown in Figure 12A, in some embodiments, two chambers 610, 612 are initially separated by a rubber (or other material) seal 614 attached to a floating sealing element. Chamber 610 may be defined by the seal 614 and the floating sealing element 110, and chamber 612 may be defined by the seal 614 and the back seal 616 of the press sealing element 112. In some embodiments, a groove connecting the two chambers may be present in the inner wall of the syringe barrel when the seal moves in one direction. In some embodiments, chamber 610 contains the lyophilized active substance of a therapeutic agent, and chamber 612 contains a carrier injectable that can be used to reconstitute the active substance. A one-way stopper 618 may be positioned proximal to the back seal 616 of the press sealing element so that the back seal 616 can move forward but not backward. When the seal 614 moves backward, the fluid in chamber 612 is pressurized. Simultaneously, as shown in Figure 12B, the movement of the seal 614 connects the two chambers. The pressurized fluid from chamber 612 then enters chamber 610 and mixes with the contents of chamber 610. Moving the seal 614 back and forth can enable efficient mixing of the two components. As shown in Figure 12C, when the seal is pulled fully backward, it engages with the back seal of the press sealing element, causing both seals to move together. In some embodiments, these seals may be provided with corresponding anchor and anchoring ports. By applying force to the press sealing element, the injection system can be activated. As shown in Figure 12D, the injection system can now be prepared and, as shown in Figure 12E, ready for use.

[0086] The mechanism for mating the seal 614 and the back seal 616 may be mechanical, adhesive, or magnetic. In some embodiments, it is shown as a mechanical anchor. In some embodiments, a therapeutic solution or suspension is stored pre-filled in the system for injection. In some embodiments, the therapeutic agent is stored in one or more vials constituting the kit, either as a ready-to-use solution or as a lyophilized powder requiring reconstitution. In these embodiments, the ready-to-use or reconstituted therapeutic agent is loaded into the system for delivery and then injected into the SCS.

[0087] In some embodiments, as described above, the injection system of the present disclosure may be used to deliver injectable drugs with a viscosity exceeding 10 centipoise (cP). In some embodiments, the ability to deliver high-viscosity therapeutic agents may depend on several parameters, such as the length of the puncture element, the diameter and cross-sectional area of ​​the lumen of the puncture element, the density of the fluid, the size of the syringe, the frictional and sliding forces between the floating sealing element and the syringe barrel, and the minimum flow rate. For example, referring to Figure 13, plot 1 plots the maximum viscosity depending on the gauge of the puncture element, using a minimum flow rate of 100 ul / min for a standard 1 ml plastic syringe / sealing element combination. In some embodiments, by increasing the frictional force between the floating sealing element and the syringe barrel, the maximum viscosity that can be injected for a puncture element of a given size may increase, as shown in plot 2. For example, to generate the data in plot 1, the frictional force between the floating sealing element and the syringe barrel was doubled. In some embodiments, viscosity modifiers can be added to the carrier fluid of the therapeutic solution or suspension, resulting in improved control during injection by enhancing tactile feedback to the user regarding the pressing sealing element.

[0088] Referring to Figure 14, the injection system of this disclosure includes a syringe barrel having an inner diameter smaller than the diameter of the floating sealing element in order to increase the frictional force against the floating sealing element. Generally, the frictional force is a function of the relative sizes (e.g., diameter and / or length) of both the floating sealing element and the inner surface of the syringe barrel, as well as the material properties (modulus of elasticity and flexural coefficient) of both the floating sealing element and the syringe barrel. As a non-limiting example, the frictional force for a 1 ml syringe has been measured to be approximately 1 N. The maximum acceptable viscosity and the frictional force are directly proportional. Therefore, to increase the limit of acceptable viscosity by a factor of 10, the frictional force would need to be increased by a factor of 10. Even small changes in the relative sizes of the floating sealing element and the syringe barrel can change the normal force against the floating sealing element, thereby enabling the administration of high-viscosity injectable drugs. In some embodiments, when no external force acts on the floating sealing element, i.e., when it is in a relaxed state, the first sealing element may have a size 1.01 to 2 times larger than the size of the lumen of the syringe barrel. In some embodiments, the first sealing element has a size 1.01 to 1.10 times larger than the size of the lumen of the syringe barrel when in a relaxed state. In some embodiments, the first sealing element may have a size 1.01 to 1.4 times larger than the lumen of the syringe barrel when in a relaxed state. In some embodiments, the diameter of the lumen of the syringe barrel may be reduced to increase the frictional force between the floating sealing element and the syringe barrel.

[0089] In some embodiments, such frictional force against the floating sealing element may be sufficient to prevent proximal movement of the floating sealing element during the pre-insertion phase of the puncture element. In other words, increasing the frictional force against the floating sealing element may have two advantages: 1) maintaining the floating sealing element in place during pre-insertion, and 2) allowing the user to deliver high-viscosity treatments. In some embodiments, the frictional or sliding force between the floating sealing element and the syringe barrel can be increased to be greater than the pre-insertion force so that the floating sealing element remains in place during pre-insertion. The pre-insertion force may depend on the geometric shape of the puncture element. In some embodiments, a viscosity modifier is added to the injectable to enable a high frictional or sliding force against the floating sealing element while the auto-stop function remains intact. In some embodiments, the viscosity of the injectable can be adjusted by increasing or decreasing the frictional force between the floating sealing element and the syringe barrel by increasing or decreasing the surface roughness of the syringe barrel.

[0090] In some embodiments, the relationship between the size of the floating sealing element and the size of the syringe barrel can be adjusted by increasing the diameter of the floating sealing element while keeping the inner diameter of the syringe barrel constant, decreasing the inner diameter of the syringe barrel while keeping the diameter of the floating sealing element constant, or a combination of these two options. In both cases, in some embodiments, the press sealing element is configured to eliminate dead volume between the sealing elements by passing through the syringe barrel and contacting the floating sealing element, as discussed above. In some embodiments, the press sealing element may be made of a softer material and / or a material that can reduce friction between the press sealing element and the syringe barrel. Additionally or alternatively, the rigid portion of the press sealing element can be made smaller in size than its elastic portion compared to the floating sealing element, thereby allowing the press sealing element to advance more easily to the floating sealing element. In some embodiments, additionally or alternatively, the diameter or shape of the puncture element can be modified to enable the delivery of high-viscosity injectable drugs using the injection system of the present disclosure.

[0091] In some embodiments, the injection system of the present disclosure is equipped with one or more safety features for limiting or controlling the depth to which the puncture element can reach the patient's eye. In some embodiments, such features can limit the distance that the floating sealing element can travel distally so that the puncture element cannot reach outside the SCS. In some embodiments, the length required for the puncture element to travel to reach the cavity interface varies from patient to patient, so such safety features must be sufficiently flexible or adjustable, and therefore the maximum insertion distance of the puncture element may be set specifically for each procedure.

[0092] Referring to Figure 15A, in some embodiments, such safety features may include a lock for selectively locking and unlocking the floating sealing element 110 in a predetermined position. In some embodiments, the lock 700 includes a sealed compartment in the distal region of the syringe barrel distal to the floating sealing element. The compartment 700 may be equipped with a valve 712 (e.g., a ball valve, butterfly valve, pinch valve, control valve, gate valve, globe valve, or puncture element valve) so that incompressible material, such as a sterile fluid, liquid (e.g., sterile saline solution), or gas, can be moved in and out of the compartment 710. Since the material in the compartment is incompressible, the floating sealing element cannot move distally when the valve is closed. The valve may be a binary valve or an adjustable valve. When the valve is opened, the incompressible material is released from the compartment, allowing the floating sealing element to move distally. To lock the floating sealing element again, the valve is closed.

[0093] The operation of the distal safety lock is illustrated in Figures 15B–15E. As shown in Figure 15B, before use of the injection system, the floating sealing element can be positioned in the desired initial position, the sealing compartment 710 can be filled with incompressible material, and the valve 712 can be closed to lock the floating sealing element in its initial position. The valve is kept closed during the syringe filling and pre-insertion of the puncture element to hold the floating sealing element in place, if applicable. As shown in Figure 15C, once the puncture element is pre-inserted into the tissue, the valve 712 is opened to release some of the incompressible material from the sealing compartment, allowing the floating sealing element to move distally and advance the puncture element to the SCS interface. In some embodiments, a recovery reservoir may be provided to recover the fluid released from the compartment. As shown in Figure 15D, once the puncture element is positioned as desired for injecting the injectable agent into the SCS (e.g., the interface between the sclera and the SCS), the valve is closed to lock the floating sealing element in place. This also ensures that the puncture element remains in the desired position. Since the fluid remaining in the compartment is incompressible, the floating sealing element cannot move distally when the valve is closed. The fluid lock can also prevent the puncture element from passing through by closing the valve after the puncture element has reached the SCS. For example, as shown in Figure 15E, the fluid lock design can keep the floating sealing element stationary even when the push sealing element could come into contact with it and move the floating sealing element forward, or even when the user accidentally continues to press the push sealing element.

[0094] In some embodiments, the viscosity of the incompressible material used in the sealed compartment may be selected to balance with the viscosity of the injectable agent. Increasing the viscosity of the fluid in the compartment increases the magnitude of the force required to expel the viscous fluid through the valve. This provides further resistance to the proximal movement of the floating sealing element, thereby increasing the sliding force of the floating sealing element.

[0095] Referring to Figure 16, in some embodiments, the opening or valve 712 in the distal region of the syringe may also be used to sterilize the section of the syringe between the floating sealing element and the distal end of the syringe. In particular, by creating an access port (e.g., a valve or hole) in a portion of the syringe barrel in front of the floating sealing element, sterilization gas or steam can be easily introduced into that portion of the syringe. In some embodiments, such an access port may be provided even without the use of a lock.

[0096] Referring to Figures 17A and 17B, in some embodiments, the safety feature for locking the floating sealing element includes a touch trigger lock 800 positioned between the floating sealing element 110 and the push sealing element 112. Similar to the lock 700 discussed above, the touch trigger lock 800 may be configured to prevent movement of the floating sealing element when the injectable agent is delivered, particularly at the end of a delivery cycle when the push sealing element may come into direct contact with the floating sealing element and push the floating sealing element forward. In some embodiments, the touch trigger lock is a spring-loaded device that springs outward toward the inside of the syringe barrel when the push sealing element comes into contact with the floating sealing element, increasing friction between one or both sealing elements and the syringe barrel. Thus, by acting as an anchor for the floating sealing element, the push sealing element, or both, when the touch trigger lock is released, they can be prevented from moving further. In some embodiments, the touch trigger lock 800 comprises a resistive member 810 and a trigger 812 for releasing the resistive member 810. The touch trigger mechanism may be located on a floating sealing element, a push sealing element, or both. During operation, the resistive member is initially hidden within the touch trigger mechanism to allow the sealing element to move freely within the syringe barrel. When the sealing elements come into contact with each other, the trigger 812 is activated, releasing the resistive member 810 from the touch trigger mechanism, significantly increasing the frictional force between the syringe barrel and the sealing element having the touch trigger mechanism, thereby preventing the sealing element from advancing distally. Essentially, the resistive member acts as a brake that locks the sealing element in place. In some embodiments, the resistive mechanism may comprise an annular spring. In its initial configuration, the spring can be compressed within the touch trigger mechanism. When the trigger is activated, the annular spring is released from the touch trigger mechanism.As the spring stretches, it comes into contact with the syringe barrel, significantly increasing the friction between one or both sealing elements and the syringe barrel, thereby locking one or both sealing elements into place.

[0097] In some embodiments, an additional or alternative mechanical structure may be provided to prevent the puncture element from advancing (e.g., another mechanical stop to prevent the push sealing element from moving beyond a predetermined point). Once the push sealing element is prevented from advancing during operation, it becomes impossible to pressurize the floating sealing element and therefore prevent it from advancing further.

[0098] In some embodiments, the injection system of the present disclosure may be pre-filled with the injectable agent during manufacturing, as described above. In some embodiments, the injection system of the present disclosure may be filled with the injectable agent immediately before administering the injectable agent to a patient. In some embodiments, the injectable agent may be supplied in a storage vial and transferred to the SCS system by the user only when the injectable agent is ready to be administered to a patient.

[0099] Referring to Figure 18, in some embodiments, the injection system of the present disclosure is provided with a rapid filling port 900 that enables loading an injectable agent from a vial 902 into an injection chamber. In some embodiments, the rapid filling port 900 comprises a receiving portion 904 configured to receive the vial 902 and to fluidly connect the vial to the injection chamber. In some embodiments, a hole or passage is created (e.g., by molding, machining, etc.) through the wall of the syringe barrel proximal to the floating sealing element 110, and the receiving portion 904 is positioned over such a hole or passage. In some embodiments, once the floating sealing element is in its initial position and the press sealing element is in contact with the floating sealing element, the rapid filling port fluidly connects to the syringe barrel in the portion between the sealing elements. Connected to that passage and partially or completely positioned therein is a side port fill needle 906 (preferably larger than the injection puncture element, e.g., an 18-gauge puncture element). Such a fill needle may be chamfered to penetrate the elastomer cap 903 of a vial 902 containing the therapeutic agent. In some embodiments, the filling puncture element of the rapid filling port may have an opening on the side of the filling puncture element rather than at the tip. This side port may be covered by a casing or self-sealing puncture membrane 908 that prevents fluid flow when in a closed position. The casing 908 may be located within its receptacle and may be biased by a spring 910 to close the fill needle port when no vial is present in the receptacle. In some embodiments, a safety cap 118 may be configured to provide an airtight seal when attached to an injection system.

[0100] During operation, as shown in Figure 19A, the vial 902 is fitted into the receiving portion 904 of the rapid filling port 900, and the sliding filling puncture element casing is separated from the side port of the filling puncture element. The filling puncture element of the rapid filling port then penetrates through the stopper of the vial, thereby fluidly connecting the internal volume of the vial to the syringe barrel through the side port of the filling puncture element. Referring to Figure 19B, when the push-sealing element 112 is withdrawn, the injectable drug flows from the vial 902 into the injection chamber. In some embodiments, a safety cap is provided on the puncture element to fluidly seal the puncture element of the injection system so that air bubbles are also not drawn into the syringe barrel when the push-sealing element is withdrawn.

[0101] Referring to Figure 19C, once the desired amount of injectable drug is loaded into the injection system, the vial can be removed from the receiving end of the rapid filling port, which allows the sliding filling puncture element casing to rise and seal the side port of the filling puncture element, thereby also sealing the syringe barrel. Removing the safety cap may allow the fluid to flow through the injection puncture element. As shown in Figure 19D, the push sealing element can be pressed until the injectable fluid reaches the tip of the injection puncture element, indicating that the removal of air from the injection puncture element is complete. In some embodiments, the injection system can be tilted upward to help remove air from the puncture element, making the injection system ready for use. This rapid filling port design may allow for clinical-stage filling of the injection system with injectable drug while maintaining sterility even outside of sterile facilities.

[0102] In some embodiments, the injection system of the present disclosure can be filled with the injectable drug from the rear. This can be done early in the manufacture of the syringe or immediately before use in a clinic.

[0103] In some embodiments, as shown in Figure 20A, the press-seal element can be removed so that the injectable agent can be added to the syringe barrel through the rear of the syringe barrel, as shown in Figure 20B. Then, as shown in Figure 20C, the press-seal element can be inserted and pushed toward the floating-seal element to remove air from within the injection puncture element and complete the preparation of the injection system for use.

[0104] In some embodiments, as shown in Figure 21A, a filling port 930 may be provided in the proximal region of the syringe barrel 102 distal to the push-sealing element 112. The injectable drug 114 can be added to the injection system through this filling port 930, and then the push-sealing element 112 can be pushed beyond the filling port 930, and as shown in Figure 21B, the push-sealing element seals the injection fluid away from the filling port. In particular, the injectable drug can be added to the injection system through the filling port using another sterile syringe / puncture element while keeping the puncture element side down (sealing the tip of the puncture element). In some embodiments, the total volume of the injectable drug may be about 80% of the volume between the sealing elements. The air can then be removed from the filling port by the push-sealing element advancing toward the floating sealing element. After the push-sealing element has moved beyond the filling port and sealed it, the syringe can be inverted so that the puncture element side is up. Next, the remaining air is released from the syringe barrel and injection puncture element by advancing the pressure sealing element further distally.

[0105] In some embodiments, as shown in Figures 22A–22C, the filling port 930 (as shown in Figures 21A–21B) may be sealed using a self-sealing seal 932 (e.g., silicone rubber or polytetrafluoroethylene or a similar polymer). Thus, the filling port may be blocked by a separate large-bore loading needle 934 of a standard syringe, but the syringe barrel of the injection system may remain sealed throughout this process. Even if the loading puncture element is removed from the filling port, the filling port will self-seal sufficiently to prevent leakage due to the pressure applied by the press-sealing element during use.

[0106] In some embodiments, as shown in Figures 23A–23D, a filling port 950 may be provided distal to the floating sealing element 110 in the distal part of the syringe barrel 102. This may allow a user to access the floating sealing element using a push tool 952 (e.g., a long, thin, rigid object that fits into its hole and is long enough to reach the outside) to position the floating sealing element at a desired location from the distal end of the syringe barrel. For example, when using a rapid filling port 900, the injection element can be extended outward so that it can be pushed through an elastomer vial stopper, and then the injectable agent can be drawn into the syringe by withdrawing the push sealing element. The push sealing element can then be further withdrawn proximal, and as a result, the floating sealing element can be pushed back to its pre-insertion position in the syringe barrel.

[0107] In some embodiments, the volume of the injection chamber is 20 to 200 microliters. For improved tactile feel, in some embodiments, the length of a single press of the press sealing element for delivering the therapeutic fluid or suspension is at least 1 centimeter. In some embodiments, the injection flow rate is targeted to be 0.2 to 20 microliters / second on average. In some embodiments, the syringe barrel is lined with silicone rubber, glass, polytetrafluoroethylene, or polypropylene to minimize adsorption of the therapeutic agent to the inner surface of the syringe barrel.

[0108] In some embodiments, referring to Figures 24A–24E, the injection system of the present disclosure is configured for safe disposal. In some embodiments, at the end of an injection cycle as shown in Figures 24A and 24B, the push sealing element 112 may come into contact with the floating sealing element 110, as shown in Figure 24C. In some embodiments, the injection system is configured such that the push plunger may connect directly or indirectly to the floating sealing element, as shown in Figure 24D. Once the sealing elements are connected, the push sealing element is withdrawn, thereby potentially drawing the floating sealing element and the puncture element into the syringe barrel, as shown in Figure 24D. In some embodiments, the puncture element is configured to bend within the syringe barrel so that it can no longer extend outside the syringe barrel, as shown in Figure 24E.

[0109] In some embodiments, the injection system of the present disclosure is used to deliver viral gene delivery vectors for treating hereditary disorders or diseases of the retina or choroid, such vectors include, but are not limited to, adeno-associated viruses (AAV), their variants or serotypes (including, but not limited to, AAV serotypes 1-11, particularly AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10 and AAV11) and recombinant serotypes (e.g., Rec2 and Rec3). AAV1, AAV2, AAV4, AAV5, AAV6, AAV7, AAV8, and AAV9 may all exhibit tropism to retinal tissue, including retinal pigment epithelium and photoreceptors, as described in https: / / www.retinalphysician.com / issues / 2020 / special-edition-2020 / vector-considerations-for-ocular-gene-therapy (which is incorporated herein by reference in its entirety). Exemplary conditions include, but are not limited to, exudative age-related macular degeneration, atrophic age-related macular degeneration (AMD), glaucoma, colloideremia, and other hereditary visual disorders and impairments. In some embodiments, the injection system is used to deliver a viral delivery vector, including but not limited to AAV or a variant thereof, to transfect retinal and / or choroidal cells (e.g., photoreceptors, pigment cells, bipolar cells, ganglion cells, horizontal cells, and amacrine cells), vascular endothelial cells, vascular smooth muscle cells, non-vascular smooth muscle cells, melanocytes, fibroblasts, and resident immune cells with anti-vascular endothelial growth factor (anti-VEGF) and an anti-vascular endothelial growth factor receptor (anti-VEGFR) gene, which, when transcribed, produces an anti-VEGF protein for treating exudative AMD. In some embodiments, the gene therapy composition may also include a promoter for the gene of interest.

[0110] In some embodiments, the injection system is used to deliver gene therapies including, but not limited to, small interfering ribonucleic acid (siRNA), short hairpin ribonucleic acid (shRNA), microribonucleic acid (microRNA), closed-end deoxyribonucleic acid (ceDNA), polymer-DNA conjugates, or clustered and regularly arranged short palindromic sequence repeats (CRISPR) and CRISPR-related protein 9 (Cas9) systems and their variants, as well as transcription activator-like effector nucleases (TALENs) and their variants, as well as zinc finger nucleases (ZFNs) and their variants, and transposon-based gene delivery (e.g., Sleeping Beauty (SB), piggyBac (PB), Tol2, or their variants). These gene therapies may be packaged in viral vectors, non-viral vectors, or nanoparticles.

[0111] In some embodiments, the injection system is used to deliver viral gene delivery vectors, non-viral gene delivery systems, or other gene therapies, achieving transfection efficiencies of less than 0.001%, 0.01%, 0.1%, 1%, 3%, 5%, 10%, 25%, 50%, 75%, or 90% for retinal and / or choroidal cells.

[0112] In some embodiments, the injection system is used to deliver small or large molecule therapies that target VEGF or VEGFR (e.g., ziv-aflibercept, pazopanib, bevacizumab, cabozantinib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib, vandetanib, ramucirumab, lenvatinib, and bevacizumab).

[0113] In some embodiments, the injection system is used to deliver gene therapy that targets, replaces, inhibits, or promotes one or more of the following genes that confer therapeutic effects to hereditary eye diseases or disorders, such as MTP, HGD, SLC16A2, POLG, ALMS1, FGFR2, PRPS1, APTX, ATM, DNMT1, TGFBI, ACTB, FGFR2, BEST1, CYP4V2, NOD2, FOXL2, ABCC9, ERCC6, CYP27A1, CHS1, SH3BP2, HDAC6, CHM, SLC9A6, NSDHL, OPN1MW, OPN1LW, OPN1SW, KERA, IGBP1, OPA3, UGT1A1, FGFR2, FGFR3, ATP6V0A 2, CTNS, EFEMP1, SALL4, ADAMTSL4, FBN1, ADAMTSL4, NR2E3, TGFBI, GLA, IKBKAP, LCAT, GALK1, GALT, GBA, GLB1, PORCN, TGFBI, OAT, ENG, CBS, MBTPS2, IKBKG, CNNM4, ATRX, GALC, TGFBI, HADHA, OCRL1, PLP1, B3GA LTL, PAH, ARX, LOXL1, TGFBI, PQBP1, RB1, IDUA, IDS, SGSH, NAGLU, HGSNAT, GNS, GALNS, GLB1, ARSB, GUSB , FGFR3, LMX1B, NHS, STAC3, NF1, NF2, NF1, MT-ATP6, NDP, RP1L1, GPR143, PABN1, HEXB, UBIAD1, AGK, RAILHBB, TIMP3, ATP2B3, ABCA4, ELOVL4, PROM1, GNAQ, SUOX, NAA10, BCOR, SOX2, OTX2, BMP4, HCCS, STRA6, VAX1, RARB , HMGB3, MAB21L2, RBM10, HEXA, TGFBI, SHOX, TAT, PTEN, VHL, VCAN, NF1, ZC4H2, ATP7B, CNGA3, CNGB3, JAG1, NOTC H2, PAX6, ELP4, FOXE3, PITX3, PITX2, FOXC1, CHD7, SEMA3E, ERCC6, ERCC8, CYP1B1, MYOC, MYOC, CYP1B1, FGFR1, F GFR2, FGFR1, FGFR2, NDN, SNRPN, PHYH, PEX7, CREBBP, EP300, OPA1, OPTN, SAG, GRK1, TWIST1, FGFR2, GPC3, OFD1, T SC1, TSC2, PRPH2, BEST1, WFS1, CISD2, COL4A5, COL4A4, COL4A3, UBE3A, CDKLS, MECP2, PTCH1, PTCH2, SUFU, NSD1 , H19, KCNQ1OT1, CDKN1C, OPN1LW, OPN1MW, EYA1, SIX1, SIX5, KIF21A, PHOX2A, ARIX, TUBB3, SMC1A, HDAC8, COL5A 1, COL5A2, COL3A1, TNXB, OPTN, ASB10, WDR36, MTND1, MTND4, MTNDS, MTND6, PAX6, PITX2, CYP1B1, FOXCl, DMPK, Z NF9, CNBP, NPC1, NPC2, SMPD1, TYR, OCA2, TYRP1 or SLC45A2, MC1R, COL1A1, COL1A2, CRTAP, LEPRE1, NPHP1, NPHP4 Examples include, but are not limited to, SDCCAG8, WDR19, CEP290, IQCB1, HESX1, OTX2, SOX2, COL2A1, COL11A1, COL11A2, COL9A1, COL9A2, MYO7A, USH2A, EDN3, EDNRB, MITF, PAX3, SNAI2, SOX10, ADAMTS10, FBN1, LTBP2, XPA, XPC, ERCC2, ERCC3, and POLH.

[0114] In some embodiments, the delivery system of the present disclosure may be used to deliver gene therapies for treating age-related macular degeneration (AMD) or diabetic macular edema (DME). In some embodiments, the delivery system of the present disclosure is used for choroidal (SCS) delivery of compositions comprising an AAV vector containing one or more genes that block VEGFR-2, optionally together with a CAG promoter. In some embodiments, other suitable promoters include, but are not limited to, human bestrophin (hVMD2), cytomegalovirus (CMV), SV40, mGluR6, CB7, UbiC, RZ, RedO, Rho, and Best1. In some embodiments, such a system may comprise a polypropylene or glass syringe, along with a 25-34 gauge puncture element, and fluoropolymer, silicone, or rubber for press-sealing element stoppers and floating-sealing element stoppers. In some embodiments, about 80-120 (e.g., 100) microliters of such gene therapy composition may be delivered over a period of 5-60 seconds. In some embodiments, the puncture element may have a bevel length of less than 2 mm, less than 1 mm, or less than 0.5 mm. The bevel angle may be greater than 15 degrees, greater than 30 degrees, or greater than 45 degrees. In some embodiments, the puncture element may be 25 gauge or greater, 27 gauge or greater, or 30 gauge or greater. In some embodiments, the needle has a second bevel to reduce the cutting force.

[0115] In some embodiments, the delivery system is used to deliver small or large molecule injectable agents such as bevacizumab, ranibizumab, aflibercept, ramucirumab, disintegrin, anti-prostaglandins, tryptophanyl-tRNA synthetase-derived polypeptides, inosine monophosphate dehydrogenase (IMPDH) inhibitors and anti-PDGF agents for treating AMD; as well as corticosteroids for treating uveitis, chorioretinitis or other inflammatory eye diseases; botulinum toxin for use in various eyes; tyrosine kinase inhibitors (e.g., vandetanib, axitinib, pazopanib, sunitinib, sorafenib) for treating pterygium, dry eye or AMD; and levobetaxolol or other beta-adrenoceptor antagonists and 5-HT1A agonists for treating retinal pathologies.

[0116] In some embodiments, the injection system is used to deliver small molecule Wnt inhibitors that reduce angiogenesis. These small molecule Wnt inhibitors include indazole-3-carboxamide compounds or analogs thereof (W02013040215A1), γ-diketones or salts or analogs thereof (W02014130869A1), azaindazole compounds or analogs thereof (e.g., 3-(1h-benzo[d]imidazole-2-yl)-1h-pyrazolo[3,4-c]pyridine) (W02016040180A1), N-(5-(3-(7-(3-fluoro (Ethyl)-3H-imidazo[4,5-c]pyridine-2-yl)-1H-indazole-5-yl)pyridine-3-yl)-3-methylbutanamide (including its amorphous and polymorphic forms) (W02017210407A1), isoquinoline-3-ylcarboxamide or its salts or analogs (including its amorphous and polymorphic forms) (W02017189823A2), diazanafthalen-3-ylcarboxamide or its salts or analogs (amorphous form (including polymorphs) (US20190127370A1), 6-(5-membered heteroaryl)isoquinoline-3-yl-(5-membered heteroaryl)carboxamide or salt or analog (including amorphous and polymorphs) (W02019084496A1), 6-(6-membered heteroaryl)isoquinoline-3-ylcarboxamide or salt or analog (including amorphous and polymorphs) (US20190125740A1), 3-(3h-imidazo[ 4,5-b]pyridine-2-yl)-1h-pyrazolo[3,4-b]pyridine (US20190119303A1), Wnt inhibitors or salts or analogs containing an indazole core (including amorphous and polymorphic forms) (W02013151708A1), 1h-pyrazolo[3,4-b]pyridine or salts or analogs (including amorphous and polymorphic forms) (W02013166396A2), 2-(1h-indazole-3-yl)-3h-imidazo[4,5-b]pyridine or salts or analogs (including amorphous and polymorphic forms) (US20190055238A1), f3-diketone, y-diketone or y-hydroxyketone or salts or analogs thereof (W02012024404A1), 3-(benzimidazole-2-yl)-indazole inhibitors or salts or analogs (including amorphous and polymorphic forms) (US10183929B2), 3-(1h-imidazo[4,5-c]pyridine-2-yl)-1h-pyrazolo[3,4-b]pyridine or salts or analogs (amorphous (Including amorphous and polymorphic forms) (US20180325910A1), 1H-pyrazolo[3,4-b]pyridine or salt or analog (including amorphous and polymorphic forms) (CY-1119844-T1), 3-(1h-imidazo[4,5-c]pyridine-2-yl)-1h-pyrazolo[3,4-c]pyridine or salt or analog (including amorphous and polymorphic forms) (US2018250269-Al), N-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridine-2-yl)-1H-indazole-5-yl)pyridine (Zin-3-yl)-3-methylbutanamide or salt or analog (including amorphous and polymorphic forms) (US20180133199A1), indazole-3-carboxamide or salt or analog (including amorphous and polymorphic forms) (US2018185343-A1), 3-(3h-imidazo[4,5-b]pyridine-2-yl)-1h-pyrazolo[3,4-c]pyridine or salt or analog (including amorphous and polymorphic forms) (US2018201624-Al), 2-(1h-indazole-3-yl)-1h-imidazo[4, 5-c]pyridine or salt or analog (including amorphous and polymorphic forms) (US-2018215753-A1), 3-(3H-imidazo[4,5-C]pyridine-2-yl)-1H-pyrazolo[3,4-C]pyridine or salt or analog (including amorphous and polymorphic forms) (US-10052331-B2), 5-substituted indazole-3-carboxamide or salt or analog (including amorphous and polymorphic forms) (US-2018127377-A1), 3-(3H-imidazo[4,5-C]pyridine-2-yl)-1H-pyrazolo[4,3-B]pyridine or salt or analog (including amorphous and polymorphic forms) (US-10188634-B2), 3-(1H-imidazo[4,5-C]pyridine-2-yl)-1H-pyrazolo[4,3-B]pyridine or salt or analog (including amorphous and polymorphic forms) (US-10195185-B2), 3-(1h-pyrrolo[2,3-b]pyridine-2-yl)-1h-indazole or salt or analog (including amorphous and polymorphic forms) (W0-2017024021-A1), 3-(1h-pyrrolo[2,3- [c]pyridine-2-yl)-1h-pyrazolo[3,4-c]pyridine or salt or analog (including amorphous and polymorphic forms) (W0-2017023975-A1), 3-(1h-indole-2-yl)-1h-pyrazolo[3,4-b]pyridine or salt or analog (including amorphous and polymorphic forms) (US-2018214428-A1), 3-(1h-pyrrolo[3,2-c]pyridine-2-yl)-1h-indazole or salt or analog (including amorphous and polymorphic forms) (US-2018221350-A 1) 3-(1h-indole-2-yl)-1h-indazole or salt or analog (including amorphous and polymorphic forms) (W0-2017023986-A1), 3-(1H-pyrrolo[2,3-B]pyridine-2-yl)-1H-pyrazolo[4,3-B]pyridine or salt or analog (including amorphous and polymorphic forms) (US-10206909-B2), 3-(1h-pyrrolo[3,2-c]pyridine-2-yl)-1h-pyrazolo[4,3-b]pyridine or salt or analog (including amorphous and polymorphic forms) ( WO-2017024003-Al), 3-(1h-pyrrolo[3,2-c]pyridine-2-yl)-1h-pyrazolo[3,4-b]pyridine or salt or analog (including amorphous and polymorphic forms) (US-2018221341-A1), 3-(3h-imidazo[4,5-b]pyridine-2-yl)-1h-pyrazolo[4,3-b]pyridine or salt or analog (including amorphous and polymorphic forms) (W0-2017024015-A1), 3-(1h-pyrrolo[2,3-c]pyridine-2-yl)-1h-pyrazolo[3,This may include 4-b]pyridine or salts or analogs (including amorphous and polymorphic forms) (US-2018221352-Al), and 3-(1H-pyrrolo[3,2-C]pyridine-2-yl)-1H-pyrazolo[3,4-C]pyridine or salts or analogs (including amorphous and polymorphic forms) (US-10206908-B2). Each reference cited herein is invoked in whole by reference.

[0117] In some embodiments, the injection system is used to deliver a suspension of an injectable agent comprising an active substance encapsulated in microcapsules, an active substance encapsulated in nanocapsules, pure protein nanoparticles, and an active substance that is poorly or insoluble in water.

[0118] In some embodiments, the injectable or capsule-encapsulated injectable is delivered with a matrix that extends the residence time. The matrix may consist of reverse thermally responsive hydrogels, self-assembling hydrogels, bioadhesive polymer networks, hydrogels, fibronectin-containing hydrogels, enzyme-responsive hydrogels, ultrasound-sensitive hydrogels, pH-sensitive hydrogels, carbohydrates, two-component or more hydrogels, and multi-component double-network hydrogels.

[0119] In some embodiments, the injectable agent is subsequently delivered via an injection system along with a penetration enhancer, such as dimethyl sulfoxide (DMSO), collagenase, elastase, protease, papain, bromelain, peptidase, lipase, alcohol, polyol, short-chain glycerides, amines, amides, cyclodextrins, fatty acids, pyrrolidone, cyclopentadecalactone, sodium N-[8-(2-hydroxylbenzoyl)amino]caprylate (SNAC), 8-(N-2-hydroxy-5-chlorobenzoyl)-aminocaprylic acid (5-CNAC), sodium caprate, sodium caprylate, omega-3 fatty acids, protease inhibitors, alkyl glycosides, chitosan, dodecyl-2-N,N-dimethylaminopropionate (DDAIP), N-methyl-2-pyrrolidone (NMP), azon, sulfoxide, surfactant, benzalkonium chloride Examples include, but are not limited to, chorides, saponins, bile salts, bile acids, cell-permeable peptides, polyarginines, low molecular weight protamines, polyserines, capric acid, gelucires, semifluorinated alkanes, terpenes, phospholipids, chelating agents, ethylenediaminetetraacetic acid (EDTA), citrates, crown ethers, and combinations thereof.

[0120] In some embodiments, an injectable formulation having one or more therapeutic formulations is delivered via an injection system together with or after the administration of one or more vasoconstrictors that reduce the outflow of the injectable formulation through the choroidal vessels. These vasoconstrictors include, but are not limited to, 25I-NBOMe, amphetamine, AMT, antihistamines, caffeine, cocaine, dopamine, dobutamine, DOM, LSA, LSD, methylphenidate, mephedrone, norepinephrine, oxymetazoline, phenylephrine, propylhexedrine, pseudoephedrine, stimulants, serotonin 5-hydroxytryptamine agonists, triptans, and tetrahydrozoline hydrochloride. In some embodiments, these active ingredients may be administered intravitreally using the injection system of this disclosure or via intravitreal injection using a standard syringe. The vasoconstrictors may be delivered before, concurrently with, or after the administration of one or more therapeutic formulations.

[0121] In some embodiments, the injectable agent delivered via the injection system covers more than 20%, 40%, 60%, or 80% of the SCS.

[0122] In some embodiments, an injectable agent delivered via an injection system, with or without one or more vasoconstrictors that reduce the outflow of the injectable agent through choroidal vessels, covers the SCS in less than 180, 120, 60, 30, or 15 minutes.

[0123] In some embodiments, the injectable agent delivered via the injection system has a retention time of less than 180, 120, 60, 30, 15, 10, or 5 minutes within the SCS.

[0124] In some embodiments, the injectable drug is delivered via an injection system in quantities of less than 500, 400, 300, 200, or 100 microliters.

[0125] In some embodiments, the injectable agent is delivered via an injection system at concentrations of 80%, 60%, 40%, 20%, 10%, 5%, 2.5%, or less than 1%.

[0126] In some embodiments, the dose percentage of the injectable agent delivered to the subretinal space via the injection system is 80%, 60%, 40%, 20%, 10%, 5%, 2.5%, or less than 1%.

[0127] In some embodiments, the injectable agent delivered via the injection system is administered at least once every 10 years, once every 5 years, once every 2 years, once every 1 year, once every 6 months, once every 3 months, once a month, or once a week.

[0128] In some embodiments, the injection system is used to deliver one or more injectable agents to treat one or more ocular causes or effects of the following diseases, including abetalipoproteinemia (Bassen-Kohnzweig syndrome), alkaptonuria, Alan Herndon-Dudley syndrome, Alpers syndrome, Alström syndrome, Apert syndrome, Arts syndrome (mental retardation, X-linked, symptomatic), ataxia-oculomotor apraxia syndrome, telangiectatic ataxia (Leuvar syndrome), autosomal dominant-cerebellar ataxia-auditory loss-narcolepsy (ADCADN), Avellino corneal dystrophy (mixed granular-lattice corneal dystrophy), Baraister-Winter syndrome, Bare- Stevenson syndrome, Best macular dystrophy, Vietti crystalline corneal-retinal dystrophy, Blau syndrome, palpebral fissure-ptosis-reverse anginal folds (BPES), Cantu syndrome, cerebroophthalmo-facial-skeletal syndrome, cerebral tendon xanthomatous dysplasia, Chediak-Higashi syndrome, cherubim syndrome, platyspondyly, characteristic brachydactyly, chondrodysplasia with hydrocephalus and microphthalmia, colloideremia, Christianson syndrome, CK syndrome, type 2 color blindness, type 1 color blindness, type 3 color blindness, keratoma, corpus callosum agenesis with intellectual disability, ocular defects, and micrognathia, Kosteff syndrome, Crigler-Nadjar, Crouzon syndrome, Crouzon syndrome with acanthosis nigricans (Crouzon exoskeleton syndrome), cutaneous laxity, Debre type, cystine storage, Doin honeycomb dystrophy (Malattia) Leventinese), Duane radial row syndrome, lens and pupillary displacement, familial lens displacement, lens displacement, isolated, S cone enhancement syndrome, corneal epithelial basement membrane dystrophy (geographic punctate fingerprint atrophy), Fabry disease (hereditary ectopic lipidosis), familial autonomic neuropathy, fish eye disease, galactokinase deficiency, galactosemia, Gaucher disease, GM1-gangliosidosis type I, GM1-gangliosidosis type II, GM1-gangliosidosis type III, Goltz syndrome, granular corneal dystrophy (Greynow's type I), cerebral gynecomastia, hereditary hemorrhagic telangiectasia (Hereditary Hemorrhagic Telangietasia (Osler-Landu-Weber disease), homocystinuria, IFAP syndrome with or without Bresheck syndrome, incontinentia pigmenti (Bloch-Salzberger syndrome), Djarili syndrome, Juberg-Marsidi syndrome, Krabbe disease, lattice corneal dystrophy, LCHAD (long-chain 3-hydroxyacyl-Coa dehydrogenase) deficiency, Lowe, Pelizaeus-Merzbach, Peters-Plass syndrome (Klaus-Kiblin syndrome), phenylketonuria, Proud syndrome, pseudoexfoliation syndrome, Reiss-Bücklars corneal dystrophy, Renpenning syndrome (intellectual retardation, X-linked, Renpenning type), retina Blastoma, retinoschisis, juvenile X-linked nephropathy, Russell-Silver syndrome, mucopolysaccharidosis type IH (Hurler syndrome), mucopolysaccharidosis type IH / S (Hurler-Schaye syndrome), mucopolysaccharidosis type IS (Schaye syndrome), mucopolysaccharidosis type II (Hunter syndrome), mucopolysaccharidosis type IIIA (Sanfilippo syndrome A), mucopolysaccharidosis type IIIB (Sanfilippo syndrome B), mucopolysaccharidosis type IIIC (Sanfilippo syndrome C), mucopolysaccharidosis type IIID (Sanfilippo syndrome D), mucopolysaccharidosis type IVA (Morcchio syndrome A), mucopolysaccharidosis type IVB (Morcchio syndrome B), mucopolysaccharidosis type VI (Maroto-Lamy syndrome), mucopolysaccharidosis type VII (Sly syndrome), Muwencke syndrome, onychopatellar syndrome, Nans-Horan syndrome Native American myopathy, neurofibromatosis type 1, neurofibromatosis type 2, neurofibromatosis-Noonan syndrome, neuropathy-ataxia-retinitis pigmentosa (NARP), Norie's disease, occult macular dystophythmia, oculoal albinism, oculopharyngeal muscular dystrophy, Sandhoff disease (GM2-gangliosidosis, type 2), Schneider corneal dystrophy.Dysrophy), Sengers syndrome, Smith-Magenis syndrome, (chromosome 17p11.2 deletion syndrome), sickle cell anemia, Sosby's retinal degeneration, spinocerebellar ataxia, X-linked I, Stargardt disease / yellow spot retina, Sturge-Weber syndrome, sulfocysteinuria (sulfite oxidase deficiency), syndromic microphthalmia 1 (Lenz microphthalmia syndrome), syndromic microphthalmia 2 (ophthalmo-facial-cardiac-dental syndrome), syndromic microphthalmia 3 (microphthalmia and esophageal atresia syndrome), syndromic microphthalmia 5, syndromic microphthalmia 6, syndromic microphthalmia 7 (Midas syndrome), Syndromic microphthalmia 9 (Matthew Wood syndrome), Syndromic microphthalmia 11, Syndromic microphthalmia 12, Syndromic microphthalmia 13, Syndromic microphthalmia 14, Tarp syndrome, Tay-Sachs disease (GM2-gangliosidosis, type I), Thiel-Behnke corneal dystrophy, Turner syndrome, hypertyrosinemia type II, Vacterl combined hydrocephalus, von Hippel-Lindau syndrome, Wagner syndrome, Watson syndrome, Weaker-Wolff syndrome, Wilson's disease, color blindness, Alagille syndrome, aniridia, anterior segment mesenchymal dysplasia, Axenfeldt syndrome. Rieger syndrome, CHARGE syndrome, Cockayne syndrome, congenital glaucoma, juvenile-onset open-angle glaucoma, Jackson-Weiss syndrome, Pfeiffer syndrome, Prader-Willi syndrome, Refsum disease, Rubinstein-Taybe syndrome, normal-tension glaucoma, Oguchi disease, Sätre-Hötsen syndrome, Simpson-Gorabi-Boehmel syndrome, tuberous sclerosis, adult-onset vitiligo macular dystrophy, Wolfram syndrome, Alport syndrome, Angelman syndrome, Valday-Biedl syndrome, basal cell nevus syndrome, Beckwith-Wiedemann syndrome, blue cone Total color blindness, branchio-otorenephrosis, Charcot-Marie-Tooth disease, cone-rod dystrophy, congenital glycosylation disorder, congenital extraocular myofibrosis, congenital nystagmus, congenital stasis nyctalopsia, Cornelia de Lange syndrome, congenital keratosis disorder, Ehlers-Danlos syndrome, Fuchs corneal endothelial dystrophy, adult-onset open-angle glaucoma, Hermansy-Padlak syndrome, Joubert syndrome, Kahns-Sayre syndrome, Leber congenital amaurosis, Leber hereditary optic nerve atrophy, Leigh syndrome, Peters anomalyThis includes, but is not limited to, retinitis pigmentosa, muscular dystrophy / dystroglycanopathy, myotonic dystrophy, Niemann-Pick disease, Noonan syndrome, neuronal ceroid lipofuscinosis, oculocutaneous albinism, optic nerve atrophy, oral-facial-digital syndrome, osteogenesis imperfecta, Senior-Loken syndrome, septic-optic dysplasia (De Morsia syndrome), spastic paraplegia, Stickler syndrome, Treacher-Collins syndrome, Usher syndrome, Waardenburg syndrome, Vaille-Marchesani syndrome, and xeroderma pigmentosum.

[0129] In some embodiments, treatment can be continued by administering multiple injections over a long period of time. The injection of the therapeutic agent may be accompanied by another agent that enables multiple deliveries. For example, AAV delivery is limited by the immune response to AAV, so the use of AAV is usually limited to a single treatment (this limitation is usually associated with intravitreal injection), while subretinal injection is immune-privileged, but damaged and affected retinas do not tolerate multiple injections without trauma. Another agent that suppresses this response (e.g., ImmTOR) can be injected before, with, or after the AAV injection to mitigate the immune response and enable AAV treatment at multiple time points. This allows for dose escalation as needed to match the patient's response.

[0130] In some embodiments, the route of administration is by injection into the SCS. In some embodiments, the hereditary disease or hereditary disorder is diagnosed by gene sequencing, which includes, but is not limited to, Sanger sequencing, next-generation sequencing, high-throughput screening, exome sequencing, Maxam-Gilbert sequencing, chain termination methods, shotgun sequencing, bridge polymerase chain reaction, single-molecule real-time sequencing, ion torrent sequencing, pyrosequencing, sequencing by synthesis, combinatorial probe anchor synthesis, sequencing by ligation, and nanopore sequencing. In some embodiments, the above-mentioned eye disease or disorder is diagnosed by eye examination, ophthalmoscopic examination, ocular coherence tomography, retinal scanning, fluorescein staining, conjunctival staining, color vision testing, optic nerve head imaging, nerve fiber layer analysis, corneal topography, electrodiagnostic testing, fluorescein angiography, ocular photography, specular microscopy, visual field testing, ocular ultrasound, and combinations thereof.

[0131] In some embodiments, a patient presented with elevated intraocular pressure and was diagnosed with early-onset juvenile primary open-angle glaucoma. Subsequently, after ophthalmoscopic examination, significant optic nerve damage occurred. Blood samples were taken and sent for genetic testing, which revealed that the patient had a mutation (mutation Y437H) in the olfactomedin domain of the myocilin (MYOC) gene, which may be involved in the cause of the disease, leading to a diagnosis of myocilin-related primary open-angle glaucoma.

[0132] Next, the patient is treated by administering, using the injection system described above, a microRNA complementary to the first 22 bases of the MYOC gene mRNA, formulated in an aqueous solution of a self-assembling hydrogel with beta-cyclodextrin and EDTA as penetration enhancers. This injection is stored as a lyophilized powder in a separate vial with a diluent before use. After injection, the hydrogel self-assembles in the SCS after delivery, providing sustained delivery of the microRNA that suppresses myocilin expression, thereby reducing the accumulation of myocilin in the trabecular meshwork and lowering intraocular pressure, thereby reducing the probability of persistent optic nerve damage in the patient.

[0133] In another specific embodiment, a boy presents with night blindness, and examination reveals a reduced visual field and some retinal degeneration. A blood sample is taken and sent for genetic testing, revealing that the patient has a mutation in the CHM gene, which encodes RAB escort protein 1 (REP1), including part or all of the CHM gene sequence, as described, for example, https: / / www.uniprot.org / uniprot / P24386 (the entirety of which is incorporated herein by reference). This supports the diagnosis of early colloideremia.

[0134] The patient is then treated by administration using the injection system described above, in which a lyophilized AAV2 vector containing a retina-specific promoter derived from a rhodopsin kinase (RK) promoter gene expressed in rods and cones, linked to the human CHM gene, is reconstituted with an aqueous diluent before injection. During reconstitution, the injection solution contains approximately 10¹³ AAV vectors per milliliter. Upon injection, this RK promoter and human CHM gene are stably transfected into photoreceptor cells, in which a modified form of REP1 is expressed, treating the patient's colloideremia.

[0135] In another specific embodiment, an elderly patient presents with central visual field defects. A standard retinal examination reveals drusen. Fluorescein angiography reveals a leaky choroidal vascular system, which is confirmed by the presence of subretinal fluid accumulation observed on optical coherence tomography (OCT). The patient is diagnosed with early neovascular age-related macular degeneration (AMD).

[0136] The patient is then treated by administration using the injection system described above, in which one or more small interfering RNA (siRNA) sequences of 21-24 nucleotides complementary to a portion of mRNA, from among the genes encoding vascular endothelial growth factor (VEGF), including but not limited to VEGF-A, VEGF-A121, VEGF-A165, VEGF-A189, VEGF-A206, VEGF-B, VEGF-C, VEGF-D, VEGF receptor (VEGFR), VEGFR-1, VEGFR-2, VEGFR-3, NOTCH-regulated ankyrin repeat protein (NRARP), and other pro-angiogenic proteins, either alone or in combination. The siRNA is delivered as a suspension on a liposome carrier. After delivery, the siRNA prevents further choroidal capillary growth and recedes capillaries by knocking down the expression of pro-angiogenic proteins, thereby reducing choroidal capillary, retinal, and macular infiltration and improving central vision. In specific embodiments, the siRNA is targeted to knock down VEGFR-2 and has a gene sequence or isoform such as that described in https: / / www.uniprot.org / uniport / P35968 (the entire sequence of which is incorporated herein by reference).

[0137] In another specific embodiment, a patient diagnosed with neovascular AMD or diabetic retinopathy is treated by administration using the above injection system, in which the AAV vector or other transfection vector contains a gene that generates an RNA sequence complementary to at least a portion of the mRNA that, when transcribed, translates to VEGFR-2. When this gene therapy is delivered to the SCS, the choroidal capillaries, also known as the choroidal capillary plate, come into contact with the delivered therapeutic agent, which is targeted to transfect cells expressing VEGFR-2. Upon transfection, the transcribed siRNA vector or shRNA vector knocks down or knocks out VEGFR-2 production, thereby reducing neovascularization and treating AMD or diabetic retinopathy.

[0138] In some embodiments, a physician may be provided with a choroidal injection assembly or kit which comprises (1) a predetermined volume of an injectable agent comprising one or more therapeutic formulations, i.e., active agent formulations, for example, an effective amount of an active agent useful for treating a patient’s ocular symptoms; (2) an injection system as described above; and (3) a syringe, if necessary, to facilitate the injection of the injectable agent into and through the membrane of the injection system.

[0139] As previously mentioned, the active substance formulation may include various forms such as solutions and suspensions of varying viscosities. The entire kit, including the formulation, injection system, and facilitating injector, is sterilized.

[0140] In some embodiments, the total volume of the active substance formulation injected into the suprachoroid space is preferably in the range of approximately 0.01 to 0.5 mL. In some embodiments, the active substance is provided in a lyophilized form and with an accompanying diluent, and a suspension can be prepared at the time of injection. In some embodiments, the active substance may be pre-mixed. In some embodiments, the injection system may be pre-filled with the pre-mixed formulation. In some embodiments, the user can fill the injection system immediately before administering the therapeutic formulation to the patient. In some embodiments, the injection system may comprise multiple chambers with fragile partitions. In some embodiments, the puncture element has an initial penetration length of 0.01 to 3 mm, and the puncture element extends further during injection. In some embodiments, the injection system and injection facilitator are pre-assembled with the formulation pre-filled and ready for use without further assembly. In some embodiments, the entire kit is packaged in a single pouch / tray to maintain sterility. In some embodiments, the components are packaged separately or together. In some embodiments, the kits are sterilized together or separately by one of the sterilization methods, including but not limited to autoclaving, ethylene oxide, and gamma irradiation.

[0141] In some embodiments, the components are located in a second package. In some embodiments, the kit is stored as a set at a temperature low enough to extend the shelf life of the effective drug. In some embodiments, the formulation is stored separately at a low temperature, while the rest of the kit is stored at room temperature.

[0142] Given the foregoing description, numerous modifications and alternative embodiments of the present invention will become apparent to those skilled in the art. Therefore, this description should be interpreted as merely illustrative and intended to teach those skilled in the art the best mode for carrying out the present invention. Details of the above structure can be substantially modified without departing from the spirit of the invention, and the exclusive use of all modifications falling within the scope of the appended claims is reserved. While embodiments have been described herein to enable a clear and concise description, it will be intended and understood that embodiments can be combined or separated in various ways without departing from the present invention. The present invention is intended to be limited only to the extent required by the appended claims and the rules of applicable law.

[0143] It should be understood that the following claims also encompass all general and specific features of the invention as described herein, as well as all descriptions relating to the scope of the invention, which can be said to lie between them as a matter of language. In certain embodiments, for example, the following items are provided: (Item 1) A syringe barrel that defines the lumen between the proximal and distal ends; A first sealing element movably disposed within the lumen; A second sealing element is movably disposed within the lumen proximal to the first sealing element, wherein the first sealing element and the A second sealing element, which forms a seal with the lumen and defines an injection chamber between them; A puncture element extending from the distal end of the first sealing element, wherein the puncture element is in fluid communication with the injection chamber to deliver an injectable agent from the injection chamber into a space within the patient's tissue. An injection system comprising, Here, one or more of the syringe barrel, the first sealing element, and the second sealing element are configured to prevent the first sealing element from moving proximal to a predetermined position, while allowing the second sealing element to come into contact with the first sealing element. When a force is applied distally to the second sealing element, the system In response to the first reaction force, the first sealing element moves distally, advancing the puncture element distally without transporting the injectable agent through the puncture element. In response to the second reaction force, the first sealing element remains stationary, and the injectable agent is transported from the injection chamber through the puncture element. An injection system configured in such a way. (Item 2) The first reaction force is due to the back pressure exerted on the puncture element as the puncture element advances through the tissue; The second reaction force is due to the back pressure exerted on the puncture element when the puncture element passes through the space within the tissue, The system described in item 1. (Item 3) The force applied to the second sealing element is sufficient to advance the first sealing element, but insufficient to deliver the injectable agent through the puncture element in response to the first reaction force; The force applied to the second sealing element is insufficient to advance the first sealing element, but is sufficient to deliver the injectable agent through the puncture element in response to the second reaction force. The system described in item 1. (Item 4) The system according to item 1, wherein a unidirectional stop is positioned in the syringe barrel between the first sealing element and the second sealing element, the unidirectional stop is configured to prevent the first sealing element from moving proximal to the unidirectional stop, while allowing the second sealing element to pass through the mechanical stop and come into contact with the first sealing element. (Item 5) The system according to item 4, wherein the unidirectional stop constitutes a compartment of the syringe barrel having a reduced diameter, and the first sealing element has a diameter sufficiently larger than the reduced diameter, so that the first sealing element cannot pass through the compartment, but the second sealing element is configured to pass through the compartment and come into contact with the first sealing element. (Item 6) The system according to item 4, wherein the unidirectional stop constitutes a portion of the inner surface of the syringe barrel having a coefficient of friction sufficient to prevent proximal movement of the first sealing element. (Item 7) The system according to item 4, wherein the aforementioned unidirectional stop includes a mechanical stop. (Item 8) The system according to item 4, wherein the unidirectional stop constitutes a foldable stop positioned between the first sealing element and the second sealing element, the foldable stop is configured to prevent the proximal movement of the first sealing element beyond the foldable stop, and is configured to fold when a distal force is applied to the foldable stop, allowing the second sealing element to pass through the foldable stop and come into contact with the first sealing element. (Item 9) The system according to item 1, wherein the first sealing element is molded such that the proximal frictional force or sliding force with respect to the first sealing element is greater than the distal frictional force or sliding force with respect to the first sealing element and greater than the insertion force of the puncture element into the tissue. (Item 10) The system according to any one of items 1 to 9, wherein the first sealing element, in a relaxed state, has a size 1.01 to 2 times larger than the size of the lumen of the syringe barrel. (Item 11) The system according to any one of items 1 to 9, wherein the first sealing element, in a relaxed state, has a size 1.01 to 1.10 times larger than the size of the lumen of the syringe barrel. (Item 12) The system according to any one of items 1 to 9, wherein the inner surface of the syringe barrel is modified to increase friction between the inner surface of the syringe barrel and the first sealing element. (Item 13) The system according to any one of items 1 to 9, further comprising a lock located distal to the first sealing element and configured to selectively lock the first sealing element in a predetermined position. (Item 14) The system according to item 13, wherein the lock comprises a sealed compartment defined in the lumen of the syringe barrel distal to the first sealing element, an incompressible material inside the compartment, and a valve for releasing the incompressible material from the compartment, wherein when the valve is closed, distal movement of the first sealing element is prevented, and when the valve is open, distal movement of the first sealing element is permitted. (Item 15) The system according to any one of items 1 to 9, further comprising a touch trigger mechanism between the first sealing element and the second sealing element, wherein the touch trigger mechanism is configured to deploy when the first sealing element comes into contact with the second sealing element to prevent distal movement of the first sealing element. (Item 16) The system according to any one of items 1 to 9, further comprising a filling port located on the surface of the syringe barrel and in fluid communication with the injection chamber. (Item 17) The aforementioned filling port, A receiving portion, positioned on the outer surface of the syringe barrel and configured to receive a vial; A flow path connecting the receiving portion and the injection chamber; A self-sealing member configured to seal the aforementioned flow path; and A puncture element disposed within the receiving portion, wherein the puncture element is configured to penetrate the self-sealing member and to connect the vial containing the injectable agent received in the receiving portion to the injection chamber by fluid. The system described in item 16, comprising: (Item 18) When the vial is received in the receiving portion, the puncture element moves toward the injection chamber, penetrates the self-sealing member, and the puncture element is movable relative to the receiving portion so that the vial and the injection chamber are connected by fluid. When the drug container is removed from the receiving portion, the puncture element moves away from the injection chamber, allowing the self-sealing member to seal the flow path, so that the puncture element is movable relative to the receiving portion. The system described in item 17. (Item 19) The system according to any one of items 1 to 9, wherein a support element is positioned near the distal portion of the puncture element, and the support element is movable in conjunction with the puncture element and the syringe barrel. (Item 20) The system according to any one of items 1 to 9, wherein the injection chamber comprises a first chamber and a second chamber, and a chamber sealing portion of the second sealing element fluidly isolates the first chamber from the second chamber, and when the chamber sealing portion moves, the first chamber and the second chamber are connected by fluid. (Item 21) The system according to any one of items 1 to 9, wherein the injection chamber comprises a first chamber and a second chamber, the first chamber and the second chamber being fluidly isolated from each other when the second sealing element is in its initial position, and the first chamber and the second chamber being fluidly connected when the second sealing element moves. (Item 22) The system according to any one of items 1 to 9, wherein the second sealing element is configured to engage with the first sealing element, and the first sealing element and the puncture element are withdrawn into the syringe barrel. (Item 23) A method for treating an eye disease, wherein the method is A step of pre-inserting the puncture element of an injection system into the sclera of a patient, wherein the injection system is A syringe barrel that defines the lumen between the proximal and distal ends; A first sealing element movably disposed within the lumen; A second sealing element movably positioned within the lumen proximal to the first sealing element, wherein the first sealing element and the second sealing element form a seal with the lumen and define an injection chamber between them; A puncture element extending from the distal end of the first sealing element, wherein the puncture element is in fluid communication with the injection chamber to deliver an injectable agent from the injection chamber into a space within the patient's tissue. Equipped with; Here, one or more of the syringe barrel, the first sealing element, and the second sealing element are such that the second sealing element is the first sealing element A process configured to prevent the first sealing element from moving proximal to a predetermined position, while allowing it to come into contact with the sealing element; A step of advancing the puncture element through the sclera by applying force to the second sealing element, wherein the force is sufficient to move the first sealing element distally and advance the puncture element distally without transporting the injectable agent through the puncture element; and The process of maintaining the force on the second sliding element so that the injectable agent is delivered from the injection chamber through the puncture element to the SCS without the first sealing element moving further distally when the puncture element has passed through the sclera and into the suprachoroidal space (SCS). Methods that include... (Item 24) The first reaction force is due to the back pressure exerted on the puncture element as the puncture element advances through the tissue; The second reaction force is due to the back pressure exerted on the puncture element when the puncture element passes through the space within the tissue. The method described in item 23. (Item 25) The force applied to the second sealing element is sufficient to advance the first sealing element, but insufficient to deliver the injectable agent through the puncture element in response to the first reaction force; The method according to item 23, wherein the force applied to the second sealing element is insufficient to advance the first sealing element, but is sufficient to deliver the injectable agent through the puncture element in response to the second reaction force. (Item 26) The method according to item 23, wherein the injection system comprises a unidirectional stop located in the syringe barrel between the first sealing element and the second sealing element, the unidirectional stop being configured to prevent the first sealing element from moving proximal to the unidirectional stop while allowing the second sealing element to pass through the mechanical stop and come into contact with the first sealing element. (Item 27) The method according to item 26, wherein the unidirectional stop constitutes a compartment of the syringe barrel having a reduced diameter, and the first sealing element has a diameter sufficiently larger than the reduced diameter, so that the first sealing element cannot pass through the compartment, but the second sealing element is configured to pass through the compartment and come into contact with the first sealing element. (Item 28) The method according to item 26, wherein the unidirectional stop constitutes a portion of the inner surface of the syringe barrel having a coefficient of friction sufficient to prevent proximal movement of the first sealing element. (Item 29) The method according to item 26, wherein the unidirectional stop includes a mechanical stop. (Item 30) The method according to item 26, wherein the unidirectional stop constitutes a foldable stop positioned between the first sealing element and the second sealing element, the foldable stop is configured to prevent the proximal movement of the first sealing element beyond the foldable stop, and is configured to fold when a distal force is applied to the foldable stop, allowing the second sealing element to pass through the foldable stop and come into contact with the first sealing element. (Item 31) The method according to item 23, wherein the first sealing element is molded such that the proximal frictional or sliding force with respect to the first sealing element is greater than the distal frictional or sliding force with respect to the first sealing element and greater than the insertion force of the puncture element into the tissue. (Item 32) The method according to any one of items 23 to 31, wherein the first sealing element, in a relaxed state, has a size 1.01 to 2 times larger than the size of the lumen of the syringe barrel. (Item 33) The method according to any one of items 23 to 31, wherein the first sealing element, in a relaxed state, has a size 1.01 to 1.10 times larger than the size of the lumen of the syringe barrel. (Item 34) The method according to any one of items 23 to 31, wherein the inner surface of the syringe barrel is modified to increase friction between the inner surface of the syringe barrel and the first sealing element. (Item 35) The method according to any one of items 23 to 31, wherein the injection system further comprises a lock located distal to the first sealing element and configured to selectively lock the first sealing element in a predetermined position. (Item 36) The method according to item 35, wherein the lock comprises a sealed compartment defined in the lumen of the syringe barrel distal to the first sealing element, an incompressible material inside the compartment, and a valve for releasing the incompressible material from the compartment, wherein when the valve is closed, distal movement of the first sealing element is prevented, and when the valve is open, distal movement of the first sealing element is permitted. (Item 37) The method according to any one of items 23 to 31, wherein the injection system further comprises a touch trigger mechanism between the first sealing element and the second sealing element, the touch trigger mechanism being configured to deploy when the first sealing element comes into contact with the second sealing element to prevent distal movement of the first sealing element. (Item 38) The method according to any one of items 23 to 31, wherein the injection system further comprises a filling port located on the surface of the syringe barrel and having fluid communication with the injection chamber. (Item 39) The aforementioned filling port, A receiving portion, positioned on the outer surface of the syringe barrel and configured to receive a vial; A flow path connecting the receiving portion and the injection chamber; A self-sealing member configured to seal the aforementioned flow path; and A puncture element disposed within the receiving portion, wherein the puncture element is configured to penetrate the self-sealing member and to connect the vial received in the receiving portion to the injection chamber with fluid. The method described in item 38, comprising: (Item 40) When the vial is received in the receiving section, the puncture element is used for injection. The puncture element is movable relative to the receiving portion so as to move toward the chamber, penetrate the self-sealing member, and connect the vial and the injection chamber by fluid. The method according to item 39, wherein when the drug container is removed from the receiving portion, the puncture element is movable relative to the receiving portion so that the puncture element moves away from the injection chamber, allowing the self-sealing member to seal the flow path. (Item 41) The method according to any one of items 23 to 31, wherein a support element is positioned near the distal portion of the puncture element, and the support element is movable in conjunction with the puncture element and the syringe barrel. (Item 42) The method according to any one of items 23 to 31, wherein the injection chamber comprises a first chamber and a second chamber, and a chamber sealing portion of the second sealing element fluidly isolates the first chamber from the second chamber, and when the chamber sealing portion moves, the first chamber and the second chamber are connected by fluid. (Item 43) The method according to any one of items 23 to 31, wherein the injection chamber comprises a first chamber and a second chamber, the first chamber and the second chamber being fluidly isolated from each other when the second sealing element is in its initial position, and the first chamber and the second chamber being fluidly connected when the second sealing element moves. (Item 44) The method according to any one of items 23 to 31, wherein the eye disease is age-related macular degeneration (AMD), diabetic macular edema (DME), glaucoma, retinal vein occlusion (RVO), uveitis, endophthalmitis, Stargardt disease, Leber congenital amaurosis (LCA), retinitis pigmentosa, or colloideremia. (Item 45) The method according to item 44, wherein the injection fluid comprises one or more injectable formulations comprising a viral delivery vector containing a gene of interest and a promoter selected to promote the gene of interest. (Item 46) The method according to item 45, wherein the target gene is an anti-VEGFR2 gene. (Item 47) The method according to item 46, wherein the delivery vector is an AAV vector. (Item 48) The method according to item 47, wherein the promoter is the CAG promoter for the anti-VEGFR2 gene. (Item 49) The method according to item 44, wherein the injection fluid comprises one or more injectable formulations comprising: bevacizumab, ranibizumab, aflibercept, ramucirumab, disintegrin, anti-prostaglandins, tryptophanyl-tRNA synthetase-derived polypeptides, inosine monophosphate dehydrogenase (IMPDH) inhibitors and anti-PDGF for treating AMD; and corticosteroids for treating uveitis, chorioretinitis or other inflammatory eye diseases; botulinum toxin for use in various eyes; and tyrosine kinase inhibitors. (Item 50) A kit for injecting an injectable drug into tissue, the kit comprises: A syringe barrel that defines the lumen between the proximal and distal ends; A first sealing element movably disposed within the lumen; A second sealing element movably positioned within the lumen proximal to the first sealing element, wherein the first sealing element and the second sealing element form a seal with the lumen and define an injection chamber between them; A puncture element extending from the distal end of the first sealing element, wherein the puncture element is in fluid communication with the injection chamber to deliver an injectable agent from the injection chamber into a space within the patient's tissue. An injection system comprising, Here, one or more of the syringe barrel, the first sealing element, and the second sealing element are configured to prevent the first sealing element from moving proximal to a predetermined position, while allowing the second sealing element to come into contact with the first sealing element. When a force is applied distally to the second sealing element, the system In response to the first reaction force, the first sealing element moves distally, advancing the puncture element distally without transporting the injectable agent through the puncture element. In response to the second reaction force, the first sealing element remains stationary, and the injectable agent is transported from the injection chamber through the puncture element. An injection system configured as follows; and A predetermined volume of the injectable fluid containing one or more injectable formulations. A kit that includes this. (Item 51) The first reaction force is due to the back pressure exerted on the puncture element as the puncture element advances through the tissue; The second reaction force is due to the back pressure exerted on the puncture element when the puncture element passes through the space within the tissue. The kit described in item 50. (Item 52) The force applied to the second sealing element is sufficient to advance the first sealing element, but insufficient to deliver the injectable agent through the puncture element in response to the first reaction force; The force applied to the second sealing element is insufficient to advance the first sealing element, but is sufficient to deliver the injectable agent through the puncture element in response to the second reaction force. The kit described in item 50. (Item 53) The injection system further comprises a unidirectional stop positioned in the syringe barrel between the first sealing element and the second sealing element, wherein the unidirectional stop is configured to prevent the first sealing element from moving proximal to the unidirectional stop, while allowing the second sealing element to pass through the mechanical stop and come into contact with the first sealing element, as described in item 50. (Item 54) The kit according to item 53, wherein the unidirectional stop constitutes a compartment of the syringe barrel having a reduced diameter, and the first sealing element has a diameter sufficiently larger than the reduced diameter, so that the first sealing element cannot pass through the compartment, but the second sealing element is configured to pass through the compartment and come into contact with the first sealing element. (Item 55) The kit according to item 53, wherein the unidirectional stop constitutes a portion of the inner surface of the syringe barrel having a coefficient of friction sufficient to prevent proximal movement of the first sealing element. (Item 56) The kit described in item 53, wherein the aforementioned unidirectional stop includes a mechanical stop. (Item 57) The kit according to item 53, wherein the unidirectional stop constitutes a foldable stop positioned between the first sealing element and the second sealing element, the foldable stop is configured to prevent the proximal movement of the first sealing element beyond the foldable stop, and when a distal force is applied to the foldable stop, it is configured to fold so that the second sealing element can pass through the foldable stop and come into contact with the first sealing element. (Item 58) The kit according to item 50, wherein the first sealing element is molded such that the proximal frictional force or sliding force with respect to the first sealing element is greater than the distal frictional force or sliding force with respect to the first sealing element and greater than the insertion force of the puncture element into the tissue. (Item 59) The kit according to any one of items 50 to 58, wherein the first sealing element, in a relaxed state, has a size 1.01 to 2 times larger than the size of the lumen of the syringe barrel. (Item 60) The kit according to any one of items 50 to 58, wherein the first sealing element, in a relaxed state, has a size 1.01 to 1.10 times larger than the size of the lumen of the syringe barrel. (Item 61) The kit according to any one of items 50 to 58, wherein the inner surface of the syringe barrel is modified to increase friction between the inner surface of the syringe barrel and the first sealing element. (Item 62) The kit according to any one of items 50 to 58, wherein the injection system further comprises a lock located distal to the first sealing element and configured to selectively lock the first sealing element in a predetermined position. (Item 63) The kit according to item 62, wherein the lock comprises a sealed compartment defined in the lumen of the syringe barrel distal to the first sealing element, an incompressible material inside the compartment, and a valve for releasing the incompressible material from the compartment, wherein when the valve is closed, distal movement of the first sealing element is prevented, and when the valve is open, distal movement of the first sealing element is permitted. (Item 64) The injection system further comprises a touch trigger mechanism between the first sealing element and the second sealing element, the touch trigger mechanism being configured to deploy when the first sealing element comes into contact with the second sealing element to prevent distal movement of the first sealing element, according to any one of items 50 to 58. (Item 65) The injection system is a filling port located on the surface of the syringe barrel. A kit as described in any one of items 50 to 58, further comprising a filling port that communicates with the injection chamber and fluid. (Item 66) The aforementioned filling port, A receiving portion, positioned on the outer surface of the syringe barrel and configured to receive a vial; A flow path connecting the receiving portion and the injection chamber; A self-sealing member configured to seal the aforementioned flow path; and A puncture element disposed within the receiving portion, wherein the puncture element is configured to penetrate the self-sealing member and to connect the vial received in the receiving portion to the injection chamber with fluid. The kit described in item 65, which includes the following: (Item 67) When the vial is received in the receiving portion, the puncture element moves toward the injection chamber, penetrates the self-sealing member, and the puncture element is movable relative to the receiving portion so that the vial and the injection chamber are connected by fluid. The kit according to item 66, wherein when the drug container is removed from the receiving portion, the puncture element is movable relative to the receiving portion so that the puncture element moves away from the injection chamber, allowing the self-sealing member to seal the flow path. (Item 68) A kit according to any one of items 50 to 58, wherein a support element is positioned near the distal end of the puncture element, and the support element is movable in conjunction with the puncture element and the syringe barrel. (Item 69) The kit according to any one of items 50 to 58, wherein the injection chamber comprises a first chamber and a second chamber, and the chamber sealing portion of the second sealing element fluidly isolates the first chamber from the second chamber, and when the chamber sealing portion moves, the first chamber and the second chamber are connected by fluid. (Item 70) The kit according to any one of items 50 to 58, wherein the injection chamber comprises a first chamber and a second chamber, the first chamber and the second chamber being fluidly isolated from each other when the second sealing element is in its initial position, and the first chamber and the second chamber being fluidly connected when the second sealing element moves. (Item 71) The aforementioned injectable agent is selected for use in treating an eye disease, as described in any one of items 50 to 58. (Item 72) The kit described in item 71, wherein the aforementioned eye disease is age-related macular degeneration (AMD), diabetic macular edema (DME), glaucoma, retinal vein occlusion (RVO), uveitis, endophthalmitis, Stargardt disease, Leber congenital amaurosis (LCA), retinitis pigmentosa, or colloideremia. (Item 73) The kit according to item 72, wherein the injection fluid comprises one or more injectable formulations comprising a viral delivery vector containing a gene of interest and a promoter selected to promote the gene of interest. (Item 74) The kit described in item 73, wherein the target gene is the anti-VEGFR2 gene. (Item 75) The kit described in item 74, wherein the delivery vector is an AAV vector. (Item 76) The kit according to item 75, wherein the promoter is the CAG promoter for the anti-VEGFR2 gene. (Item 77) The kit according to item 72, wherein the injection fluid comprises one or more injectable formulations comprising: bevacizumab, ranibizumab, aflibercept, ramucirumab, disintegrin, anti-prostaglandins, tryptophanyl-tRNA synthetase-derived polypeptides, inosine monophosphate dehydrogenase (IMPDH) inhibitors and anti-PDGF for treating AMD; corticosteroids for treating uveitis, chorioretinitis or other inflammatory eye diseases; botulinum toxin for use in various eyes; and tyrosine kinase inhibitors.

Claims

1. A syringe barrel that defines the lumen between the proximal and distal ends; A first sealing element movably disposed within the lumen; A second sealing element movably disposed within the lumen proximal to the first sealing element, wherein the first sealing element and the second sealing element form a seal with the lumen and define an injection chamber between them; A puncture element extending from the distal end of the first sealing element, wherein the puncture element is in fluid communication with the injection chamber to deliver an injectable agent from the injection chamber into a space within the patient's tissue; and A unidirectional stop disposed within the syringe barrel between the first sealing element and the second sealing element, wherein the unidirectional stop is During the pre-insertion of the puncture element into the tissue, it comes into contact with the first sealing element. To prevent the first sealing element from moving proximal to the unidirectional stop during the delivery of the injectable agent, and A unidirectional stop is configured to allow the second sealing element to pass through the unidirectional stop and come into contact with the first sealing element after the delivery of the injectable agent. An injection system equipped with the following features.

2. The system according to claim 1, wherein the unidirectional stop constitutes a compartment of the syringe barrel having a reduced diameter, and the first sealing element has a diameter sufficiently larger than the reduced diameter, so that the first sealing element cannot pass through the compartment, but the second sealing element is configured to pass through the compartment and come into contact with the first sealing element.

3. The system according to claim 1, wherein the unidirectional stop constitutes a portion of the inner surface of the syringe barrel having a coefficient of friction sufficient to prevent the proximal movement of the first sealing element.

4. The system according to claim 1, wherein the unidirectional stop includes a mechanical stop.

5. The system according to claim 1, wherein the unidirectional stop constitutes a foldable stop positioned between the first sealing element and the second sealing element, the foldable stop is configured to prevent the proximal movement of the first sealing element beyond the foldable stop, and is configured to fold when a distal force is applied to the foldable stop, allowing the second sealing element to pass through the foldable stop and come into contact with the first sealing element.

6. The system according to claim 1, wherein the first sealing element is molded such that a first frictional or sliding force in the proximal direction relative to the first sealing element is greater than a second frictional or sliding force in the distal direction relative to the first sealing element and greater than the insertion force of the puncture element into the tissue.

7. The system according to any one of claims 1 to 6, wherein the first sealing element, in a relaxed state, has a size 1.01 to 2 times larger than the size of the lumen of the syringe barrel.

8. The system according to any one of claims 1 to 6, wherein the first sealing element, in a relaxed state, has a size 1.01 to 1.10 times larger than the size of the lumen of the syringe barrel.

9. The system according to any one of claims 1 to 6, wherein the inner surface of the syringe barrel is modified to increase friction between the inner surface of the syringe barrel and the first sealing element.

10. The system according to any one of claims 1 to 6, further comprising a lock disposed distal to the first sealing element and configured to selectively lock the first sealing element in a predetermined position.

11. The system according to claim 10, wherein the lock comprises a sealed compartment defined in the lumen of the syringe barrel distal to the first sealing element, an incompressible material inside the compartment, and a valve for releasing the incompressible material from the compartment, wherein when the valve is closed, distal movement of the first sealing element is prevented, and when the valve is open, distal movement of the first sealing element is permitted.

12. The system according to any one of claims 1 to 6, further comprising a touch trigger mechanism between the first sealing element and the second sealing element, wherein the touch trigger mechanism is configured to deploy when the first sealing element comes into contact with the second sealing element to prevent distal movement of the first sealing element.

13. The system according to any one of claims 1 to 6, further comprising a filling port located on the surface of the syringe barrel and in fluid communication with the injection chamber.

14. The aforementioned filling port, A receiving portion positioned on the outer surface of the syringe barrel and configured to receive a vial; A flow path connecting the receiving portion and the injection chamber; A self-sealing member configured to seal the aforementioned flow path; and A puncture element disposed within the receiving portion, wherein the puncture element penetrates the self-sealing member and is configured to fluidly connect the vial containing the injectable agent and received within the receiving portion to the injection chamber. The system according to claim 13, comprising:

15. When the vial is received in the receiving portion, the puncture element moves toward the injection chamber, penetrates the self-sealing member, and is movable relative to the receiving portion so as to connect the vial to the injection chamber with fluid. When the vial is removed from the receiving portion, the puncture element moves away from the injection chamber, allowing the self-sealing member to seal the flow path, so that the puncture element is movable relative to the receiving portion. The system according to claim 14.

16. The system according to any one of claims 1 to 6, wherein a support element is positioned near the distal portion of the puncture element, and the support element is movable in conjunction with the puncture element and the syringe barrel.

17. The system according to any one of claims 1 to 6, wherein the injection chamber comprises a first chamber and a second chamber, and a chamber sealing portion fluidly isolates the first chamber from the second chamber, and when the chamber sealing portion moves, the first chamber and the second chamber are connected by fluid.

18. The system according to any one of claims 1 to 6, wherein the injection chamber comprises a first chamber and a second chamber, the first chamber and the second chamber are fluidly isolated from each other when the chamber sealing portion is in its initial position, and the first chamber and the second chamber are fluidly connected when the chamber sealing portion moves.

19. The system according to any one of claims 1 to 6, wherein the second sealing element is configured to engage with the first sealing element, and the first sealing element and the puncture element are withdrawn into the syringe barrel.

20. A kit for injecting an injectable drug into tissue, the kit comprises: A syringe barrel that defines the lumen between the proximal and distal ends; A first sealing element movably disposed within the lumen; A second sealing element movably disposed within the lumen proximal to the first sealing element, wherein the first sealing element and the second sealing element form a seal with the lumen and define an injection chamber between them; A puncture element extending from the distal end of the first sealing element, wherein the puncture element is in fluid communication with the injection chamber to deliver an injectable agent from the injection chamber into a space within the patient's tissue; A unidirectional stop disposed within the syringe barrel between the first sealing element and the second sealing element, wherein the unidirectional stop is During the pre-insertion of the puncture element into the tissue, it comes into contact with the first sealing element. To prevent the first sealing element from moving proximal to the unidirectional stop during the delivery of the injectable agent, and A unidirectional stop is configured to allow the second sealing element to pass through the unidirectional stop and come into contact with the first sealing element after the delivery of the injectable agent. An injection system comprising; and A predetermined volume of injectable fluid containing one or more injectable formulations. A kit that includes this.

21. The kit according to claim 20, wherein the injection system further comprises a lock located distal to the first sealing element and configured to selectively lock the first sealing element in a predetermined position.

22. The injection system further comprises a touch trigger mechanism between the first sealing element and the second sealing element, wherein the touch trigger mechanism is configured to deploy when the first sealing element comes into contact with the second sealing element to prevent distal movement of the first sealing element, according to claim 20.

23. The kit according to claim 20, wherein the injection system further comprises a filling port located on the surface of the syringe barrel and having fluid communication with the injection chamber.

24. The aforementioned filling port, A receiving portion positioned on the outer surface of the syringe barrel and configured to receive a vial; A flow path connecting the receiving portion and the injection chamber; A self-sealing member configured to seal the aforementioned flow path; and The puncture element is disposed within the receiving portion, and the puncture element is configured to penetrate the self-sealing member and to connect the vial received in the receiving portion to the injection chamber with fluid. The kit according to claim 23, comprising:

25. The kit according to claim 20, wherein the injection chamber comprises a first chamber and a second chamber, and a chamber sealing portion fluidly isolates the first chamber from the second chamber, and when the chamber sealing portion moves, the first chamber and the second chamber are connected by fluid.

26. The kit according to claim 20, wherein the injection chamber comprises a first chamber and a second chamber, the first chamber and the second chamber being fluidly isolated from each other when the chamber sealing portion is in its initial position, and the first chamber and the second chamber being fluidly connected when the chamber sealing portion moves.

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