EA046786B1 - MOTOR-EQUIPPED INJECTION SYSTEM AND METHOD OF ITS APPLICATION - Google Patents

Description

Related applications

The present invention claims benefit and priority to U.S. Provisional Application Serial No. 63/064,975, filed August 13, 2020, the contents of which are incorporated herein by reference in their entirety.

Technical field

The present invention relates to a system and method that allows injection into a cavity or void and, in particular, through tissue into a cavity or void in the human body, for example, into the suprachoroidal space in the tissue of the eye.

State of the art

The present invention relates to a device and method that allows for the delivery of a variety of therapeutic agents into a cavity or emptiness of the human body and, in particular, into ocular tissue in the posterior segment of the eye through the suprachoroidal space. Diseases of the posterior segment of the eye are a leading cause of irreversible visual impairment that affects millions of people and can lead to blindness if left untreated. They include a variety of diseases such as age-related macular degeneration (AMD), diabetic retinopathy, diabetic macular edema (DME), choroidermeia (CHM), retinal vein occlusion (RVO). ), uveitis and endophthalmitis. Although pharmaceutical agents may be available to prevent disease progression in many cases, systemic delivery does not provide therapeutic concentrations in the posterior segment of the eye due to the blood barrier in the eye.

Recently, research has been conducted into the suprachoroidal space (SCS) as a potential route for drug delivery to the back of the eye. The suprachoroidal space is the potential space between the sclera and the choroid. Medicine delivered into this space can travel around the eyeball to the posterior segment of the eye. This route of drug delivery has been shown to be more effective for treating the posterior segment of the eye than intravitreal injections. However, due to its simplicity, intravitreal injection is preferred over the surgical procedure previously used for suprachoroidal delivery. Traditionally, suprachoroidal delivery has been accomplished by creating a small incision using a scalpel, followed by delivery using a needle or cannula. Recently, a microneedle with a predetermined short length has been used to target the suprachoroidal space, which allows penetration only to a certain depth. Because scleral thickness varies significantly across patient populations, hollow microneedle injection requires either prior mapping of ocular geometric characteristics or trial and error. If the needle is too long, it can easily penetrate the thin suprachoroidal space to inject the drug into the vitreous; and if it is too short, it ensures delivery to the sclera. The sclera is 10 times stiffer than the choroid and 200 times stiffer than the retina, making it even more difficult to puncture the sclera without performing an intravitreal injection. In some cases, it is necessary to inject a small volume (on the order of 100 μl) of the therapeutic agent into the suprachoroidal space, and it must be injected with sufficient force to overcome the positive resistance of intraocular pressure pressing the choroid against the sclera in order to achieve wide coverage of the posterior segment of the eye. This may be difficult to achieve with a conventional manual syringe.

Accordingly, there is a need to develop an improved suprachoroidal drug delivery system and method that allows for precise, consistent, and safe targeting of the suprachoroidal space and provides broad coverage of the posterior segment of the eye.

The essence of the invention

In accordance with some aspects of the present invention, there is provided an injection system comprising an injection assembly comprising a syringe barrel defining a lumen between a proximal end and a distal end, and a second sealing element movably positioned within said lumen to dispense an injectable agent from an injection chamber formed in a syringe barrel, and a piercing element configured to deliver the injection agent to a space in the patient's tissue. Tissue is less permeable to the injecting agent than space. The injection system also includes a support platform configured to support the injection unit and secure the injection unit relative to the injection site, a drive unit configured to control the operation of the injection unit, one or more sensors configured to control one or more forces on the injection unit and a controller in communication with one or more sensors to receive information about one or more forces in the injection system. The controller is configured to control, based on said information, the operation of the drive unit to move the piercing element through the tissue towards the space so that the injection agent remains

- 1 046786 in the injection chamber until the piercing element connects the injection chamber to the fluid space.

In some embodiments, the injection assembly further includes a first sealing element movably positioned within said lumen distal to the second sealing element, wherein the first sealing element and the second sealing element form a seal with respect to the lumen and define an injection chamber therebetween . The piercing element is configured to be in fluid communication with the injection chamber to deliver the injection agent from the injection chamber to a space in the patient's tissue. When a force is applied to the second sealing element in the distal direction, in response to the first counter force, as the piercing element is advanced through the tissue, the first sealing element moves in the distal direction, advancing the piercing element in the distal direction, without transferring the injection agent through the piercing element, and in in response to the second counter force, when the injection chamber is fluidly coupled to the space, the first sealing element remains stationary and the injection agent is transferred from the injection chamber through the piercing element.

In some embodiments, the drive assembly is coupled to the second sealing element to apply a force to the second sealing element to progressively move the second element in a distal direction. In some embodiments, the drive assembly includes a linear actuator coupled to the second sealing element for applying a force to the second sealing element to progressively move the second element in a distal direction. In some embodiments, the drive assembly includes a first drive configured to translate the syringe barrel relative to the support platform, and a second drive coupled to the second sealing element to translate the second sealing element relative to the syringe barrel. The one or more sensors may include a first load cell configured to sense a force on the syringe barrel, and the one or more sensors may include a second load cell configured to sense a force on a second sealing member. In some embodiments, the one or more sensors comprise one or more of a pressure sensor, a force sensor, a strain sensor, a position sensor, or a flow sensor.

In some embodiments, the controller is programmed to implement one or more feedback loops to control the first reaction force and the second reaction force. In some embodiments, the controller is programmed to implement one or more feedback loops to monitor the pre-insertion of a piercing element into tissue, wherein the one or more feedback loops are configured to monitor an increase in force on the piercing element, detect a decrease in force on the piercing element, and, based on the specified reduction, ensuring the advancement of the piercing element at a predetermined distance for introducing the piercing element into the tissue. In some embodiments, the controller is programmed to implement one or more feedback loops to monitor the progress of the piercing element through the tissue, wherein the one or more feedback loops are configured to sense a load on the second sealing element and detect a reduction in load when the piercing element reaches a space in fabrics. In some embodiments, the controller is programmed to implement one or more feedback loops to control the introduction of an injection agent into the space, wherein the one or more feedback loops are configured to control the speed or distance of advancement of the second sealing element. In some embodiments, the controller is programmed to cause the piercing element to be retracted a predetermined distance when one or more sensors detect a decrease in load on the second sealing element. In some embodiments, the controller is programmed to control the distance to stop the piercing element when the piercing element enters the space.

In some embodiments, the tissue is the conjunctiva and the space is the subconjunctival space. In some embodiments, the tissue is sclera and the space is suprachoroidal space. In some embodiments, the tissue is sclera and choroid and the space is intravitreal space. In some embodiments, the tissue is the cornea and the space is the anterior chamber of the eye.

In some aspects, the present invention relates to an injection system that includes an injection unit comprising a syringe barrel defining a lumen between a proximal end and a distal end, a first sealing element, and a second sealing element movably positioned within said lumen. The second sealing element is placed distal to the first sealing element to form an injection chamber. The piercing element is connected via a fluid medium to the injection chamber and is made with

- 2 046786 the ability to deliver the injectable agent from the injection chamber into a space in the patient's tissue. Tissue is less permeable to the injecting agent than space. The injection system also includes a support platform configured to support the injection unit and secure the injection unit relative to the injection site, a drive unit configured to translate one or both of the syringe barrel or the second sealing element relative to the support platform, one or more sensors, configured to monitor one or more forces on the injection unit, and a controller in communication with one or more sensors to receive information about the one or more forces on the injection system. A controller in communication with one or more sensors receives information about one or more forces in the injection system and is configured, based on said information, to control a drive assembly to advance the piercing element through the tissue toward the space as the drive assembly progressively moves the second sealing element. element in the distal direction. In response to the first counter force when the piercing element is advanced through the tissue, the first sealing element moves in the distal direction, advancing the piercing element in the distal direction without transferring the injection agent through the piercing element, and in response to the second reaction force when the injection chamber is connected at fluid with space, the first sealing element remains stationary and the injection agent is transferred from the injection chamber through the piercing element.

In some embodiments, the drive assembly is configured to move the syringe barrel and the second sealing element independently of each other relative to the support platform. In some embodiments, the drive assembly is coupled to the second sealing element to apply a force to the second sealing element to progressively move the second element in a distal direction. In some embodiments, the drive assembly includes a linear actuator coupled to the second sealing element for applying a force to the second sealing element to progressively move the second element in a distal direction. In some embodiments, the drive assembly includes a first drive configured to translate the syringe barrel relative to the support platform, and a second drive coupled to the second sealing element to move the second sealing element relative to the syringe barrel.

In some embodiments, the one or more sensors include a first load cell configured to measure force on the syringe barrel. In some embodiments, the one or more sensors include a second load cell configured to measure force on the second sealing element. In some embodiments, the one or more sensors comprise one or more of a pressure sensor, a force sensor, a strain sensor, a position sensor, or a flow sensor.

In some embodiments, the controller is programmed to implement one or more feedback loops to control the first reaction force and the second reaction force. In some embodiments, the controller is programmed to implement one or more feedback loops to control the pre-insertion of the piercing element into the tissue. One or more feedback loops may be configured to monitor an increase in force on the piercing element, detect a decrease in force on the piercing element, and, based on the decrease, cause the piercing element to advance a predetermined distance to introduce the piercing element into tissue. In some embodiments, the controller is programmed to implement one or more feedback loops to monitor the progress of the piercing element through the tissue, wherein the one or more feedback loops are configured to sense a load on the second sealing element and detect a reduction in load when the piercing element reaches a space in fabrics. In some embodiments, the controller is programmed to implement one or more feedback loops to control the introduction of an injection agent into the space, wherein the one or more feedback loops are configured to control the speed or distance of advancement of the second sealing element. In some embodiments, the controller is programmed to cause the piercing element to be retracted a predetermined distance when one or more sensors detect a decrease in load on the second sealing element. In some embodiments, the controller is programmed to control the distance to stop the piercing element when the piercing element enters the space.

In some embodiments, the tissue is the conjunctiva and the space is the subconjunctival space. In some embodiments, the tissue is sclera and the space is suprachoroidal space. In some embodiments, the tissue is sclera and choroid and the space is intravitreal space. In some embodiments, the tissue is the cornea and the space is the anterior chamber of the eye.

- 3 046786

A method for delivering an injectable agent is proposed, which includes introducing a piercing element into the tissue. The piercing element may be configured to deliver the injectable agent from the injection chamber to a space in the tissue, the tissue having a greater density than the space such that the tissue is less permeable to the injectable agent than the space. The method also includes advancing, using a drive assembly, a piercing element through tissue toward a space, monitoring one or more forces on the piercing element using one or more sensors, and controlling, using a controller in communication with one or more sensors, the drive assembly to advancing the piercing element through the tissue toward the space such that the injection agent remains in the injection chamber until the piercing element fluidly connects the injection chamber to the space.

In some embodiments, the piercing element is located at the distal end of the injection assembly comprising a syringe barrel defining a lumen between the proximal end and the distal end, and first and second sealing elements movably positioned within said lumen to dispense the injectable agent from the injection chamber. In some embodiments, in response to a first counter force of one or more forces on the piercing element as it advances through tissue, the first sealing element moves in a distal direction, advancing the piercing element in the distal direction, without transferring the injectable agent through the piercing element. In some embodiments, in response to a second counter force of one or more forces on the piercing element, when the injection chamber is fluidly coupled to the space, the first sealing element remains stationary and the second sealing element moves in a distal direction such that the injectable agent is transferred from injection chamber through the piercing element into the space.

In some embodiments, the tissue is the conjunctiva and the space is the subconjunctival space. In some embodiments, the tissue is sclera and the space is suprachoroidal space. In some embodiments, the tissue is sclera and choroid and the space is intravitreal space. In some embodiments, the tissue is the cornea and the space is the anterior chamber of the eye.

A method of delivering an injectable agent is proposed, which involves placing an injection unit next to the tissue. The injection unit contains a syringe cylinder forming a lumen between the proximal end and the distal end, and a second sealing element placed with the ability to move inside the specified lumen with the possibility of dispensing an injection agent from the injection chamber formed in the syringe cylinder, and a piercing element passing with the possibility of delivering the injection agent. agent into the space in the tissue. The tissue has a greater density than the space, so that the tissue is less permeable to the injectable agent than the space. The method also includes monitoring one or more forces on the injection unit using one or more sensors and controlling the injection unit using forces in the injection system using a controller in communication with the one or more sensors to advance the piercing element through the tissue toward the space in such a way so that the injection agent remains in the injection chamber until the piercing element connects the injection chamber to the fluid space.

In some embodiments, in response to a first counter force of one or more forces on the piercing element as it advances through tissue, the first sealing element moves in a distal direction, advancing the piercing element in the distal direction, without transferring the injectable agent through the piercing element. In some embodiments, in response to a second counter force of one or more forces on the piercing element, when the injection chamber is fluidly coupled to the space, the first sealing element remains stationary and the second sealing element moves in a distal direction such that the injectable agent is transferred from injection chamber through the piercing element into the space. In some embodiments, the method further includes securing the injection unit relative to the injection site in the tissue.

In some embodiments, the tissue is the conjunctiva and the space is the subconjunctival space. In some embodiments, the tissue is sclera and the space is suprachoroidal space. In some embodiments, the tissue is sclera and choroid and the space is intravitreal space. In some embodiments, the tissue is the cornea and the space is the anterior chamber of the eye.

List of drawings

The present invention is further described in the following detailed description with reference to the specified number of drawings using non-limiting and non-limiting

- 4 046786 example embodiments in which like reference numerals represent like parts in several views in the drawings and in which:

in fig. 1A is an exemplary time (or displacement) versus force graph showing the forces experienced by a motorized injection system when injecting a therapeutic agent into tissue;

in fig. 1B is an exemplary piston position versus force graph showing the forces experienced by a motorized injection system when injecting a therapeutic agent into tissue;

in fig. 2 shows an exemplary embodiment of a motorized injection system;

in fig. 3A and 3B show an exemplary embodiment of a drive assembly for a syringe barrel and a syringe plunger;

in fig. 4 shows an exemplary embodiment of means for attaching and stabilizing a motorized injection system at an injection site;

in fig. 5A shows an exemplary embodiment of the injection system;

in fig. 5B depicts an exemplary method of using the embodiment of the injection system of FIG. 5A;

in fig. 6A, 6B, 6C and 6D depict an embodiment of a motorized injection system with an automatic syringe stop function;

in fig. 7A and 7B are block diagrams illustrating the application of the system shown in FIG. 6A-6D;

in fig. 8A, 8B, 8C, 8D and 8E illustrate an embodiment of a motorized injection system with an automatic syringe stop function;

in fig. 9A and 9B are block diagrams illustrating the application of the system shown in FIG. 8A-8E;

in fig. 10A, 10B, 10C, 10D and 10E illustrate an embodiment of a motorized injection system with an automatic syringe stop function;

in fig. 11A and 11B are block diagrams illustrating the application of the system shown in FIG. 10A-10E;

in fig. 12 illustrates an embodiment of an injection system according to the present invention having a quick fill port;

in fig. 13A,B and 14A,B illustrate an example of a process for filling an injection system according to the present invention through a quick fill port;

in fig. 15A, B show an example of the filling process of the injection system according to the present invention;

in fig. 16A, B illustrates an example of a process for filling an injection system according to the present invention through a port at the proximal end;

in fig. 17A-17C illustrate an example of a process for filling an injection system according to the present invention through a port sealed with a self-sealing polymer;

in fig. 18A-18D depict embodiments of an injection system according to the present invention having a port at the distal end; and in fig. 19 depicts an exemplary embodiment of a computing system for use with various embodiments of the present invention.

Although the above drawings show the disclosed embodiments, other embodiments are also possible, as noted in the discussion. In the present invention, embodiments are given by way of example and not limitation. Numerous other modifications and embodiments may be proposed by those skilled in the art without departing from the scope and spirit of the embodiments disclosed herein.

Information confirming the possibility of implementing the invention

The present invention provides a motorized injection system for delivering a therapeutic agent to a potential space or cavity in tissue. In some embodiments, such systems can be used to deliver a drug into the suprachoroidal space. In some embodiments, such systems are automated and consist of sensors and feedback loops. Thus, the systems of the present invention can be designed to accurately, consistently and safely target the suprachoroidal space and provide broad coverage of the posterior segment of the eye.

In some embodiments, the injection system includes a syringe barrel for holding one or more injectable agents, a penetrating element (also called a needle, but similar devices can be used) attached to the syringe barrel for fluid communication with the syringe barrel, and a sealing element (also called a pusher plunger) to force the injecting agent from the syringe barrel through the needle. As described in more detail below, the injection system may include a conventional syringe or a syringe with

- 5 046786 automatic stop function with multiple sealing elements, as described in more detail below.

In fig. 1A and 1B depict the forces experienced by a motorized injection system when introducing a therapeutic agent into a tissue cavity through a piercing member or piercing element (interchangeably referred to as a needle, but a similar device may also be used). In stage I, the needle is first inserted into the tissue (for example, the sclera of the eye). With reference to FIG. 1A, during pre-injection of the needle into the tissue (moving the injection system towards the tissue), a load sensor attached to the injection system detects a force increasing until the needle pierces the tissue. When the tissue is pierced, the load can be reduced. With reference to FIG. 1B, which shows the applied load after completion of stage I, after completion of administration, increased pressure may be applied to the contents of the injection system by advancing the push plunger. At this stage, the load on the plunger may remain constant as the plunger advances until the pressure in the syringe barrel begins to increase. Then, in stage II, the needle is advanced through the tissue towards a cavity (eg, the suprachoroidal space of the eye). At this stage, due to the low water permeability of the fabric, the contents of the injection system remain under pressure. The load on the injection system increases and may correspond to the horizontal section of the graph. At stage III-a, the tip of the needle enters a cavity (for example, the suprachoroidal space of the eye). Because the density of the cavity is less than the density of the tissue, the cavity exerts less back pressure on the needle compared to the tissue. Accordingly, as soon as the needle lumen opens into the cavity, the load on the plunger drops due to a decrease in back pressure. This drop in backpressure indicates that the needle lumen is in the cavity, and further advancement of the needle deeper into the cavity can be prevented (either by the present system or by an automatic adjustment design, as discussed below). In some embodiments, the therapeutic agent may be under pressure that is not sufficient to force the therapeutic agent into the tissue, but sufficient to force the therapeutic agent into the lumen. Accordingly, the pressure of the pressurized therapeutic agent decreases as soon as the lumen of the needle opens into the cavity and the needle ceases to move forward as a result of the application of force to the pushing plunger. In stage III-b, the therapeutic agent is introduced into the cavity at a selected rate while force is applied to the needle plunger. The force required to administer the therapeutic agent may depend on the density and viscosity of the therapeutic agent, the frictional or sliding force between the plunger and the drug chamber, the internal diameter of the drug chamber, the length of the needle, and the internal diameter of the needle. In some embodiments, when the needle reaches the cavity, the system may continue to advance the push plunger to continuously introduce the therapeutic agent into the cavity. In some embodiments, the pushing plunger may stop once the needle lumen reaches the cavity and then advance again to introduce the therapeutic agent into the cavity.

With reference to FIG. 2, a motorized injection system 10 according to the present invention includes a housing or support platform 12 that supports the injection system 14, a drive assembly or drive mechanism 16, and one or more sensors for measuring load on the injection system or components thereof. The support platform 12 is configured to secure the automatic injection system in a fixed position relative to the injection site. In some embodiments, the motorized injection system 10 may further include a controller in communication with the drive assembly or one or more sensors to control the injection process. In some embodiments, the controller may be configured to control the speed and force of the injection. In some embodiments, the controller may be configured to provide a feedback mechanism to the user. In some embodiments, the controller may be configured to initiate movement of the syringe, the push plunger, or both in response to feedback from the load cell or load sensors, alone or in combination with recording the distances traveled by the push plunger, the syringe, or the differential movement of one relative to another.

In some embodiments, the injection system may include a syringe comprising a syringe barrel defining a drug chamber for storing a therapeutic agent, a needle 15 in fluid communication with the drug chamber for administering the therapeutic agent from the drug chamber, and a plunger 11 slidably located within the barrel of the syringe and configured to expel the therapeutic agent from the drug chamber through the needle 15.

In some embodiments, a standard syringe may be used such that the drug chamber may have a volume of from about 0.1 to 20 mL, but larger or smaller syringes may also be used. In some embodiments, the drug chamber may have a volume of approximately 0.1, 0.5, 1, 3, 5, or 10 mL before expulsion

- 6 046786 fluid.

In some embodiments, the needle may be a standard 34G to 25G needle. In some embodiments, the needle may be a standard 30G needle. Needles of various sizes can be used to deliver the therapeutic agent into the suprachoroidal space, as discussed above. In some embodiments, particularly for compositions with higher viscosities, such as greater than 10 centipoise, needles with larger lumens may be used. The need for a pre-injection step required to block fluid flow may limit the range of needle bore diameters and bevel sizes that can be effectively used to target the suprachoroidal space. In some embodiments, based on the minimum thickness of the human sclera, optimal results may be obtained by limiting the pre-insertion depth to about 0.5 millimeters (e.g., about 0.05 mm to 0.5 mm) or less if the needle is inserted perpendicularly surface of the sclera. When inserting at an angle other than straight, it may be sufficient to insert a needle with a longer bevel without piercing the sclera. For example, based on geometric correlation, a 30-gauge needle with a standard bevel (angle: 12 degrees, length: 1.45 mm) inserted at an angle of approximately 20° to the surface or less will achieve a depth of less than 0.5 millimeter when measured at right angles to the surface. Likewise, larger needles with longer bevel lengths can be used. Shorter bevels provide a greater range of pre-injection angles for a given needle size. Generally speaking, needles with an outer diameter that is smaller than the thickness of the sclera (approximately 0.5 mm) are convenient to use to access the suprachoroidal space, and the angle of needle insertion is determined based on the length of the beveled tip. In some embodiments, the drug chamber volume is between 20 and 200 microliters. To enhance tactile sensation and signal-to-noise ratio for the distance sensing elements, in some embodiments, the stroke length of the push plunger for delivering the therapeutic fluid or suspension is at least 1 centimeter in length. For some embodiments, the injection flow rate will average between 0.2 and 20 microliters per second. In some embodiments, the syringe barrel is coated with silicone oil, silicone rubber, rubber, glass, polytetrafluoroethylene, or polypropylene to minimize adsorption of the therapeutic agent to the interior surface of the syringe barrel.

In some embodiments, varying the friction between the syringe barrel and the plunger may allow system performance to be optimized. For example, the system may be sized such that the coefficients of static and kinetic friction are approximately equal to eliminate the possibility of unintentional acceleration of the needle. On the other hand, the coefficient of static friction may be higher than the coefficient of kinetic friction, so that after the needle stops in the cavity, it must overcome a high force barrier. The high static friction of the needle plunger also allows for high fluid flow during injection while maintaining needle tip position. In some embodiments, the kinetic friction of the needle plunger is high enough to stop the needle from moving once the lumen opens into the cavity. However, the kinetic coefficient can still be limited so that the internal pressure within the syringe barrel is not so high as to cause tissue destruction or damage.

With reference to FIG. 3A and 3B, in some embodiments, the drive assembly is configured to independently control the syringe barrel (eg, to pre-inject a needle into tissue) and the syringe plunger. The drive unit is configured to move the syringe barrel relative to the support platform 12 towards the patient for preliminary insertion of the needle into the tissue, and then away from the patient to remove the needle from the tissue. The drive assembly also applies force to the plunger to translate the plunger within the barrel of the syringe to advance the needle through the tissue toward the cavity and to dispense the therapeutic agent from the drug chamber. In some embodiments, the drive assembly may include separate drives for the syringe barrel and plunger. In some embodiments, each such actuator may include a linear actuator coupled to the syringe barrel or plunger and a load cell for measuring the load on the syringe barrel or plunger. As shown in FIG. 3A, B, the drive mechanism 20, 22 may include a motor 24, 26, respectively, configured to cause movement of the drive mechanisms 20, 22, for example, through a lead screw 25, 27 and an actuator 32, 34. Each of the drive mechanisms 20, 22 may also include at least one load sensor 28, 30 configured to sense a load on the syringe barrel or syringe plunger, respectively. In some embodiments, this design allows the system to advance the syringe barrel without advancing the plunger while simultaneously measuring force. For example, as the barrel of a syringe moves, the pushing plunger may move with it. When pre-inserting the needle on the syringe barrel, the force is measured. After before

- 7 046786 boiling introduction measure the force on the pushing plunger. During pre-insertion, when a force is detected indicating needle-tissue contact, the needle moves forward a set distance with the needle lumen entering the tissue.

In some embodiments, the linear actuator may be a mechanical actuator comprising, for example, a lead screw and a nut or gear driven by an electric motor, but other designs may be used. In some embodiments, pneumatic, hydraulic, electromechanical, magnetic, or other types of linear actuators may also be used. In some embodiments, a single actuator may be used to drive both the syringe barrel and the plunger. Different movements of the syringe barrel and plunger can be achieved by engaging/disengaging the gear mechanism. In some embodiments, linear movement of the push plunger may be provided by hydraulic pressure.

With reference to FIG. 4, the motorized injection system of the present invention may also include means for attaching and stabilizing the system relative to the injection site. In this way, the user's hands can be free while maintaining a fixed x-y location for injection when the syringe barrel is held in place by the attachment and stabilization system. In other cases, the syringe barrel is fixed only in the x-y plane and the syringe can be moved by the user in the z plane towards or away from the eye to perform the injection. In some embodiments, for injection into the suprachoroidal space, the motorized injection system may include an adjustable headband 200 that can be adjusted to size using a ratchet or other mechanism, such as the ratcheting size adjuster 202 shown in FIG. 4. In some embodiments, the system can be installed on other parts of the patient's face, such as the eye sockets, temples, jaws, ears, nose, etc. In some embodiments, the motorized injection system may be attached to a stationary bracket that may be pressed against the patient's face (similar to an ophthalmic examination). Additionally or alternatively, the motorized injection system of the present invention may include a guide support 204, such as a tripod, biped, or monopod, that is either attached to the headband of the motorized injection system 10 or to both the headband and the motorized injection system. 10 to ensure stability of the injection system relative to the eye. In some embodiments, the motorized injection system of the present invention may further include a contact pad that can be pressed against the tissue into which the therapeutic agent is being injected to stabilize the injection site or adjust the angle of injection. In some embodiments, the stabilizing tripod mentioned above may be used to hold the eye in place. For example, for ocular injections, such a pad may be sized and shaped to prevent circular movements of the eyeballs when the user presses on the sclera (controlled relative injection angle). In some embodiments, the component used to prevent significant rotation of the eye may be an independent device that is not attached to the motorized injection system.

Sensors and feedback loops.

In some embodiments, the motorized system of the present invention includes a plurality of sensors configured to measure one or more parameters throughout the injection process. The one or more sensors may communicate with the controller to implement one or more feedback loops to control various stages of the injection process. Sensors or other mechanisms of various types may be used to control the injection steps, including, but not limited to, strain gauges or load sensors, such as pressure sensors, strain sensors, and/or force sensors, as will be discussed in more detail below.

In some embodiments, the load that the drive assembly applies to the syringe barrel and push plunger may be measured and reported to the controller. In some embodiments, the load may be measured using one or more load cells. Such load cells may be incorporated into the needle, the needle plunger, the push plunger, or both, or otherwise configured to receive a signal from them. In some embodiments, such load may be measured by the torque on the motor based on its correlation with the current drawn by the motor. In some embodiments, the motorized injection system may further include one or more sensors for monitoring the position or movement of the injection system as a whole, or the syringe barrel or plunger individually. Such information may be used, for example, to determine the distance traveled by an injection system, a syringe barrel or plunger, a needle plunger, a combination thereof, or individually. In some embodiments, a motorized system

- 8 046786 the topic may include one or more sensors for monitoring the position or speed at which the syringe barrel or plunger moves, in combination or separately. For example, such information may be used to control the flow of a therapeutic agent or to prevent a push plunger from exceeding the required injection volume. In some embodiments, the flow rate may be monitored using a high precision flow sensor including microfluidic mass flow sensors.

In some embodiments, the system of the present invention is also configured to sense the pressure in the syringe. In some embodiments, the pressure may be measured indirectly by monitoring the load on the plunger. In some embodiments, the system may be designed such that the coefficients of kinetic and static friction between the plunger and the syringe barrel are close to 1 to more accurately determine fluid pressure. In some embodiments, the motorized injection system may further include one or more pressure sensors, force sensors, or strain sensors to directly measure the pressure of the therapeutic agent in the drug chamber.

In some embodiments, the relative position of the push plunger relative to the needle plunger in the case of an auto-stop syringe is monitored, or relative to the needle tip in the case of a standard syringe, to determine the volume of therapeutic agent drawn into the syringe or injected into the cavity. In some embodiments, the movement distance measured after pre-insertion may have limits set to minimize the likelihood of movement beyond a predetermined position.

In some embodiments, one or more feedback loops may be implemented based on load sharing in stages I-III-a (as discussed above with respect to FIGS. 1A,B). In some embodiments, the feedback loop is configured to monitor the axial load on the system during stage I pre-insertion of the needle into the tissue. In some embodiments, the load sensor may be configured to measure, directly or indirectly, the axial load applied to the needle. During pre-insertion, the axial load on the needle increases as the needle is inserted into the tissue and decreases as the needle pierces the tissue. Accordingly, in some embodiments, the feedback loop is configured to monitor the load on the needle to control pre-insertion and determine when the needle enters the tissue. In some embodiments, the feedback loop may be configured to regulate the pressure of the therapeutic agent in the drug chamber after insertion of the needle into the tissue. In some embodiments, the load on the plunger and/or the distance traveled by the plunger can be monitored to determine when the pressure of the therapeutic agent reaches a desired value. In some embodiments, the feedback loop is configured to control the movement of the needle through the tissue toward the cavity during stage II and stage IIIa. In some embodiments, the pressure of the therapeutic agent in the syringe barrel can be monitored, for example, by measuring the load on the push plunger. In some embodiments, the applied load may be sinusoidal at a high frequency and the response curve may be measured using an internal pressure sensor. The needle can be advanced through the tissue until the plunger load or therapeutic agent pressure decreases, indicating that the needle has reached the cavity, the lumen of the needle is in fluid communication with the cavity and the therapeutic agent can be delivered into the cavity. cavity. In some embodiments, a feedback loop may be provided to control the introduction of the therapeutic agent into the cavity in step III-b. In some embodiments, such a feedback loop is configured to control the flow of the therapeutic agent, for example, control the speed of movement of the plunger or the pressure of the therapeutic agent. In some embodiments, the feedback loop is configured to control the distance traveled by the plunger (relative to the required injection volume). In some embodiments, the load on the plunger can be controlled as the plunger moves through the syringe barrel. When the plunger reaches the end of the barrel or some other stop that prevents any further distal movement of the plunger, the load on the plunger begins to increase as the drive mechanism continues to apply force to the plunger in the distal direction. This increase in plunger load at the end of stage III-b indicates that insertion has been completed and the needle can be removed from the patient.

Various embodiments of the present invention may include one or more of the feedback loops discussed above, depending on the design of the system or the level of control required by the user, among other factors.

Syringe design.

In some embodiments, in a motorized injection system according to

- 9 046786 The present invention can be used with a conventional syringe. Such a syringe may include a syringe barrel for holding one or more injectable agents, a needle attached to the syringe barrel and in fluid communication with the barrel, and a plunger for displacing the injectable agent from the syringe barrel through the needle.

In some embodiments, an adjustable injection system (also called an auto-stop injection system) may be used that automatically adjusts the depth of penetration of the needle into the tissue/cavity. With reference to FIG. 5A, the auto-stop syringe 300 may include a syringe barrel 302 having a proximal end 302p and a distal end 302d, a push plunger 304 movably positioned in the syringe barrel 302 and forming a seal with the syringe barrel, a needle plunger 306 located in a syringe barrel movable distally relative to the pushing plunger such that a chamber for the drug is formed in the syringe barrel between the pushing plunger and the needle plunger. In some embodiments, a needle plunger seat 310 may be provided to control proximal movement of the needle plunger, and in some embodiments, the push plunger may be configured to move past the needle plunger seat.

The movable needle 308 is supported by the needle plunger such that as the needle plunger moves, the needle can also move, the needle being in fluid communication with the drug chamber for the purpose of delivering the therapeutic agent from the drug chamber to the patient. The needle may be coupled to the needle plunger using a variety of methods. In some embodiments, the needle is inserted into a rubber plunger and secured with a water-resistant adhesive. In some embodiments, the plunger may be molded around the needle. In some embodiments, a needle with threads on the outer surface may be screwed into the plunger.

Fig. 5B further illustrates the operation of a syringe with an auto-stop function (drive mechanism/support assembly not shown). In stage I, the needle is first inserted into the tissue (for example, the sclera of the eye). In some embodiments, the needle may be inserted tangentially to the sclera such that the tip of the needle is directed toward the posterior segment of the eye. Then, in stage II, a force is applied to the push plunger, which pushes the needle plunger forward to push the needle deeper through the tissue toward a cavity (eg, the suprachoroidal space of the eye). At stage III-a, the tip of the needle enters the cavity and as soon as the lumen of the needle opens into the cavity, the needle plunger automatically stops and, thus, the depth of penetration of the needle into the cavity is limited. The precision and miniaturization of the auto-stop syringe allows for precise targeting of the needle plunger and stopping it in a thin potential cavity such as the suprachoroidal space. In Stage III-B, as the operator continues to press the push plunger, the therapeutic agent in the drug chamber is delivered into the cavity and the needle is held in its position at the interface between the tissue and the cavity. In some embodiments, the fluid flow vector is ensured to be parallel to the suprachoroidal space to provide wide coverage of the posterior segment of the eye, rather than using fluid force to displace the choroidal and retinal tissues radially.

An exemplary auto-stop syringe configured to deliver therapeutic agents into the suprachoroidal space is disclosed in US Application No. 16/469,567, filed June 13, 2019, and PCT Application PCT/US2020/051702, filed September 20, 2020, all of which are fully incorporated incorporated into this document by reference. In some embodiments, design variables such as syringe geometry, needle geometry, flow rate, viscosity, and friction forces are interrelated and can be designed as discussed in Chitnis, G.D., Verma, M.K.S., Lamazouade, J. et al. A resistance-sensing mechanical injector for the precise delivery of liquids to target tissue. Nat Biomed Eng 3, 621-631 (2019), which is incorporated herein in its entirety. In some embodiments, insertion force may be considered when selecting various design variables. As a result, the system is capable of delivering drugs and gene therapeutics that preferentially localize to the suprachoroidal space, including agents intended to treat choroidal and retinal diseases and disorders. It should be noted that although the direct administration system is described in the present invention in connection with the delivery of a drug to the suprachoroidal cavity, the systems and methods disclosed herein can be used to deliver therapeutic agents to other cavities or cavities of the human body.

In some embodiments, the auto-stop syringe is pre-filled with a therapeutic agent. In some embodiments, the therapeutic agent is contained in one or more vials that are connected through a quick-fill port to a syringe barrel (for example, as described in co-pending application PCT/US2020/051702, filed September 20, 2020, incorporated herein in its entirety document

- 10 046786 by reference), in which any valves that were previously manually operated during filling during operation can then be actuated by a motor or solenoid valve during filling.

Operating a motorized injection system.

Depending on whether the filling process is automated, the motorized injection system may be attached to the patient's head and/or eye before or after filling with the therapeutic agent. In some embodiments, the adjustable headband may be secured around the patient's head. In some embodiments, the distal end of the motorized injection system may be attached to external landmark areas around the eye orbit.

The position of the motorized injection system can be adjusted to achieve the desired angle of needle insertion, which will depend on the bevel, to introduce the lumen into the tissue. Once the motorized injection system is in place, the tip of the needle may be placed close to the scleral surface, for example, up to about 2 centimeters, up to about 1 centimeter, or up to about 0.5 centimeters from the scleral surface. In some embodiments, such distance may be from about 0.1 cm to about 2 cm, from about 0.1 cm to about 1 cm, or from about 0.1 cm to about 0.5 cm. In some embodiments, to facilitate initial An acoustic or laser rangefinder can be used to position the needle tip. The user then signals via a button or touch screen to begin the injection process.

Motorized syringe drives for syringes with automatic stop function

As a non-limiting example, the use of a motorized injection system with an auto-stop syringe is described with reference to FIG. 6A6D and fig. 7A, B.

With reference to FIG. 6A, once the user initiates the injection process, the auto-stop syringe is advanced toward the ocular surface. In some embodiments, to achieve this, the syringe barrel 102 and push plunger 112 move synchronously at the same speed toward the eye until the load sensor detects that the needle 116 has been inserted into the sclera. During advancement of a syringe with an automatic stop function, the load on the syringe barrel, needle guide or needle is detected, for example, using a load sensor or a force sensor. In some embodiments, this promotion may be performed manually. Once the tip of the needle reaches the sclera, the load will increase with the contact force. In some embodiments, the load measured at this stage is the axial load experienced by the needle. The load continues to increase until the needle pierces the sclera, after which the load is reduced. Once the load is reduced, indicating scleral puncture, the auto-stop syringe and floating needle will advance until the needle lumen is completely inserted into the sclera. In some embodiments, the system may perform a fixed needle advance to determine when the needle lumen is fully inserted after detecting a scleral break. In some embodiments, full insertion may be detected by slightly advancing the push plunger to determine whether pressure buildup or leakage occurs.

Once the needle is inserted into the sclera, the movement of the syringe barrel stops and the pushing plunger is advanced into the syringe barrel to create pressure in the contents of the syringe barrel. In some embodiments, the push plunger is advanced a predetermined or user-defined distance, or until a preset or user-defined load is reached on a load sensor attached to the push plunger or its attachment, indicating that the needle lumen is fully inserted into sclera In some embodiments, this step is skipped.

In some embodiments, an optional elastomeric contact pad 320 may be used to prevent circular movements of the eyeballs, pressed against the sclera by a device operator, such as a physician. This allows you to control the relative angle of insertion.

With reference to FIG. 6B, when the needle is pre-inserted into the sclera, the syringe barrel 102 is locked in place and the push plunger 112 is advanced to push the tip of the needle through the sclera. Pressure is maintained inside the syringe barrel while the needle is advanced through the sclera due to the low permeability of the sclera, resulting in fluid being trapped inside the syringe with an auto-stop feature. The therapeutic agent cannot be injected into the sclera due to the back pressure created by the dense scleral tissue. Instead, advancement of the push plunger also results in advancement of the needle plunger and needle toward the suprachoroidal space. The syringe barrel holder stops and the plunger continues to move, causing the second plunger (ie, the needle plunger) to move toward the suprachoroidal space.

With reference to FIG. 6C, when the needle 116 reaches the suprachoroidal space, the pressure is

- 11 046786 the amount of medium inside the syringe barrel decreases, which can be determined using a load sensor or a pusher plunger pressure sensor. In some embodiments, detecting the relative movement of the push plunger approaching the needle plunger may also or alternatively be used to determine when the cavity will be reached. By reducing the back pressure created by the suprachoroidal space compared to the back pressure created by the sclera, the needle stops advancing and the therapeutic agent is pushed through the needle into the suprachoroidal space. The pushing plunger 112 continues to advance at a predetermined or user-specified speed and/or a predetermined distance or user-specified distance to deliver a fixed volume of liquid therapeutic agent into the suprachoroidal space.

With reference to FIG. 6D, when the push plunger 112 moves a predetermined or user-defined distance corresponding to the required injection volume, or the push plunger senses an increase in load corresponding to reaching the needle plunger, the push plunger mount will stop moving forward. In some embodiments, the amount of such increased load may be set based on the static friction of the needle plunger such that the pushing plunger cannot advance the needle plunger.

Once the therapeutic agent has been delivered to the suprachoroidal space, the user can remove the syringe needle from the eye. In some embodiments, the syringe may be removed manually. In some embodiments, the entire auto-stop syringe is retracted away from the eye until the needle is no longer in contact with the sclera. This can be achieved by returning the auto-stop syringe to its original position or by returning it to at least the point at which the needle tip initially detected an increase in load corresponding to contact with the scleral surface.

In some embodiments, one or more feedback loops may be used to monitor the operation of the auto-stop syringe. In some embodiments, the first feedback loop may control pre-insertion of the needle into the sclera. For example, during insertion of a needle into the sclera (moving a full syringe toward the eye), a load sensor attached to the needle or syringe barrel may sense an increase in force until the needle pierces the sclera. When piercing, the load is reduced, and then the needle moves further a given distance until the lumen of the needle is inserted into the sclera, and then until the full syringe stops moving.

In some embodiments, a second feedback loop may be provided to control the advancement of the needle through the sclera. For example, after pre-insertion of the needle is completed, the syringe barrel is locked in place and the push plunger is advanced, and the load on the push plunger is measured. The load on the pusher plunger increases and may correspond to the horizontal portion of the graph as the needle advances through the sclera. The load is reduced as soon as the needle lumen reaches the suprachoroidal space.

In some embodiments, a third feedback loop may be provided to control delivery of the therapeutic agent into the suprachoroidal space. For example, the push plunger may advance at a predetermined speed until a certain distance has been traveled (corresponding to the required injection volume) or until the push plunger reaches the needle plunger to avoid moving the needle beyond a predetermined position.

As described in more detail in FIG. 7A, B, the method of delivering a therapeutic agent to the eye may begin with installation of a fixation device at step 400. At step 402, a syringe containing the therapeutic agent may be loaded into a motorized injector. At step 404, a motorized injector containing a syringe may be loaded into a locking mechanism coupled to the patient (the needle is not in contact with the sclera). At step 406, the user may press a button or operate another mechanism to initiate the injection. At step 408, the entire syringe may be moved forward to engage the needle with the sclera. At step 410, if the syringe load sensor indicates an increase in load, the syringe is moved forward a predetermined distance to pre-inject the needle and block the needle lumen with the sclera (step 412). If the syringe load sensor does not indicate an increase in load, then the syringe continues to move forward (step 408) until the load increases.

When the syringe barrel load sensor indicates an increase in load, the position of the syringe barrel is fixed and the push plunger moves forward relative to the syringe at step 414. At step 416, if the push plunger load sensor indicates a load greater than the force required to insert into the suprachoroidal space, then the push plunger moves forward relative to the syringe (step 414). If the push plunger load sensor does not indicate a load greater than the force for insertion into the suprachoroidal space, then at step 418 the push plunger may continue to be pushed forward. If the load is similar to the force required to insert into the suprachoroidal space, or if a decrease in internal pressure is detected, the position of the pushing plunger should be monitored to control the distance

- 12 046786 which moves the pushing plunger, which can be used, for example, to prevent the pushing plunger from colliding with the needle plunger or to control the amount of injection agent delivered into the suprachoroidal space.

At step 420, if the forward movement of the push plunger maintains the force measured by the push plunger load sensor, then based on the position of the push plunger, it is determined whether a predetermined amount of therapeutic agent has been delivered (step 422). If not, the system continues to push the push plunger forward (step 418). If so, the system stops pushing the push plunger forward (step 426). If the force measured by the push plunger load sensor is not maintained as the push plunger moves forward (step 420), then at step 424, if the load increases significantly, this indicates that all of the therapeutic agent has been delivered and the push plunger is at the end of the injection chamber. The system then stops moving the push plunger forward (step 426).

Motorized syringe drives for standard syringes.

By way of non-limiting example, the use of a motorized injection system with an auto-stop syringe is described with reference to FIG. 8A-8E and figs. 9A, B.

With reference to FIG. 8A, after the user initiates the injection process, the entire syringe is advanced toward the surface of the eye, moving the syringe barrel 502 and push plunger 504 at approximately the same speed until the load sensor detects the needle being inserted into the sclera. As the syringe advances, a load sensor that contacts the syringe barrel or needle 508 senses the load. Once the tip of the needle reaches the sclera, the load will increase with the contact force. The load will increase until the needle pierces the sclera, after which the load will decrease. Once the load is reduced, indicating scleral puncture, the syringe and needle will be advanced until the needle lumen is completely inserted into the sclera.

With reference to FIG. 8B, when the needle is inserted into the sclera, the syringe barrel 502 is held in place and remains stationary while the syringe plunger is advanced a predetermined or user-defined distance or until a preset or user-defined load on the load cell is reached, attached to the pusher plunger or its mounting. This movement of the plunger results in an increase in the pressure of the therapeutic agent, which is recorded as a load on the syringe plunger.

With reference to FIG. 8C, the full syringe is then advanced into the sclera using a motorized syringe drive to propel the tip of the needle 508 through the sclera. The pressure in the syringe barrel is maintained while the needle blocks the exit of the fluid, and the syringe is advanced through the sclera due to the low permeability of the sclera, causing the fluid to remain inside the syringe until the lumen of the needle reaches the suprachoroidal space.

With reference to FIG. 8D, when the lumen of the needle 508 reaches the suprachoroidal space, the fluid pressure (ie, the load) on the push plunger is reduced because the lumen is no longer blocked and the fluid can flow out, which is detected by the load against which the syringe plunger is controlled. When a drop in load on the syringe plunger is detected, the syringe barrel stops in place. The push plunger is then advanced at a predetermined or user-defined speed to deliver the therapeutic agent into the suprachoroidal space.

With reference to FIG. 8E, when the push plunger 504 moves a predetermined or user-defined distance corresponding to the required injection volume or the entire payload, or the push plunger detects an increased load corresponding to reaching the end of the syringe barrel, the push plunger attachment stops moving forward. Delivery of the entire payload can be detected using a load sensor based on the increase in force as the plunger interacts with the distal end of the syringe when the syringe is emptied.

Once the therapeutic agent has been delivered to the suprachoroidal space, the user can remove the syringe needle from the eye. In some embodiments, the syringe may be removed manually. In some embodiments, the entire syringe is retracted away from the eye until the needle is no longer in contact with the sclera. This can be achieved by returning the syringe to its original position or by returning it to at least the point at which the increase in load corresponding to contact with the scleral surface was initially determined using the needle tip.

In some embodiments, one or more feedback loops may be used to monitor the operation of the auto-stop syringe. In some embodiments, a first feedback loop may be provided to control insertion of the needle into the sclera. For example, when a needle is pre-inserted into the sclera (moving the entire syringe toward the eye), a load sensor attached to the needle or syringe barrel detects an increase in force until the needle pierces the sclera, but then a decrease in load occurs. Once a drop is detected, the needle can be advanced a predetermined distance until the needle lumen is inserted into the sclera, at which point the syringe barrel is stopped. In some embodiments, the implementation may be provided

- 13 046786 swarm feedback loop to create pressure in the contents of the syringe barrel. For example, when pre-administration is completed, the syringe barrel is locked in place and the push plunger is advanced, with the plunger load or therapeutic agent pressure being measured until a predetermined load, distance or pressure is achieved to produce therapeutic agent pressure. In some embodiments, a third feedback loop is provided to control the load on the needle as it advances through the sclera. In some embodiments, the load on the needle can be controlled indirectly. For example, when the contents of the syringe are under pressure, the entire syringe will advance until the force on the pushing plunger is relieved, indicating that the lumen of the syringe has reached the suprachoroidal space. In some embodiments, when the needle is secured to the tip of the syringe, the load on the syringe can be monitored as the load indicates the load on the needle. In some embodiments, once the cavity is reached, a fourth feedback loop may be used to deliver the therapeutic agent to the suprachoroidal space. For example, when a needle enters the suprachoroidal space, the plunger is advanced at a predetermined speed until a certain distance has been traveled (corresponding to the required injection volume) or until the pushing plunger reaches the needle plunger to avoid moving the needle beyond the predetermined position.

As described in more detail in FIG. 9A, B, implementation of the method of delivering a therapeutic agent to the eye may begin with the installation of a fixation device at step 600. At step 602, a syringe containing the therapeutic agent may be loaded into a motorized injector. At step 604, a motorized injector containing a syringe may be loaded into a locking mechanism coupled to the patient (the needle is not in contact with the sclera). At step 606, the user may press a button or operate another mechanism to initiate the injection. At step 608, the entire syringe may be moved forward to engage the needle with the sclera. At step 610, if the syringe load sensor indicates an increase in load, the syringe is moved forward a predetermined distance to pre-inject the needle and block the needle lumen with the sclera (step 612). If the syringe load sensor does not indicate an increase in load, then the syringe continues to move forward (step 608) until the load increases.

At step 614, the push plunger is pushed to create a known amount of pressure in the internal fluid, and at step 616, both the syringe and push plunger are moved to move the entire syringe. At step 618, it is determined whether the push plunger load sensor indicates a decrease in internal pressure. If this is the case, and if the load is similar to the force required to insert into the suprachoroidal space, or if a decrease in internal pressure is detected, it is necessary to monitor the position of the push plunger and continue to push the push plunger forward (step 620). If this is not the case, the syringe and pusher plunger must be moved to move the entire syringe (step 616).

At step 622, if the forward movement of the push plunger maintains the force measured by the push plunger load sensor, then based on the position of the push plunger, it is determined whether a predetermined amount of therapeutic agent has been delivered (step 624). If not, then the system continues to push the push plunger forward (step 626). If so, then the system stops pushing the push plunger forward (step 628). If the force measured by the push plunger load sensor is not maintained as the push plunger moves forward (step 622), then at step 626, if the load increases significantly, this indicates that all of the therapeutic agent has been delivered and the push plunger is now in direct contact with needle plunger. The system then stops moving the plunger forward (step 628).

Specifically, in some embodiments, at step 614, the plunger is pushed to pressurize the internal fluid by a known amount, and at step 616, both the barrel and the plunger are moved to move the entire syringe. At step 618, the internal pressure of the fluid is continuously checked. If the load cell indicates a drop in pressure, it is necessary to monitor the position, hold the cylinder in place, and continue to push the plunger forward to deliver the therapeutic agent into the suprachoroidal space. At step 618, if the plunger load sensor has not yet detected a drop in load, the entire syringe should be advanced. When the plunger load sensor detects a decrease in load, the syringe barrel stops advancing and only the push plunger advances at step 620. At step 622, monitoring of the push plunger load sensor continues. While the load on the push plunger is controlled, the push plunger advances forward, delivering the therapeutic agent until the required volume of therapeutic agent is delivered (step 624), at which point the push plunger advances to a stop (step 628). Alternatively, the push plunger load sensor detects an increase in load indicating that the push plunger has reached the distal portion of the syringe (step 626), after which the push plunger's advance is stopped (step 628).

In some embodiments, with reference to FIGS. 10A-10E and figs. 11A, B, after the lumen of the needle is inserted into the sclera, instead of advancing the full syringe, it can freely move

- 14 046786 The mount is attached to the syringe barrel and only the push plunger mount is advanced. As shown in FIG. 10A, the syringe barrel 702 and the plunger 704 may be moved synchronously toward the eye until the load sensor detects that the needle 708 has been inserted into the sclera. In fig. 10B, when the needle tip is inserted, the syringe barrel 702 is held in place and the push plunger is advanced to generate fluid pressure, which is recorded as a load on the push plunger. In fig. 10C, when a pressure load is reached on the push plunger 704, the stop on the syringe barrel is released so that it can move freely, and then the push plunger is advanced. In fig. 10D, when the lumen of the needle 708 reaches the suprachoroidal space, the load on the pushing plunger 704 is reduced because the lumen is no longer blocked and fluid can flow out; the pusher plunger is then advanced to deliver the therapeutic agent into the suprachoroidal space. In fig. 10E, the push plunger 704 may be advanced a predetermined distance to deliver a known volume, or it may be pushed to deliver the entire payload. Delivery of the entire payload can be detected by the load cell based on the increase in force as the plunger interacts with the distal end of the syringe when the syringe is emptied.

Thus, when the lumen of the needle reaches the suprachoroidal space, as indicated by a decrease in the load on the push plunger load cell, the syringe barrel can then be locked in place and the syringe plunger can be advanced to directly deliver the therapeutic agent into the suprachoroidal space, thus essentially provide automatic stop of the needle of a standard syringe when used in combination with a syringe drive. In such embodiments, a feedback loop may be provided to control the movement of the needle through the sclera. In some embodiments, the syringe barrel does not lock into place upon reaching the suprachoroidal space and the needle remains in the cavity as the push plunger advances due to decreased fluid resistance in the needle lumen. For example, when the contents of a syringe barrel are pressurized, a mechanical stop on the syringe barrel will release. The plunger is then advanced, pushing the tip of the needle through the sclera until it reaches the suprachoroidal space. Upon reaching the suprachoroidal space, the needle will automatically stop as the pressure inside the syringe barrel decreases due to fluid flowing from the needle tip into the suprachoroidal space.

As described in more detail in FIG. 11A, B, implementation of the method of delivering a therapeutic agent to the eye may begin with installation of a locking device at step 800. At step 802, a syringe containing the therapeutic agent may be loaded into a motorized injector. At step 804, a motorized injector containing a syringe may be loaded into a locking mechanism coupled to the patient (the needle is not in contact with the sclera). At step 806, the user may press a button or operate another mechanism to initiate the injection. At step 808, the entire syringe may be moved forward to engage the needle with the sclera. At step 810, if the syringe load sensor indicates an increase in load, the syringe is moved forward a predetermined distance to pre-inject the needle and block the needle lumen with the sclera (step 812). If this is not the case, then the syringe continues to move forward (step 808) until the load increases.

When the syringe load sensor indicates an increase in load, the push plunger is depressed at step 814 without any restrictions on axial movement in the syringe and both the syringe and push plunger are moved forward. At step 816, if the load on the push plunger is similar to the force required to insert into the suprachoroidal space, or if a decrease in internal pressure is detected, the position of the push plunger must be monitored and the push plunger must continue to push forward. If necessary, the system may continue to push the push plunger forward while the syringe may be locked (step 818). If the push plunger load sensor does not indicate a decrease in internal pressure, then the push plunger is pushed as indicated at step 814.

At step 820, if the forward movement of the push plunger maintains the force measured by the push plunger load sensor, then based on the position of the push plunger, it is determined whether a predetermined amount of therapeutic agent has been delivered (step 822). If this is not the case, then the system continues to push the push plunger forward while the syringe position is locked (step 818). If so, then the system stops pushing the push plunger forward (step 826). If the force measured by the push plunger load sensor is not maintained as the push plunger moves forward (step 820), then at step 824, if the load increases significantly, this indicates that all of the therapeutic agent has been delivered and the push plunger is now in direct contact with the distal end of the syringe. The system then stops moving the push plunger forward (step 826).

Graphical user interface.

A graphical user interface is included in some embodiments. For example, such a user interface could allow the user to initiate an injection, control the injection

- 15 046786 tion at stages I-III-b and, if necessary, interrupt the injection. In some embodiments, a means of providing auditory feedback to the user is also provided. In some embodiments, lamps, a graphic display, and/or sounds are used as an indicator to indicate one or more of the following events: setting the insertion angle, filling the syringe with the therapeutic agent, priming the syringe to remove any trapped air, turning on the device, advancing the needle toward sclera when piercing the sclera, when reaching the suprachoroidal space, when delivering a therapeutic agent, when removing the needle from the eye.

In some embodiments, the graphical user interface allows the user to enter certain patient parameters, including intraocular pressure, scleral thickness, eye size, etc. In some other embodiments, the graphical user interface prompts for patient information and generates a report upon completion of the injection, and in others In embodiments, patient information is obtained using a one- or two-dimensional barcode scanner or a near field scanner (NFC, Near Field Communication). In some embodiments, the injector may connect to an external server to upload this information and/or download necessary information for the case, such as the disease being treated, data about the prescribed therapeutic agent, and dosage information.

In some embodiments, a display on the motorized syringe drive is used to display instructions to the user and request input from the user regarding when to proceed to the next step of the injection process, beginning with filling the syringe and ending with the completion of the injection into the suprachoroidal space. In some embodiments, the graphical user interface also allows the user to enter injection process parameters such as, for example, distance traveled by the system or component thereof, pressure or load thresholds on the system or components thereof, volume of therapeutic agent loaded, volume of therapeutic agent delivered, flow rate injection, duration of injection, angle of injection, or maximum distance of needle movement after piercing the sclera. In some embodiments, the user may select the desired injection volume and/or flow rate. In some embodiments, the position of the push plunger, needle tip, and/or floating plunger, and/or the load detected by the needle tip load sensor and/or the push plunger load sensor is displayed.

In some embodiments, a camera is provided, focused on the tissue surface, that presents the user with an enlarged real-time video image on a display so that the user can observe the piercing of the sclera and the final removal of the needle. In some embodiments, the chamber may facilitate pre-administration where the user manually pre-inserts the needle tip and then activates the automated system to complete delivery of the therapeutic agent to the cavity. In some embodiments, the injector may include a one-dimensional or two-dimensional barcode scanner to record the disposable syringe and the therapeutic agent used for injection.

Distance to needle stop and its excess.

As discussed above, in some embodiments, the motorized injection system of the present invention may be equipped with one or more safety elements to limit or control movement of the needle beyond a predetermined position. In some embodiments, additionally or alternatively, movement of the needle beyond a predetermined position can be controlled by controlling the distance to stop the needle plunger. The stopping distance is the distance traveled by the needle plunger after the needle lumen reaches the cavity and delivery of the therapeutic agent begins. The distance to stop is determined by how quickly the pressure in the syringe barrel drops below the frictional resistance of the needle plunger. This distance can be characterized as the relationship (similarly, flow through a hollow needle is characterized by the Hagen-Poiseuille equation) between the frictional resistance of the needle plunger, the internal diameter of the needle, the length of the needle, the bevel of the needle, the internal diameter of the syringe barrel, the viscosity of the composition, the force applied to the pushing plunger , mechanical properties of device components. In some embodiments, the distance to stop may be predicted based on the time required to release the pressure and the speed at which the needle was moved. The stopping distance may depend on the volumetric elasticity of the syringe assembly and the compressibility of the fluid. In some embodiments, movement beyond a predetermined position based on distance to stop may be controlled by one or more of the safety elements described above. In some embodiments, the distance to stop may depend on the time required to engage and drive the motorized feedback loop. As long as any part of the needle opening is open to the suprachoroidal space, the payload will be delivered to the suprachoroidal space. Consequently, the permissible distance to the stop directly depends on the size and bevel of the lumen. For example, a 30G needle with a lumen diameter of 0.160 mm with a standard 12° bevel angle can extend beyond the target position by ~0.8 mm while maintaining lumen contact with the supra.

- 16 046786 rachoroidal space. To ensure optimal fluid flow and maximum lumen opening into the suprachoroidal space, the needle should be positioned so that the suprachoroidal space is centered relative to the geometric shape of the lumen, i.e. for a 30G needle with a 12° bevel angle, the stop distance of ~0.4 mm would be centered in the suprachoroidal space relative to the lumen. A distance to a stop of less than 0.4 mm is also allowed.

In some embodiments, movement beyond a predetermined stopping distance is corrected by using a motorized syringe actuator that retracts the syringe barrel to ensure that the suprachoroidal space is centrally located relative to the geometric shape of the lumen. For example, for a 30G needle with a 12° bevel angle, if the stop distance is greater than 0.4mm, the needle can be retracted/retracted to center it. In some embodiments, the syringe barrel is retracted a fixed distance to counteract the volumetric elasticity of the syringe assembly and the compressibility of the fluid. In other embodiments, the retraction distance includes the position of the syringe barrel at which a reduction in the force on the push plunger is first detected after passing the sclera. In some embodiments, the abduction distance takes into account the measured deformation of the sclera upon contact with the needle prior to puncture. In some embodiments, the determination of the retraction distance takes into account the known or measured time required for the motorized feedback loop to detect and engage to stop the syringe.

Automatic syringe filling.

In some embodiments, the auto-stop syringe of the present invention may be prefilled with a therapeutic agent during manufacture as described above. In some embodiments, the auto-stop syringe of the present invention may be filled with a therapeutic agent in a physician's office, pharmacy, or surgery before administering the therapeutic agent to a patient. In some embodiments, the therapeutic agent may be provided in a storage vial and may be transferred into the suprachoroidal system by the user only after the therapeutic agent is ready for administration to the patient.

In some embodiments, as shown in FIG. 12, the injection system of the present invention includes a quick fill port 900 that allows the injection agent to be loaded into the injection chamber from a vial 902. In some embodiments, the quick fill port 900 includes a receptacle 904 configured to receive the vial 902 to provide a connection across fluid medium of a bottle with an injection chamber. In some embodiments, a hole or passage is formed into the wall of the syringe barrel proximal to the needle plunger 110 (eg, by molding, machining, etc.) and a receptacle 904 is positioned over the hole or passage.

In some embodiments, when the needle plunger is set to its initial position and the push plunger is brought into contact with the needle plunger, a fluid connection is provided between the sealing elements of the quick fill port to the barrel of the syringe. Attached to the passage, partially or completely located therein, is a side port filling needle 906 (preferably larger than an injection piercing element, such as an 18 gauge piercing element). Such a filling needle may be beveled to pierce the elastomeric cap 903 of the vial 902 containing the therapeutic agent. In some embodiments, the fast fill port piercing element may have an opening on the side of the filling piercing element rather than at the tip. This side port may be closed by a casing or a self-sealing pierceable membrane 908 that blocks fluid flow in the closed position. The housing 908 may be located within the receptacle and may be pressed by a spring 910 to close the fill needle port when a vial is not present in the receptacle. In some embodiments, the protective cap 118 may be configured to provide an airtight seal when attached to the injection system.

During operation, as shown in FIG. 13A, B and FIG. 14A, B, a syringe with an automatic stop function is connected to a support platform and a drive unit of a motorized injection system. The vial 902 is then snapped into the receptacle 904 of the quick fill port 900, which causes the sliding fill piercing housing to be pushed away from the side port of the fill piercing element. The quick fill port piercing element then penetrates the vial stopper to provide a fluid connection between the interior of the vial and the syringe barrel through the side port of the filling piercing element. The quick fill port priming needle then penetrates the vial stopper to provide a fluid connection between the interior of the vial 902 and the syringe barrel through the side priming needle port. As a result, the therapeutic agent flows out of the vial 902 into

- 17 046786 syringe cylinder when the pushing plunger is retracted by the drive unit. In some embodiments, a protective cap is provided on the piercing element of the injection system to seal the piercing element from fluid so that when the push seal element is retracted, bubbles are not drawn into the syringe barrel.

Once the auto-stop syringe is filled with the required amount of therapeutic agent, the vial can be removed from the quick fill port receiver, causing the sliding fill needle guard to rise up, sealing the side port of the fill needle, which will also seal the syringe barrel. The protective cap can be removed to allow fluid to flow through the injection needle. The drive assembly can be activated to advance the push plunger until fluid appears at the tip of the injection needle, indicating that air has been removed from the injection needle. The auto-stop syringe is now ready for use. This quick-fill port design allows the auto-stop syringe to be filled with a therapeutic agent in the physician's office while maintaining sterility outside the cleanroom.

In some embodiments, the auto-stop syringe of the present invention may be filled with a therapeutic agent. This may be performed during initial manufacture of the syringe or in the doctor's office immediately before use.

In some embodiments, as shown in FIG. 15A, B, the push plunger 112 can be removed so that the therapeutic agent 114 can be added to the barrel of the syringe 102 through the rear of the syringe barrel. The push piston can then be inserted and pushed towards the needle plunger 110 to remove air from the injection needle.

In some embodiments, as shown in FIG. 16A, B, a filling port 930 may be provided in the proximal region of the syringe barrel 102 further distal to the pushing plunger 112. The therapeutic agent 114 can be added to the auto-stop syringe through this filling port 930 and then the pushing plunger 112 may be advanced past the filling port 930 such that the pushing plunger 112 isolates the therapeutic fluid from the filling port. Specifically, the therapeutic agent can be added to the auto-stop syringe through the filling port using another sterile syringe/another sterile needle, with the needle held side down (needle tip locked). In some embodiments, the total volume of therapeutic agent may be approximately 80% of the volume between the plungers. The push plunger can then be pushed towards the needle plunger to remove air through the filling port. Once the push plunger has passed the filling port, which blocks the filling port, the syringe can be reversed to raise the needle side up. The push plunger is then advanced further distally to release any remaining air from the syringe barrel and injection needle.

In some embodiments, as shown in FIG. 17A-17C, fill port 930 may be sealed with a self-sealing seal or polymer 932 (eg, silicone rubber or polytetrafluoroethylene). Thus, a separate, larger diameter loading needle 934 of a standard syringe can be inserted into the filling port to perform filling, while the barrel of the auto-stop syringe can remain sealed throughout the entire process. When the loading needle is removed from the filling port, the filling port self-seals sufficiently to prevent leakage under the pressure exerted by the pushing plunger during use.

In some embodiments, as shown in FIG. 18A-18D, a filling port 950 may be provided at a distal portion of the syringe barrel 102 in front of the needle plunger 110. This allows the user to access the needle plunger using a push tool 952 (eg, a long, thin, rigid object that can be inserted into the hole and is long enough to reach the location). Thus, the injection needle can be extended outward so that it can be pushed through the elastomeric stopper of the vial, after which the therapeutic agent can be drawn into the syringe by retracting the push plunger. The push plunger can then be retracted further proximally so that the needle plunger can be retracted back to the pre-injection position within the syringe barrel.

Using an injection system.

In some embodiments, the injection system of the present invention is used to deliver a viral gene delivery vector or vectors, including, but not limited to, adeno-associated virus (AAV), a variant or serotype thereof, 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 such as Rec2 and Rec3, for the treatment of hereditary retinal or choroidal disease. AAV1, AAV2, AAV4, AAV5, AAV6, AAV7, AAV8 and AAV9 may exhibit tropism for retinal tissue, including the retinal pigment epithelium and

- 18 046786 photoreceptors as described in https://www.retinalphysician.com/issues/2020/special-edition2020/vector-considerations-for-ocular-gene-therapy, incorporated herein by reference in its entirety. By way of example, diseases may include, but are not limited to, wet age-related macular degeneration, dry age-related macular degeneration (AMD), glaucoma, choroideremia, and other inherited diseases and vision disorders. In some embodiments, the injection system is used to deliver a viral vector or vectors, including, but not limited to, adeno-associated virus or a variant thereof, to transfect retinal and/or choroidal cells, including, but not limited to, photoreceptors, pigmented cells, bipolar cells, ganglion cells cells, horizontal cells and amacrine cells, vascular endothelial cells, vascular smooth muscle cells, non-vascular smooth muscle cells, melanocytes, fibroblasts, resident immunocompetent cells with anti-vascular endothelial growth factor (anti-VEGF) and inhibitor factor receptor gene vascular endothelial growth factor receptor (anti-VEGFR), which when read produces an anti-VEGF protein or proteins for the treatment of wet age-related macular degeneration (AMD). In some embodiments, gene therapy compositions may also include a promoter for the target gene.

In some embodiments, the injection system is used to deliver gene therapeutics, including, but not limited to, small interfering ribonucleic acid (siRNA), short hairpin ribonucleic acid (shRNA), micro-ribonucleic acid , microRNA), closed-end-deoxyribonucleic acid (ceDNA), polymer-DNA conjugates or clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (CRISPR-) systems associated protein 9, Cas9) and their variants, transcription activator-like effector nuclease (TALEN) and their variants, zinc finger nuclease (ZFN) and their variants, as well as delivery transposon-based genes such as Sleeping Beauty (SB), piggyBac (PB), Tol2 or variants thereof. These gene therapeutics can be packaged into viral vectors, non-viral vectors, or nanoparticles.

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

In some embodiments, the injection system is used to deliver small molecule or macromolecular therapeutics directed against VEGF or VEGFR, such as ziv-aflibercept, pazopanib, bevacizumab, cabozantinib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib, vandetanib, among others. , ramucirumab, lenvatinib and bevacizumab.

In some embodiments, the injection system is used to deliver gene therapeutics that target, replace, inhibit, or activate one or more of the following genes to provide a therapeutic effect for an inherited ocular disease or disorder, including, but not limited to, MTP, HGD , SLC16A2, POLG, ALMS1, FGFR2, PRPS1, ARTX, ATM, DNMT1, TGFBI, ACTB, FGFR2, BEST1, CYP4V2, NOD2, FOXL2, ABC9, ERCC6, CYP27A1, CHS1, SH3BP2, HDAC6, CHM, SLC9A6, NSDHL, OPN1MW , OPN1LW, OPN1SW, KERA, IGBP1, OPA3, UGT1A1, FGFR2, FGFR3, ATP6V0A2, 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, B3GALTL, 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, RAIL HBB, 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, NOTCH2, PAX6, ELP4, FOXE3, PITX3, PITX2, FOXC1, CHD7, SEMA3E, ERCC6, ERCC8, CYP1B1, MYOC, MYOC, CYP1B1, FGFR1, FGFR2, FGFR1, FGFR2, NDN, SNRPN, PHYH, PEX7, CREBBP, EP300, OPA1, OPTN, SAG, GRK1, TWIST1, FGFR2, GPC3, OFD1, TSC1, 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, COL5A1, COL5A2, COL3A1, TNXB, OPTN, ASB10, 6, MTND1, MTND4, MTNDS, MTND6, PAX6, PITX2, CYP1B1, FOXCl, DMPK, ZNF9, CNBP, NPC1, NPC2, SMPD1, TYR, OCA2, TYRP1 or SLC45A2, MC1R, COL1A1, COL1A2, CRTAP, LEPRE1, NPHP1, NPHP4 SDCCAG8 , WDR19, Cep290, IQCB1, HESX1, OTX2, SOX2, COL2A1, COL11A1, COL11A2, COL9A1, COL9A2, My7A, USH2A, EdN3, EdNRB, MITF, PAX3, SNAI2, Sox10, AdamTS10, FBN1 LTBP2, XPA, XPC, ERCC2 , ERCC3 and POLH.

In some embodiments, the delivery system of the present invention may

- 19 046786 be used to deliver gene therapeutics for the treatment of age-related macular degeneration (AMD) or diabetic macular edema (DME). In some embodiments, the delivery system of the present invention is used for suprachoroidal (SCS) delivery of a composition comprising an adeno-associated virus vector comprising one or more VEGFR-2 blocking genes, optionally 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 include a 25-34 gauge piercing element with a polypropylene or glass syringe and a fluoropolymer, silicone or rubber push seal stopper and a push seal stopper. In some embodiments, approximately 80-120 (eg, 100) microliters of such gene therapy composition can be delivered within 560 seconds. In some embodiments, the piercing element may have a bevel length of less than 2 mm, less than 1 mm, or less than 0.5 mm. The bevel angle can be more than 15 degrees, more than 30 degrees, or even more than 45 degrees. In some embodiments, the piercing element may be 25 gauge or greater, 27 gauge or greater, or 30 gauge or greater. In some embodiments, the needle has an additional bevel to reduce cutting force.

In some embodiments, the delivery system is used to deliver small molecule or macromolecular injectable agents, such as anti-VEGF drugs, including, but not limited to, bevacizumab, ranibizumab, aflibercept, ramucirumab, disintegrins, antiprostaglandins, tryptophanyl-tRNA synthetase-derived polypeptides, Inosine monophosphate dehydrogenase (IMPDH) and anti-PDGF inhibitors for the treatment of age-related macular degeneration; and corticosteroids to treat uveitis, chorioretinitis, or other inflammatory eye diseases; botulinum toxin for various eye treatment applications; tyrosine kinase inhibitors (such as vandetanib, axitinib, pazopanib, sunitinib, sorafenib) to treat pterygium, dry eye syndrome, or age-related macular degeneration; Levobetaxolol or other beta-adrenergic receptor antagonists and 5-HT1A agonists for the treatment of retinal pathologies.

In some embodiments, the injection system is used to deliver small molecule Wnt inhibitors to reduce angiogenesis. These small molecule Wnt inhibitors may include an indazole-3-carboxamide compound or analogs thereof (WO 2013040215 A1), γ-diketones or salts or analogs thereof (WO 2014130869 A1), an azindazole compound or analogs thereof (for example, 3-(1hbenzoSchimidazole-2- y1)-1^pyrazolo[3,4-c]pyridine) (WO 2016040180 A1), No(5-(3-(7-(3-fluorophenyl)-3Nimidazo[4,5-c]pyridine-2-y1 )-1H-indazol-5-yl)pyridin-3-y1)-3-methylbutanamide, including its amorphous and polymorphic forms (WO 2017210407 A1), carboxamides, or salts of isoquinoline-3-y1 or analogs, including their amorphous and polymorphic forms forms (WO 2017189823 A2), carboxamides, or salts of diazanaphthalin-3-yl or analogues, including amorphous and polymorphic forms (US 20190127370 A1), carboxamides, or salts of 6-(5-membered heteroaryl)isoquinoline-3-y1-(5 -membered heteroaryl) or analogs, including amorphous and polymorphic forms (WO 2019084496 A1), carboxamides, or salts of 6-(6-membered heteroaryl and aryl)isoquinolin-3-yl or analogs, including amorphous and polymorphic forms (US 20190125740 A1) , 3-(3h-imidazo[4,5-b]pyridine-2-y1)-1h-pyrazolo[3,4-b]pyridine (US 20190119303 A1), Wnt inhibitors containing an indazole core or salt, or analogues, including amorphous and polymorphic forms (WO 2013151708 A1), 1^pyrazolo[3,4-b]pyridines, or salts or analogues, including amorphous and polymorphic forms (WO 2013166396 A2), 2-(1h-indazole-3-y1) -3h-imidazo[4,5-b]pyridine, or salt or analogs, including amorphous and polymorphic forms (US 20190055238 A1), β-diketone, y-diketone or yhydroxyketone, or salts or analogs thereof (WO 2012024404 A1), 3-(benzoimidazol-2-yl)indazole inhibitors, or salt or analogues, including amorphous and polymorphic forms (US 10183929 B2), 3-(1himidazo[4,5-c]pyridin-2-y1)-1^pyrazolo[ 3,4-b]pyridine, or salt or analogs, including amorphous and polymorphic forms (US 20180325910 A1), 1H-pyrazolo[3,4-b]pyridines, or salts or analogs, including amorphous and polymorphic forms (CY-1119844 -T1), 3-(111-imidazo[4.5-c|pyridin-2-y1)-111pyrazolo[3,4-c]pyridine, or its salts or analogues, including amorphous and polymorphic forms (US2018250269-A1), No. (5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-c]pyridin-2-y1)-1H-indazol-5-yl)pyridin-3y1)-3-methylbutanamide, or salt or analogs, including amorphous and polymorphic forms (US 20180133199A1), indazole-3-carboxamides, or salt or analogs, including amorphous and polymorphic forms (US-2018185343-A1), 3-(3-imidazo[4,5-b ]pyridine-2-y1)-1^pyrazolo[3,4-c]pyridine, or salt, or analogues, including amorphous and polymorphic forms (US-2018201624-A1), 2-(111-indazole-3-y1) -111imidazo[4,5-c|pyridine, or salt or analogues, including amorphous and polymorphic forms (US2018215753-A1), 3-(3H-imidazo[4,5-C]pyridine-2-y1)-1H-pyrazolo [3,4-C]pyridine, or salt or analogs, including amorphous and polymorphic forms (US-10052331-B2), 5-substituted indazole-3-carboxamides, or salts or analogs, including amorphous and polymorphic forms (US-2018127377 -A1), 3-(3Nimidazo[4,5-C|pyridin-2-y1)-1H-pyrazolo[4,3-B|pyridines, or salts or analogues, including amorphous and polymorphic forms (US-10188634-B2 ), 3-(1H-imidazo[4,5-C]pyridine-2-y1)-1H-pyrazolo[4,3- 20 046786

B]pyridines, or salts or analogs, including amorphous and polymorphic forms (US-10195185-B2), 3-(1hpyrrho.to[2,3-b|pyridin-2-y1)-11gindazoles, or salts or analogs, including amorphous and polymorphic forms (WO-2017024021-A1), 3-(11-pyrrolo[2,3-c]pyridin-2-y1)-11-pyrazolo[3,4-c]pyridines, or salts or analogues, including amorphous and polymorphic forms (WO-2017023975-A1), 3-(111-indole-2-y1)-111pyrazolo[3,4-b]pyridines, or salts or analogues, including amorphous and polymorphic forms (US2018214428-A1), 3-(11-pyrrolo[3,2-c]pyridin-2-y1)-11-indazoles, or salts or analogues, including amorphous and polymorphic forms (US-2018221350-A1), 3-(11-indole-2 -y1)-11-indazoles, or salts or analogues, including amorphous and polymorphic forms (WO-2017023986-A1), 3-(1H-pyrrolo[2,3B]pyridine-2-y1)-1H-pyrazolo[4, 3-B]pyridines, or salts or analogues and including amorphous and polymorphic forms (US-10206909-B2), 3-(11-pyrrolo[3,2-c]pyridin-2-y1)-11-pyrazolo[4, 3-b]pyridines, or salts or analogues, including amorphous and polymorphic forms (WO-2017024003-A1), 3-(11-pyrrolo[3,2c]pyridin-2-y1)-11-pyrazolo[3,4- b]pyridines, or salts or analogues, including amorphous and polymorphic forms (US-2018221341-A1), 3-(31-imidazo[4,5-b]pyridine-2-y1)-11-pyrazolo[4,3- b]pyridines, or salts or analogues, including amorphous and polymorphic forms (WO-2017024015-A1), 3-(11-pyrrolo[2,3c]pyridin-2-y1)-11-pyrazolo[3,4-b] pyridines, or salts or analogs, including amorphous and polymorphic forms (US-2018221352-A1), 3-(1H-pyrrolo[3,2-C]pyridin-2-IL)-1H-pyrazolo[3,4-C] pyridines, or salts or analogues, including amorphous and polymorphic forms (US-10206908-B2). Each of the documents referred to herein is incorporated by reference in its entirety.

In some embodiments, the injection system is used to deliver suspensions of injectable agents, including microencapsulated agents, nanoencapsulated agents, pure protein nanoparticles, and poorly soluble or water-insoluble agents.

In some embodiments, the injectable agent or encapsulated injectable agent is delivered with a matrix that increases residence time. This matrix may consist of inversely thermosensitive hydrogels, self-assembling hydrogels, bioadhesive polymer networks, hydrogels, fibronectin hydrogels, enzyme-responsive hydrogels, ultrasound-responsive hydrogels, pH-sensitive hydrogels, carbohydrates, two or more component hydrogels, and multicomponent double network hydrogels. .

In some embodiments, the injectable agent is delivered via an injection system followed by the use of a penetration enhancer such as dimethylsulfoxide (DMSO), collagenases, elastases, proteases, papain, bromelain, peptidases, lipases, alcohols, polyols, glycerides, etc. short chain, amines, amides, cyclodextrins, fatty acids, pyrrolidones, cyclopentadecalactone, Sodium N-[8-(2hydroxylbenzoyl)amino]caprylate, SNAC), sodium 8-(No. 2-hydroxy-5-chloro-benzoyl)-aminocaprylic (8(N-2-hydroxy-5-chloro-benzoy1)-amino-caprylic, 5-CNAC) acid, sodium caprate, sodium caprylate, omega-3 fatty acids, protease inhibitors, alkyl glycosides, chitosan, dodecyl-2-N,Ndimethylaminopropionate (Dodecyl-2-N,N-dimethylamino propionate, DDAIP), Nmethyl-2-pyrrolidone (NMP), azones, sulfoxides, surface -active substances, benzylalkonium chloride, saponin, bile salts, bile acids, cell penetrating peptides, polyarginine, low molecular weight protamine, polyserine, capric acid, gelucirs, semi-fluorinated alkanes, terpenes, phospholipids, chelators, ethylenediamine tetraacetic acid, EDTA), citrate, crown ethers and combinations thereof.

In some embodiments, an injectable agent including one or more therapeutic compositions is delivered by an injectable system concomitantly with or subsequent to the administration of one or more vasoconstrictors to reduce the outflow of the injectable agent through the choroidal blood vessels, including, but not limited to, 25I-NBOMe , amphetamines, AMTs, antihistamines, caffeine, cocaine, dopamine, dobutamine, DOM, LSA, LSD, methylphenidate, mephedrone, norepinephrine, oxymetazoline, phenylephrine, propylhexedrine, pseudoephedrine, stimulants, 5-hydroxytryptamine serotonin agonists, triptans and tetrahydrozoline hydrochloride. In some embodiments, these agents can be administered using the injection system of the present invention into the suprachoroidal space or by performing an intravitreal injection using a standard syringe. Vasoconstrictor agents may be delivered prior to, concurrently with, or subsequent to administration of one or more therapeutic compositions.

In some embodiments, the injectable agent delivered by the injection system provides greater than 20%, 40%, 60%, or 80% coverage of the suprachoroidal space.

In some embodiments, the injectable agent, delivered by an injectable system, with or without one or more vasoconstrictor agents to reduce the outflow of the injectable agent through the choroidal blood vessels, provides coverage of the suprachoroidal space in less than 180, 120, 60, 30, or 15 minutes.

In some embodiments, the injectable agent delivered by the injectable system has a residence time in the suprachoroidal space of less than 180, 120, 60, 30, 15, 10, or 5 minutes.

- 21 046786

In some embodiments, the injectable agent is delivered by an injection system in a volume of less than 500, 400, 300, 200, or 100 microliters.

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

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

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

In some embodiments, an injection system is used to deliver one or a plurality of injectable agents to treat one or more of the causes or consequences of the following ocular diseases, including, but not limited to, abetalipoproteinemia (Bassen-Kornzweig syndrome), alkaptonuria, Allan-Herndon syndrome, Dudley (Allan-HerndonDudley), Alpers syndrome, Alstrom syndrome, Apert syndrome, Arts syndrome (mental retardation, X-linked gene, syndrome 18), ataxia syndrome - oculomotor disorders, ataxia -telangiectasia (Louis-Bar syndrome), autosomal dominant cerebellar ataxia, deafness and narcolepsy (Autosomal Dominant Cerebellar Ataxia Deafness and Narcolepsy, ADCADN), Avellino corneal dystrophy (combined granular-lattice corneal dystrophy), Baraitser-Winter syndrome 1, Beare-Stevenson syndrome, Best macular dystrophy, Bietti crystalline corneoretinal dystrophy, Blau syndrome, blepharophimosis, ptosis and epicanthus inversion Inversus, BPES), Cantu syndrome, cerebrooculofacioskeletal syndrome, cerebrotendinous xanthomatosis, Chediak-Higashi syndrome, cherubism, chondrodysplasia with platyspondylia, distinguishable brachydactyly, hydrocephalus and microphthalmia, choroideremia, Christianson syndrome, SK , color blindness, deutan, protan, tritanopia, flat cornea, corpus callosum, agenesis with mental retardation, ocular coloboma and micrognathia, Costeff syndrome, Crigler-Najjar syndrome, Crouzon syndrome, Crouzon syndrome with papillary pigmentary dystrophy of the skin (Crouzon syndrome with acanthosis nigricans), flaccid skin syndrome, flaccid skin syndrome of the Debre type (Debre)), cystinosis, Doyne's honeycomb dystrophy (Leventin's disease (Malattia Leventiese)), Duane-ray syndrome, ectopia lentis and pupils, lens ectopia, familial lens ectopia, isolated, enhanced S-type cone syndrome, corneal basement membrane epithelial dystrophy (dystrophy in the form of a map with dotted fingerprints), Fabry disease (hereditary, lipid metabolism disorder), hereditary autonomic dystonia, 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 (Grenow type I). Groenouw), spiral atrophy, hereditary hemorrhagic telangiettasia (Osler-Rendu-Weber disease), homocystinuria, IFAP syndrome with or without Bresheck syndrome, pigment incontinence (Bloch-Sulzberger syndrome). Sulzberger syndrome), Jalili syndrome, Juberg-Marsidi syndrome, Krabbe disease, lattice corneal dystrophy, LCHAD deficiency (long-chain 3-hydroxyacyl-coa dehydrogenase), Lowe, Pelizaeus-Merzbacher, Peters syndrome -Plus (Lowe, Pelizaeus-Merzbacher, Peters-Plus), (Krause-Kivlin syndrome), phenylketonuria, Proud syndrome, pseudoexfoliation syndrome, ReisBucklers corneal dystrophy, Renpenning syndrome ) (mental retardation, X-linked gene, Renpenning type), retinoblastoma, retinoschisis, juvenile X-linked gene, Russell-Silver syndrome, mucopolysaccharidosis type IH (Hurler syndrome), mucopolysaccharidosis type IH/S (Hurler-Scheie syndrome), mucopolysaccharidosis type IS (Scheie 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 (Morquio syndrome A), mucopolysaccharidosis type IVB (syndrome B Morquio), mucopolysaccharidosis type VI (Maroteaux-Lamy syndrome), mucopolysaccharidosis type VII (Sly syndrome), Muenke syndrome, Nail-Patella syndrome, indigenous myopathy Americans - Nance-Horan syndrome, neurofibromatosis type I, neurofibromatosis type II, neurofibromatosis - Noonan syndrome, neuropathy, ataxia and retinitis, pigmentosis (NARP), Norrie disease, hidden macular dystonia, ocular albinism, oculopharyngeal muscular dystrophy, Sandhoff disease (GM2 gangliosidosis, type II), Schnyder corneal dystrophy, Sengers syndrome, Smith-Magenis syndrome (chromosome 17p11.2 deletion syndrome), sickle cell anemia, Sorsby fundus dystrophy, spinocerebellar ataxia, X-linked gene 1, Stargardt/fundus disease, Flavimaculatus, Sturge-Weber syndrome

- 22 046786

Weber), sulfocysteinuria (sulfite oxidase deficiency), syndromic microphthalmia 1 (Lenz microphthalmia syndrome), syndromic microphthalmia 2 (oculofaciocardiodental 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 (Tau-Sachs) (GM2 gangliosidosis type I), Thiel-Behnke corneal dystrophy, Turner syndrome, tyrosinemia type II, Vacterl association with hydrocephalus, Von Hippel-Lindau syndrome ), Wagner syndrome, Watson syndrome, Wieacker-Wolff syndrome, Wilson disease, achromatopsia, Alagille syndrome, aniridia, anterior segment mesenchymal dysgenesis, Axenfeld-Rieger syndrome ( Axenfeld-Rieger), Charge syndrome, Cockayne syndrome, glaucoma, congenital glaucoma, juvenile-onset open-angle disease, Jackson-Weiss syndrome, Pfeiffer syndrome, Prader-Willi syndrome Willi), RefSum disease, Rubinstein-Taybi syndrome, normal pressure glaucoma, Oguchi disease, Saethre-Chotzen syndrome, Simpson-Golabi-Behmel syndrome, tuberous sclerosis, acquired vitelline macular degeneration, Wolfram syndrome, Alport syndrome, Angelman syndrome, Bardet-Biedl syndrome, basal cell nevus syndrome, Beckwith-Wiedemann syndrome , blue cone monochromasia, branchiootorenal syndrome, Charcot-Marie-Tooth disease, cone-rod dystrophy, congenital disorder of glycosylation, congenital fibrosis of the extraocular muscles, congenital nystagmus, congenital permanent night blindness, Cornelia de Lange syndrome de Lange), congenital dyskeratosis, Ehlers-Danlos syndrome, Fuch endothelial corneal dystrophy, acquired open-angle glaucoma, Hermansy-Pudlak syndrome, Joubert syndrome, Kearns-Sayre syndrome ( Kearns-Sayre), Leber congenital amaurosis, Leber hereditary optic neuropathy, Leigh syndrome, Peters anomaly, retinitis pigmentosa, muscular dystrophy - dystroglycanopathy, myotonic dystrophy, Niemann-Pick disease Pick), Noonan syndrome, neuronal ceroid lipofuscinosis, oculocutaneous albinism, optic atrophy, orofacial syndrome, imperfect bone formation, Senior-Loken syndrome, septic-optic dysplasia (de Morsier syndrome), spastic paraplegia, Stickler syndrome, Treacher Collins syndrome, Usher syndrome, Waardenburg syndrome, Weill-Marchesani syndrome and xeroderma pigmentosum.

In some embodiments, multiple injections may be administered to continue therapy. Administration of the therapeutic agent may be accompanied by administration of another agent providing multiple delivery. For example, the delivery of adeno-associated virus is limited by the immune response to it, which typically limits the use of adeno-associated virus to a single injection, the limitation usually being intravitreal administration, and although subretinal administration is preferable from an immune point of view, damaged and diseased retina do not tolerate multiple injections without injury. Another agent (such as ImmTOR) that suppresses this response can be administered before, after, or concurrently with adeno-associated virus administration to moderate the immune response and provide therapy for adeno-associated virus over multiple time points. This allows the dose to be titrated, if necessary, depending on the patient's response.

In some embodiments, the method of administration is to perform an injection into the suprachoroidal space. In some embodiments, a genetic disease or disorder is diagnosed using genetic sequencing, including, but not limited to, Sanger sequencing, next generation sequencing, high throughput screening, exome sequencing, Maxam-Gilbert sequencing, chain termination techniques, shotgun sequencing, Bridge polymerase chain reaction, single molecule real-time sequencing, ion flow sequencing, pyrosequencing, sequencing by synthesis, sequencing by synthesis with a combinatorial anchor probe, sequencing by ligation, and nanopore sequencing. In some embodiments, the ocular disease or disorder is diagnosed by eye examination, ophthalmoscopy, ocular coherence tomography, retinal scanning, fluorescein staining, conjunctival staining, color vision testing, optic disc imaging, nerve fiber layer analysis, corneal topography, electrodiagnostic testing, fluorescein angiography, photographing the eye, counting corneal endothelial cells, determining the visual field, ultrasound of the eye, and a combination of these methods.

In some embodiments, the patient has elevated intraocular pressure and is diagnosed with early stage juvenile primary open-angle glaucoma before the

- 23 046786 significant damage to the optic nerve after examination with an ophthalmoscope. A blood sample is collected and sent for genetic testing, which determines that the patient has a mutation in the olfactomedin domain of his myocilin (MYOC) gene, namely the Y437H mutation, which likely caused the disease, leading to the diagnosis of associated myocilin of primary open-angle glaucoma.

Using an injection system, the patient is then administered a dose of microRNA complementary to the first 22 bases of the mRNA for the MYOC gene, prepared in an aqueous solution of a self-assembling hydrogel with beta-cyclodextrin and ethylenediaminetetraacetic acid as permeation enhancers. Before use, the injection solution is stored as a lyophilized powder in vials separately from the diluent. Once injected, the hydrogel self-assembles into the suprachoroidal space upon delivery, allowing for sustained delivery of microRNA that inhibits the expression of myocilin, resulting in decreased accumulation of myocilin in the trabecular meshwork, resulting in decreased intraocular pressure and thus decreased likelihood of optic nerve damage in the patient.

In yet another specific embodiment, a male child has night blindness and upon examination reveals a reduced field of vision and some retinal degeneration. A blood sample is taken from the patient and sent for genetic testing, which determines that the patient has a mutation in his CHM gene containing part or all of the CHM gene sequence, as described, for example, in the document https://www.uniprot.org /uniprot/P24386, incorporated herein by reference in its entirety, which encodes RAB escort protein 1 (REP1), supporting the diagnosis of early stage choroideremia.

The patient is then dosed using an injection system in which a lyophilized AAV2 vector containing a retinal-specific promoter derived from the rhodopsin kinase (RK) promoter gene expressed in rods and cones, associated with the human SNM gene, is reconstituted with its aqueous diluent before administration. When reconstituted, the injection agent solution contains approximately 1013 adeno-associated virus vectors per milliliter. After injection, the RK promoter and the human CHM gene will be stably transfected into photoreceptor cells, which will express the corrected form of REP 1, thereby treating the patient's choroideremia.

In yet another specific embodiment, the elderly patient has central vision defects. During a routine examination of the retina, drusen are detected. Fluorescein angiography detects leaks in the choroidal vasculature, as evidenced by the presence of subretinal fluid collection observed using optical coherence tomography (OCT). The patient is diagnosed with the early stage of neovascular age-related macular degeneration (AMD).

The patient is then administered, using an injection system, a dose of short interfering RNA (siRNA) sequences of 21 to 24 nucleotides complementary to portions of the mRNA for one or more of the following vascular endothelial growth factor (VEGF), alone or in combinations of any of its subtypes, 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 angiogenesis-promoting protein-encoding genes, siRNA are delivered in suspensions of liposomal carriers. Once delivered, siRNA inhibits the expression of the protein or proteins that promote angiogenesis, thereby preventing additional choroidal capillary growth and causing capillary regression, resulting in reduced retinal and macular invasion of choroidal capillaries and improved central vision. In a specific embodiment, the siRNA targets VEGFR-2, which has the gene sequence or isoforms thereof described in httos://www.uniDrot.org/uniDort/P35968, incorporated herein in its entirety.

In yet another specific embodiment, a patient diagnosed with neovascular age-related macular degeneration or diabetic retinopathy is dosed using an injection system in which an adeno-associated virus vector or other transfection vector contains a gene that, when read, produces an RNA sequence complementary to at least a portion of the mRNA that translated into VEGFR-2. When this gene therapeutic is delivered into the suprachoroidal space, choroidal capillaries, also called choriocapillaris, are contacted with the delivered therapeutic, designed to transfect cells that express VEGFR-2. When transfected, siRNA or shRNA readout vectors suppress or abolish VEGFR-2 production, thereby reducing neovascularization, for the treatment of age-related macular degeneration or diabetic retinopathy.

In some embodiments, a physician may be provided with a suprachoroidal injection kit or kit that includes (1) an injectable agent volume containing one or more therapeutic agent compositions, i.e., active agent compositions, e.g.

- 24 046786 containing an effective amount of an agent suitable for treating a patient's eye disease; (2) the injection system described above; and (3), if necessary, an injector for facilitating delivery of the injection agent to and through the membrane of the injection system.

As described above, the agent composition may include various forms, such as solutions and suspensions of varying viscosity. The entire specified kit must be sterile, including the composition, injection system and auxiliary injector.

In some embodiments, the total volume of the active agent composition to be administered into the suprachoroidal space is preferably in the range of about 0.01-0.5 ml. In some embodiments, the active agent may be provided in lyophilized form and in an accompanying diluent to create a suspension during injection. In some embodiments, the active agent may be premixed. In some embodiments, the injection system may be pre-filled with a pre-mixed composition. In some embodiments, the user may prime the injection system immediately prior to administering the therapeutic composition to the patient. In some embodiments, the injection system may include multiple chambers with soft dividers. In some embodiments, the piercing element has an initial penetration length of 0.01 to 3 mm and the piercing element extends further as the injection is performed. In some embodiments, the injection system and injection aid may be pre-assembled, pre-filled with drug, and ready for use without the need for any additional assembly. In some embodiments, the entire kit is packaged in a single pouch/tray to maintain sterility. In some embodiments, the components are packaged individually or in combination with each other. In some embodiments, the kit is sterilized as a whole or individually using one of a number of sterilization methods including, but not limited to, autoclaving, ethylene oxide, gamma radiation, etc.

In some embodiments, the components are in secondary packaging. In some embodiments, the kit is stored as a collection of components at a sufficiently low temperature to prolong the life of the active pharmaceutical agent. In some embodiments, the composition is stored separately at a low temperature while the rest of the kit is stored at room temperature.

Computer systems for use with injection systems.

Systems of the present invention may include a controller for controlling the operation of injection systems of the present invention. In some embodiments, such a controller may be a computer system for collecting and analyzing sensor information used by the system to control the injection unit. Any suitable computing systems may be used to implement the computing devices and methods/functionality described herein, and may be converted into a particular system to perform the operations and functions described herein by modifications to the hardware, software, and firmware providing in a manner significantly greater in complexity than simply executing the software on a typical computing device, as would be apparent to those skilled in the art. One illustrative example of such a computing device 1900 is depicted in FIG. 19. Computing device 1900 is merely an illustrative example of a suitable computing environment and is not intended to limit the scope of the present invention in any way. The computing device shown in FIG. 19 may include a workstation, server, laptop, desktop computer, handheld device, mobile device, tablet computer, or other computing devices as will be apparent to those skilled in the art. While computing device 1900 is depicted for illustrative purposes, in embodiments of the present invention, any number of computing devices 1900 may be used to implement one embodiment of the present invention using any number of different methods. Accordingly, embodiments of the present invention are not limited to a single computing device 1900, as will be apparent to one skilled in the art, and are not limited to a single type of implementation or configuration of the exemplary computing device 1900.

Computing device 1900 may include a bus 1910 that may be directly or indirectly coupled to one or more of the following exemplary components: a memory device 1912, one or more processors 1914, one or more presentation components 1916, input ports 1918 /output, with I/O components 1920 and power supply 1924. One skilled in the art will appreciate that bus 1910 may include one or more buses, such as an address bus, a data bus, or any combination thereof. It will also be apparent to one skilled in the art that, depending on the intended applications and areas of use of a particular embodiment, many of these components

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Claims (23)

nents can be implemented as a single device. Likewise, in some cases, a single component may be implemented as multiple devices. Thus, FIG. 19 merely illustrates an exemplary computing device that may be used to implement one or more embodiments of the present invention, and is not intended to limit the present invention in any way. Computing device 1900 may include or interface with a variety of computer-readable media. For example, the computer-readable medium may include random access memory (RAM); read only memory (ROM); Electronically Erasable Programmable Read Only Memory (EEPROM); Flash ROM or other storage device technologies; CD-ROM, digital versatile disk (DVD), or other optical or holographic media; magnetic cassettes, magnetic tape, magnetic disk storage, or other magnetic storage devices that can be used to encode information and can be accessed by computing device 1900. Storage device 1912 may include computer storage media in the form of short-term and/or long-term storage. Storage device 1912 may be removable, non-removable, or any combination of removable and non-removable devices. Examples of hardware devices include devices such as hard diskette drives, semiconductor storage devices, optical disk drives, and the like. Computing device 1900 may include one or more processors that read data from components such as storage device 1912, various 1920 I/O components, etc. Presentation component(s) 1916 present data indications to a user or other device. Exemplary components for presentation include a display device, a speaker, a printing component, a vibrating component, etc. The I/O ports 1918 are configured to allow the computing device 1900 to be logically connected to other devices, such as I/O components 1920. Some of the I/O components 1920 may be built into the computing device 1900. Examples of such I/O components 1920 include a microphone, joystick, recorder, gamepad, satellite dish, scanner, printer, wireless device, network device, and the like. Various changes and alternative embodiments of the present invention will become apparent to those skilled in the art upon reading the foregoing description. Accordingly, this description should be considered illustrative only and intended to provide those skilled in the art with the best way to carry out the present invention. Details of construction may vary substantially without departing from the spirit of the present invention, and the exclusive use of all changes falling within the scope of the appended claims is reserved. The embodiments have been described herein so as to provide a clear and concise description, but it is intended and appreciated that the embodiments may be combined or separated in various ways without departing from the present invention. It is intended that the present invention be limited only to the extent required by the appended claims and applicable law. Moreover, it is to be understood that the following claims are intended to cover all the general and specific features of the present invention described herein, and all statements contained within the scope of the present invention, which, from a linguistic point of view, may be said to be included between them. CLAIM 1. Injection system containing: an injection unit comprising a syringe barrel defining a lumen between a proximal end and a distal end, and a second sealing element movably positioned within said lumen to dispense an injection agent from an injection chamber formed in the syringe barrel, and a piercing element configured to deliver an injectable agent into a space in the patient's tissue, said tissue being less permeable to the injectable agent than the space; a support platform configured to support the injection unit and secure the injection unit relative to the injection site; a drive unit configured to control the operation of the injection unit; one or more sensors configured to monitor one or more forces on the injection unit; And - 26 046786 a controller in communication with one or more sensors to receive information about one or more forces in the injection system and configured to control, based on said information, the operation of a drive unit to advance the piercing element through the tissue towards the space so that the injection agent remained in the injection chamber until the piercing element connected the injection chamber to the fluid space. 2. The injection system according to claim 1, in which the injection unit additionally contains: a first sealing element placed with the ability to move inside said lumen distally with respect to the second sealing element, wherein the first sealing element and the second sealing element form a seal with respect to the lumen and define an injection chamber between them, and the piercing element is in fluid communication with the injection chamber a chamber for delivering an injectable agent from the injection chamber to a space in the patient's tissue, wherein when a force is applied to the second sealing element in a distal direction, in response to the first counter force as the piercing element is advanced through the tissue, the first sealing element is moved in a distal direction, advancing the piercing element element in the distal direction, without transferring the injection agent through the piercing element, and in response to the second reaction force, when the injection chamber is fluidly connected to the space, the first sealing element remains stationary and the injection agent is transferred from the injection chamber through the piercing element. 3. Injection system containing: an injection unit comprising a syringe barrel defining a lumen between a proximal end and a distal end, a first sealing element and a second sealing element movably positioned within said lumen, the second sealing element being disposed distal to the first sealing element to form an injection chamber, and a piercing element fluidly coupled to the injection chamber and configured to deliver an injectable agent from the injection chamber to a space in the patient's tissue, the tissue being less permeable to the injectable agent than the space; a support platform configured to support the injection unit and secure the injection unit relative to the injection site; a drive assembly configured to translate one or both of the syringe barrel or the second sealing element relative to the support platform; one or more sensors configured to monitor one or more forces on the injection unit; and a controller in communication with one or more sensors to receive information about one or more forces in the injection system and configured to control, based on said information, a drive assembly to advance the piercing element through the tissue toward the space as the drive assembly progressively moves the second a sealing member in a distal direction, in response to the first counter force, as the piercing member advances through the tissue, the first sealing member moves in a distal direction, propelling the piercing member in a distal direction, without transferring the injection agent through the piercing member, and in response to the second counter force When the injection chamber is fluidly connected to the space, the first sealing element remains stationary and the injection agent is transferred from the injection chamber through the piercing element. 4. Injection system according to any one of claims 1-3, in which the drive unit is configured to independently move the syringe barrel and the second sealing element relative to the support platform. 5. The injection system according to any one of claims 1 to 3, wherein the drive assembly is coupled to the second sealing element to apply a force to the second sealing element to progressively move the second element in a distal direction. 6. The injection system according to any one of claims 1 to 3, wherein the drive assembly comprises a linear actuator coupled to the second sealing element for applying a force to the second sealing element to progressively move the second element in a distal direction. 7. The injection system according to any one of claims 1 to 3, in which the drive unit comprises a first drive configured to translate the syringe barrel relative to the support platform, and a second drive connected to the second sealing element for translationally moving the second sealing element relative to the barrel syringe. 8. The injection system of claim 7, wherein the one or more sensors comprise a first sensor at - 27 046786 load, designed to measure the force on the syringe cylinder. 9. The injection system of claim 7, wherein the one or more sensors comprise a second load cell configured to measure force on the second sealing element. 10. The injection system according to any one of claims 1 to 3, wherein the one or more sensors comprise one or more of a pressure sensor, a force sensor, a strain sensor, a position sensor or a flow sensor. 11. The injection system of claim 2 or 3, wherein the controller is programmed to implement one or more feedback loops to control the first reaction force and the second reaction force. 12. The injection system according to any one of claims 1 to 10, in which the controller is programmed to implement one or more feedback loops to control the preliminary introduction of the piercing element into the tissue, and one or more feedback loops are configured to control the increase in force on the piercing element element, detecting a decrease in force on the piercing element and, based on said decrease, causing the piercing element to advance a predetermined distance to introduce the piercing element into the tissue. 13. The injection system according to any one of claims 1 to 10, wherein the controller is programmed to implement one or more feedback loops to control the progress of the piercing element through the tissue, and one or more feedback loops are configured to sense the load on the second sealing element and detecting a decrease in load when the piercing element reaches a space in the tissue. 14. The injection system according to any one of claims 1 to 10, wherein the controller is programmed to implement one or more feedback loops to control the introduction of the injection agent into the space, and one or more feedback loops are configured to control the speed or distance of advancement of the second sealant element. 15. The injection system according to any one of claims 1 to 10, wherein the controller is programmed to cause the piercing element to be retracted a predetermined distance when one or more sensors detect a decrease in load on the second sealing element. 16. The injection system according to any one of claims 1 to 10, wherein the controller is programmed to control the distance to stop the piercing element when the piercing element enters the space. 17. An injection system according to any one of claims 1 to 10, wherein the tissue is the conjunctiva and the space is the subconjunctival space. 18. The injection system according to any one of claims 1 to 10, wherein the tissue is sclera and the space is suprachoroidal space. 19. The injection system according to any one of claims 1 to 10, wherein the tissue is sclera and choroid and the space is intravitreal space. 20. An injection system according to any one of claims 1 to 10, wherein the tissue is the cornea and the space is the anterior chamber of the eye. 21. A method of delivering an injectable agent, including: providing an injection system according to any one of paragraphs. 1-20; introducing a piercing element into tissue, wherein the piercing element is configured to deliver an injectable agent from the injection chamber to a space in the tissue, the tissue having a greater density than the space such that the tissue is less permeable to the injectable agent than the space; advancing, using a drive unit, the piercing element through the tissue towards the space; monitoring one or more forces on the piercing element using one or more sensors and controlling, using a controller in communication with the one or more sensors, a drive assembly to advance the piercing element through the tissue toward the space so that the injectable agent remains in the injection chamber until the piercing element connects the injection chamber to the fluid space. 22. The method according to claim 21, according to which the piercing element is located at the distal end of the injection unit containing the syringe barrel, forming a lumen between the proximal end and the distal end, as well as first and second sealing elements placed with the ability to move inside the specified lumen for dispensing the injection agent from the injection chamber. 23. A method of delivering an injectable agent, including: providing an injection system according to any one of claims 1 to 20; positioning the injection unit adjacent to tissue, the tissue having a greater density than the space, such that the tissue is less permeable to the injection agent than the space; control of one or more forces on the injection unit using one or more sensors