Ophthalmic delivery device

Abstract

A cannula device for applying a composition containing an active agent to the eye is provided. The invention accordingly provides a method of treating an ocular disease or condition. The invention also correspondingly provides a method of injecting a material.

Description

[0001] This application is a divisional application of the invention patent application with application date of September 14, 2018, application number 201880074386.7, and invention name “Ophthalmic Delivery Device”. Technical Field

[0002] The present application relates to ophthalmic medical devices and related methods, and in particular, to cannula devices and methods of injecting materials for administering compositions containing active agents to the eye. Background Art

[0003] Due to the unique anatomy and physiology of the eye, there are multiple barriers that prevent drugs or active therapeutic agents from being transported in large quantities to the ocular tissues. The permeability of the blood vessels of the eye is limited by the blood-ocular barrier that regulates the intraocular fluid. Because of these blood-ocular barriers, systemically administered drugs cannot reach significant concentrations in the ocular tissues. Most of the drugs in topical drops applied to the surface of the cornea are washed into the nasolacrimal duct by tears. In the tear film, the time for the drug to penetrate the cornea and reach the intraocular space is limited. Some drugs can be delivered to the front of the eye by drops, but significant therapeutic concentrations are achieved in the back of the eye, and the retina is generally not accessible by topical administration methods.

[0004] Many diseases that cause vision loss involve the posterior retina where color vision and reading occur. To treat the back of the eye and the posterior retina, drugs are often injected into the eye. Subconjunctival injections are used to place the drug reservoir below the outer layer of the eye, but the extremely high lymphatic flow in the conjunctiva causes the drug to be quickly transported away from the eye. Subconjunctival injections are generally ineffective for achieving high drug levels in the back of the eye.

[0005] Sub-Ton's injection is sometimes used to place medications in a more posterior position beneath the conjunctiva and Tenon's sac of the eye to deliver medications to the posterior region of the eye. Sub-Ton's injection has been shown to be useful for steroid administration, but many drugs do not reach significant levels of drug in the retinal tissue after sub-Ton's injection. The tip of the injection needle is inserted deep into the posterior shell of the eye, where it cannot be directly observed. This technique requires experience and careful technique to avoid physical damage to the eye or misplacement of the medication.

[0006] Intravitreal injections tend to place the drug directly into the vitreous cavity, which generally requires smaller amounts of drug than sub-Tenon's injections. The half-life of the drug is limited by the continuous movement of fluid in the vitreous toward the anterior chamber. This vitreous flow washes out the drug over time and exposes the drug to other tissues of the eye in the path of the flow. Intravitreal administration of drugs (e.g., steroids) is associated with complications such as cataract progression caused by exposure of the drug to the lens during forward flow from the vitreous cavity and increased intraocular pressure caused by exposure of the drug to the trabecular meshwork.

[0007] The suprachoroidal space between the choroid and sclera and the supraciliary space between the ciliary body and sclera are more difficult to locate but can also be used for drug injection. Unlike intravitreal injection, the fluid in the suprachoroidal space and supraciliary space flows posteriorly. This flow can help drugs injected into the suprachoroidal space or supraciliary space reach the posterior tissues and posterior retina. Small drug particle size is ideal for migration in the suprachoroidal space or supraciliary space, but small drug particles release the drug at a faster rate, thereby shortening the durability of drug treatment.

[0008] A potential problem with all injections of drugs below the sclera into the eye is that the introduction of foreign volume into the eye can cause an increase in intraocular pressure (IOP). An increase in IOP can cause pain and potential damage to the optic nerve. For highly active drugs, small injection volumes can be used without causing a significant, dramatic rise in IOP, such as 0.05 ml of an anti-VEGF drug. However, for larger volumes, such as 0.1 ml of a steroid, the IOP may rise significantly and may result in an acute pain period and loss of vision. Summary of the invention

[0009] In accordance with the foregoing discussion, the present invention provides a device designed for minimally invasive insertion or placement of a flexible cannula or catheter in the suprachoroidal space or supraciliary space of the eye to administer a material containing an active agent. The cannula or catheter comprises an elongated tubular element that is placed in the suprachoroidal space or supraciliary space by passing through the lumen of a needle or trocar. Surgical instruments having a sharp distal tip for insertion into a cannula or catheter are generally described as trocars, which are used interchangeably with the term "needle" in this application. In this application, the term "cannula" is used interchangeably with the term "catheter". The present invention is an intubation device comprising a needle or trocar, a flexible cannula or catheter, and a mechanism for facilitating insertion of the cannula into the suprachoroidal space or supraciliary space.

[0010] Although the material containing the active agent can be injected into the suprachoroidal space or the supraciliary space with a needle, the length of the needle bevel at the distal end of the needle lumen opening is significant relative to the thickness of the tissue covering the suprachoroidal space or the supraciliary space, which is 1 mm or even longer for a small hypodermic needle. As a result, the choroid or the ciliary body may be punctured by the needle during injection into the suprachoroidal space or the supraciliary space. Although the material containing the active agent can be injected into the suprachoroidal space or the supraciliary space, the penetration of the underlying tissue creates a pathway for the active agent to easily leak into the intraocular space (e.g., vitreous body). For active agents that need to avoid high intraocular levels, directly injecting the material containing the active agent into the suprachoroidal space or the supraciliary space with a needle may result in poor control of the distribution of the active agent. A flexible cannula is introduced into the suprachoroidal space or the supraciliary space using a trocar, and the cannula is pushed away from the tissue penetration site by the trocar and the material containing the active agent is applied through the cannula to avoid direct leakage of the active agent into the intraocular space. Additionally, advancement of the cannula allows positioning of the active agent administration site proximate to the desired tissue to be treated (eg, the posterior retina).

[0011] The cannula device includes an elongated syringe with a hollow needle at the distal end, wherein the lumen of the needle serves as a reservoir for at least a portion of a flexible cannula, and also includes a mechanism for advancing the flexible cannula through the needle and pushing it out from the distal end of the needle into the tissue space. The cannula can be manually advanced by, for example, a sliding mechanism that is designed to be manually controlled by holding the device by fingers. The cannula can also be advanced by a plunger with a force element, such as a spring or a gas reservoir, that provides a force to the cannula to advance or stretch the cannula from the distal end of the needle. The distal end of the cannula is sized to have a diameter less than or equal to the inner diameter of the needle lumen. In one embodiment, the stretching force is activated immediately while or after the needle tip is advanced into the tissue.

[0012] In one embodiment, the cannula device further comprises a distal element comprising a tissue interface having a distal seal secured to the distal end of the cannula device so as to seal the needle lumen during application of the extension force. By applying pressure on the tissue surface with the distal end of the cannula device, the distal seal can be penetrated by or deformed by the distal tip of the needle, and the penetrated distal element becomes slidable on the needle to allow the needle to be advanced into the tissue. The penetration of the distal seal opens a path for the cannula to be advanced from the distal end of the needle. The force element of the cannula device having the distal element and the distal seal is activated before or simultaneously with the penetration of the distal seal by the needle and the advancement of the needle tip into the tissue, thereby enabling simple one-handed operation of the cannula device to apply the cannula to the suprachoroidal space or supraciliary space of the eye.

[0013] In one embodiment, the distal tip of the needle is curved or includes an internal deflection element within the needle lumen to direct the cannula at an angle to the long axis of the needle during delivery of the flexible cannula. In one embodiment, the distal tip of the cannula is curved in an unconstrained state and once extended from the distal tip of the needle, the cannula is directed at an angle to the long axis of the needle. In another embodiment, the cannula is directed at an angle to the long axis of the needle during extension in a posterior direction. In another embodiment, the cannula is directed at an angle to the long axis of the needle during extension in a direction away from tissue beneath the tissue space.

[0014] In one embodiment, the distal tip of the cannula comprises a tubular section having a length of 1 mm to 3 mm that is more flexible than the proximal portion of the cannula. In one embodiment, the distal tip of the cannula has a lubricious coating on the outer surface to minimize trauma and friction when in contact with tissue. In one embodiment, the distal tip of the cannula is rounded or shaped to be atraumatic when in contact with tissue.

[0015] In one embodiment, the distal tip of the cannula is illuminated when in the suprachoroidal or supraciliary space to provide visualization of the distal tip position, thereby identifying and allowing the cannula to be positioned to administer the material containing the active agent. When in the suprachoroidal or supraciliary space, the light emitted by the illuminated cannula passes through the overlying sclera, providing a visual feature that allows the cannula position to be verified before administering the active agent. The illuminated cannula also provides a headlight effect from the distal tip of the needle when the distal tip is configured in the needle lumen. The headlight is no longer visible on the surface of the eye when the needle bevel enters the sclera, thereby indicating to the user that the cannula is in the proper position to apply the stretching force.

[0016] In one embodiment, the cannula provides a fluid connection through the cannula device so that a flowable material for application (e.g., a composition containing an active agent) can be delivered to a tissue space (e.g., the suprachoroidal space or the supraciliary space) through the lumen of the cannula. In one embodiment, the cannula device comprises a reservoir for application material, which can be delivered to a tissue space, such as the suprachoroidal space or the supraciliary space, through the lumen of the cannula. In one embodiment, the cannula device comprises a reservoir for application material, which can be delivered to a tissue space, such as the suprachoroidal space or the supraciliary space, through the lumen of the cannula, wherein the application material is a semisolid composition.

[0017] Inventions related to cannula devices include specific formulations of semisolid materials for administration containing active agents or drugs. In the present application, the terms "active agent", "drug" and "therapeutic agent" are used interchangeably. In the context of the present application, a semisolid material refers to a material that does not flow without pressure and maintains a position that is locally located in the eye immediately after delivery. In one embodiment, a semisolid material for injection is provided, which includes drug particles in a semisolid excipient or excipient mixture. In one embodiment, the drug particles are microspheres containing active agents made of one or more biodegradable or bioerodible polymers. In order to minimize the frequency of application to the patient, in some embodiments, the microspheres containing active agents are constructed to provide a slow release of the active agent. In some embodiments, the active agent in the microspheres is mainly in the form of an amorphous solid dispersion. In some embodiments, the microspheres are suspended in a viscoelastic excipient to facilitate flow characteristics delivered by a small needle or cannula. In one embodiment, the semisolid material for injection containing microspheres containing active agents is in the form of a freeze-dried material, and the freeze-dried material is quickly reconstituted with an aqueous fluid just before administration. In one embodiment, the semisolid material for injection comprising microspheres containing an active agent and a viscoelastic excipient is in the form of a lyophilized material that is rapidly reconstituted with an aqueous fluid immediately prior to administration.

[0018] While semisolid formulations containing active agents are ideal for the cannula devices of the present invention, the formulations can also be used for all other forms of ophthalmic drug injections, including intravitreal, subconjunctival, sub-Tenon's, and intracameral, for delivery to the suprachoroidal or supraciliary spaces. The size of the particles and concentration in a semisolid or viscous vehicle enables injection of small volumes through a small gauge needle or cannula.

[0019] These and other aspects of the invention will become apparent from consideration of the following detailed description, taken in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] Figure 1 An embodiment of an intubation device for extending a flexible cannula into a tissue space of an eye is depicted.

[0021] Figure 2 , 2 A and 2B depict embodiments of an intubation device for extending an illuminated flexible cannula having a straight tip and a curved tip into a tissue space of an eye.

[0022] Figure 3 An embodiment of an intubation device for extending a flexible cannula into a tissue space of an eye having an actuation trigger and a friction velocity dampener is depicted.

[0023] Figure 3A Depicted Figure 3 A magnified detail of the device's trigger mechanism.

[0024] Figure 3B Depicted Figure 3 Zoomed-in detail of the velocity damper mechanism of the device.

[0025] Figure 3C Depicted Figure 3 Magnified detail of the distal tip of the flexible cannula of the device.

[0026] Figure 4 An embodiment of an intubation device for extending a flexible cannula into a tissue space of an eye is depicted, the intubation device having a distal element and a distal seal.

[0027] Figure 5 An embodiment of an intubation device for extending a flexible cannula into a tissue space of an eye is depicted, the intubation device having a distal element and a distal seal, and having a reservoir containing a material for administration.

[0028] Figure 6 One embodiment of a distal tip of an intubation device having a retractable element is depicted.

[0029] Figure 7 Depicted is an enlarged detail of one embodiment of a distal tip of an intubation device having a retractable element.

[0030] Figure 8 One embodiment of a distal tip of an intubation device is depicted in an uncontracted state.

[0031] Fig. 9 An embodiment of an intubation device is depicted in a collapsed state.

[0032] Fig.10 An embodiment of an cannula device needle having a curved distal tip to guide the cannula at an angle to the long axis of the needle is depicted.

[0033] Fig.11 An embodiment of an cannula device needle having an internal deflection element in the lumen of the needle at the distal tip to guide the cannula at an angle to the long axis of the needle is depicted.

[0034] Fig.12 An embodiment of an cannula device needle is depicted having a localized internal deflection element in the needle lumen at the distal tip to guide the cannula at an angle to the long axis of the needle.

[0035] Fig.13 A delivery device is depicted that discharges a semisolid composition for administration.

[0036] Fig.14 Depicted is a solid or semisolid composition for administration shaped as an elongated body.

[0037] Fig.14A Depicted Fig.14A A magnified detail of the composition.

[0038] Fig.15 is a graph of test results of minimum sealing force of tissue interface.

[0039] Fig.16 is a graph of the drug elution characteristics of PLGA polymer microspheres.

[0040] Fig.17 It is a graph of drug elution characteristics of 75:25 PLGA polymer microspheres.

[0041] Fig.18 It is a graph of drug elution characteristics of 85:15 PLGA polymer microspheres.

[0042] Fig.19 is a graph of vitreous drug content.

[0043] Fig. 20 is a graph of the drug content of the choroid.

[0044] Fig.21 is a graph of retinal drug levels. DETAILED DESCRIPTION

[0045] The present invention is a device for minimally invasive cannulation of the suprachoroidal space or the supraciliary space. After cannulation, the device can be used for delivering a material for application (e.g., a composition containing an active agent) into the gap through a cannula. In particular, the material for application is a composition comprising a fluid, a suspension, a semisolid or a solid active agent. The active agent can be a material for providing a therapeutic or diagnostic effect for treating the eye. The active agent can include a drug, a diagnostic agent, a gene therapy agent, a therapeutic cell or a means for physical repair of the tissue.

[0046] Placing the cannula in the suprachoroidal or supraciliary space of the eye provides a means of delivering a composition containing an active agent to a location in the interstitial space that is distal to the site of tissue penetration. The cannula device of the present invention allows for administration of a composition containing an active agent and directs the composition containing an active agent from an anterior tissue entry site (e.g., the pars plana) toward the posterior retina. The cannula device can also be designed to deliver a composition containing an active agent to a specific site of the eye to treat a localized disease such as a tumor.

[0047] The cannulation device includes an elongated syringe having a hollow needle at a distal end and a cannula including an elongated tubular element, wherein the lumen of the needle serves as a reservoir for at least a portion of the tubular element. The device also includes an extension mechanism to advance the cannula through the lumen of the needle and to push the distal portion of the cannula out of the distal end of the needle. The mechanism can be mechanically coupled to the cannula by a push rod or a plunger between the push rod and the cannula. Alternatively, the end of the mechanism can be directly engaged to a portion of the cannula. When holding the device, the mechanism can be manually activated with a finger, such as with a sliding actuator or a lever on the device body. Manual activation allows the user to finely control the speed and degree of cannula extension.

[0048] In one embodiment, the cannula device includes a force element such as a spring or a gas reservoir, which provides force so that the cannula is advanced or stretched through the needle lumen and pushed out into the tissue gap from the far end of the needle. The force element can be mechanically connected to the cannula by a push rod or a plunger between the push rod and the cannula. Alternatively, the end of the force element can be directly matched to a part of the cannula. The force element, the force element plunger or the force element push rod can be connected to the cannula by a connecting sleeve or other forms of connectors. Before use, the distal end of the cannula is in the main body of the needle and the cannula device. The cannula is configured to extend from the distal tip of the needle once it is launched by the force element. The length of the cannula allows the far end of the cannula to extend from the distal tip of the needle when stretched. The cannula is configured to have a stretch length from the distal tip of the needle to the expected delivery site of the composition containing an active agent. In one embodiment, the length of the cannula starting from the distal tip of the needle in the stretched state is 2mm (0.08 inch) to 15mm (0.6 inch). A cannula with a very short extension length can be used to guide the application material from the needle penetration site in a preferred direction. In particular, an extension length of 5 mm (0.2 inch) to 12 mm (0.5 inch) from the distal tip of the needle enables the cannula to be introduced into the eye at the pars plana to avoid potential damage to the retina and place the distal tip of the cannula near the posterior retina, thereby delivering the application material to the visually most important part of the eye. The extension force can be activated immediately or simultaneously after the needle tip is pushed into the tissue. Activation can be performed by releasing the force element by the user or by a mechanism at the distal tip of the device.

[0049] The cannula is sized to have a diameter less than or equal to the inner diameter of the needle lumen, and the cannula is slidably disposed in the needle lumen. The cannula has a proximal end for receiving a composition containing an active agent and a distal tip for delivering the composition containing an active agent. In one embodiment, the distal tip of the cannula is configured to have a circular profile to provide a non-invasive tip for entering the interstitial space without penetrating the underlying tissue. The circular profile can be formed by heat treatment of the distal tip of the cannula, by directly molding the distal tip, laser processing of the tip, or by applying another material to the distal tip. The material applied can be the same as the cannula material in the solvent dispersion, or a material different from the cannula material in the solvent dispersion, or an adhesive. The non-invasive distal tip can also be formed as a separate component and connected to the distal end of the cannula by heat or adhesive means. In one embodiment, the distal end of the cannula is bent or bent at an angle when not constrained. The bent or kinked cannula is straight when placed in the lumen of the needle, but once deployed from the lumen of the needle, resumes its unconstrained configuration, directing the cannula tip at an angle to the long axis of the needle, typically in the direction of the needle bevel. The bend or kink can be used in conjunction with a means for identifying the orientation of the needle bevel to direct the cannula toward the posterior region of the eye, away from underlying tissue, or both. The cannula can be bent along its entire length or bend or kink at the distal portion of the cannula. The cannula can have a compound bend, such as a curve with a smaller radius at the distal tip than the curve in the proximal portion of the cannula.

[0050] In one embodiment, the cannula is illuminated when it is in the suprachoroidal or supraciliary space to provide visual guidance of the cannula position. It has been found that the illuminated cannula in the suprachoroidal or supraciliary space can be seen through the overlying sclera and conjunctiva. However, if the cannula is located in the intraocular space (e.g., vitreous body), illumination cannot be seen through the overlying tissue. It is found that the light output of 100 microwatts (μW) to 700 microwatts (μW) emitted from the cannula provides good visibility of the cannula position through the sclera and conjunctiva. The cannula can be illuminated by coupling a light source to an optical fiber, which is connected to the cannula lumen extending to the far end of the cannula or within the cannula lumen extending to the far end of the cannula. In another embodiment, the cannula is illuminated by using a cannula material with a refractive index that can provide all or part of internal reflection, so that the cannula is used as an optical fiber without the wall, outer diameter, or lumen of the cannula being hindered by a separate optical fiber. In particular, the use of the sleeve wall to conduct light along the length eliminates the optical fiber in the lumen, thereby maximizing the effective lumen diameter and the ability to deliver active agents (particularly active agents that cannot be delivered by the lumen with flow path irregularities or suspensions of shaped solid compositions). Using the sleeve material to conduct light can be enhanced by using a reflective or low-refractive-index coating on the outside of the sleeve. The illumination of the sleeve can be customized by using a coating and the geometry of the light introduced into the sleeve, so that only the far end of the sleeve, the entire length of the sleeve or the selected area of ​​the sleeve is illuminated. In another embodiment, the sleeve can be illuminated by directing a light source to the near end of the sleeve and allowing light to be transmitted to the distal tip along the wall of the sleeve, so that the user can better distinguish the position of the entire length of the sleeve. Alternatively, light can be introduced by directing light to the sharp bend in the proximal portion of the sleeve. The sleeve can also include the feature of illuminating a fragment or discrete portion of the sleeve with a higher intensity than the surrounding portion. For example, a groove or a textured ring can be incorporated into the sleeve outer surface, which will provide a bright spot. When the cannula has been fully extended, these points can act as depth marks or indicators. By constructing the far end of the illuminated cannula in the lumen of the needle, light is projected through the needle lumen to provide a projected light or headlight from the far end of the device. The headlight is aligned directly with the needle, illuminating a point on the tissue to provide a target to confirm the position and provide guidance to the user. As the distal tip of the needle approaches the tissue surface, the illuminated target usually becomes smaller, providing a visual guide to the distance to the tissue surface. Once the bevel of the needle is inserted into the tissue, the headlight is absorbed and is no longer visible on the surface of the eye, indicating that the cannula has been positioned to activate the extension mechanism. The far end of the cannula is placed in the needle to be positioned at the proximal end of the needle bevel or just near the proximal end of the needle bevel. The distance from the far end of the needle bevel to the far end of the cannula is 0 to 5 mm, which is sufficient to provide a headlight function and responsively extend the cannula. The light source can be a separate unit, and the light output is coupled to the intubation device and the cannula through a fiber optic connector. Alternatively, the light source can be integrated into the intubation device.While activating cannula extension, illuminating the cannula and observing the position of the cannula through the overlying tissue can provide control and assurance for insertion into the desired tissue gap. The light source can be any light emitting device, such as a halogen light source, an LED light source, or a laser light source.

[0051] In another embodiment, the material for application (e.g., composition containing active agent) is guided to the proximal end of the cannula from a connector (e.g., a Luer fitting or an injection port communicated with the proximal end of the cannula). The connector or injection port may be located on or connected to the device. In another embodiment, the material for application (e.g., composition containing active agent) is located in a reservoir in the main body of the cannula device, and the path for transferring the material for application connects the reservoir to the lumen of the cannula. The size of the reservoir may be configured to be applicable to the volume of material to be delivered. The size of the reservoir may be designed to be used for a delivery volume in the range of, for example, 0.1 microliters to 500 microliters. The material for application in the reservoir may be delivered manually by a plunger or delivered by the actuation of a force element, and the force element acts on the plunger so that the plunger moves in the reservoir and provides a delivery force on the material for application. For the application of small volumes, the lumen of the cannula may also serve as a reservoir of a composition containing an active agent. For small volume administration, the lumen of the cannula can serve as a reservoir for the composition comprising the active agent, and the plunger can be configured to move distally within the lumen of the cannula to provide a delivery force on the material for administration.

[0052] In some embodiments, the distal end of the cannula device consists of an exposed needle comprising at least a distal portion of a flexible cannula. While or after the needle is inserted into the tissue overlying the desired target tissue gap, the extension of the cannula is actuated. In one embodiment, the extension of the cannula is performed by manually advancing the cannula with a mechanism on the device connected to the proximal portion of the cannula. In another embodiment, the extension of the cannula is performed by actuating a force element coupled to the proximal portion of the cannula. The speed and degree of cannula extension can be controlled by using a propulsion mechanism and actuation to allow careful gradual extension. In the process of the user gradually extending the cannula, a cannula illuminated is used to provide guidance.

[0053] In some embodiments, the distal end of the cannula device is composed of a distal element surrounding the distal end of the needle. The distal element serves as a tissue interface, wherein the distal seal is fixed to the distal end of the cannula device, thereby sealing the needle lumen in the process of applying a stretching force. By applying pressure on the tissue surface with the distal end of the cannula device, the distal seal can be penetrated by the distal tip of the needle, and the penetrated distal element becomes slidable on the needle so that the needle can be advanced into the tissue. The penetration of the distal seal opens the path of the cannula delivered from the distal end of the needle. The cannula device with a force element is activated before or at the same time when the distal seal is penetrated by the needle and the needle tip is advanced into the tissue. The resulting self-actuated stretching mechanism ensures that the delivery path of the cannula is opened immediately when the needle is placed in the tissue, regardless of the direction and speed of the needle insertion. The self-actuated mechanism enables a simple one-handed operation of the cannula device to apply the cannula to the suprachoroidal space or the supraciliary space of the eye.

[0054] In one embodiment, the distal element includes a tissue interface and a distal seal mounted on a tubular distal housing. The tubular distal housing is assembled to the outside of the needle and can be sealed to the surface of the needle at certain points along its length. In one embodiment, the housing can be sealed by an elastomeric element, which is compressed between the housing and the needle. The elastomeric element can therefore be annular. In one embodiment, the elastomeric element can be compressed between the housing and the body of the device. The elastomeric element can be located at or near the near end of the housing. In one embodiment, the elastomeric element is used as a seal between the housing and the needle. In one embodiment, the elastomeric element acts as a friction element or component, limiting the travel of the housing in the proximal direction, thereby applying force to the tissue surface through the tissue interface when the needle penetrates the tissue. In some embodiments, the distal element includes a tissue interface and a distal seal, and is slidably connected to the outside of the needle without a distal housing. The distal element is connected to the distal tip of the needle, but is not freely movable or sliding from the end of the needle to the proximal end due to the distal seal. The distal element includes a tissue interface with a distal seal, or a tissue interface with a distal seal and a connected housing. After the cannula device is irrigated or activated for use, the sleeve is under the effect of the stretching force from the force element but cannot move through the distal seal. The tissue interface is placed on the surface of the eye, and the device is manually advanced, thereby forcing the needle to pass through the distal seal, and then pass through the outer surface of the eye to enter the tissue below. The distal element becomes slidable from the end of the needle to the proximal end after penetrating the distal seal, so that the tissue interface is kept on or near the surface of the eye during the process of the needle being advanced into the tissue. When the distal tip of the needle passes the distal seal, the force source immediately causes the sleeve to extend from the needle tip and enter the tissue gap.

[0055] In one embodiment, the tissue interface and the distal seal are fixed to a housing disposed around the needle. The housing may include a cylindrical element fixed to the distal end of the body of the device at the proximal end of the housing. The housing may include a foldable, twistable or deformable element that enables the distal end of the housing to be slidably retracted along the needle, thereby allowing the needle tip to penetrate the distal seal. In some embodiments, the distal element is fixed to the distal tip of the needle by other means.

[0056] In one embodiment, the cannula device includes an elongated barrel having a hollow needle at a distal end, a cannula to be extended that resides at least partially in the lumen of the needle, and a force element (e.g., a spring or a source of pressurized gas) that mechanically couples the cannula to extend the cannula. When the distal tip of the device reaches the gap, the extension of the cannula can be manually actuated by activating the force element or by the action of the needle penetrating the tissue to place the cannula in the tissue gap.

[0057] In one embodiment, the operation of the device mechanism opens a path for the cannula to start extending from the needle tip immediately when the needle penetrates the distal seal just before the needle enters the target tissue. Since the cannula is under the extension force before or at the same time as the distal seal is penetrated by the needle tip, the extension is triggered only by the placement of the needle and the subsequent advancement of the needle through the tissue interface. This enables the time of the extension action to be accurately and automatically controlled only due to the needle tip entering the target tissue. The resulting self-actuated mechanism eliminates the need for a separate control mechanism (such as a valve or trigger on the intubation device body), so the cannula can be extended without special finger positioning or using a second hand. Therefore, the intubation device enables intubation with one hand, so that the other hand of the physician can stabilize the eye or perform other actions to facilitate the use of the device for surgery. The self-actuated intubation mechanism also eliminates the user's need to determine when to start extending, which is particularly useful when it is difficult to locate the target tissue gap due to small target size, lack of visualization and anatomical variability (such as suprachoroidal space or supraciliary space).

[0058] The cannulation device allows the user to precisely control the position of the needle during use. The needle is fixed to the body of the device so that the distal tip of the needle is directly controlled when the device is held. In embodiments where the extension force is provided by a force element, it is not necessary to hold or push the cannula by hand holding the device, thereby allowing the device to be held and used in a natural, highly controllable position, such as with a writing instrument or scalpel. Typically, the needle is arranged parallel to the elongated body or barrel of the device.

[0059] Once the needle is inserted into the eye, the cannula cannot extend or stretch from the distal tip of the needle until the distal end of the needle reaches the gap to accommodate the cannula. In particular, the scleral tissue is very elastic and effectively seals the needle tip when the needle tip passes through the suprachoroidal space or the supraciliary space, so the unique properties of the sclera do not allow the cannula to enter the sclera. Once the needle tip reaches the lower gap such as the suprachoroidal space or the supraciliary space, the cannula can be pushed out of the needle and stretched in the gap. Through this mechanism, the cannula is guided to a position where the cannula can be accommodated at the distal tip of the needle. After the cannula is stretched, the application material such as a composition containing an active agent can be delivered to the eye through the inner cavity of the cannula. In one embodiment, the cannula is coupled to a force element for stretching. The distal tip of the needle is pushed into the surface of the eye, and when the bevel of the needle is in the eye, the force element is activated to apply a stretching force to the cannula. The needle is further advanced until the needle tip reaches the suprachoroidal or supraciliary space, sufficient to allow the cannula to self-extend into the space.

[0060] The flexible cannula of the cannula device is designed to have appropriate mechanical properties, with appropriate flexural modulus to allow the cannula to bend to advance into the suprachoroidal space or the supraciliary space, and with appropriate axial compression stiffness to allow the cannula to be advanced into the gap by a stretching mechanism acting on the proximal portion of the cannula. The mechanical properties can be appropriately adjusted by selecting the cannula material and the cannula size. In addition, the cannula may have features for adjusting the mechanical properties. Reinforcement elements such as wires may be placed in the lumen or wall of the cannula to increase the axial buckling strength. The distal tip of the cannula may also be reinforced, for example, using a coil or coating to simultaneously adjust the buckling strength and flexibility of the distal portion of the cannula. The coil may be made of metal or a high modulus polymer and placed on the outer surface of the cannula, the inner surface of the cannula, or the wall of the cannula. In one embodiment, the distal portion of the cannula and the cannula tip are formed by a material that is softer or more flexible than the proximal portion of the cannula to form a soft tip structure. The 1 mm to 3 mm long distal portion of the softer material coupled to the harder proximal portion of the cannula allows extension through a needle with a soft distal tip that minimizes penetration and trauma during extension into the supraciliary or supraciliary space. The cannula can be made of polymers such as polyether block amides (PEBA), polyamides, perfluoroalkoxy polymers, fluorinated ethylene propylene polymers, ethylene-tetrafluoroethylene copolymers, ethylene-chlorotrifluoroethylene copolymers, polystyrene, polytetrafluoroethylene, polyvinylidene, polyethylene, polypropylene, polyethylene-propylene block copolymers, polyurethanes, polyethylene terephthalate, polydimethylsiloxane, polysiloxane copolymers, polyvinyl chloride, polyetherimide, and polyimide. For some applications, the cannula can be made of a flexible metal such as nickel titanium superelastic alloy (nitinol).

[0061] With appropriate needle length and orientation, the device can be used to extend the cannula and deliver the material for administration to the subconjunctival space, suprachoroidal space, supraciliary space, subretinal space, subTenon's space, vitreous cavity, or anterior chamber.

[0062] The needle comprises a rigid material having a diameter that allows the cannula to pass through the lumen of the needle, typically in the range of 20-40 gauge, e.g., less than 0.9 mm (0.04 in) outer diameter and 0.6 mm (0.02 in) inner diameter, wherein the needle length is suitable for reaching the desired tissue space. The needle is fixed to the body or barrel of the device and typically does not slide or move relative to the body to provide precise control of the needle depth during tissue penetration.

[0063] The distal tip of the needle can be beveled or pointed to aid penetration. The bevel can be designed to aid access to a specific target. For example, a short bevel with an 18-degree bevel can be used to insert into narrower spaces, such as the subconjunctival space or the space below the Tenon's capsule. A medium bevel needle with a 15-degree bevel can be used to insert into spaces such as the suprachoroidal space or the supraciliary space. A longer bevel (e.g., a 12-degree bevel) can be used to insert into the anterior chamber or posterior chamber.

[0064] In one embodiment, the device includes a distal element and a distal seal, and complementary bevels in the lumen of the distal element provide a close fit between the distal seal and the bevel of the needle. The bevel of the needle is aligned with the bevel in the lumen of the distal element. The distalmost portion of the distal element can be flat or inclined to assist the orientation of the needle in the process of penetrating tissue, thereby helping to reach certain tissue gaps. For example, the tissue contact bevel surface of the distal element can help target the cannula to a shallower tissue target, such as the subconjunctival space, the space under the fascial capsule of the eye, and in some areas of the suprachoroidal space. The angle of the tissue contact surface of the distal element can be 90 degrees (for vertical insertion) to 15 degrees with the axis of the distal element. The device can include a guide at the distal tip to help insert the needle into the eye at an angle at a selected angle. The guide can be composed of an angled pillar or an angled plate extending from the far end of the device to contact the eye before the needle is inserted. The guide may also consist of a post extending from the body to provide a reference for estimating the needle insertion angle.

[0065] In some applications of the present invention, it may be desirable for the distal tip of the needle to guide the cannula at an angle to the long axis of the needle. Such a design reduces the force of the cannula on the underlying tissue of the target tissue space such as the ciliary body or choroid, and can also be used to guide the cannula in a desired direction, such as to the posterior region of the suprachoroidal space near the macular region of the retina. The distal tip of the needle can be bent in a range of 5 to 60 degrees to guide the cannula. The distal tip of the needle can also have an internal deflection element in the lumen of the needle in the region of the bevel of the needle. The internal deflection element can be a protrusion, an inclined surface, or a ramp to guide the cannula away from the long axis of the needle. The internal deflection element can be positioned along the entire length of the needle bevel, or positioned at a position separated from the proximal end of the bevel. In one embodiment, the internal deflection element is located at 20% to 80% of the length of the needle bevel, 25% to 75% of the length of the needle bevel, or 30% to 60% of the length of the needle bevel from the distal end of the bevel. The body of the device may include labels or indicators to provide the user with the orientation of the guide cannula, such as the orientation of the needle bevel or symbols indicating the direction in which the deflection element will deflect the cannula.

[0066] The needle can be made of metal, ceramic, high modulus polymer or glass. The length of the needle in the tissue is selected to match the target location of the cannula and the target location changes caused by anatomical variability. The effective total length of the needle is the length that the needle can be advanced into the tissue. In an embodiment of the device with a distal element around the needle, the effective total length of the needle is the length from the distal tip of the needle to the distal surface of the tissue interface when the distal element completes all proximal strokes. The distal element slidably moves on the needle during the advancement of the needle into the tissue, so that the length of the needle protruding through the distal element during the advancement into the tissue can be gradually increased.

[0067] In some embodiments, once the needle reaches the appropriate position (which may be less than the effective full length of the needle), the cannula is extended. Depending on the extended length of the cannula and the user's manual advancement speed, the release of force and the resulting extension time occur quickly within about 0.1 seconds to 3 seconds.

[0068] In an embodiment with a force element for stretching the cannula, the speed of stretching can be controlled by the amount of force applied by the force element. The stretching time, about 0.1 to 3 seconds, can also be controlled by a damping or friction mechanism coupled to the advancement of the cannula to limit the advancement or extension speed of the cannula. The damping or friction element can be configured to have an amount of damping or friction coupled to the degree of stretching to balance the nonlinear force delivery of the force element (such as a spring). In one embodiment, a friction wheel engages with a plunger shaft coupled to the near end of the cannula. During the stretching process, the friction wheel slows down the plunger speed according to the amount of friction. The friction can be adjusted along the stretching distance by increasing contact with the plunger shaft or by a varying friction coefficient (e.g., the amount of texture along the length of the shaft). Typically, when the stretching force from the compression force is the largest, the friction is configured to be greater during the initial stretching process and is configured to reduce friction during the movement of the plunger toward the entire stretching length. The stretching mechanism can include features that communicate with the user with visual and tactile feedback when the cannula is stretched from the needle to indicate that the needle does not need to be further advanced. The controlled speed extension event provides the user with sufficient time to stop needle advancement, resulting in an effective variable needle length to accommodate patients with different tissue thicknesses. Embodiments of the device with an effective variable needle length and self-actuated extension can be used to perform cannulation into spaces that are not normally open, such as the subconjunctival space, the sub-Tenon's fascial space, the suprachoroidal space, and the supraciliary space. For the subconjunctival space and the sub-Tenon's fascial space, the effective total length of the needle is in the range of 0.35 mm (0.01 inch) to 2 mm (0.08 inch) depending on the angle of needle insertion. For the suprachoroidal space and the supraciliary space, the effective total length of the needle is in the range of 1 mm (0.04 inch) to 5 mm (0.16 inch) depending on the angle of needle insertion. For the vitreous cavity, the effective total length of the needle is in the range of 5 mm to 15 mm. The effective total length of the needle can be, for example, 0.3 mm (0.011 inch) to 3 mm (0.12 inch), 0.35 (0.014 inch) to 2 mm (0.08 inch), 1 mm (0.04 inch) to 4 mm (0.16 inch), 10 (0.39 inch) to 15 mm (0.59 inch).

[0069] In one embodiment, the distal element applies a sealing force pointing to the distal end to the tissue surface to maintain the seal on the eye surface. The sealing force is designed to be sufficient to block the flow of applied material from the needle channel during the application process of the delivery material. The sealing force is minimized to prevent the tissue of the gap that is normally closed or the gap that is nearly closed (for example, the choroidal space or the ciliary body supracervical space) from being compressed, which will prevent insertion into the gap or increase intraocular pressure, thereby limiting the movement of the applied material into the normally closed or nearly closed gap. In one embodiment, the distal element maintains contact with the tissue surface, but does not apply a sealing force pointing to the distal end to the tissue surface to maintain the seal on the eye surface. In one embodiment, the distal element contacts the eye surface during the process in which the distal tip of the needle penetrates the distal seal of the distal element, but after the needle penetrates the distal seal and enters the eye tissue, the distal element will not maintain contact with the eye surface.

[0070] In the embodiment with tissue interface and distal seal, tissue interface and distal seal can comprise soft polymer, rubber or other material, make needle can penetrate but can not core the seal material.Can select tissue interface and distal seal material to provide compliance to eye surface in the process of needle insertion into eye tissue, and also seal the stretching path from needle until needle is advanced through distal seal.Once needle penetrates distal seal, needle is advanced through outer eye tissue, arrives desired cannula position.Tissue interface and distal seal remain on eye surface.Distal seal has enough elasticity, to prevent under extension force before needle is advanced through distal seal, due to cannula rupture.The part of distal seal located in the path of needle is also thin enough, so that needle can penetrate without excessive force.In the area penetrated by needle, the thickness of distal seal is usually in the range of 250 microns (0.01 inches) to 1500 microns (0.06 inches).

[0071] In one embodiment, sealing force is provided by a compressible or contractible element between the device body and the proximal end of the distal element or the distal housing. In one embodiment, the tissue interface provides sealing force by compression of the tissue interface or elastic compressible element in the distal element. In one embodiment, the distal element is constructed so that the length can be elastically reduced during the needle advancement process to apply sealing force. In one embodiment, a friction element arranged in or around the distal element increases the force required to move the distal element proximally, thereby promoting the contact of the tissue interface with the surface of the eye during the needle advancement process and maintaining the seal to the surface of the eye. The friction of the distal element to the needle can be adjusted according to the movement of the distal element to the proximal end during the needle advancement process. In order to adjust the size of the force applied by the tissue interface during the interface along the needle length to the proximal end, the friction increase can be obtained by increasing the contact or surface texture between the outer surface of the distal element and the needle, or by reducing the hardness of the distal element. Friction can change along the path of travel of the needle along the distal element. For example, low friction can be provided in the initial travel path of the distal element to facilitate insertion of the needle into the eye tissue, and friction can be increased after a needle length corresponding to the needle bevel length is inserted into the eye tissue. The travel length of the distal element under the influence of the high friction area is in the range of 0.3 mm (0.01 inch) to 2 mm (0.08 inch).

[0072] In one embodiment, the device includes a distal element having a distal seal, which is connected to the device body by one or more contractile elements. The contractile element is configured to not allow an increase in length to prevent the distal seal from being offset from the needle tip when a stretching force is applied to the cannula before the needle penetrates the distal seal. The contractile element allows a decrease in length so that the distal element can move proximally during the advancement of the needle into the tissue. In one embodiment, the contractile element includes one or more slender struts that can be deformed, bent or folded away from the needle during the proximal advancement of the distal element. In one embodiment, the contractile element includes a section of tube coaxial with the needle, the tube being cut to form an opening along the axial length of the tube to form a contractile strut. The shape and configuration of the contractile strut can be adjusted to provide the desired force-displacement characteristics of the contractile element. The relationship between force and displacement can be linear or non-linear. In one embodiment, the contractile element provides a force that changes from a spring-like force that increases per unit displacement to a constant force that is independent of displacement, thereby maintaining contact between the tissue interface and the distal seal and the surface of the eye without excessively applying force to advance the needle further into the eye. In another embodiment, the contractile element provides a very low force per unit displacement to facilitate the needle to enter the tissue, and increases the force after the needle bevel is inserted into the tissue. Applying a force exceeding 80 grams (0.18 pounds) to 100 grams (0.22 pounds) can limit the ability of the cannula to enter a closed gap (e.g., the suprachoroidal space or the supraciliary space). In one embodiment, the tissue interface applies a force in the range of 40 grams (0.09 pounds) to 80 grams (0.18 pounds). The transition in force size is designed to occur after the needle bevel length is inserted into the eye tissue, corresponding to a compression or contraction of the contractile element of 0.3 mm (0.01 inches) to 2 mm (0.08 inches). In one embodiment, the contractile element provides contact between the tissue interface and the surface of the eye during the initial insertion of the needle into the eye tissue, but after the bevel of the needle is fully inserted into the tissue, the contractile element contracts to provide little or no resistance to the movement of the distal element along the needle toward the proximal end. The contractile element can be assembled from components of tubular construction, or alternatively cut from a section of tube (e.g., laser-processed nickel-titanium alloy (e.g., nitinol) tube, or polyimide tube). Suitable materials for the distal contractile element include, but are not limited to, stainless steel, spring tempered steel, superelastic nickel-titanium alloy, cobalt-chromium alloy, oil-tempered chromium silicon, polyimide, and polyetherimide. The contractile element can be disposed between the elongated body and the distal element, such as between the syringe and the housing (if any) of the distal element. The contractile element can be fixed to the body and the distal element of the device so that the distal element can slide proximally on the needle but will not move distally from its initial position.

[0073] In some embodiments of the device including a distal seal and a tissue interface, the tissue interface provides a sealing function. The sealing force provided by the tissue interface is within the range used to provide a seal to the needle track, but is less than a force that would close the tissue gap to prevent the cannula from moving into the suprachoroidal space or the supraciliary space. The tissue contact surface area is 0.45 mm 2 (0.0007in 2 ) to 5.07mm 2 (0.008in 2 ) range of tissue interface is suitable for sealing needle tract. Suitable materials for tissue interface and distal seal include but are not limited to natural rubber, silicone rubber and thermoplastic elastomer (such as polyurethane). The rigidity of rubber or elastomer can be selected to provide a suitable combination of compliance to tissue surface and the sealing property of the inner cavity of the far end of the needle. The selection of the material of the tissue interface can also minimize the sealing force that may prevent the sleeve from moving into the tissue gap. The rubber or elastomer must also be able to be penetrated or deformed by the distal tip of the needle to trigger the release of the sleeve. The rubber or elastomer with a Shore A hardness of 10 to 70, 10 to 50 or 10 to 30 is suitable for use as a sealing element. Suitable materials for the distal housing include but are not limited to polypropylene, polyethylene, polycarbonate, polysulfone, polyetheretherketone, acrylonitrile-butadiene-styrene, polystyrene, polyamide and polyurethane.

[0074] In one embodiment, the body or syringe of the device contains a reservoir and provides an outer surface for holding the device when in use. The reservoir may include a tubular cylinder connected to the proximal end of the needle at its distal end, and a slidable plunger is provided in the lumen of the tubular body. The reservoir can also provide for the insertion of a cartridge containing a material for administration, wherein the plunger of the device moves a slidable seal located in the proximal end of the cartridge to deliver the material. The body of the device can be made of various thermoplastic materials suitable for medical use, such as polypropylene, polyamide, polycarbonate, polysulfone, polyethylene, cyclic polyolefin, polystyrene and polymethyl methacrylate. The body may include external features, such as textures or finger impressions, to allow the user to grasp and use the device in a more ergonomic manner. The body may include indicators or measurement marks to provide an indication of the amount of material being delivered. The body may include a transparent material or a section of transparent material to allow the movement of the material for administration or the plunger in the reservoir to be visualized, thereby visually indicating the delivery situation. The plunger may have markings to aid in visualizing the loading and release of the reservoir for administration. The body of the device may include labels or indicators to provide the user with the orientation of the guide cannula, such as the orientation of the needle bevel or a symbol of the direction in which the deflection element will deflect the distal tip of the cannula during extension.

[0075] In some embodiments of the present invention, the device includes a tool for providing a stretching force to the sleeve. In some embodiments of the present invention, the device includes a tool for providing a force to deliver a material for application from a reservoir in the device. The tool for providing a deployment force to the sleeve can be manually actuated by any acceptable actuating device, and an acceptable actuating device is for example included in a button or lever in the device, or alternatively actuated by a trigger mechanism on the far end of the device when the tissue is penetrated by a needle. The tool for providing a force for delivering a material for application from a reservoir in the device can be manually actuated by any acceptable actuating device (for example, a button or lever included in the device) or alternatively by a trigger mechanism coupled with the stretching of the sleeve. The tool described herein can be, for example, a compressible reservoir or lever, which can be "squeezed" or compressed by a user (directly or indirectly) to achieve the stretching of the sleeve or the delivery of the material for application. Alternatively, in one embodiment, the tool is a mechanism with a biasing tool or a force element (for example, a compression spring or pressurized gas).

[0076] The device may be disposable and / or single use. Alternatively, the device may be reusable.

[0077] In some embodiments, the device includes a distal seal, wherein the distal seal acts to prevent the sleeve from being disengaged from the needle when the device is activated by the activation of a force element before the needle contacts the eye. This can be achieved by a seal between the needle lumen and the outside of the device. Such a seal can be achieved by making the seal directly contact the needle tip, or can be achieved by using a distal element housing, the size of which is appropriately set so that a seal is provided around the needle shaft when the housing is placed on the needle tip. For example, the outer diameter of the needle can be complementary to the inner diameter of the housing to provide a seal. In an embodiment of the present invention, the seal can only block enough of the needle lumen to prevent the sleeve from extending until the seal moves proximally, thereby completely exposing the opening of the lumen. In such an embodiment, the distal seal is a partial seal and does not cover the entire needle lumen at the far end of the needle. Therefore, the seal can include a deformable protrusion that is sufficient to prevent the sleeve from extending, and the deformable protrusion extends into the lumen at the far end of the needle or extends to a protrusion at the far end of the lumen at the far end of the lumen. Penetration for such distal seal embodiments may be achieved by the distal tip of the needle deforming the protrusion as the needle passes through the protrusion. Embodiments of the invention describing needle penetration of distal seals are also suitable for use with partial seals formed by protrusions extending toward or through the lumen at the distal tip of the needle.

[0078] In general, as described above, some embodiments of the device provide for self-actuated extension of the cannula such that once the needle reaches the desired delivery site in the eye (e.g., the suprachoroidal space or the supraciliary space), the cannula automatically extends. Self-actuation can be performed by a device having a distal seal to prevent cannula extension associated with an extension force actuated before or simultaneously with the insertion of the needle tip into the tissue. Self-actuation can be performed by a device having a trigger on the distal end that activates the extension force while or immediately after the needle tip is inserted into the tissue. In this way, the device can be operated with one hand. The effective needle length and needle insertion angle can be appropriately designed to target a specific cannulation site at a corresponding depth in the eye. In some embodiments, the device can include a retaining tool to retain the distal element on the needle once the device is activated.

[0079] In the embodiment of the device with bare needle without distal element or distal seal at the distal tip, the maximum needle depth is the length of the needle from the distal tip to the far end of the device body or the length between the stopper placed between the needle and the body. In the embodiment of the device with distal element and distal seal, the distance between the proximal end of the distal element and the far end of the elongated body or elongated syringe (and the design of any compressible or shrinkable element that may exist) can be arranged to determine the maximum needle penetration depth. Considering any distance and / or the use of any compressible or shrinkable element between the needle tip and the distal seal / tissue interface, the distance between the proximal end of the distal element and the far end of the elongated body or elongated syringe can be equal to the maximum needle penetration depth. Therefore, the distance between the position and size of the distal element, the needle, and the needle tip and the distal seal / tissue interface (if any) can be constructed to determine the maximum needle penetration depth. Those skilled in the art can design the device accordingly according to the present invention.

[0080] In this way, the device can include a tool for determining the maximum needle penetration depth to control the cannula depth entering the eye. The needle can include a separate element that stops the advancement of the needle, such as an annular ridge, a stopper, or a clamp. In some embodiments, the element used to prevent the needle from further advancing during operation can be movable so that the maximum needle penetration depth can be determined by the user. In this embodiment, the needle can include a mark so that the user can select an appropriate maximum penetration depth. In another embodiment, the needle penetration depth can be determined by a compressible element, such as the compressible element by increasing rigidity when the element is compressed or by other mechanical means to only allow the desired needle to advance. Therefore, the present invention provides a device with a fixed maximum needle penetration depth suitable for targeting target tissue. Based on the present disclosure, it is obvious to the technician to design a suitable maximum needle penetration depth for achieving a fixed maximum needle penetration depth. Of course, the maximum depth of needle penetration can be within a certain tolerance range. The maximum needle penetration depth is also referred to as effective needle length in this article.

[0081] In one embodiment, the material for application (e.g., a composition containing an active agent) is pre-loaded in the intubation device, whereby the device is used as a storage container for the material for application before use. In one embodiment, after the material for application is placed and sealed in the intubation device, the pre-loaded intubation device is sterilized for use. Sterilization can be accomplished by established methods such as heating or ionizing radiation. In one embodiment, before use, the material for application is pre-loaded in the device as a dry material, which is reconstituted by the liquid introduced into the device. The intubation device may include a port or connector that is fluidly connected to the device reservoir to facilitate the reconstitution of the material for application in the intubation device. In another embodiment, the material for application is contained in a reservoir such as a cartridge vial, and is sterilized or aseptically prepared separately from the intubation device. The cartridge vial and the intubation device are designed to allow the user to insert the cartridge vial into the intubation device before use. In another embodiment, the material for administration is contained in a reservoir such as a cartridge vial, which comprises two reservoir compartments, one compartment for the lyophilized material for administration and another compartment for the reconstitution fluid. Prior to administration, the reconstitution fluid is transferred to the material compartment to reconstitute the lyophilized material.

[0082] Figure 1An embodiment of the cannulation device is depicted in FIG. The device includes a hollow syringe 1 having a proximal syringe end cap 2. A plunger 3 is slidably passed through the end cap. The plunger has an inner cavity 4, and a flexible sleeve tubular element 5 resides in the inner cavity 4. The flexible sleeve 5 is fixed in an appropriate position of the plunger 3. The distal tip of the flexible sleeve has a rounded non-invasive tip 6. The plunger compression spring 7 provides a force directed to the distal end on the plunger 3 and the flexible sleeve 5. A bevel needle 8 is connected and fixed to the distal end of the syringe 1 so that the needle 8 does not move relative to the syringe 1 to directly control the position of the needle tip when manipulating the position of the syringe 1. The flexible sleeve 5 moves distally under the force of the plunger compression spring 7. The proximal end of the plunger 3 terminates in an interface such as a Luer fitting 9 to allow the delivery of the application material through the plunger inner cavity 4 and the flexible sleeve 5.

[0083] Figure 2 , 2 Two embodiments of the distal tip of the cannula device are depicted in A and 2B. Figure 2 In FIG. 1 , the flexible cannula 5 is shown extending beyond the distal tip of the beveled needle 8, which is connected to the hollow barrel 10. Figure 2 In one embodiment shown in A, the distal tip of the flexible sleeve 5 is straight. Figure 2 In the second embodiment shown in B, the distal tip of the flexible sleeve 5 comprises a curved tip 11. Both embodiments are shown with illumination 12 emanating from the distal tip of the flexible sleeve 5.

[0084] Figure 3 An embodiment of the device is shown. The device includes a main shaft 13 slidably disposed within a housing assembly 14. The main shaft includes a distal flexible sleeve assembly 15, a coupling assembly 16, an internal fluid line 17, and an optical fiber 18. The internal fluid line 17 is connected to a female Luer connector 9 via an external fluid line 36, and the optical fiber terminates at an optical connector 19.

[0085] The housing assembly includes left and right main housing elements 20 and 21, a proximal cap 2 and a distal nose cone 22. A bevel tip hollow needle 8 is bonded into the lumen of the distal nose cone. The distal tip of the needle 8 can be configured with a bevel having a hypodermic syringe type or lancet type multi-faceted geometry or another bevel geometry suitable for the application.

[0086] The spindle 13 is pushed forward by the spindle compression spring 7 which acts as a force element. Figure 3As shown in Figure 1, the advancement is started by actuation of the trigger 23. The trigger includes a lifting point 24, which engages with the connector assembly 16 to keep the spindle 13 in the retracted position before use. When the trigger 23 is actuated, the trigger lifting point 24 translates upward and the trigger lifting point disengages from the connector assembly 16, so that the spindle 13 translates forward under the force of the spindle compression spring 7. The trigger 23 can be made of a rigid or semi-rigid material, such as acrylonitrile-butadiene-styrene, high-density polyethylene or polycarbonate. The trigger 23 can be machined, molded or 3D printed. The force required to actuate the trigger 23 depends on the material properties of the trigger and the thickness and length of the flexible portion of the trigger body. The thinner the material, the less force is required to deflect the actuation trigger and thus actuate the device. The spindle compression spring 7 can be made of piano wire, stainless steel wire, Elgiloy alloy or similar materials. The length of the spindle compression spring 7 ranges from 63.5 mm (2.5 inches) to 127 mm (5.0 inches), the spring wire diameter ranges from 0.23 mm (0.009 inches) to 0.51 mm (0.020 inches), and the elastic force ranges from 0.007 N / mm (0.04 lbs / in) to 0.044 N / mm (0.25 lbs / in), preferably 0.011 N / mm (0.06 lbs / in) to 0.018 N / mm (0.10 lbs / in). The housing assembly 14 can be mechanically molded or 3D printed from plastic (e.g., acrylonitrile butadiene styrene, glass-filled acrylonitrile butadiene, styrene, polycarbonate, nylon, glass-filled nylon) or metal (e.g., stainless steel, titanium, aluminum, or similar materials).

[0087] The actuation trigger 23 is characterized in that, when actuated, it first forces the main shaft 13 to move a short distance proximally in order to break any static friction in the system before lifting the trigger lift point 24 and allowing the main shaft 13 to travel in the distal direction. The distal section of the main shaft includes a coupler assembly 16 and a flexible sleeve assembly 15. When actuated, the flexible sleeve assembly 15 is advanced distally outward through the lumen of the bevel needle 8. The size of the flexible sleeve assembly 15 is designed to allow the flexible sleeve to slide freely in the lumen of the needle 8. The size of the bevel needle ranges from 21 gauge to 31 gauge.

[0088] The translation speed of the spindle 13 is controlled by an adjustable friction speed damper assembly 25, such as Figure 3b. The adjustable friction speed damper assembly 25 includes a pivot arm 26 (on which a reduction wheel 27 is mounted via an axle 28), a proximal bushing 29, a distal bushing 30, a speed control adjustment screw 31, and a speed control compression spring 32. The pivot arm 26 rotates freely on a pivot arm shaft 33 mounted to the interior of the housing 14. The speed control spring can be a torsion spring or a compression spring and is used to apply a compressive force to the pivot arm 26. The speed control spring can be made of piano wire, stainless steel wire, or the like. The reduction wheel 27 can be made of a variety of elastic materials (e.g., Buna N, silicone, Viton, EPDM) or of a rigid material (e.g., polycarbonate, nylon, or ABS or the like). The reduction wheel shaft 28 and the pivot arm shaft 33 can be made of a smooth rigid material, such as stainless steel, titanium, copper, aluminum, or the like. The pivot arm 26 may be molded, machined, or printed from a rigid material such as polycarbonate, acrylonitrile butadiene styrene, Ultem, nylon, acetal, polysulfone, or the like. The pivot arm adjustment screw has a thread range of 1 to 5 threads per mm (24 to 120 threads per inch) to allow fine adjustment of the spindle advance speed.

[0089] The speed of advancement of the spindle 13 is controlled by the force of the damping wheel on the spindle and the friction on the bushings 29 and 30. The advancement speed is controlled by the degree of compression of the speed control compression spring 32 on the pivot arm 26, which in turn transmits force to the polymer wheel 27 in frictional contact with the spindle 13. The speed control adjustment screw 31 is advanced or retracted to change the compression of the spring. The spindle 13 is slidably disposed in the proximal bushing 29 and the distal bushing 30. The proximal bushing 29 and the distal bushing 30 can be machined or molded and are ideally made of a low friction polymer material such as polytetrafluoroethylene, fluorinated ethylene propylene, polyethylene, ultra-high molecular weight polyethylene, Ultem, acrylonitrile-butadiene-styrene or similar materials. The proximal bushing and the distal bushing can be optionally incorporated into the left and right housing assembly portions of the assembly.

[0090] The tubular spindle 13 is hollow and can be made of a rigid material (stainless steel, titanium, aluminum, acrylonitrile butadiene styrene, polycarbonate, glass-filled nylon or similar material) and ideally has a low friction, smooth outer surface. The inner lumen diameter of the spindle 13 is sized to allow the internal fluid line 17 and the optical cable 18 to be disposed within the lumen.

[0091] like Figure 3As shown in Fig. 3, the flexible sleeve assembly 15 includes a distal sleeve soft tip 34, a flexible sleeve body 35 and a flexible sleeve proximal support 37. The size of the flexible sleeve assembly is set to be able to slide freely through the inner cavity of the bevel needle 8. The distal soft tip 34 includes a polymer with a lower hardness than the flexible sleeve body 35. The far end of the soft tip is configured with an atraumatic tip 6, which is configured as a tip with a rounded arc, an angled angle or a spherical shape. Ideally, the soft tip and the main shaft should be made of the same type of polymer. The soft tip is preferably connected to the main body by thermal means, but the distal tip can be connected to the main body using adhesives, ultrasound or other means. The main body and the soft tip can be made of an elastomer (e.g., polyurethane, polyurethane copolymer, polysiloxane, polysiloxane copolymer, polyether block amide or similar materials). The size of the flexible sleeve may range from 0.18 mm (0.007 in) to 0.51 mm (0.020 in) in outer diameter and 0.08 mm (0.003 in) to 0.46 mm (0.018 in) in inner diameter.

[0092] The flexible cannula assembly 15 is supported by a thin tubular flexible cannula proximal support 37. The proximal support serves to prevent the cannula assembly from kinking within the device as the cannula is advanced under the force of the primary compression spring. The proximal support may be made of materials such as stainless steel, titanium, polyimide, polytetrafluoroethylene, polycarbonate, or the like. The flexible cannula proximal support 36 is sized to fit over the exterior of the flexible cannula assembly 15 and within the lumen of the bevel needle 8.

[0093] The optical cable 18 is aligned with the flexible sleeve assembly 15 in the center and is in close proximity to the proximal end of the flexible sleeve assembly 15. The optical cable 18 transmits light from a light source (not shown) to the proximal end of the flexible sleeve assembly 15, causing the entire sleeve to illuminate. The illuminated sleeve allows the user to view the sleeve through the scleral tissue, thereby locating and verifying the position of the sleeve during surgery. The optical cable 18 is made of plastic optical fiber to obtain flexibility, and the optical fiber diameter can be 0.25mm (0.010 inches) to 2mm (0.08 inches). The gap or clearance between the far end of the optical cable 18 and the proximal end of the flexible sleeve assembly 15 can be constructed to attenuate the light intensity transmitted to the flexible sleeve assembly 15 and the light output of the sleeve. Alternatively, an attenuator can be placed between the far end of the optical cable 18 and the proximal end of the flexible sleeve assembly 15 to adjust the light output of the sleeve. The device is generally constructed to provide a light output of 100μW to 700μW.

[0094] The internal fluid line 17 is disposed within the main shaft 13 and offset from the optical cable 18. The internal fluid line 17 allows fluids and flowable semi-solid materials to enter the coupling assembly 16 and enter the inner cavity of the flexible sleeve assembly 15. The internal fluid line 17 passes through the main shaft 13 and is connected to the external fluid line 36 at the proximal end. The proximal end of the external fluid line 36 terminates in a female Luer fitting 9, which is used to connect to an external device, such as a syringe for delivering a therapeutic agent. The internal fluid line 17 includes a rigid tube with an outer diameter of 0.25 mm (0.010 inches) to 1.5 mm (0.060 inches) and an inner diameter of 0.13 mm (0.005 inches) to 1.4 mm (0.055 inches), and can be made of materials such as stainless steel, titanium, polyimide, polytetrafluoroethylene, polycarbonate or similar materials. The external fluid line 36 comprises a flexible tube having an outer diameter of 0.5 mm (0.020 in) to 3.2 mm (0.125 in) and an inner diameter of 0.25 mm (0.010 in) to 2.54 mm (0.10 in), and may be made of an elastomer such as polyurethane, polyurethane copolymer, polysiloxane, polysiloxane copolymer, polyether block amide, polyvinyl chloride, or similar materials.

[0095] The device can be used to deliver very small amounts of therapeutic agents in the range of 10 microliters to 250 microliters. In some embodiments, the device can be used to deliver high-value therapeutic agents in situations where the amount used in surgery must be carefully controlled and losses minimized. In order to deliver small volumes, the dead space within the fluid path of the device must be controlled and minimized. The device can be configured to have a dead space of less than 75 microliters, less than 50 microliters, or less than 25 microliters.

[0096] Figure 4 An embodiment of the cannulation device is depicted in . The device includes a hollow syringe 1 having a proximal syringe end cap 2. A plunger 3 slidably passes through the end cap. The plunger has an inner cavity 4, and a flexible sleeve tubular element 5 passes through the inner cavity 4. The flexible sleeve 5 is fixed in an appropriate position of the plunger 3. The distal tip of the flexible sleeve has a rounded atraumatic tip 6. The plunger compression spring 7 provides a distally directed force on the plunger 3 and the flexible sleeve 5. A bevel needle 8 is connected and fixed to the distal end of the hollow syringe 1 so that the needle 8 does not move relative to the syringe 1 to provide direct control of the position of the needle tip when manipulating the position of the syringe 1.

[0097] When the tissue interface and distal seal 38 are opened by the distal tip of the needle 8, the flexible sleeve 5 moves distally under the force of the plunger compression spring 7. The tissue interface and distal seal 38 are connected to the distal end of the contractile element 39. The contractile element 39 is connected to the distal end of the syringe 37 and provides a distally directed force on the tissue interface and distal seal 38, thereby pressing the tissue interface and distal seal 38 onto the tissue surface. The proximal end of the flexible sleeve 5 terminates in an interface such as a Luer fitting 9 to allow the delivery of the application material through the flexible sleeve 5.

[0098] Figure 5 One embodiment of the cannulation device is depicted in . The device is constructed as a hollow syringe 13 having a hollow body 40, which is slidably housed in the hollow syringe and contains a reservoir 41 for the material to be administered. The distal end of the reservoir body 40 is connected to the flexible sleeve tubular element 5. A tubular reservoir plunger 42 is slidably located inside the reservoir, and a connector, such as a Luer fitting 9, is connected to the proximal end of the reservoir plunger to allow filling of the reservoir. The connector includes a one-way valve 43 to prevent backflow of the material to be administered after filling the reservoir. The reservoir plunger compression spring 44 provides force to discharge the material to be administered.

[0099] The reservoir body 40 acts as a plunger within the hollow barrel for extending the flexible tubular cannula 5. A reservoir compression spring 44 resides above the hollow body 40. The reservoir compression spring 44 provides the force to extend the flexible cannula 5.

[0100] The bevel needle 8 is connected and fixed to the distal end of the syringe 13 so that when the position of the syringe 13 is manipulated, the needle 8 does not move relative to the syringe 13 to provide direct control of the needle tip position. The distal end of the flexible sleeve assembly 15 is configured within the lumen of the bevel needle 8. When the tissue interface and distal seal 38 are opened by the distal tip 8 of the needle, the flexible sleeve 5 moves distally under the force of the reservoir compression spring 44.

[0101] In one embodiment, the distal tip of the device comprises a retractable element. Figure 6 The device depicted in Figure 7 , which includes a distal segment, a central retractable segment, and a proximal segment. The tissue interface and distal seal 38 are arranged around the distal tubular shaft 45. The inner cavity of the distal tubular shaft 45 contains an internal seal 46, which seals the gap between the distal tubular shaft 45 and the bevel needle 8. The central segment includes one or more segments 47 that serve as retractable elements. The retractable element 47 is connected to or integrated with the distal tubular shaft 45 and the proximal tubular shaft 48. The proximal tubular shaft 48 is connected to the syringe 1 of the device, which provides an anchor point for the retractable element and prevents distal movement of the tissue interface and distal seal 38. Figure 8The distal section of the device is shown in an uncontracted state. The tissue interface and distal seal 38 and the distal tubular shaft 45 are provided at the end of the contractile element 47. The proximal tubular shaft 48 is anchored to the barrel 1 .

[0102] Fig. 9 The distal section of the device is shown in a retracted state. The force of advancing the device into the tissue causes the retractable element 47 to deform, thereby causing the distal tubular shaft 45 to slide proximally with the tissue interface and the distal seal 38 along the needle 8 toward the distal end of the barrel 1. The distal tip of the needle 8 has penetrated the tissue interface and the distal seal 38.

[0103] In some embodiments, the distal tip of the needle is configured to direct the tubular element at an angle to the long axis of the needle. Fig.10 The needle tip depicted, the distal tip of the needle 49 can be bent to guide the tubular element. Fig.11 The depicted needle tip, the distal tip of the needle 50 may have an internal deflection element 51 within the lumen of the needle in the region of the bevel of the needle. Fig.12 The depicted needle tip, the distal tip of the needle 50 may have an internal deflection element 52 positioned within the lumen of the needle in the bevel region of the needle.

[0104] The described embodiment of cannula device can be used in combination, to insert sleeve tube into tissue gap and apply fluid, semisolid or solid.In one embodiment, the structure of the distal end portion of cannula device comprises the distal element of tissue interface and distal seal on the far end of pin.Cannula and reservoir for delivering material can be configured to apply fluid, semisolid, solid or implant from sleeve tube.In some embodiments, the inner chamber of sleeve tube can also serve as a part of reservoir or reservoir for applying material.

[0105] In order to use in the intubation device, lubricants or lubricating coatings can be used to assist intubation. In order to use in the device and extend into the eye, the coating should provide lubricity immediately when the tissue contacts. Some lubricants (such as polyvinyl pyrrolidone coatings commonly used on vascular catheters) require one to five minutes of moisture contact to provide lubricity, and are not suitable for use with the intubation device. Suitable lubricants for cannula include but are not limited to oils, waxes, lipids, fatty acids, polymers and polymer solvent mixtures. Polymers include but are not limited to water-soluble polymers (such as polyethylene glycol and polypropylene glycol) and polymer lubricants (such as polysiloxanes). Polymer solvent mixtures include but are not limited to aqueous preparations of water-soluble polymers (such as polyethylene oxide, polyethylene glycol and glycosaminoglycans). Polymer solvent mixtures also include organic solvent preparations of silicone fluids or polyethylene glycol. Polymer solvent mixtures can be prepared together with polymers in the high molecular weight form to provide durability and polymers in the low molecular weight form to provide increased lubricity. Lubricants can be applied to the entire cannula or distal portion. Lubricants can be applied by spraying or dipping the cannula. Lubricant can be unbound with the cannula surface, covalently bonded with the cannula surface, or unbound with the cannula surface and covalently bonded with the cannula surface. Suitable covalent adhesives include photoreactive groups, photoinitiators, silanes, isocyanates, polyisocyanates and epoxides coupled with lubricants. Lubricant can also be mechanically coupled with the cannula surface by contacting a lubricant in the form of a polymer in the solvent for the cannula material to form an interpenetrating polymer composition on the cannula surface. The far end of the pin lumen can also serve as a small reservoir of lubricant to coat the cannula during the stretching process.

[0106] The material for administration may be a fluid, semisolid or solid composition of the active agent for delivery to the suprachoroidal space, the supraciliary space or other spaces of the eye (e.g., the vitreous cavity, the subconjunctival cavity, the sub-Tenon's space and the subretinal space). The active agent is dissolved, dispersed or suspended in the fluid or semisolid formulation. Alternatively, the active agent may be formulated as a solid composition. The active agent may also be distributed in the composition in the form of particles. In one embodiment, the composition comprises a plurality of drug-containing particles 53 formed in a semisolid 54, such as Fig.13 It is schematically shown in FIG.

[0107] In order to deliver semisolid in the suprachoroidal space or the supraciliary space, compositions is placed in the eye from the outer surface of the eye by cannula, so that material is preferentially positioned in the suprachoroidal space or the supraciliary space near the far end of cannula.After being placed in the suprachoroidal space or the supraciliary space, semisolid compositions transform, degrade or dissolve into independent drug-containing particles, and these particles may migrate in this gap so that active agent is distributed. The semisolid quality of drug particles allows to inject a large amount of drugs with very small volume, to prevent the intraocular pressure that occurs when the drug that is suspended in the fluid, for example, from being used in an equal amount, increases sharply. Semisolid preparations enable the medicine of effective dose to be delivered with 5 microliters to 100 microliters, 10 microliters to 50 microliters or 15 microliters to 40 microliters.

[0108] In one embodiment, the composition comprises a plurality of drug-containing particles 53 formed into a shaped solid 55, such as Fig.14 and Fig.14A Schematically shown in. The formed solid 55 comprising a plurality of drug-containing particles 53 can be in the shape of a plug, a tube or a cylinder. In one embodiment, the formed solid is an elongated body, and its diameter is approximately the inner diameter of the sleeve for placing the formed solid in the interstitial space. The range of diameter can be 0.60mm (0.02 inch) to 0.159mm (0.006 inch). According to the dosage of the active agent and the content of the active agent in the particles, the length of the formed solid can be 1 mm (0.04 inch) to 50 mm (2 inches) or for example 1 mm (0.04 inch) to 25 mm (1 inch). The formed solid resides in the inner cavity of the sleeve and is delivered from the sleeve by the hydraulic pressure, pneumatic or mechanical force from the device. After being placed in the suprachoroidal space or the ciliary body supracavity, the formed solid composition is transformed, degraded or dissolved into a separate active agent-containing particle, which can migrate in the gap. The shaped solid quality of the particles allows for the injection of large amounts of active agent in a very small volume to prevent the dramatic increase in intraocular pressure that occurs, for example, when administering an equal amount of active agent suspended in a liquid. The volume of the shaped solid injected can be 0.1 microliter to 10 microliters or, for example, 0.1 microliter to 5 microliters.

[0109] The particles of the active agent can be in the form of active agent crystals of a selected size range. The particles of the active agent can be made into the form of microspheres by making the active agent into spherical particles or by preparing the active agent with a polymer and making microspheres by the combination. The microspheres containing the active agent can be made by any known means for microsphere manufacturing (e.g., by spray drying, emulsion or coagulation). Using non-toxic polymers, the active agent is kept in the microspheres so that the release rate of the active agent can be adjusted by polymer composition, active agent content and microsphere size. The microspheres with an active agent content of 10wt% to 50wt% can provide appropriate release. Using a polymer with a selected solubility enables both water-soluble and water-insoluble active agents to be incorporated into the microspheres. Suitable polymers include, but are not limited to, non-toxic water-soluble polymers such as polyvinyl pyrrolidone, polyvinyl pyrrolidone-vinyl acetate copolymers, polyvinyl alcohol, polyethylene glycol, and polyethylene oxide; biodegradable polymers such as polyhydroxybutyrate, polydioxanone, polyorthoesters, polycaprolactone, polycaprolactone copolymers, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymers, polylactic acid-glycolic acid-ethylene oxide copolymers; and biopolymers such as gelatin, collagen, glycosaminoglycans, cellulose, chemically modified cellulose, dextran, alginate, chitin, and chemically modified chitin.

[0110] Particularly for hydrophobic active agents, in laboratory tests, microspheres with an average volume diameter of 3 to 14 microns and composed of polylactic-co-glycolic acid having a lactic acid to glycolic acid stoichiometric ratio (L to G) of 75:25 and 85:15 were found to provide a release half-life of 12 to 80 weeks. The small diameter of the microspheres allows injection through small gauge needles and cannulas, thereby administering the active agent with minimal invasiveness.

[0111] For microspheres with a relatively narrow size distribution (e.g., a coefficient of variation of 10% to 25%), the rate of drug release can be adjusted by the average microsphere size. The choice of polymer in the microsphere and the form of the active agent (e.g., crystalline or amorphous solid dispersion) provide a general release range that can be effectively adjusted using microsphere size selection.

[0112] Alternatively, approximately spherical or other uniformly shaped active agent particles can be prepared by milling larger active agent particles or by controlled crystallization. The active agent particles and active agent-containing microspheres can also each be coated with a polymer layer to form active agent particles having an outer surface coating or barrier coating. The coating may comprise non-toxic water-soluble polymers, including but not limited to: polyvinyl pyrrolidone, polyvinyl pyrrolidone-vinyl acetate copolymer, polyvinyl alcohol, polyethylene glycol and polyethylene oxide; biodegradable polymers such as polyhydroxybutyrate, polydioxanone, polyorthoesters, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, acid-terminated polylactic acid-glycolic acid copolymer, polylactic acid-glycolic acid-ethylene oxide copolymer, polylactic acid-polyethylene glycol copolymer, polycaprolactone, polycaprolactone copolymer and polycaprolactone-polyethylene glycol copolymer; and biomaterials such as gelatin, collagen, glycosaminoglycans, cellulose, chemically modified cellulose, dextran, alginate, chitin, chemically modified chitin, lipids, fatty acids and sterols.

[0113] In one embodiment, a plurality of particles containing active agents are formed into semisolid compositions, which flow when injection pressure is applied, but once applied to tissue, semisolid materials are formed at the delivery position. The semisolid form containing active agent particles at high concentrations in the range of 70mg / ml to 200mg / ml provides the ability to deliver sufficient amounts of active agents to provide sustained delivery of therapeutic levels. Aggregation during injection is minimized by using microspheres or spherical particles, which contributes to the ability of injection compositions. The ability to inject semisolids with high particle concentrations is achieved by using excipients, which suspend particles in aqueous preparations, and also provide viscoelastic properties to promote particle flow during injection. Suitable viscoelastic excipients include polyethylene glycol, polyethylene oxide, high molecular weight polyvinyl pyrrolidone and biopolymers, such as hyaluronic acid and chondroitin sulfate. In one embodiment, semisolids are prepared together with 70mg / m to 200mg / ml microspheres and an excipient mixture comprising viscoelastic excipients and physiological buffers.

[0114] In one embodiment, a plurality of particles containing active agents are formed into a solid or semisolid with an excipient. Suitable excipients include, but are not limited to, non-toxic water-soluble polymers such as polyvinyl pyrrolidone, polyvinyl pyrrolidone-vinyl acetate copolymers, polyvinyl alcohol, polyethylene glycol, and polyethylene oxide; biodegradable polymers such as polyhydroxybutyrate, polydioxanone, polyorthoesters, polycaprolactone, polycaprolactone copolymers, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymers, and polylactic acid-glycolic acid-ethylene oxide copolymers; and biomaterials such as gelatin, collagen, glycosaminoglycans, cellulose, chemically modified cellulose, dextran, alginate, chitin, and chemically modified chitin. Solid or semisolid compositions can be formulated with a mixture of different excipients. The particles containing active agents are mixed with excipients in a suitable solvent or diluent that dissolves or forms a dispersion of the excipient, but does not rapidly extract the drug from the particles or dissolve the particles. In one embodiment, the semi-solid composition is injected as a mixture, dispersion or suspension by a solvent. In one embodiment, the solid or semi-solid composition is formed or extruded in a mold, and dried to form a solid of the desired size for application. The ideal choice for the application of the shaped solid or semi-solid composition is an elongated shape, and its outer diameter is set to be suitable for the lumen of a small diameter cannula or needle of No. 20 or less (corresponding to a diameter of 0.60mm (0.02 inch) or less). In one embodiment, the outer diameter of the shaped solid or semi-solid composition is set to be suitable for the lumen of a cannula or needle of No. 25 or less (corresponding to a diameter of 0.26mm (0.01 inch) or less). In one embodiment, the outer diameter of the shaped solid or semi-solid composition is set to be suitable for the lumen of a cannula or needle of No. 27 or less (corresponding to a diameter of 0.20mm (0.008 inch) or less).

[0115] In one embodiment, the semisolid composition is dried, for example, by freeze drying or air drying, and rehydrated before administration. The semisolid composition may have an excipient that helps to recover, such as salt, sugar, water-soluble polymer and surfactant. For freeze-dried preparations, fillers such as sucrose, mannitol, glycine, polyvidone or dextran are used to help produce loose freeze-dried products with large channels or holes to improve the recovery rate. Before freezing and freeze drying, an excipient such as a surfactant, salt, sugar or trehalose used as a recovery adjuvant to increase the recovery rate of the freeze-dried composition can be added. In one embodiment, the semisolid composition comprises microspheres, which comprise an active agent, a viscoelastic polymer, a filler and a physiological buffer, and the physiological buffer is freeze-dried to produce a dry product to enhance shelf life stability. The composition can be reconstituted with water immediately before use. In one embodiment, the composition may additionally comprise an excipient (such as trehalose) to accelerate recovery. The combination of components must be carefully balanced to provide the lyophilized composition with physical stability without particle aggregation, rapid rehydration, physical properties that provide reconstitution stability without particle aggregation, flow properties for administration through small lumens, and at the same time, provide a physiologically compatible osmotic pressure and pH.

[0116] In one embodiment, the size of the particles containing the active agent is set to be smaller than the inner diameter of the sleeve to allow the particles to be closely packed in the formed solid or semi-solid to enhance mechanical properties. The average diameter of such particles containing the active agent will be 5 microns to 100 microns (e.g., 10 microns (0.0004 inches) to 50 microns (0.002 inches)), and can include a mixture whose diameter promotes close packing. The average diameter or median diameter of the particles can be 5 microns (0.0002 inches) to 100 microns (0.004 inches), for example, 10 microns (0.0004 inches) to 50 microns (0.002 inches), 10 microns (0.0004 inches) to 40 microns (0.0016 inches), 10 microns (0.0004 inches) to 30 microns (0.0012 inches), or 10 microns (0.0004 inches) to 20 microns (0.0008 inches).

[0117] It is desirable to disperse and migrate particles containing active agents to promote uniform distribution of particles in the eye. The dissolution of the excipient and the release of the resulting particles containing active agents can be triggered by fluid absorption in the interstitial space, for example due to the ionic environment, dissolution of the excipient or ambient temperature. In one embodiment, the excipient includes a lipid or fatty acid having a melting temperature between room temperature and the temperature of the interstitial space of the eye tissue, and the melting temperature is approximately 37 degrees Celsius (for example, the melting temperature is 21 to 37 degrees Celsius, 25 to 37 degrees Celsius, or 30 to 35 degrees Celsius). The rate at which a single particle containing active agents is released from a solid or semisolid composition can be customized by adding a hydrophilic or amphipathic agent, which increases the dissolution rate of the excipient of the solid or semisolid composition. Depending on the amount and composition of the material for administration, the release of particles containing active agents can last for hours, days or weeks. For example, a maximum amount (or minimum amount, depending on the formulation) of 50% particles containing active agents can be released after 1 hour, 6 hours, 12 hours, 1 day, 3 days or 1 week.

[0118] Solid or semi-solid compositions can act through the ionic environment of the interstitial space to provide dissolution, such as can be provided by ionically cross-linked polymers (e.g., sodium alginate). Solid or semi-solid compositions can be dissolved in the interstitial space by temperature triggering, for example, by lipids and fatty acids having a melt transition temperature greater than room temperature (about 20° C.) and less than or equal to the temperature in the interstitial space of the eye (about 37 degrees Celsius). Such lipids and fatty acids include, but are not limited to, capric acid, erucic acid, 1,2-dicerol-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, and 1,2-pentacyl-sn-glycero-3-phosphocholine and mixtures thereof.

[0119] Due to the small size of the particles containing active agents, the release of the active agent from the particles may be too fast to provide a sustained active agent effect after application to the eye. An object of the present invention is to provide particles containing active agents (i.e., controlled release formulations) with extended release kinetics. In one embodiment, the active agent is incorporated into a polymer matrix, which produces a poor drug diffusion path, thereby slowing down the release of the active agent compared to the active agent without a polymer matrix. In one embodiment, the particles containing active agents are coated with a barrier layer, such as a polymer or other compound. The barrier material generally has a chemical property different from that of the active agent, so that compared with particles containing active agents without a barrier coating, the active agent is not easily dissolved by the barrier coating and slows down the release of the active agent. One method of selecting a barrier coating is a material having a distribution coefficient or log P different from that of the active agent, wherein the increased difference increases the barrier to the release of the active agent. In one embodiment, a single active agent particle is coated with a barrier coating having an increased water solubility or a reduced log P compared to the active agent to form a barrier coating on each particle. Barrier materials may include, but are not limited to, non-toxic water-soluble polymers including polyvinyl pyrrolidone, polyvinyl pyrrolidone-vinyl acetate copolymers, polyvinyl alcohol, polyethylene glycol, and polyethylene oxide; biodegradable polymers such as polyorthoester-ethylene oxide copolymers, acid-terminated polylactic acid-glycolic acid copolymers, polylactic acid-glycolic acid-ethylene oxide copolymers, polylactic acid-polyethylene glycol copolymers, and polycaprolactone-polyethylene glycol copolymers; and biomaterials such as gelatin, collagen, glycosaminoglycans, cellulose, chemically modified cellulose, dextran, alginate, chitin, and chemically modified chitin. In one embodiment, individual active agent particles are coated with a barrier coating having reduced water solubility or increased log P compared to the active agent to form a barrier coating on each particle, the barrier coating including, but not limited to, biodegradable polymers such as polyhydroxybutyrate, polydioxanone, polyorthoester, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, acid-terminated polylactic acid-glycolic acid copolymer, polylactic acid-glycolic acid-ethylene oxide copolymer, polylactic acid-polyethylene glycol copolymer, polycaprolactone, polycaprolactone copolymer, and polycaprolactone-polyethylene glycol copolymer; and biomaterials such as chemically modified chitin, lipids, fatty acids, and sterols. The active agent particles can be coated by any known means for particle coating, such as spray drying, electrostatic spraying, or chemical deposition. In one embodiment, as in Fig.14 and Fig.14A As schematically shown, the shaped solid or semi-solid material 54 includes a plurality of active agent particles 53 encapsulated or coated with a barrier material 54 (eg, a soluble polymer or other coating) to modify the release characteristics and / or mechanical properties of the active agent.

[0120] Although the active agent of the composition is mainly contained in a plurality of particles, part of the active agent may also be formulated in an excipient. The active agent in the excipient may prevent the active agent from being extracted or diffused from the particles during processing or storage. The active agent in the excipient may also provide a rapid release component for the active agent preparation to trigger the therapeutic effect of the active agent while allowing the active agent in the particles to provide sustained delivery to maintain the therapeutic effect.

[0121] In one embodiment, the active agent composition comprises an active agent and an excipient comprising a biodegradable or bioerodible material. The biodegradable or bioerodible material can be composed of, for example, but not limited to, polyhydroxybutyrate, polydioxanone, polyorthoester, polycaprolactone, polycaprolactone copolymer, polycaprolactone-polyethylene glycol copolymer, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, acid-terminated polylactic acid-glycolic acid copolymer or polylactic acid-glycolic acid-ethylene oxide copolymer, gelatin, collagen, glycosaminoglycan, cellulose, chemically modified cellulose, dextran, alginate, chitin, chemically modified chitin, lipid, fatty acid or sterol. The active agent can be dispersed in a biodegradable or bioerodible material as an amorphous solid dispersion. The active agent can be dispersed in a biodegradable or bioerodible material as multiple crystals. The active agent can be dispersed in a biodegradable or bioerodible material as both an amorphous solid dispersion and a crystal. The active agent composition can be shaped as an elongated solid or semisolid for application to the eye tissue space. After being placed in the tissue, the active agent is released from the composition so that the active agent is diffused into the tissue of the eye, and can be assisted by the flow of the fluid in the tissue space. In the case where the active agent is a solid amorphous dispersion form, a biodegradable material or a bioerodible material is selected to provide the desired active agent load and active agent release characteristics. In the case where the active agent is a dispersed crystal, the amount of the active agent, the characteristics of the biodegradable material or the bioerodible material and the crystal form of the active agent can be selected to provide the required active agent load and release characteristics. The active agent crystal can also be coated with an excipient to reduce the active agent release rate of the composition. In the case where the active agent is released by contacting with moisture in a hydrated tissue environment, the active agent composition is applied in the form of a dry solid composition or a freeze-dried preparation immediately recovered before use. In one embodiment, the composition has an extended release of the active agent. The active agent may elute from the composition with a half-life of 14 to 360 days, 21 to 270 days, 30 to 180 days, or 60 to 90 days.

[0122] The present invention can deliver various drugs as active agents to the eye for the treatment of ocular diseases and conditions, including inflammation, infection, macular degeneration, retinal degeneration, angiogenesis, proliferative vitreoretinopathy, glaucoma and edema. Useful drugs include, but are not limited to, steroids, nonsteroidal anti-inflammatory agents, antibiotics, VEGF inhibitors, PDGF inhibitors, anti-TNF-α agents, mTOR inhibitors, prostaglandin analogs, cell therapy, neuroprotectants, antihypertensive agents, antihistamines, aminosterols and nucleic acid-based therapeutic agents. The drug can be a soluble solution, suspension, gel, semisolid, microsphere, formed solid or implant.

[0123] In one embodiment, the active agent is pre-loaded in the device at manufacturing time before use. In one embodiment, the force source that provides the extension force to the cannula can be activated before or simultaneously with use. In one embodiment, activation is achieved by a mechanism to preload the force element from the outside of the device (for example, by a movable proximal handle connected to the plunger), such as compressing a spring. In one embodiment, the force source is preloaded during the manufacturing process and the preload force is stabilized by a stop mechanism. As in the previous embodiments of the present invention, the stop mechanism is released before or simultaneously with use, thereby applying an extension force on the cannula before the cannula contacts or penetrates the eye, and triggering the cannula to extend by advancing the needle into the eye.

[0124] As indicated, the present invention can deliver a variety of drugs as active agents to the eye for the treatment of various ocular diseases and conditions, including inflammation, cancer, infection, macular degeneration, retinal degeneration, angiogenesis, proliferative vitreoretinopathy, glaucoma, and edema. Useful drugs include, but are not limited to: steroids, such as corticosteroids, including dexamethasone, fluocinolone, loteprednol, difluprednate, fluorometholone, prednisolone, medrysone, triamcinolone acetonide, betamethasone, and rimexolone; nonsteroidal anti-inflammatory agents, such as salicylic acid derivatives, indoleacetic acid derivatives, arylacetic acid derivatives, arylpropionic acid derivatives, and enolic acid derivatives, including bromfenac, diclofenac, flurbiprofen, ketorolac tromethamine, and nepafenac; antibiotics, including azithromycin, bacitracin, besifloxacin, ciprofloxacin, erythromycin, gatifloxacin, sirolimus ... , gentamicin, levofloxacin, moxifloxacin, ofloxacin, sulfacetamide and tobramycin; VEGF inhibitors, such as tyrosine kinase inhibitors, VEGF antibodies, VEGF antibody fragments, VEGF binding fusion proteins; PDGF inhibitors, PDGF antibodies, PDGF antibody fragments, PDGF binding fusion proteins; anti-TNF-α agents, such as TNF-α antibodies, TNF-α antibody fragments and TNF binding fusion proteins, including infliximab, etanercept, adalimumab, certolizumab pegol and golimumab; mTOR inhibitors, such as sirolimus, sirolimus analogs, everolimus, temsirolimus, and mTOR kinase inhibitors; cell therapies, such as mesenchymal cells or cells transfected to produce therapeutic compounds; glaucoma agents, such as prostaglandin analogs, beta blockers, alpha agonists, carbonic anhydrase inhibitors, and rho kinase inhibitors; oncology agents, such as melphalan, topotecan, methotrexate, rituximab, carboplatin, and 5-FU; neuroprotectants, such as antioxidants, calcineurin inhibitors, NOS inhibitors, sigma-1 regulators, and leukemia inhibitors. regulators, AMPA antagonists, calcium channel blockers, DNA gyrase inhibitors, DNA polymerase inhibitors, RNA polymerase inhibitors and histone-deacetylase inhibitors; antihypertensive agents such as prostaglandin analogs, beta blockers, alpha agonists and carbonic anhydrase inhibitors; aminosterols such as squalamine; antihistamines such as H1 receptor antagonists and histamine H2 receptor antagonists; therapeutic proteins and nucleic acid-based therapeutics such as gene vectors, gene editing therapeutics, plasmids, therapeutic mRNA, guide RNA and siRNA.

[0125] In one embodiment of the invention, a pharmaceutical composition of the invention is provided for use in medicine, particularly in ophthalmic medicine. In another embodiment of the invention, a pharmaceutical composition of the invention is provided for use in the treatment of an ocular disease or condition. The ocular disease or condition may be inflammation, infection, macular degeneration, retinal degeneration, angiogenesis, proliferative vitreoretinopathy, glaucoma, uveitis, an ocular tumor, or edema. In some embodiments, the pharmaceutical composition is administered by delivery via a cannula, particularly a cannula placed via an intubation device of the invention.

[0126] In one embodiment, a method for treating a disease or condition by delivering a liquid or semisolid material to a diseased area is provided, the method comprising: placing the distal end of a cannula device according to any one of claims 1 to 40 on the surface of the diseased area and advancing the needle of the device into the diseased area; advancing a tubular element while providing illumination to the proximal end of the tubular element to illuminate the distal tip of the tubular element; advancing the distal tip of the tubular element into the diseased area; and delivering the material for administration to the gap.

[0127] In another embodiment, the disease or condition is inflammation or infection. In another embodiment, the inflammation is selected from the group consisting of sinusitis, osteoarthritis, rheumatoid arthritis, joint inflammation, rhinitis and postoperative inflammation or a combination thereof.

[0128] In another embodiment, the disease or condition is an ocular disease or condition. In another embodiment, the ocular disease or condition can be selected from the group consisting of blepharitis, allergic conjunctivitis, macular degeneration, retinal degeneration, angiogenesis, proliferative vitreoretinopathy, glaucoma, ocular tumors, uveitis or edema, or a combination thereof.

[0129] In one embodiment, a method of treating an ocular disease or condition is provided by administering a pharmaceutical composition to the eye, such as to the suprachoroidal space or the supraciliary space, using the cannula device of the present invention. The pharmaceutical composition may be dissolved or converted into a plurality of drug-containing particles that migrate from the site of administration (e.g., the suprachoroidal space or the supraciliary space) after administration. The ocular disease or condition may be inflammation, infection, macular degeneration, retinal degeneration, angiogenesis, proliferative vitreoretinopathy, glaucoma, an ocular tumor, or edema.

[0130] In another embodiment of the present invention, a kit is provided that includes an intubation device as described herein and a component of a pharmaceutical composition of the present invention. The pharmaceutical composition can be pre-loaded in a delivery device. Alternatively, the pharmaceutical composition can be provided as a plurality of discrete dosage forms suitable for insertion into a delivery device. Thus, the kit can also provide the pharmaceutical composition in the form of a plurality of discrete dosage forms together with the intubation device.

[0131] In other embodiments, the material for administration includes steroids, nonsteroidal anti-inflammatory agents, antibiotics, VEGF inhibitors, anti-TNF-α agents, mTOR inhibitors, cell therapy, antihypertensive agents, antihistamines, aminosterols, neuroprotectants or therapeutic agents based on nucleic acids. Steroids include dexamethasone, dexamethasone acetate, fluocinolone, loteprednol, difluprednate, fluorometholone, prednisolone, medrysone, triamcinolone acetonide, betamethasone, rimexolone, beclomethasone dipropionate, budesonide, fluticasone dipropionate, furoate mometasone or ciclesonide. Nonsteroidal anti-inflammatory agents include bromfenac, diclofenac, flurbiprofen, ketorolac tromethamine or nepafenac. Antihistamines include cetirizine, loratadine, fexofenadine hydrochloride, olopatadine, alcaftadine, epinastine or ketotifen. Anti-TNF-α agents include infliximab, etanercept, adalimumab, certolizumab pegol or golimumab. mTOR inhibitors include sirolimus, everolimus, temsirolimus or mTOR kinase inhibitors. Cell therapy inhibitors include mesenchymal cells or cells transfected to produce therapeutic compounds. Neuroprotectants include antioxidants, calcineurin inhibitors, NOS inhibitors, σ-1 modulators, AMPA antagonists, calcium channel blockers, DNA gyrase inhibitors, DNA polymerase inhibitors, RNA polymerase inhibitors and histone-deacetylase inhibitors. Nucleic acid-based therapeutics include gene vectors, gene editing therapeutics, plasmids, guide RNAs and siRNAs.

[0132] The present invention will now be described with reference to various embodiments, which are provided for illustrative purposes only and are not to be construed as limiting the scope of the invention.

[0133] Example:

[0134] Example 1. Fabrication of an intubation device for placing an illuminated flexible cannula in a tissue space of the eye

[0135] A device according to an embodiment of the present invention was manufactured. The device consists of a body with a 27-gauge distal needle and an illuminated flexible cannula designed to be slidably extended through the needle. The body includes a housing and a drive mechanism for semi-automatically advancing the cannula. The cannula is connected to a syringe to deliver fluid. Illumination of the cannula is provided by a 532nm green laser.

[0136] The cannula is made of a polyurethane tube with a Shore hardness of 55D, an inner diameter of 0.13 mm, an outer diameter of 0.25 mm, and a length of 30 mm. A polyimide reinforced tube with an inner diameter of 0.25 mm, an outer diameter of 0.28 mm, and a length of 20 mm is placed on the proximal end of the polyurethane tube, leaving 10 mm of polyurethane as the distal flexible cannula segment.

[0137] The main body housing is made from a 0.5cc insulin syringe. The syringe plunger is discarded and the syringe needle is removed from the distal end of the syringe barrel. The proximal lumen of the syringe barrel is tapped with 8-32 turns of thread to accommodate the proximal stop screw. A 27-gauge ultra-thin wall hypodermic needle with an inner diameter of 0.3mm, an outer diameter of 0.41mm, and a length of 20mm is bonded into the syringe barrel. The needles are placed so that the 2.5mm needle extends distally from the syringe tip and the 14mm needle extends proximally within the syringe barrel bore. An "L" shaped slot is machined into the side of the syringe barrel to accommodate the tubing elements for fluid delivery and to serve as a trigger for cannula extension.

[0138] The drive mechanism is made of a shaft assembly and a compression spring, which acts as a force element to extend the sleeve. The shaft assembly consists of a proximal tube, a central connector, and a distal mounting subassembly. The proximal tube is made of a 17-gauge thin-wall hypodermic injection tube with an inner diameter of 1.19 mm, an outer diameter of 1.45 mm, and a length of 87 mm. The central connector is made of an acetal polymer tube with an inner diameter of 1.57 mm, an outer diameter of 3.18 mm, and a length of 16 mm. A side hole with a diameter of 0.36 mm is drilled in the central connector 7.3 mm from the distal end. The distal mounting assembly is made of two sections of polyetheretherketone (PEEK) tube with an outer diameter of 1.58 mm. The inner diameter of the proximal section is 0.35 mm, which is sized to accommodate the sleeve. The inner diameter of the distal section is 0.65 mm, which is sized to accommodate the support tube. The support tube is made of 23 gauge thin wall hypodermic tubing with an inner diameter of 0.43 mm, an outer diameter of 0.64 mm, and a length of 16.6 mm. The support tube bonded into the distal segment provides support to prevent the cannula from bending during extension. The support tube is slidably disposed over the proximal end of the 27 gauge needle inside the syringe barrel, thereby placing the distal end of the cannula within the proximal end of the lumen of the 27 gauge needle.

[0139] The proximal end of the cannula is bonded into the proximal PEEK segment of the mounting subassembly. The distal PEEK segment with the support tube bonded appropriately is slid over the cannula and the two PEEK segments are bonded together. The subassembly is pressed into the distal end of the central connector until the proximal end of the subassembly is just distal to the side hole in the connector. The proximal tube is inserted into the central connector until the distal end is just proximal to the side hole and then bonded appropriately. The gap between the mounting assembly and the proximal tube allows fluid to flow from the side hole into the central connector and then into the lumen of the cannula. A section of plastic optical fiber (POF) is inserted into the proximal tube and advanced until it is flush with the distal end of the tube. The assembly allows light from the POF to be incident on the end of the polyurethane cannula. The POF consists of a polymethyl methacrylate core with a diameter of 0.46mm, coated with a fluorinated polymer and then wrapped with polyethylene with an outer diameter of 1mm. The POF is cut into 700mm lengths. The proximal end of the POF is inserted into a machined connector fitting connected to a green laser. When the laser is activated, light is transmitted through the POF to the proximal end of the cannula. The light is transmitted through the cannula with enough light emerging from the cannula wall to illuminate the length of the cannula and enough light conduction to provide a sharply illuminated distal tip.

[0140] The compression spring provides the force element to extend the cannula. The spring is made of stainless steel wire with a diameter of 0.22 mm and has an outer diameter of 2.6 mm and a length of 33 mm. The spring is placed on the proximal tube with the distal end close to the center connector. The proximal stop is made of a 16 mm long 8-23 threaded nylon hex socket screw. A hole with a diameter of 1.5 mm is drilled on the axis of the screw to slidably mount on the proximal tube. The screw is screwed into the proximal end of the syringe barrel to provide a proximal stop for the compression spring. A Shore 50A hardness silicone O-ring with an inner diameter of 1.1 mm and an outer diameter of 3.6 mm is placed on the proximal tube near the stop. The O-ring acts as a friction element to reduce the extension rate of the cannula.

[0141] The fluid connection to the cannula is made through a side tube. The side tube consists of a section of 27-gauge stainless steel hypodermic injection tubing with an inner diameter of 0.20 mm, an outer diameter of 0.41 mm, and a 90-degree bend. One end of the tube is inserted into the side hole of the central connector through a slot in the syringe barrel. A section of polyurethane tubing with an inner diameter of 0.25 mm, an outer diameter of 0.51 mm, and a length of 120 mm is connected to the open end of the hypodermic injection tube. A 30-gauge blunt Luer needle adapter is inserted into the proximal end of the polyurethane tube to connect a syringe or other fluid delivery element. Retract and rotate the drive mechanism with the connected cannula so that the side tube stops in the short leg of the "L" shaped slot. In this configuration, the device is in a locked state and the cannula cannot be extended. In use, the device is ready to be extended by manually pushing the side tube into the slot as a ready or activated state. By pushing the slide tube out of the slot, the cannula is observed to be advanced by the drive mechanism and extend from the needle tip.

[0142] Example 2. Cannulation device for placing an illuminated flexible cannula in the suprachoroidal space

[0143] A device according to Example 1 was prepared. The drive mechanism was retracted and the side tube was placed in the short leg of the syringe slot, holding the device in the locked state. A 0.25cc syringe was filled with a 0.1% fluorescein solution and connected to the Luer connector at the end of the fluid connection tube. The green laser was turned on and the cannula was illuminated. A cadaveric porcine eye was prepared. The 27-gauge needle of the device was inserted into the sclera at the pars plana at an acute angle to the back of the eye and advanced until the bevel was substantially within the sclera. The side tube was pushed laterally into the slot, bringing the device into the ready state. The cannula could not be advanced because the distal tip was within the scleral tissue. The needle was further advanced into the eye. When the needle tip entered the suprachoroidal space, the cannula automatically extended under the action of the compression spring. The illuminated cannula could be observed below the sclera as a green line extending posteriorly from the needle entry site.

[0144] 0.1 cc of fluorescein was injected through the cannula. The cannula was withdrawn from the eye. The sclera was cut over the application site and the suprachoroidal space was accessed, and washout of fluorescein was observed, confirming that the injection was in the suprachoroidal space.

[0145] Example 3. Cannulation device for placing an illuminated flexible cannula in the vitreous cavity

[0146] The device according to Example 1 was prepared as in Example 2. A cadaveric porcine eye was prepared. A 27-gauge needle was inserted at the pars plana perpendicular to the surface of the eye. The cannula was extended as in Example 2. No illuminated cannula was observed beneath the sclera, but an illuminated cannula was observed through the cornea, indicating placement within the vitreous cavity.

[0147] Example 4. Fabrication of a cannula device having a curved flexible cannula for placing a cannula in an ocular tissue space

[0148] A device similar to that described in Example 1 was fabricated. The distal 2 mm of the cannula was formed at an angle of approximately 45 degrees. The cannula was placed on the formed wire and heated to 90°C for 30 seconds. The cannula was incorporated into the device and bent toward the bevel of the needle. The device and cadaveric porcine eye were prepared as in Example 2. The needle was inserted into the eye at an angle to the surface with the bevel of the needle pointing toward the outside of the eye. The device was actuated and the needle advanced. The cannula was extended and a scleral incision was made over an area distal to the needle. The cannula was observed in the suprachoroidal space.

[0149] Example 5

[0150] A device according to one embodiment of the present invention is manufactured to inject a fluid material into the suprachoroidal space of the eye. The tubular spindle is made of a 12-gauge thin-walled stainless steel hypodermic injection tube having an outer diameter of 0.109 inches (2.77 mm), an inner diameter of 0.091 inches (2.31 mm), a length of 5.5 inches (139.7 mm), and an outer surface that is electropolished. The spindle compression spring is made of a stainless steel wire having a diameter of 0.010 inches (0.25 mm), an outer diameter of 0.155 inches (2.31 mm), and a free length of 3.63 inches (92.2 mm). The compression spring has a spring rate of 0.119 pounds (0.53 N) per inch (25.4 mm) at a spring height of 2.040 inches (51.82 mm) and a spring rate of 0.146 pounds (0.65 N) at a spring height of 1.683 inches (42.75 mm). The coupler assembly is made of polycarbonate and has features that interact with the trigger lift point and holes to accommodate the centrally located fiber optic cable, offset internal fluid lines and tubular spindle.

[0151] The optical cable was made using ESKA Fiber Optic SH-2001-J, with a fiber of 0.020 inches (0.51 mm) and a jacket outer diameter of 0.040 inches (1.02 mm), cut into 84 inches (213.4 cm) long and stripped of 1.5 inches (38.1 mm) of insulation at the far end. The internal fluid line was made of 5.03 inches (127.76 mm) long 25-gauge thin-wall hypodermic tubing and sandblasted for 0.25 inches (6.35 mm) at each end to increase adhesive adhesion. The internal fluid line and the stripped end of the optical cable were both bonded to the connector assembly. The spindle was slid over the near end of the optical cable and the internal fluid line and bonded to the connector assembly.

[0152] The outer fluid line was made of 80A durometer polyurethane, had an inner diameter of 0.014 inches (0.36 mm), a thickness of 0.019 inches (0.48 mm), and a length of 11.0 inches (279.4 mm). The outer fluid line was bonded to the proximal end of the inner fluid line.

[0153] The proximal and distal bushings are made of UHMWPE with an inner diameter of 0.112 inches (2.84mm) and an outer diameter of 0.25 inches (6.35mm). The main shaft compression spring and bushing slide over the optical cable, external fluid line and main shaft until the connector assembly. The end cap is made of polycarbonate and slides over the near end of the optical cable and the internal fluid line for connection to the near end of the housing. A custom female Luer fitting with an internal dead volume of 5 microliters is bonded to the near end of the external fluid line. An optical connector is made for connection to an external light source, with an inner diameter of 0.042 inches (1.07mm) and bonded to the end of the optical cable.

[0154] The flexible sleeve assembly is made of a 55D hardness polyurethane tube with an inner diameter of 0.005 inches (0.13 mm) and an outer diameter of 0.0098 inches (0.25 mm) for the body and an 80A hardness polyurethane tube with an inner diameter of 0.005 inches (0.13 mm) and an outer diameter of 0.0098 inches (0.25 mm) for the flexible sleeve soft tip. The soft tip with a length of 0.070 inches (1.78 mm) is heat fused to the body, and the distal end of the soft tip is polished so that the edge of the distal end of the soft tip is rounded.

[0155] The flexible sleeve proximal support is made of polyimide tubing with an inner diameter of 0.0102 inches (0.26 mm), a wall thickness of 0.0005 inches (0.013 mm), and a length of 0.86 inches (21.84 mm). The sleeve proximal support is slid over the sleeve assembly and bonded in place. The flexible sleeve proximal support is then bonded to the distal end of the coupler assembly.

[0156] The speed control compression spring is made of stainless steel spring wire with a diameter of 0.015 inches (0.38mm) and a free length of 0.175 inches (4.45mm), an outer diameter of 0.106 inches (2.69mm), and a spring rate of 28.75 pounds (127.9N) per inch (25.4mm). The spring has 3 active coils and 2 inactive coils with closed ends and grounded ends. A Buna N quad ring of size AS568-004 is used as the polymer speed control wheel. A stainless steel pin with a diameter of 0.078 inches (1.98mm) and a length of 0.187 inches (4.75) is used as the speed control wheel shaft, and a stainless steel pin with a diameter of 0.063 inches (1.60mm) and a length of 0.375 inches (9.53mm) is used as the pivot arm shaft.

[0157] The pivot arm is machined from polycarbonate. The speed control adjustment screw is made from 304 stainless steel and has a 4-40 turn thread with one end machined down to 0.072" (1.83mm) in diameter. The speed control wheel axle passes through the pivot arm and speed control wheel and is held in place by friction against the inside of the speed control wheel.

[0158] The housing assembly is machined from polycarbonate and has a 4-40 turn threaded hole at the proximal end for the speed control adjustment screw and a hole drilled for the pivot arm pin. The pivot arm pin is press fit into one side of the housing. The speed control adjustment screw is threaded into the hole in the housing. The pivot arm with the speed control wheel is mounted on the press fit pivot arm shaft and the speed control compression spring is placed between the pivot arm and the speed control adjustment screw.

[0159] The trigger is machined from polycarbonate and the flexible portion of the trigger is 0.028" (0.71mm) thick. The trigger is placed between the housing halves, the assembled spindle is placed under the speed control polymer wheel, the bushing is placed in the cavity of the housing halves, and the housing assembly halves are bonded together.

[0160] The bevel needle is made of 27 gauge 304 stainless steel ultra-thin wall hypodermic injection tubing. The inner diameter of the tube is 0.0115 inches (0.292mm), the outer diameter is 0.0165 inches (0.42mm), and the length is 0.80 inches (20.32mm). The distal tip is polished into a lancet-type bevel with a primary bevel angle of 15 degrees. The nose cone is made of polycarbonate, and the bevel needle is bonded to the nose cone with 3mm of the needle extending from the distal surface of the nose cone and the bevel needle is oriented horizontally compared to the centerline of the housing. The nose cone is bonded to the distal end of the housing assembly, and the distal end of the cannula is placed at the proximal end of the needle so that the distal tip of the cannula is approximately 0.5 to 1 mm near the proximal end of the needle bevel.

[0161] Example 6. Cannula device with distal element and deflecting needle for placement of a flexible cannula in the suprachoroidal space

[0162] A device according to an embodiment of the present invention is manufactured for extending a flexible cannula into the suprachoroidal space or supraciliary space of the eye. The syringe element is made by cutting off the proximal end of a 0.5 ml insulin syringe to obtain a 30 mm long syringe. The integrated needle is removed from the syringe to connect a standard Luer hub needle. The distal tip of the syringe is cut off, leaving the remaining portion of the Luer cone that can firmly hold the Luer hub needle. The syringe end cap is made of a nylon 10-32 hexagon socket screw with a thread length of 4.5 mm. A through hole with a diameter of 1.86 mm is drilled through the end cap to allow the plunger to slide freely through the end cap. The plunger shaft is made of a Teflon-coated tubular stainless steel rod with an outer diameter of 1.8 mm, an inner diameter of 0.8 mm, and a length of 43 mm. The distal end of the shaft is turned down to a diameter of 1.74 mm and a stainless steel washer with an outer diameter of 4.1 mm, an inner diameter of 1.70 mm and a thickness of 0.5 mm is press fit onto the rod to provide a distal stop for the plunger spring. The proximal end of the rod is drilled out to a diameter of 1.55 mm. A compression spring with an outer diameter of 3.1 mm, a wire diameter of 0.18 mm and a length of 31.8 mm is placed on the shaft of the plunger and the syringe end cap is then slid over the plunger shaft at the proximal end of the spring. The plunger assembly is placed in the syringe housing and the end cap is press fit into the proximal end of the syringe to secure the plunger assembly within the syringe.

[0163] The deflection needle is made from a 27 gauge x 13 mm thin wall hypodermic needle. The distal tip of the needle is bent toward the bevel to form a ramped inner surface. The back side of the needle opposite the original bevel is rolled in a manner similar to a standard lancet tip with primary and secondary bevels to create a sharp tip for tissue penetration. A 24 gauge 3 cm long thin wall tubing is press fit into the needle hub against the proximal end of the 27 gauge needle. The 24 gauge tubing acts as a support tube to prevent the flexible cannula from kinking during extension. The needle assembly is mounted on the syringe assembly.

[0164] Manufacture flexible cannula.The cannula shaft is composed of a proximal segment of a PEBAX polymer tube with a Shore hardness of 72D, a length of 50mm, an inner diameter of 0.30mm, and an outer diameter of 0.38mm. The proximal end of the proximal segment is connected to a No. 30 blunt Luer tube adapter. The distal segment of a polyolefin polymer tube with a length of 75mm, an inner diameter of 0.12mm, and an outer diameter of 0.20mm is bonded to the distal end of the proximal segment. A nickel-titanium (nitinol) reinforcing wire with a diameter of 0.75mm is inserted into the flexible cannula to provide pushability for the thin-walled distal cannula. The distal end of the cannula is formed into a circular non-invasive tip using cyanoacrylic adhesive. The flexible cannula is inserted via a plunger and a needle assembly and then fixed in place at the proximal end of the plunger shaft. After fully extended, the flexible cannula extends beyond the needle tip by 15mm.

[0165] A safety mechanism is included in the device to prevent the plunger spring force from causing premature actuation of the plunger. Two shallow grooves are made in the plunger 19 mm from the distal tip, 180 degrees apart and perpendicular to the axis of the plunger. The distance between the groove surfaces is 1.5 mm. The retaining clip is made of a brass sheet with a width of 6.3 mm and a length of 18 mm. A slot with a width of 1.6 mm and a length of 8.8 mm is machined in the retaining clip. The slot is cut in the center of the short side of the retaining clip and spans the long axis direction.

[0166] The molded cylindrical tissue interface and distal sealing element are made of 70 Shore A hardness silicone rubber. The length of the distal element is 3.7mm and the diameter is 1.75mm. The distal element has an inner cavity with a length of 2.7mm and a diameter of 0.38mm. The far end of the inner cavity of the distal element is configured to have a bevel shape that conforms to the far end of the needle. The distal sealing element is connected to the distal tip of the needle so that the needle bevel contacts the inner cavity bevel, thereby sealing the distal tip of the needle. The non-bevel portion of the inner cavity acts as a slidable seal on the shaft of the needle, and provides enough friction to the needle shaft, so that the distal tip is kept against the surface of the eye during the process of advancing the needle through the distal seal of 1mm thickness.

[0167] When in use, the plunger is retracted to compress the plunger spring and withdraw the flexible sleeve until the plunger slot is exposed proximally to the end cap. The retaining clip is placed on the plunger so that the slot on the retaining clip engages with the slot on the plunger shaft. The retaining clip is then held against the proximal end surface of the end cap by the spring force to prevent the plunger from moving.

[0168] A 1cc syringe was filled with 0.5ml of 0.01% fluorescein solution. The syringe was connected to the female Luer fitting on the proximal end of the cannula. A cadaveric porcine eye was prepared by inflating the posterior chamber to a pressure of approximately 20mmHg. A target penetration site 4mm posterior to the limbus of the eye was selected for insertion of the device needle to extend the flexible cannula. The retaining clip was removed from the plunger shaft. The tissue interface and distal seal were placed against the scleral surface, and the needle tip was then advanced through the distal seal and into the tissue with the needle bevel facing the posterior of the eye. Once the needle lumen reached the suprachoroidal space, the cannula was free to exit the needle and was extended by the push rod under the force of the plunger spring. Once the plunger was seen to have been activated, 0.05ml of fluorescein was injected through the flexible cannula and into the suprachoroidal space. A radial incision was made through the sclera at the location of the flexible cannula to expose the suprachoroidal space. Once the suprachoroidal space is entered, the fluorescein solution can be seen overflowing from the suprachoroidal space and further cutting is allowed in order to directly visualize the flexible cannula shaft in the suprachoroidal space.

[0169] Example 7. Cannula device with distal seal for placement of a flexible cannula in the suprachoroidal space

[0170] A device according to an embodiment of the present invention is manufactured. The device comprises a cannula element, a needle with a distal seal, a cannula support element, a force element and a housing.

[0171] The sleeve element is made of a distal flexible tubular section, a connecting tube and a proximal Luer adapter to complete the flow path of the material to be applied. The distal flexible tubular element is made of a PEBAX tube with a hardness of 72D of 75mm, an inner diameter of 0.12mm and an outer diameter of 0.18mm. The near end of the flexible sleeve is pulled through a polyimide support tube with a length of 25mm, an inner diameter of 0.18mm and an outer diameter of 1.59mm, so that a 20mm flexible sleeve extends from the support tube to the proximal end. The support spring is made of a nickel-titanium alloy (nitinol) wire with a diameter of 0.1mm. The support spring is 25mm in length and 0.2mm in inner diameter. The spring is wound with a pitch of 0.48mm and has a closed end. The nitinol spring is shaped by applying 480°C hot air. The support spring is placed on the polyimide support tube. The support tube and spring prevent the flexible sleeve from shrinking or kinking in the sleeve support element. The proximal end of the flexible cannula was bonded to the inside of a polyetheretherketone (PEEK) tube having a length of 10 mm, an inner diameter of 0.17 mm, and an outer diameter of 1.59 mm, and a 10 mm flexible tube extended proximally from the PEEK tube. A connecting tube consisting of polyethylene having a length of 250 mm, an inner diameter of 0.28 mm, and an outer diameter of 0.61 mm was placed on the exposed distal end of the flexible cannula and bonded to the PEEK tube.

[0172] The needle was made of a 27 gauge thin wall needle 32 mm long. The needle was bonded into a polyethylene Luer hub with the beveled tip of the needle extending 3 mm from the distal end of the hub. The distal seal was made of a molded 50A durometer silicone elastomer 3 mm long and 0.75 mm outer diameter. The proximal tip was constructed with a blind hole 2.1 mm long and 0.3 mm in diameter and had a flat distal tip. The distal seal was placed on the needle in the final step of device assembly.

[0173] The sleeve support element is made of a distal tube, a connecting tube and a proximal tube. The distal tube is made of a PEEK tube with a length of 30mm, an inner diameter of 0.5mm and an outer diameter of 1.59mm. The proximal support element tube is made of a stainless steel tube with a length of 110mm, an inner diameter of 1.32mm and an outer diameter of 1.57mm. The support element connecting tube is made of an acetal (Delrin) tube with a length of 25mm, an inner diameter of 1.59mm and an outer diameter of 3.2mm. A hole with a diameter of 1.9mm is drilled in the proximal end of the support element connecting tube to receive the distal end of the force element spring support tube. The distal support element tube is placed on a flexible sleeve and abuts against the sleeve PEEK tube, covering the section containing the support tube and the support spring. The proximal support tube is placed on the sleeve connecting tube and bonded to the sleeve PEEK tube. The support element connecting tube is placed on the distal tube, the sleeve PEEK tube and the proximal support tube connector, so that the assembly is kept together.

[0174] The force element is made of a spring support tube, a compression spring and a proximal adjustable stop. The force element spring support tube is made of a stainless steel tube with a length of 140mm, an inner diameter of 1.6mm and an outer diameter of 2mm. The compression spring is made of stainless steel spring tempered wire with a diameter of 0.26mm. The compression spring is 100mm long, has an inner diameter of 2.6mm, a pitch of 1.4mm, and has a closed end. The adjustable stop is made of a 38mm long 10-32 nylon hexagon socket screw 38 with a through hole drilled in the shaft with a diameter of 2.2mm. The spring support tube is placed on the polyethylene sleeve connecting tube and press-fitted into the proximal end of the Delrin sleeve support element connecting tube, thereby completing the subassembly consisting of the sleeve element, sleeve support element and spring support tube.

[0175] The housing consists of a distal body and a proximal body, which are made of a modified polycarbonate 1mm syringe body. The distal body is modified by cutting off the finger-shaped flange, and then the proximal end is drilled and tapped (8mm deep) with a 5 / 16-18 thread. The syringe distal Luer lock connector is retained. The proximal body is modified by cutting off the finger-shaped flange, and then the proximal body is drilled and tapped (19mm deep) with a 10-32 turn thread. The far end of the proximal body is machined and screwed onto a 5 / 16-18 thread with a length of 7.6mm. In this way, the distal body and the proximal body are connected by the 5 / 16-18 threaded portion for assembling the device.

[0176] The device is assembled by placing the cannula element, cannula support element and force element spring support tube assembly in the distal housing. A compression spring is placed on the spring support tube and the proximal housing is connected to the distal housing. The distal end of the flexible cannula is inserted into the inner cavity of the needle and the needle and the needle Luer hub are connected to the distal housing Luer connector. The proximal end of the needle is slidably disposed in the distal PEEK tube of the cannula support element. The proximal end of the needle is close to the cannula support spring. The force element adjustable stop is placed above the cannula connection tube and screwed into the proximal end of the proximal housing. A No. 30 Luer needle adapter is inserted into the proximal end of the cannula connection tube so that a syringe can be connected to deliver the material to be administered.

[0177] With the mechanism in the extended configuration, the flexible cannula is configured to extend 12 mm from the distal tip of the needle. The adjustable stop is screwed into the assembly so that the force element compression spring has just enough force to overcome the compression of the cannula support spring, allowing the cannula to be extended when the device is activated. The proximal end of the force element support rod protrudes from the proximal end of the adjustable stop. A silicone O-ring that fits tightly on the force element support rod is temporarily placed over the support rod. The O-ring is used to hold the mechanism in the retracted configuration while the distal seal is placed over the needle tip. The O-ring is removed, leaving the device in a state ready to extend.

[0178] A 0.25 ml syringe was filled with 100 microliters of 0.1% fluorescein solution and connected to the proximal Luer fitting of the device. The cadaveric porcine eye was prepared by inflating to a pressure of 17 mmHg. The distal seal of the device was placed against the sclera at the pars plana, approximately 6 mm posterior to the limbus. The device was angled approximately 30 degrees to the surface of the eyeball with the needle bevel opening facing posteriorly. The device was advanced so that the needle tip could penetrate the distal seal and enter the scleral tissue. When the needle tip reached the suprachoroidal space, the flexible cannula was advanced under the force of the force element compression spring. After extension, the fluorescein solution was injected through the device. The device was retracted and set aside. A subscleral incision was made from the area of ​​needle penetration, extending posteriorly toward the target area at the distal end of the extended cannula. The dissection revealed the fluorescein solution in the suprachoroidal space.

[0179] Example 8. Low Sealing Force Tissue Interface

[0180] Tissue interfaces were fabricated in a manner similar to that described in Example 5. Tissue interfaces of two different outer diameters were fabricated: 1.75 mm diameter and 2.50 mm diameter. Liquid silicone elastomers of four different hardnesses (Shore 10A, 30A, 50A, and 70A) were used to fabricate tissue interface samples of each diameter.

[0181] An experimental arrangement was prepared to determine the sealing force of various samples of tissue interfaces. A length of 8.3 mm long PEEK tubing was placed over a 27 gauge x 13 mm thin wall hypodermic needle as a stop so as not to allow the tissue seal to travel proximally during testing. The tissue seal to be tested was then placed over the needle tip. The length of the PEEK tubing was dimensioned to allow approximately half of the needle bevel portion to protrude through the distal surface of the tissue interface. A test surface consisting of a silicone elastomer pad with a hardness of Shore 50A and a thickness of 3.2 mm was used. The needle was mounted to a tee fitting, which in turn was mounted on the shaft of a 250 N load-bearing digital dynamometer mounted on a motorized test bench. The side legs of the tee fitting were first connected to a certain length of tubing and then to a Luer fitting and a three-way valve. A 10 cc syringe filled with water was connected to the valve. A ring stand was used to hold the syringe vertically. Testing was performed using two different constant pressures, which were generated by applying fixed weights of 1030 grams and 1656 grams to the finger flange of the syringe plunger, respectively. The cross-sectional area of ​​the syringe interior is 1.64×10 -4 m 2 , corresponding to fluid pressures of 6.18×104Pa and 9.93×104Pa respectively.

[0182] Move the needle tip downward until the tissue interface is in close contact with the silicone test pad for testing. Gently push the test station motor downward until approximately 30 grams of force are applied to the tissue interface. Open the three-way valve and observe the perimeter of the tissue interface for leaks. Close the valve and then move the needle downward until approximately 35 grams of force are applied. Open the valve and observe the tissue interface for leaks. Increase the tissue interface pressure on the test pad in this manner in 5 grams of force increments until no leaks are observed (e.g., a seal is achieved) and the force is recorded. Repeat the test with a second syringe pressure weight. This test was performed on two different tissue interface diameters and four different hardnesses (Tables 1 and Fig.15 ). Two samples of each tissue interface were tested three times each, for a total of six data points per test condition. The silicone test pad was moved after each test so that the needle penetrated a new site each time.

[0183] Table 1. Minimum sealing force (grams-force) for tissue interface test specimens (mean and standard deviation). Grouped by tissue interface diameter and fluid pressure as a function of hardness.

[0184]

[0185] Example 9. Semisolid pharmaceutical composition

[0186] A semisolid pharmaceutical composition was prepared. 1.5 wt% polyethylene oxide (PolyOxWSR-303) with an average molecular weight of 7 million Daltons was dispersed in deionized water. Dexamethasone crystals with an average diameter of about 2 microns were mixed into the polyethylene oxide dispersion at a concentration of 8 wt%. The semisolid composition was opaque due to the dispersed dexamethasone crystals.

[0187] The cannula device according to Example 7 was manufactured to inject a semi-solid composition into the suprachoroidal space of the eye. The cannula was configured with an extended length of 10 mm. Prior to use, the distal 3 to 5 mm of the cannula was coated with a lubricating polymer composition comprising 50 wt% polyethylene glycol having a MW of 100,000 Daltons and 50 wt% polyethylene glycol having a MW of 20,000 Daltons.

[0188] The enucleated pig eye was prepared by infusion to 17 mm Hg. The distal tip of the cannula device was placed on the ciliary body flat area of ​​the eye and pushed into the eye, with the bevel directed posteriorly. Once the needle tip reaches the appropriate depth to enter the suprachoroidal space, self-actuated extension of the cannula will be observed. Approximately 100 microliters of semisolid pharmaceutical composition were applied to the proximal end of the cannula by a female Luer lock connector. After application, scleral dissection was performed from the needle penetration site to the area 10 mm behind the cannula from the needle penetration site. Dissection of the suprachoroidal space showed the semisolid composition in the posterior region of the suprachoroidal space. No vitreous cavity perforation was observed.

[0189] Example 10. Microspheres for controlled release of corticosteroids

[0190] Microspheres containing active agents are prepared to provide controlled release of the agent after administration. Biodegradable polymers are used to make microspheres and encapsulate active agents. The polymers include polylactic-co-glycolic acid (PLGA) with ester end groups in different stoichiometric ratios of lactic acid and glycolic acid (L and G), with different molecular weights represented by intrinsic viscosity. Table 2 lists the polymers used for microsphere manufacturing.

[0191] Table 2. Biodegradable polymers of microspheres

[0192]

[0193] The polymer is dispersed in an organic solvent mixture, which contains a solvent for the polymer (e.g., dichloromethane (DCM), chloroform, ethyl acetate, isopropyl acetate), mixed with a solvent that assists in solubilizing the active agent (e.g., tetrahydrofuran (THF) or methanol (MeOH)). In some manufactures, more than one solvent is used to assist in solubilizing the active agent. The polymer is dispersed at a solid concentration of about 3.2 wt% to 4.3 wt% by mixing the polymer in the solvent system for about 4 to 24 hours until fully dispersed. Dexamethasone acetate is also added to the dispersion as an active agent at a concentration of about 20 wt% to 50 wt% of the total solids (polymer plus drug).

[0194] The polymer and drug dispersion are emulsified in an aqueous dispersion of polyvinyl alcohol at a concentration of approximately 2.5wt% to 6wt%, wherein the dispersion forms the discontinuous phase of the emulsion. Emulsification is performed at 25 degrees Celsius. After tempering for about 8 to 30 hours to allow the microspheres to form and harden, the resulting microsphere suspension is collected by filtration. The microspheres are suspended in water containing 0.01wt% to 0.05wt% polysorbate 20 surfactant to rinse and prevent aggregation. The suspension is centrifuged at 2,500rpm and the microspheres are collected. Rinsing is repeated to remove residual polyvinyl alcohol. The collected microspheres are suspended in water, frozen and lyophilized to produce a dry, free-flowing powder.

[0195] Microscopic examination of the microsphere powder samples showed the collection of spherical microspheres. The microsphere samples were suspended in an aqueous solution of 0.1 wt% polysorbate 20 surfactant and analyzed with a Coulter LS200 laser diffraction particle size analyzer. The resulting particle size distribution showed a volume average particle size range of about 3.9 to 14.3 microns with a coefficient of variation of about 10.4% to 19.2%. Repeated microsphere manufacturing demonstrated the ability to control the average particle size from about 3 microns to 14 microns by varying the polymer, polymer solids concentration, solvent conditions, and emulsification conditions.

[0196] The microsphere sample containing dexamethasone acetate was dissolved in acetonitrile to extract the active agent from the microsphere. The acetonitrile extract was filtered through a 0.2 micron filter and analyzed by reverse phase high performance liquid chromatography (RP-HPLC). Based on the response factor obtained by the analysis of the dexamethasone acetate standard solution, the obtained peak of dexamethasone acetate was used to calculate the active agent concentration of the extract. The active agent content in the microsphere was determined by the concentration of the active agent relative to the amount of microsphere extracted. By adjusting the concentration of the active agent in the polymer dispersion, it was found that the active agent content of the microsphere was controlled. The microsphere can be produced with an active agent content of 16.1wt% to 42wt%. A series of microsphere preparations are provided using the obtained microspheres with different average particle sizes and active agent contents. Table 3 lists the manufacturing conditions of the microspheres containing the active agent and the obtained volume average particle size and active agent content.

[0197] Table 3. Fabrication of drug-containing microspheres

[0198]

[0199] Polarization microscopy of the dried microsphere powder showed no significant amount of free active agent crystals. Differential scanning calorimetry was performed on a sample of the dried microsphere powder. Thermal spectroscopy was performed at a rate of 10 to 15 degrees per minute to characterize the microspheres. In the range of 50°C to 60°C, a thermal transition due to the polymer was observed. In the range of 143°C to 163°C, an exothermic peak due to active agent recrystallization was observed. In the range of 203°C to 221°C, an endothermic peak due to active agent melting was observed. The active agent recrystallization enthalpy was calculated to be approximately 88.5% to 94.0% of the active agent melting enthalpy, indicating that the active agent is primarily in the form of an amorphous solid dispersion in the polymer.

[0200] The weighed microsphere samples from the manufacturing are placed in vials containing physiological buffer, wherein the active agent concentration is 0.1 micrograms per milliliter. The vials are placed on a rotating platform at 200rpm in an incubator at 37°C to facilitate mixing. Buffer samples are taken out regularly and the active agent concentration is measured by RP-HPLC. The resulting data are used to determine the active agent (drug) elution profile of the microspheres, thereby determining the release rate of each microsphere preparation. The elution data conform to the Korsmeyer-Peppas model equation for drug release. Elution tests have been performed on various microsphere preparations with different average particle sizes, active agent loadings, and polymers. Fig.16 Depicted are the elution profiles of PLGA microspheres with different L to G stoichiometric ratios from modeling data. As the L to G stoichiometric ratio of the polymer in the microsphere formulation decreases, the microspheres exhibit faster release. Fig.17 Depicted are the elution profiles of PLGA microspheres with a stoichiometric ratio of L to G of 75:25 and different average diameters from the data. As the average diameter of the microspheres decreases, the microspheres exhibit faster release. Fig.18 Elution profiles of PLGA microspheres with an L to G stoichiometry of 85:15 and different average diameters from the data are depicted. The microspheres exhibit faster release as the average diameter of the microspheres decreases. Although actual in vivo release may differ from characterization of drug elution in the laboratory, modeling data showed drug half-lives ranging from 5 weeks to 80 weeks, demonstrating that microspheres can be designed with a variety of release profiles.

[0201] Example 11. Semisolid Pharmaceutical Compositions Having Microspheres Containing Active Agents

[0202] Various semisolid preparations for injection materials containing the microspheres of Example 10 were prepared. The preparations were designed to allow lyophilization to promote stability and rapid reconstitution with sterile water for administration. Mannitol at a concentration of 1wt% to 10wt%, trehalose at a concentration of 1wt% to 3wt%, and sodium hyaluronate at a concentration of 0.3wt% to 1.0wt% were dissolved in 10 mmol to 25 mmol sodium phosphate buffer as an excipient mixture for microspheres. In one preparation, mannitol at a concentration of 4wt%, trehalose at a concentration of 1wt%, sodium hyaluronate at a concentration of 0.75wt%, and sodium hyaluronate of two different molecular weights were used. Sodium phosphate was prepared in deionized water using sodium dihydrogen phosphate and disodium hydrogen phosphate in a ratio of 7.4 to make the final pH. The excipient mixture was sterilized by filtration through a 0.2 micron sterile filter. The viscosity of the excipient formulations was also characterized on a Brookfield viscometer, demonstrating a zero shear viscosity of 726 mPas for the formulation with 700K MW hyaluronic acid and 1,585 mPas for the formulation with 1.5M MW hyaluronic acid.

[0203] The dexamethasone acetate PLGA-coated microspheres were sterilized by ionizing radiation and then mixed with the excipient mixture at 50 mg / ml to 150 mg / ml. A formulation with good suspension stability was prepared in which the concentration of the microspheres was 62 mg / mL to 125 mg / ml.

[0204] Use the "tip to tip" syringe mixing technique to mix and form a suspension of microspheres in the excipient mixture. Fill the final mixed formulation into vials and freeze at -70°C for at least 30 minutes. Place the frozen vials in a lyophilizer and lyophilize to dryness.

[0205] The lyophilized formulations were reconstituted to a microsphere concentration of 125 mg / ml by adding sterile water for injection for administration. The reconstituted formulations were tested on a freezing point osmometer and showed an osmotic pressure concentration in the range of 300 mOsM to 850 mOsM. Table 4 lists the formulations prepared and characterized. All formulations showed suitable suspension stability before lyophilization to allow freezing and lyophilization. All formulations were shown to be reconstituted to a uniform semisolid for administration.

[0206] Table 4. Semisolid microsphere formulations

[0207]

[0208] The reconstituted formulations were injected using the device of Example 1, showing good injectability and visual homogeneity of the injected material. The injectable formulations were also able to be injected using a 1 ml syringe through a 0.5 inch long 31 gauge needle. All of the injectable material formulations in Table 4 showed good suspension stability, with the ability to be injected without additional mixing for at least 30 minutes after reconstitution.

[0209] Example 12. Soft-tipped cannula for cannulation of small tissue spaces

[0210] To compare the deflection and penetration characteristics of various soft distal tip lengths, experiments were conducted in which soft tips of varying lengths on the cannula of Example 5 were advanced at various angles toward a tissue model (7 wt% hi-bloom gelatin). Soft distal tips of lengths of 0.85 mm, 1.5 mm, 2.0 mm, 2.5 mm, and 3 mm made of 80A durometer polyurethane tubing were tested on the distal end of a 55D durometer polyurethane cannula. The distal end of the soft tip was polished to minimize the sharp leading edge. The cannula was advanced toward the gel surface at a speed of 270 mm / min. The catheter was advanced through a 27-gauge ultrathin wall needle with the distal edge of the needle bevel positioned to contact the gelatin surface or to be embedded in the gelatin to varying degrees. The bevel opening of the needle was covered with a 50 Shore A silicone elastomer sheet simulating the sclera. The catheter was advanced 4.5 mm and the deflection relative to the gelatin surface or penetration of the gel was visually observed. The tests were performed with the needle bevel at 90 degrees (perpendicular), 45 degrees, and 60 degrees relative to the gel surface. The test results showed that under the least stringent conditions where the needle contacted the gelatin surface and was at a 45-degree angle, the 0.85mm long soft tip was insufficiently deflected and penetrated the clear gelatin. The cannula with a 1.5mm long soft tip was deflected relative to the surface, the needle contacted the gelatin at a 45-degree angle. The cannula with a 2.0mm long soft tip was deflected relative to the surface, the needle contacted the gelatin at a 90-degree angle, and the needle was buried or deeply buried at a 45-degree needle angle. The cannula with a 2.5mm soft tip was deflected at all angles, the needle contacted the gelatin surface, and the needle was buried or deeply buried in the gelatin at 45 degrees. The cannula with a 3.0mm soft tip deflected relative to the gelatin under all conditions and angles. The test results show that soft tip cannulas with soft tip lengths greater than 0.85 mm have very good deflection characteristics and soft tip lengths of at least 1.5 mm have very good deflection characteristics.

[0211] Example 13. Intubation of a live pig eye using an intubation device

[0212] The device manufactured in Example 5 was tested in a porcine animal model. Before use, silicone oil lubricant was applied to the distal tip of the cannula to lubricate the distal 3 to 5 mm. The animal was anesthetized and placed in lateral recumbency. A sterile drape was placed on the eye and the eyelid was opened. A speculum was placed to keep the eyelid open. A 5-0 Vicryl suture was placed at the limbus of the selected clock injection site to provide traction. The process was performed by an observer using a surgical magnifying glass without direct observation under a microscope. The device for testing was connected to an external light source (iLumen fiber optic illuminator, Ellex iScience). The light output of the cannula of the device was measured using a Thorlabs optical power meter (PM100D with S140C / S120-FC sensor), indicating that the light output range was 165mW to 700mW.

[0213] The needle tip is inserted into the eye at the pars plana region while approaching a 45-degree angle to the ocular surface. The illuminated cannula provides a "headlight" through the needle and illuminates the tissue surface directly in front of the needle, allowing the needle to be advanced in the tissue until the headlight disappears, visually demonstrating that the needle bevel is in the scleral tissue. The trigger button on the device is activated and the device is then advanced slowly and steadily until the cannula automatically extends. The transscleral illumination from the cannula shaft and tip is observed to confirm the position of the cannula and the in situ configuration of the cannula.

[0214] The device was tested at 28 sites in the eye, and in 27 cases the cannula was observed to be located in the suprachoroidal space through the overlapping sclera and conjunctiva as an illuminated line starting near the needle insertion site in the supraciliary space or the anterior portion of the supraciliary space and extending posteriorly to the bright distal tip of the supraciliary space. Illumination from the cannula shaft clearly indicated that the cannula was pointing posteriorly from the needle insertion site. A test was performed where the cannula was deliberately placed into the vitreous cavity, resulting in no illumination visible through the sclera, but light was visible through the pupil, indicating that the device was not located in the supraciliary space or supraciliary space, but rather in the intraocular space.

[0215] The device was prepared with a 0.25 ml syringe filled with the semisolid microsphere formulation of Example 10 (25 mM sodium phosphate, 4 wt% mannitol, 1 wt% trehalose, 0.75 wt% high molecular weight sodium hyaluronate). After the needle of the device was inserted into the sclera and the cannula was observed to extend into the suprachoroidal space by transscleral illumination, 100 microliters of the formulation was injected into the suprachoroidal space. Due to the large amount of injection into the eye, a small amount of injected material was observed at the needle injection site during the removal of the cannula. No injected material was observed in the vitreous body when indirect funduscopy was performed, indicating successful suprachoroidal administration of the injected material.

[0216] Example 14. Pharmacokinetics of Semisolid Pharmaceutical Compositions Containing Controlled Drug Release Microspheres

[0217] A microsphere formulation with an average diameter of 9.7 microns and a dexamethasone acetate drug load of 35 wt% was prepared from a PLGA polymer as described in Example 10 with a stoichiometric ratio of L to G of 75:25 and an intrinsic viscosity of 0.75 dL / g. The microspheres were prepared at a concentration of 70 mg / ml in the injection material formulation of Example 11. A second microsphere formulation with an average diameter of 9.7 microns and a dexamethasone acetate drug load of 35 wt% was prepared from a PLGA polymer as described in Example 10 with a stoichiometric ratio of L to G of 85:15 and an intrinsic viscosity of 0.78 dL / g. The microspheres were prepared at a concentration of 70 mg / ml in the injection material formulation of Example 11.

[0218] Two injection material preparations were applied to the suprachoroidal space of New Zealand white rabbits as test articles to determine their ocular pharmacokinetic characteristics. The animals were anesthetized, placed in lateral recumbency, and the head was covered to expose the eyes. An eyelid speculum was placed in the eye. The test article was vortexed and drawn into a microliter calibrated syringe. The site on the eye between the rectus muscles was used to introduce the cannula portion of the cannula of Example 12, which was connected to the female Luer fitting. A 5-0 Vicryl suture was placed near the site to prevent excessive eye movement. The optical fiber was manufactured on the male Luer fitting to be assembled in the female Luer connector. When the Luer fittings were connected together, the far end of the optical fiber abutted the near end of the cannula, providing an optical path from the light source to the cannula. The near end of the optical fiber terminated in an optical connector, which was connected to the light source of Example 12. The conjunctiva and the underlying sclera were cut at the pars plana through a 2mm to 3mm radial incision to expose the suprachoroidal space and the underlying choroid. The illuminated cannula is placed in the incision, and the cannula is oriented 4mm to 5mm behind. The position of the cannula in the suprachoroidal space is confirmed by the position of the illumination through the sclera. The optical fiber is disconnected from the cannula, and the syringe containing the injection material is connected to the cannula female Luer connector. The incision is sutured around the cannula using horizontal mattress sutures to stabilize the site. The syringe plunger is pressed down to apply the injection material through the cannula to deliver 40 microliters of injection material to the suprachoroidal space. Remove the cannula and reposition the conjunctiva. Funduscopy is performed on the eyes to confirm that the drug test article is not injected into the vitreous body. According to the nursing guide, the bridle suture (bridlesuture) and the speculum are removed, the eyes are rinsed and antibiotic ointment is applied. Each test article is applied to six eyes.

[0219] Eyes were collected on days 7, 14, 30, 60, 90 and 120 after administration of each test article. The eyes were dissected to separate the choroid, retina and vitreous tissues. The drug concentration of the tissues was determined by LC-MS. The results showed the concentration of dexamethasone acetate and the concentration of dexamethasone formed by the hydrolysis of dexamethasone acetate in vivo. Fig.19 , Fig. 20 and Fig.21The pharmacokinetic profiles in depict the total dexamethasone in both forms over the time period tested. Fig.19 Vitreous tissue drug concentrations resulting from administration of the two test articles are depicted. Both test articles showed low total drug concentrations in the vitreous due to suprachoroidal administration and the slow sustained release properties of the test article formulations. Fig. 20 Choroidal tissue drug concentrations resulting from administration of the two test articles are depicted. Fig.21 Retinal tissue drug concentrations resulting from administration of the two test articles are depicted. The 85:15 PLGA microsphere formulation showed consistently high levels of total dexamethasone in the retina and choroid over 120 days. The 75:25 PLGA microsphere formulation showed high levels of total dexamethasone in the retina and choroid over 60 days, with a significant decrease in tissue drug concentrations at 90 and 120 days.

Claims

1. A cannula device for administering a composition containing an active agent to an eye, comprising: an elongated body having a hollow needle at a distal end; a cannula comprising an elongated tubular element having an atraumatic distal tip, wherein the elongated tubular element is configured to conduct light from a proximal portion of the elongated tubular element to a distal tip of the elongated tubular element, and wherein at least a portion of the tubular element is contained within the lumen of the needle prior to expansion; a mechanism for advancing the elongated tubular element through the needle; a mechanical coupling element connecting the mechanism for advancing the elongated tubular element to the tubular element; as well as A connector or injection port, which is connected to the proximal end of the tubular element for delivering a composition containing an active agent; wherein: the mechanism for advancing the slender tubular element is activated simultaneously with or after the distal tip of the needle is placed in the eye; and the mechanism for advancing the slender tubular element acts to push the tubular element out of the distal end of the needle and into the suprachoroidal space or the supraciliary space.

2. A cannula device for administering a composition containing an active agent to an eye, comprising: an elongated body having a hollow needle at a distal end; a cannula comprising an elongated tubular element having an atraumatic distal tip, wherein the elongated tubular element is configured to conduct light from a proximal portion of the elongated tubular element to a distal tip of the elongated tubular element, and wherein at least a portion of the tubular element is contained within the lumen of the needle prior to expansion; a mechanism for advancing the elongated tubular element through the needle; a mechanical coupling element connecting the mechanism for advancing the elongated tubular element to the tubular element; a reservoir for containing a composition comprising an active agent for administration and in communication with the proximal end of the tubular element; and wherein: the mechanism for advancing the elongated tubular element is activated simultaneously with or after the distal tip of the needle is placed in the eye; and The mechanism for advancing the elongated tubular element acts to push the tubular element out of the distal tip of the needle and into the suprachoroidal space or the supraciliary space.

3. A cannula device for administering a composition containing an active agent to an eye, comprising: an elongated body having a hollow needle at a distal end; a cannula comprising an elongated tubular element having an atraumatic distal tip, wherein the elongated tubular element is configured to conduct light from a proximal portion of the elongated tubular element to a distal tip of the elongated tubular element, and wherein at least a portion of the tubular element is contained within the lumen of the needle prior to expansion; a mechanism for advancing the elongated tubular element through the needle; a mechanical coupling element connecting the mechanism for advancing the elongated tubular element to the tubular element; a distal element having a distal seal connected to the distal tip of the device so as to seal or block the needle lumen to prevent the tubular element from being ejected from the needle; and a connector or injection port in communication with the proximal end of the tubular element for delivering a composition comprising an active agent; wherein: the mechanism for advancing the elongated tubular element is activated simultaneously with or after the distal tip of the needle is placed in the eye; The distal seal acts as a tissue interface and can be penetrated by the distal tip of the needle by applying pressure on the surface of the eye with the distal tip of the device; a penetrating distal element becoming slidable over the needle to advance the needle into tissue; The pierced distal seal opens a path for advancing the tubular element from the distal tip of the needle; and The mechanism for advancing the elongated tubular element acts to push the tubular element out of the distal tip of the needle and into the suprachoroidal space or the supraciliary space.

4. A cannula device for administering a composition containing an active agent to an eye, comprising: an elongated body having a hollow needle at a distal end; a cannula comprising an elongated tubular element having an atraumatic distal tip, wherein the elongated tubular element is configured to conduct light from a proximal portion of the elongated tubular element to a distal tip of the elongated tubular element, and wherein at least a portion of the tubular element is contained within the lumen of the needle prior to expansion; a mechanism for advancing the elongated tubular element through the needle; a mechanical coupling element connecting the mechanism for advancing the elongated tubular element to the tubular element; a distal element having a distal seal connected to the distal tip of the device so as to seal or block the needle lumen to prevent the tubular element from being ejected from the needle; and a reservoir for containing a composition containing an active agent for administration and in communication with the proximal end of the tubular element; wherein: the mechanism for advancing the elongated tubular element is activated simultaneously with or after the distal tip of the needle is placed in the eye; The distal seal acts as a tissue interface and can be penetrated by the distal tip of the needle by applying pressure on the surface of the eye with the distal tip of the device; a penetrating distal element becoming slidable over the needle to advance the needle into tissue; The pierced distal seal opens a path for advancing the tubular element from the distal tip of the needle; and The mechanism for advancing the elongated tubular element acts to push the tubular element out of the distal tip of the needle and into the suprachoroidal space or the supraciliary space.

5. The device according to any one of claims 1 to 4, characterized in that The elongated tubular element is configured for light transmission by incorporating optical fibers into or within the tubular element.

6. The device according to any one of claims 1 to 4, characterized in that The elongated tubular element is configured to conduct light along a wall of the elongated tubular element.

7. The device according to any one of claims 1 to 6, characterized in that The elongated tubular element has a curved configuration in an unconstrained state and regains the curved configuration when extended from the distal tip of the needle.

8. The device according to any one of claims 1 to 7, characterized in that The mechanism for advancing the elongated tubular element is configured for manual advancement.

9. The device according to any one of claims 1 to 7, characterized in that The mechanism for advancing the elongated tubular element includes a force element that provides an extension force to advance the tubular element through a needle lumen.

10. The device according to claim 3 or 4, characterized in that The distal seal includes a deformable protrusion extending into the lumen at the distal tip of the needle or into a protrusion extending into the lumen distal to the distal tip sufficient to prevent the tubular element from stretching under the stretching force.

11. The device according to claim 3 or 4, characterized in that Additionally included is a contractile element between the body of the device and the distal element, wherein the contractile element is configured to prevent distal movement of the distal element.

12. The device according to claim 11, characterized in that The contractile element comprises an elongated strut.

13. The device according to claim 11, characterized in that The contractile element comprises Nitinol or polyimide.

14. The device according to any one of claims 11 to 13, characterized in that The contractile element is configured to provide a forward force on the distal element during penetration of the distal seal by the distal tip of the needle.

15. The device according to claim 14, characterized in that The forward force is in the range of 40 g-f to 82 g-f.

16. The device according to claim 14, characterized in that The contractile element is configured to provide a constant force after an initial force applied during the first 0.5 mm of proximal travel of the distal element along the needle.

17. The device according to claim 3 or 4, characterized in that The distal seal acts as a tissue interface, wherein the distal seal comprises an elastomer having a Shore A durometer of 10 to 30.

18. The device according to claim 3 or 4, characterized in that The distal seal is mounted on the tubular distal housing.

19. The device according to claim 9, characterized in that The force element providing the extension force to advance the tubular element is a spring mechanically coupled to a plunger.

20. The device according to claim 9, characterized in that The force element is a pressurized gas.

21. The device according to claim 19 or 20, characterized in that A damping mechanism or friction element is also included to limit the speed at which the sleeve extends.

22. The intubation device according to any one of claims 19 to 21, characterized in that The extension force is activated by a mechanism to compress the force element from outside the device.

23. The intubation device according to any one of claims 19 to 21, characterized in that The force element is constrained prior to use, and the extension force is activated by mechanically releasing the constrained force element.

24. A device according to any preceding claim, characterised in that The needle includes a curved distal tip for directing the tubular element at an angle to the long axis of the needle.

25. A device according to any preceding claim, characterised in that The needle includes an internal deflection element with a needle bevel positioned within the lumen of the needle to direct the tubular element at an angle to the long axis of the needle.

26. An intubation device according to any preceding claim, characterised in that The cannula device is used to deliver a composition containing an active agent to the suprachoroidal space or the supraciliary space with an effective total needle length of 1 mm to 5 mm.

27. An intubation device according to any preceding claim, characterized in that The cannula device is used to deliver a composition containing an active agent to the vitreous cavity with an effective total needle length of 5 mm to 15 mm.

28. An intubation device according to any preceding claim, characterized in that The cannula device is used to deliver a composition containing an active agent to the subconjunctival space or the sub-Tenon's capsule space with an effective total needle length of 0.35 mm to 2 mm.

29. The device according to claim 2 or 4, characterized in that Also included is a material for application in the reservoir, wherein the material for application is a fluid or a semisolid.

30. An intubation device, comprising: an elongated body having a hollow needle at a distal end; a tubular member having a lumen, the tubular member extending through the needle; a pathway for transfer of liquid or semisolid material from the elongated body to the proximal lumen of the tubular member; a mechanism for advancing an elongated tubular element through said needle; wherein: The tubular element is configured to transmit light from a proximal portion of the tubular element to a distal tip of the tubular element.

31. The intubation device according to claim 30, characterized in that Also included is a force element and an actuator for activating the force element, the force element being configured to exert a forwardly directed extension force on the tubular element to advance the tubular element through the needle lumen.

32. The device according to claim 30 or 31, characterized in that The tubular element is configured to conduct light along a wall of the tubular element.

33. The device according to claim 32, characterized in that The tubular element comprises a polymer and a low refractive index coating.

34. The device according to any one of claims 30 to 33, characterized in that The needle includes a curved distal tip to direct the tubular element toward the posterior region of the eye at an angle to the long axis of the needle.

35. The device according to any one of claims 30 to 34, characterized in that The needle includes an internal deflection element with a needle bevel positioned within the lumen of the needle to direct the tubular element toward the posterior region of the eye at an angle to the long axis of the needle.

36. The device according to any one of claims 30 to 35, characterized in that The distal tip of the cannula comprises a material that is more flexible than the proximal portion of the cannula.

37. The device according to claim 36, characterized in that The distal tip of the cannula comprises a length of at least 1 mm of more flexible material.

38. The device according to any one of claims 30 to 37, characterized in that The elongated tubular element has a curved configuration in an unconstrained state and regains the curved configuration when extended from the distal tip of the needle.

39. The device according to any one of claims 30 to 38, characterized in that Also included is a connector or port on the elongated body to provide a pathway for liquid or semisolid material to be transferred to the proximal lumen of the tubular member.

40. The device according to any one of claims 30 to 39, characterized in that Also included is a reservoir of an active agent-containing material within the elongated body and a pathway for transfer of the active agent-containing material from the reservoir to the proximal lumen of the tubular element.

41. The device according to any one of claims 1 to 40, characterized in that Light transmitted from the proximal portion of the tubular element provides illumination at the distal tip of the tubular element.

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