Ophthalmic delivery device

Abstract

To provide a cannulation device for administering an active agent containing composition into the eye.SOLUTION: The device includes a hollow cylinder 1 having a proximal cylindrical end cap 2. A plunger 3 penetrates the cylindrical end cap in a slidable manner. The plunger includes a lumen 4 attached with a flexible cannula tubular element 5. A flexible cannula 5 is fixed to a prescribed position of the plunger 3. The tip of the flexible cannula has a rounded noninvasive tip 6. A plunger compression spring 7 applies force in the distal direction to the plunger 3 and the flexible cannula 5. The flexible cannula 5 moves to a distal position by receiving the force of the plunger compression spring 7. A proximal terminal of the plunger 3 is terminated at a contact point of a lure joint 9 or the like and can deliver a substance for administration through the plunger lumen 4 and the flexible cannula 5.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The following patent applications, namely PCT / EP2015 / 071520, PCT / EP2015 / 071522 and PCT / GB2017 / 050731, are incorporated herein by reference.

Background Art

[0002] Due to the unique anatomical form and physiological function of the eye, there are multiple barriers that prevent significant transport of drugs or therapeutic active ingredients to eye tissues. The blood vessels of the eye are restricted in permeability due to the blood-eye barrier that regulates the intraocular fluid. Due to this blood-eye barrier, systemically administered drugs do not reach significant concentrations in eye tissues. Drugs administered to the corneal surface by topical instillation are mostly washed away 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 anterior part of the eye by eye drops, but it is generally not possible to achieve significant therapeutic concentrations in the posterior part of the eye or the retina by local administration methods.

[0003] Many diseases that cause visual impairment are related to the posterior retina where color vision and reading occur. To treat the posterior part of the eye or the posterior retina, drugs are usually injected into the eye. Subconjunctival injection is used to place a drug sustained-release formulation under the outer layer of the eye. However, the very high lymphatic fluid flow in the conjunctiva leads to rapid transport of drugs from the eye. Subconjunctival injection is generally not effective in achieving high drug concentrations in the posterior part of the eye.

[0004] Sub-Tenon injection may be used to place a drug subconjunctivally and in the sub-Tenon's capsule, a more posterior location in the eye, to deliver the drug to the posterior region of the eye. Sub-Tenon injection has been demonstrated to be useful for the administration of steroids. However, many drugs do not reach meaningful drug levels in the retinal tissue even with Sub-Tenon injection. The tip of the injection needle is placed deep within the posterior globe of the eye where the tip of the needle cannot be directly observed. Experience and careful technique are required to avoid physical damage to the eye or misplacement of the drug.

[0005] Intravitreal injection is performed to directly inject a drug into the vitreous cavity and generally requires a smaller amount of drug compared to Sub-Tenon injection. The half-life of the drug is rate-limited by the fluid within the vitreous that continuously moves towards the anterior chamber. This vitreous flow washes the drug away over time and exposes the drug to other tissues of the eye within the flow path. Drugs such as steroids administered intravitreally flow anteriorly from the vitreous cavity and are associated with complications such as progression of cataracts due to drug exposure to the lens and increased intraocular pressure from drug exposure to the zonular fibers.

[0006] The suprachoroidal space between the choroid and the sclera and the supra-ciliary space between the ciliary body and the sclera are more difficult to identify but can be used for drug injection. Unlike intravitreal injection, the fluid in the suprachoroidal space and supra-ciliary space flows posteriorly. This flow helps the drug injected into the suprachoroidal space and supra-ciliary space reach the posterior tissues and the posterior part of the retina. A small drug particle size is ideal for movement within the suprachoroidal space or supra-ciliary space. However, small drug particles release the drug at a faster rate, thereby reducing the duration of drug therapy. SUMMARY OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION

[0007] For all drug injections into the eye under the sclera, one potential problem is the increase in intraocular pressure (IOP) due to the additional volume introduced into the eye. An increase in IOP can cause pain and potential damage to the optic nerve. For highly active drugs, they can be used without a significant acute IOP increase with a small injection volume, for example, 0.05 mL of an anti-VEGF drug. However, for larger volumes such as 0.1 mL of a steroid, the increase in IOP is significant and can cause an acute pain period and vision loss.

Means for Solving the Problem

[0008] In accordance with the above considerations, the present invention provides an apparatus designed to minimize the invasion by inserting or placing a flexible cannula or catheter for the purpose of administering an active ingredient-containing substance into the suprachoroidal space or the supra-ciliary body space of the eye. The cannula or catheter comprises an elongated tubular element disposed within the suprachoroidal space or the supra-ciliary body space through the lumen of a needle or a trocar. A surgical instrument having a sharp tip, often described as a trocar, is used in the same sense as the term "needle" in this application for inserting the cannula or catheter. The term "cannula" is used in the same sense as the term "catheter" in this application. The present invention is an intubation device incorporating a needle or trocar, a flexible cannula or catheter, and a mechanism for facilitating the insertion of the cannula into the suprachoroidal space or the supra-ciliary body space.

[0009] While an active ingredient-containing substance is being injected into the suprachoroidal space or the supra-ciliary body space using a needle, the bevel length of the needle distal to the opening of the needle lumen is significantly longer compared to the thickness of the tissue covering the suprachoroidal space or the supra-ciliary body space, and is 1 mm or more even for a small-diameter hypodermic needle. As a result, when injecting into the suprachoroidal space or the supra-ciliary body space, the needle penetrates the choroid or the ciliary body. The active ingredient-containing substance is injected into the suprachoroidal space or the supra-ciliary body space, but by penetrating the underlying tissue, a path is created through which the active ingredient can easily leak into the intraocular space such as the vitreous body. For active ingredients for which it is desirable to avoid high intraocular concentrations, directly injecting the active ingredient-containing substance into the suprachoroidal space or the supra-ciliary body space using a needle may result in insufficient control of the distribution of the active ingredient. Using a trocar to introduce a flexible cannula into the suprachoroidal space or the supra-ciliary body space, advancing the cannula from the tissue penetration site by the trocar, and administering the active ingredient-containing substance through the cannula prevent the active ingredient from leaking directly into the intraocular space. Furthermore, by advancing the cannula, it becomes possible to position the administration site of the active ingredient near the desired tissue to be treated, such as the posterior retina.

[0010] The intubation device includes an elongated tube having a hollow needle at its distal end, where the lumen of the needle functions as a container for at least a part of the flexible cannula. Further, the intubation device includes a mechanism for advancing the flexible cannula through the needle and protruding into the tissue space from the distal end of the needle. The cannula can be manually advanced using a sliding mechanism or the like designed to be manually controlled by holding the device with a finger. The cannula can also be advanced or deployed from the distal end of the needle by a plunger with a force element such as a spring or a gas container that applies force to the cannula. The distal end of the cannula is sized to have a diameter equal to or less than the inner diameter of the needle lumen. In one embodiment, the deployment force is activated simultaneously with or immediately after the advancement of the needle tip into the tissue.

[0011] In one embodiment, the cannulation device incorporates a distal element including a tissue contact having a distal seal fixed to the distal end of the cannulation device, thereby sealing the needle lumen during application of the deployment force. The distal seal is penetrated or deformed by the tip of the needle by applying pressure to the tissue surface at the distal end of the cannulation device, and the penetrated distal element is slidable over the needle, advancing the needle into the tissue. Penetration of the distal seal opens the advancement path of the cannula from the distal end of the needle. The force element of the cannulation device with the distal element and the distal seal activates before or simultaneously with the needle penetrating the distal seal and the needle tip advancing into the tissue, thereby enabling a convenient one-handed operation of the cannulation device for administering the cannula into the suprachoroidal space or the supra-ciliary body cavity of the eye.

[0012] In one embodiment, the distal end of the needle is curved or incorporates an internal deflection element in the needle lumen to direct the cannula obliquely from the longitudinal axis of the needle during delivery of the flexible cannula. In one embodiment, the distal end of the cannula is curved in an unconstrained state and is directed obliquely from the longitudinal axis of the needle once deployed from the tip of the needle. In another embodiment, the cannula is directed obliquely from the longitudinal axis of the needle during rearward deployment. In another embodiment, the cannula is directed obliquely from the longitudinal axis of the needle while deploying away from the tissue underlying the tissue space.

[0013] In one embodiment, the tip of the cannula comprises a tubular portion 1-3 mm in length that is more flexible than the proximal portion of the cannula. In one embodiment, the distal end 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 tip of the cannula is rounded or has properties such that it is non-invasive when in contact with tissue.

[0014] In another embodiment, the distal end of the cannula is illuminated to provide visualization of the position of the distal end in order to identify and direct the cannula for administration of the active ingredient-containing substance in the suprachoroidal space or supra-ciliary body space. In the suprachoroidal space or supra-ciliary body space, the light emitted by the illuminated cannula has visual characteristics through the overlying sclera, enabling confirmation of the position of the cannula prior to administration of the active ingredient. When the illuminating cannula is configured with the distal end of the lumen of the needle, it provides an anterior illumination effect from the distal end of the needle. When the needle bevel enters the sclera, the anterior illumination is no longer visible on the surface of the eye, indicating to the user that the cannula is in a position where deployment force is applied.

[0015] In one embodiment, the cannula provides a fluid connection via the insertion device to enable delivery of a flowable substance for administration, such as an active ingredient-containing composition, through the lumen of the cannula into a tissue space such as the suprachoroidal space or supra-ciliary body space. In one embodiment, the insertion device comprises a container for the substance for administration that is delivered through the lumen of the cannula into a tissue space such as the suprachoroidal space or supra-ciliary body space. In one embodiment, the insertion device comprises a container for the substance for administration that is delivered through the lumen of the cannula into a tissue space such as the suprachoroidal space or supra-ciliary body space, where the substance for administration is a semi-solid composition.

[0016] The related inventions of the intubation device include specific formulations of a semi-solid substance for administration containing an active ingredient or drug. In the present application, the terms "active ingredient", "drug" and "therapeutic agent" are used in the same meaning. In the context of the present application, a semi-solid substance refers to a substance that does not flow without pressure and remains localized at the internal eye site immediately after delivery. In one embodiment, the injectable semi-solid substance is provided as containing drug particles in a semi-solid excipient or a mixture of excipients. In one embodiment, the drug particles contain an active ingredient and are microparticles made from one or more biodegradable or bioerodible polymers. In some embodiments, in order to minimize the frequency of administration to the patient, the active ingredient-containing microparticles are configured to release the active ingredient in a sustained manner. In one embodiment, the active ingredient in the microparticles is mainly in the form of an amorphous solid dispersion. In one embodiment, the microparticles are suspended in a viscoelastic excipient and given fluidity when delivered through a small-bore needle or cannula. In one embodiment, the injectable semi-solid substance containing active ingredient-containing microparticles is in the form of a lyophilized substance so as to be rapidly reconstituted with a liquid immediately before administration. In one embodiment, the injectable semi-solid substance containing active ingredient-containing microparticles and the viscoelastic excipient are in the form of a lyophilized substance so as to be rapidly reconstituted with a liquid immediately before administration.

[0017] The active ingredient-containing semi-solid substance is suitable for delivery to the suprachoroidal space or supra-ciliary body cavity with respect to the intubation device of the present invention, and at the same time is useful for all other forms of eye injection including intravitreal injection, subconjunctival injection, sub-Tenon's injection and intracameral injection. The size and concentration of the particles in the semi-solid or viscous excipient allow for a small volume injection through a small-bore needle or cannula.

[0018] The above and other aspects of the present invention will become apparent from consideration of the following detailed description in conjunction with the drawings and charts.

Brief Description of the Drawings

[0019]

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DETAILED DESCRIPTION OF THE INVENTION

[0020] The present invention is a device that minimizes the invasion by intubation into the suprachoroidal space or the supra-ciliary body space. After intubation, the device can be used to deliver an administration substance, such as an active ingredient-containing composition, into the space through the cannula. The administration substance is specifically a liquid, suspension, semi-solid or solid active ingredient-containing composition. The active ingredient is a substance that provides a therapeutic or diagnostic effect for the treatment of the eye. The active ingredient may include drugs, diagnostic agents, gene therapy agents, therapeutic cells or means for body tissue repair.

[0021] By placing a cannula into the suprachoroidal space or the supra-ciliary body cavity, a means is provided for delivering an active ingredient-containing composition to a spatial position remote from the tissue penetration site. The cannulation device of the present invention enables the active ingredient-containing composition to be administered from a forward tissue administration site such as the pars plana to the posterior retina and to be directed. The cannulation device can be designed and used to deliver an active ingredient-containing composition to a specific site in the eye for treating local diseases such as tumors.

[0022] The cannulation device comprises an elongated cylinder having a hollow needle at its distal end and a cannula having an elongated tubular element. Here, the needle lumen functions as a container for at least a part of the tubular element. The device also comprises a deployment mechanism for advancing the cannula through the needle lumen and exiting the distal end of the cannula from the distal end of the needle. This mechanism may be mechanically coupled by a push rod or plunger between the push rod and the cannula. Alternatively, the end of the mechanism may be directly coupled to a part of the cannula. When the mechanism has a sliding actuator or lever or the like on the main body of the device, it can be manually actuated by a finger. Manual activation enables fine adjustment of the deployment speed and range of the cannula by the user.

[0023] In one embodiment, the cannula insertion device includes a force element such as a spring or a gas container that advances or deploys the cannula through the needle lumen and provides a force to protrude the cannula from the distal end of the needle into the tissue space. The force element 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 force element may be directly coupled to a part of the cannula. The force element, the force element plunger or the force element push rod may be coupled to the cannula by a connecting cylinder or other shaped fixture. Prior to use, the distal end of the cannula is within the needle and the body of the cannula insertion device. The cannula is configured to extend from the tip of the needle when deployed by the force element. The cannula has a length that allows the distal end of the cannula to extend from the tip of the needle when deployed. The cannula is configured with a length that is deployed from the tip of the needle to the delivery target site of the active ingredient-containing composition. In one embodiment, the length of the cannula from the tip of the needle in the deployed state is in the range of 2 mm (0.08 inches) to 15 mm (0.6 inches). A cannula with a very short deployed length is useful for directing the administered substance in a desired direction from the penetration site of the needle. In particular, if the deployment length from the tip of the needle is 5 mm (0.2 inches) to 12 mm (0.5 inches), potential damage to the retina by the cannula introduced into the eye at the pars plana can be avoided, and the tip of the cannula can be placed near the posterior retina to deliver the administered substance to the most visually important part of the eye. The deployment force can be activated immediately after or simultaneously with the advancement of the needle tip into the tissue. This activation can be performed by the user releasing the force element or by a mechanism at the tip of the device.

[0024] The cannula has a size with a diameter equal to or less than the inner diameter of the needle lumen and is slidably disposed within the needle lumen. The cannula has a proximal end for receiving the active ingredient-containing composition and a distal end for delivering the active ingredient-containing composition. In one embodiment, the distal end of the cannula is configured to have a rounded outer shape that provides a non-invasive tip for entering the tissue space without penetrating the underlying tissue. The rounded outer shape can be created by heat treatment of the cannula tip, by direct molding of the tip, by laser machining of the tip, or by application of additional material to the tip. The material applied may be the same material as the cannula material in a solvent dispersion, a different material from the cannula material in a solvent dispersion, or an adhesive substance. Also, the non-invasive tip may be formed as a separate component and attached to the distal end of the cannula by heat or adhesive means. In one embodiment, the distal end of the cannula is angled or curved obliquely when unrestrained. The angled or curved cannula is straight when disposed within the lumen of the needle, but when deployed from the lumen of the needle, it returns to its unrestrained shape and typically directs the cannula obliquely from the long axis of the needle in the direction of the needle bevel angle. The angling or bending can be used with specific means of the needle bevel angle that direct the cannula towards the posterior region of the eye or both from the underlying tissue. The cannula can be bent along its entire length or bent or curved at the distal end portion of the cannula. The cannula can have a composite curve such that the radius of the distal end is smaller compared to the curve in the proximal portion of the cannula.

[0025] In one embodiment, the cannula is illuminated to visually guide the position of the cannula in the suprachoroidal space or supra-ciliary body space. It has been found that in the suprachoroidal space or supra-ciliary body space, the illuminated cannula can be visualized through the overlying sclera and conjunctiva. However, when the cannula is located in the intraocular space such as the vitreous body, the illumination cannot be visualized through the overlying tissue. A light output of 100 to 700 microwatts (μW) from the cannula has been found to provide good visualization of the position of the cannula through the sclera and conjunctiva. The cannula can be illuminated by connecting a light source to the lumen of the cannula extending to the distal end of the cannula or to an optical fiber connected within the lumen. In another embodiment, the cannula is illuminated using a cannula material having a refractive index that provides total internal reflection or partial internal reflection. Thereby, a cannula without obstructions in the wall that is the outer diameter or lumen of the cannula with an independent optical fiber is used as an optical fiber. In particular, when using the cannula wall to transmit light along its entire length, the optical fiber within the lumen is removed, thereby maximizing the effective lumen diameter and also maximizing the delivery capacity of active ingredients, especially suspensions of active ingredients or formed solid compositions that cannot be delivered through a lumen with irregularities in the flow path. The transmission of light using the cannula material is enhanced by using a reflective or low refractive index coating on the outside of the cannula. The illumination of the cannula can be adjusted by using coatings introduced into the cannula and the arrangement of light to illuminate only the distal end of the cannula, the entire length of the cannula, or a selected region of the cannula. In another embodiment, a light source is directed towards the proximal end of the cannula and the cannula is illuminated by transmitting light along the wall of the cannula to the tip, enabling the user to better identify the position of the entire length of the cannula. Alternatively, the light may be introduced at the sharp bend in the proximal portion of the cannula. The cannula may also incorporate a mechanism for illuminating a portion or individual portions of the cannula with a higher intensity than the surrounding portions. For example, a groove that provides a bright spot or a ring with surface roughness can be incorporated on the outer surface of the cannula.These spots function as depth markers or indicate when the cannula is fully deployed. By configuring the distal end of the cannula illuminated within the lumen of the needle, light is projected through the needle lumen to provide projected or front illumination light from the distal end of the device. The front illumination light shines directly on the spot on the tissue along the needle, provides a target for position confirmation, and guides the user. The illuminated target typically becomes smaller as the tip of the needle approaches the tissue surface, providing a visual guide to the distance to the tissue surface. When the needle bevel is inserted into the tissue, the front illumination light is absorbed and is no longer visible on the surface of the eye. This indicates that the cannula has reached the position for actuation of the deployment mechanism. The distal end of the cannula is positioned within the needle such that it is at or just proximal to the proximal end of the needle bevel. A distance of 0 to 5 mm from the distal end of the needle bevel to the distal end of the cannula is sufficient to provide good front illumination function and responsive deployment of the cannula. The light source may be a separate unit or an optical output coupled to the cannulation device and cannula via an optical fiber connector. Alternatively, the light source may be integrated with the cannulation device. Observation of the illumination of the cannula during the deployment operation of the cannula and the position of the cannula through the overlying tissue provides control and confidence in the insertion of the cannula into the desired tissue space. The light source may be any light-emitting device such as a halogen light source, an LED light source, or a laser light source.

[0026] In other embodiments, the substance for administration, such as the active ingredient-containing composition, is moved into the proximal end of the cannula from a connector such as a luer connector or an injection port that communicates with the proximal end of the cannula. The connector or injection port may be installed on the device or attached to the device. In other embodiments, the substance for administration, such as the active ingredient-containing composition, is placed in a container of the cannulation device body, and the transfer path of the substance for administration connects the container to the lumen of the cannula. The size of the container is configured to be appropriate for the volume of the substance to be delivered. The container may be sized, for example, to be suitable for a delivery volume in the range of 0.1 microliters to 500 microliters. The substance for administration in the container can be manually delivered by moving the plunger in the container by a plunger or by the operation of a force element acting on the plunger to apply a delivery force to the substance for administration. In the case of a small amount of administration, the lumen of the cannula also serves as a container for the active ingredient-containing composition. In the case of a small amount of administration, the lumen of the cannula may function as a container for the active ingredient-containing composition, and the plunger may be configured to move distally in the lumen of the cannula to apply a delivery force to the substance for administration.

[0027] In some embodiments, the distal end of the cannulation device consists of an exposed needle that includes at least the distal portion of the flexible cannula. The deployment of the cannula is actuated simultaneously with or after the insertion of the needle into the tissue covering the desired target tissue space. In one embodiment, the deployment of the cannula is performed by manual advancement of the cannula using a mechanism on the device coupled to the proximal portion of the cannula. In another embodiment, the deployment of the cannula is performed by the actuation of a force element coupled to the proximal portion of the cannula. The rate and extent of cannula deployment can be controlled by the use and operation of an advancement mechanism that allows for careful and gradual deployment. The use of an illuminated cannula provides guidance to the user during the gradual deployment of the cannula.

[0028] In some embodiments, the distal end of the cannulation device comprises a tip element that includes the distal end of the needle. This tip element functions as a tissue interface with a tip seal fixed to the distal end of the cannulation device and seals the needle lumen during application of the deployment force. The tip seal applies pressure to the tissue surface at the distal end of the cannulation device such that the tip element is penetrated by the tip of the needle and the penetrated tip element is slidable over the needle to advance the needle into the tissue. Penetration of the tip seal opens the delivery path for the cannula from the distal end of the needle. The cannulation device with the force element activates either before or simultaneously with the needle penetrating the tip seal and the needle tip advancing into the tissue. The resulting self-activating deployment mechanism ensures opening of the delivery path for the cannula as soon as the needle is positioned within the tissue, regardless of the direction and speed of needle insertion. The self-activating mechanism enables convenient one-handed operation of the cannulation device for administering the cannula into the suprachoroidal or supra-ciliary body chamber of the eye.

[0029] In one embodiment, the distal element comprises a tissue contact and a distal seal mounted on a tubular distal housing. The tubular distal housing is sized to fit over the needle and can be sealed to the surface of the needle at several points along the entire length of the needle. In one embodiment, the housing may be sealed by an elastic element compressed between the housing and the needle. Thus, the elastic element may be annular. In one embodiment, the elastic element may be compressed between the housing of the device and the body. The elastic element may be present at or near the proximal end of the housing. In one embodiment, the elastic element serves as a seal between the housing and the needle. In one embodiment, the elastic element functions as a friction element or component that limits proximal movement of the housing, thereby applying a force to the tissue surface by the tissue contact when the needle penetrates the tissue. In certain embodiments, the distal element comprises a tissue contact and a distal seal and is slidably mounted over the outside of the needle without a distal housing. The distal element comprising a tissue contact integral with the distal seal, or a tissue contact integral with the distal seal and the attached housing, is attached to the tip of the needle but is free to move or slide proximally from the end of the needle by the distal seal. After or during operation of the cannula after the insertion device is prepared for use, the cannula is under the deployment force from the force element but cannot move through the distal seal. The tissue contact is placed on the surface of the eye and the device is advanced manually. Thereby, the needle is pushed through the distal seal and then pushed into the underlying tissue through the outer surface of the eye. The distal element becomes slidable proximally from the end of the needle after penetrating the distal seal and holds the tissue contact on or near the eye surface during advancement of the needle into the tissue. When the tip of the needle penetrates the distal seal, the power source immediately enables deployment of the cannula from the needle tip into the tissue space.

[0030] In one embodiment, the tissue contact and the distal seal are secured to a housing disposed around the needle. The housing can include a cylindrical element secured to the distal end of the device body at the proximal end of the housing. The housing can include foldable, bendable, or deformable elements that allow the distal end of the housing to slide rearwardly along the needle while allowing the tip of the needle to penetrate the distal seal. In some embodiments, the distal element is secured to the tip of the needle via other means.

[0031] In one embodiment, the cannulation device includes an elongate tube having a hollow needle at its distal end, a cannula that is at least partially present and deployed within the needle lumen, and a force element such as a spring or a pressurized gas source that is mechanically coupled to the cannula for deploying the cannula. The deployment of the cannula can be actuated manually by activating the force element to place the cannula in the tissue space when the tip of the device reaches the tissue space, or by the penetration of the needle into the tissue.

[0032] In one embodiment, the operation of the device mechanism opens a path for the cannula to deploy from the tip of the needle as soon as the needle penetrates through a distal seal that occurs immediately before the needle enters the target tissue. Since the cannula is placed under a deployment force before or simultaneously with the distal seal being penetrated by the tip of the needle, the deployment of the cannula is caused only by the placement of the needle through the tissue contact point and the subsequent advancement. Thereby, the timing of the deployment operation by only the tip of the needle entering the target tissue can be accurately and automatically controlled. The resulting self-actuating mechanism does not require a separate control mechanism such as a valve or trigger on the body of the cannulation device. Thus, the cannula can be deployed without the need for special finger positioning or the use of an assistant. As a result, the present cannulation device enables cannulation to be performed with one hand, allowing the physician to stabilize the eye with the other hand and perform other operations that facilitate the surgery using the device. Further, the self-actuating cannulation mechanism eliminates the need for the user to determine the start of deployment and is particularly useful when the target tissue space is small in size, such as the suprachoroidal space or the supra-ciliary body space, not visualizable, and difficult to locate due to anatomical variability.

[0033] The cannulation device enables accurate control of the position of the needle by the user during use. The needle is fixed to the body of the device and allows direct control of the tip of the needle when the device is held. In embodiments where a deployment force is applied by a force element, the cannula does not need to be held or advanced by the hand holding the device, and the device can be held and used naturally and in a highly controllable position, together with, for example, a pen or a scalpel. Generally, the needle is disposed along the elongated body or tube of the device.

[0034] Once the needle is inserted into the eye, the cannula cannot extend or deploy from the distal end of the needle until the space for receiving the cannula reaches the distal end of the needle. In particular, the scleral tissue is very elastic, and the unique properties of the sclera prevent the cannula from entering the sclera in order to effectively seal the needle tip during passage of the needle tip into the suprachoroidal space or supra-ciliary body space. When the needle tip reaches a lower layer space such as the suprachoroidal space or supra-ciliary body space, the cannula can advance from the needle and be deployed into the space. By this mechanism, the cannula is oriented to a position where it can receive the cannula at the tip of the needle. After deployment of the cannula, a substance for administration, such as an active ingredient-containing composition, can be delivered to the eye through the lumen of the cannula. In one embodiment, the cannula is coupled to a force element for deployment. When the distal end of the needle is advanced to the surface of the eye and the needle bevel is within the eye, the force element is actuated and a deployment force is placed on the cannula. The needle is further advanced until the needle tip reaches the suprachoroidal space or supra-ciliary body space and the cannula is sufficient to self-deploy into the space.

[0035] The flexible cannula of the cannulation device is designed to have appropriate mechanical properties, having an appropriate flexural modulus such that the cannula bends to advance into the suprachoroidal space or supra-ciliary body cavity, and having an appropriate axial compressive stiffness such that the cannula advances into the cavity by a deployment mechanism acting on the proximal portion of the cannula. The mechanical properties can be appropriately adjusted by the selection of the cannula material and cannula dimensions. Further, the cannula can have a mechanism for adjusting the mechanical properties. A rigid element such as a wire may be disposed in the lumen or wall of the cannula to increase the axial buckling strength. The tip of the cannula may be reinforced, for example, by a coil or coating to adjust the buckling strength and flexibility of the distal end portion of the cannula. The coil can be made of metal or a highly elastic polymer and can be disposed on the outer surface, inner surface of the cannula or within the wall of the cannula. In one embodiment, the tip portion of the cannula and the cannula tip are formed of a softer or more flexible material than the proximal portion of the cannula to form a soft tip structure. The distal end portion of the softer material having a length of 1 mm to 3 mm, coupled to the stiffer proximal portion of the cannula, can be deployed through a needle having a soft tip that minimizes tissue penetration and trauma during deployment into the suprachoroidal space or supra-ciliary body cavity. The cannula may be made of polymers such as polyether block amide (PEBA), polyamide, perfluoroalkoxy polymer, fluorinated ethylene propylene polymer, ethylene tetrafluoroethylene copolymer, ethylene chlorotrifluoroethylene copolymer polystyrene, polytetrafluoroethylene, polyvinylidene, polyethylene, polypropylene, polyethylene-propylene block copolymer, polyurethane, polyethylene terephthalate, polydimethylsiloxane, polysiloxane copolymer, polyvinyl chloride, polyetherimide and polyimide. For some applications, the cannula may be made of an elastic metal such as nickel-titanium superelastic alloy (nitinol).

[0036] An apparatus having an appropriate needle length and orientation can be used to deploy a cannula and deliver an administered substance to the subconjunctival space, suprachoroidal space, supra ciliary body space and subretinal space, sub-Tenon's space, vitreous cavity or anterior chamber.

[0037] 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 gauge to 40 gauge (e.g., less than 0.9 mm (0.04 inch) outer diameter, 0.6 mm (0.02 inch) inner diameter), and the length of the needle is suitable for reaching the target tissue. The needle is fixed to the body or barrel of the apparatus and does not normally slide or move relative to the body in order to accurately control the depth of the needle while penetrating the tissue.

[0038] The tip of the needle may be beveled or sharpened to assist penetration. The bevel angle can be designed to facilitate entry into a particular tissue. For example, a short bevel angle of 18 degrees can be used to insert a cannula into a narrow space such as the subconjunctival space or sub-Tenon's space. A medium bevel angle needle with a 15-degree bevel angle can be used to insert a cannula into a space such as the suprachoroidal space or supra ciliary body space. A long bevel angle such as 12 degrees can be used to insert a cannula into the anterior chamber or posterior chamber.

[0039] In one embodiment, the device incorporates a distal element and a distal seal having an angulation complementary to the lumen of the distal element for juxtaposing the distal seal in proximity to the needle bevel. The bevel of the needle is aligned with the angulation within the lumen of the distal element. The most distal portion of the distal element may be flat or angled to assist in guiding the direction of the needle while penetrating tissue and to aid in reaching a particular tissue space. For example, the angled tissue contact surface of the distal element can assist in targeting cannulation to shallow tissue targets in some regions of the subconjunctival space, the sub-Tenon's space, and the suprachoroidal space. The angle of the tissue contact surface of the distal element may range from 90 degrees from the axis of the distal element for perpendicular insertion to 15 degrees from the axis. The device can incorporate a guide at the tip to assist in inserting the needle into the eye at a selected angle. The guide may be composed of an angled strut or an angled plate extending from the distal end of the device to contact the eye prior to needle insertion. The guide may also be composed of a strut extending from the body to provide a reference for estimating the angle of needle insertion.

[0040] In some applications of the present invention, the tip of the needle is preferably directed obliquely from the long axis of the needle towards the cannula. Such a design reduces the force of the cannula on the underlying tissue of the target tissue space, such as the ciliary body or the choroid, and can also be used to direct the cannula in a desired direction, such as towards the posterior region of the suprachoroidal space near the macula of the retina. The tip of the needle can be bent in the range of 5 to 60 degrees to guide the cannula. The tip of the needle can also have an internal deflection element within the needle lumen in the bevel region of the needle. The internal deflection element can be a protrusion, an inclined surface, or an inclined path that can direct the cannula away from the long axis of the needle. The internal deflection element may be located along the entire length of the needle bevel or at separate positions from the proximal end of the bevel. In one embodiment, the internal deflection element is placed at a position that is 20% to 80%, 25% to 75%, or 30% to 60% of the length of the needle bevel from the distal end of the bevel. The device body can incorporate a marker or indicator, such as an indication of the orientation of the needle bevel or the direction in which the deflection element deflects the cannula, so that the user can direct the orientation of the cannulation.

[0041] The needle can be composed of metal, ceramic, highly elastic polymer or glass. The length of the needle in the tissue is selected to match the target position of the cannulation and the variation of the target position due to anatomical variability. The substantial total length of the needle is the length of the needle that can advance into the tissue. In an embodiment of the device with a distal element surrounding the needle, the substantial total length of the needle is the length of the tip of the needle reaching the end face of the tissue contact when the distal element achieves a complete proximal movement. The distal element is slidably movable along the needle during the advancement of the needle into the tissue, allowing a gradual increase in the length of the needle protruding through the distal element during the advancement into the tissue.

[0042] In some embodiments, the cannula is deployed when the needle reaches an appropriate position, which may be less than the substantial total length of the needle. The release of the force for deployment and the resulting time occur rapidly in about 0.1 to 3 seconds depending on the deployment length of the cannula and the manual advancement speed by the user.

[0043] In embodiments with a force element for deploying the cannula, the deployment speed can be controlled by the amount of force applied by the force element. The time for deployment of about 0.1 to 3 seconds is controlled by a braking or frictional mechanism paired with the advancement of the cannula, and can also limit the advancement or deployment speed of the cannula. The braking or frictional mechanism has a braking or frictional amount paired with the degree of deployment set, and can maintain the balance of the non-linear force delivery of a force element such as a spring. In one embodiment, the friction wheel engages a plunger shaft connected to the proximal end of the cannula. During deployment, the friction wheel slows the plunger speed according to the amount of friction. The friction can be adjusted along the deployment distance by increasing the contact with the plunger shaft or by a change in the coefficient of friction such as the amount of texture along the shaft length. Usually, when the deployment force from the compression force is maximum, the friction is configured to be large at the initial deployment, and the friction is configured to decrease towards the full deployment length as the plunger moves. The deployment mechanism can incorporate a mechanism to communicate to the user, by both visual and tactile feedback, to indicate that no additional advancement of the needle is required when deploying the cannula from the needle. The progression of the deployment at a controlled speed gives the user sufficient time to stop the advancement of the needle and gives a variable effective needle length corresponding to the inter-patient difference in tissue thickness. Embodiments of the device with an effective variable needle length and self-actuation of the deployment are useful for cannulation of spaces that are normally not open, such as the subconjunctival space, sub-Tenon's space, suprachoroidal space and supra-ciliary space. For the subconjunctival space and sub-Tenon's space, the total effective length of the needle is in the range of 0.35 mm (0.01 inch) to 2 mm (0.08 inch) depending on the insertion angle of the needle. For the suprachoroidal space and supra-ciliary space, the total effective length of the needle is in the range of 1 mm (0.04 inch) to 5 mm (0.16 inch) depending on the insertion angle of the needle. For the vitreous cavity, the total effective length of the needle is in the range of 5 mm to 15 mm. For example, the total effective needle length can be 0.3 mm (0.011 inch) to 3 mm (0.12 inch), 0.35 mm (0.014 inch) to 2 mm (0.08 inch), 1 mm (0.04 inch) to 4 mm (0.16 inch) or 10 mm (0.39 inch) to 15 mm (0.59 inch).

[0044] In one embodiment, the distal element applies a sealing force in the distal direction with respect to the tissue surface and maintains a seal on the eye surface. This sealing force is designed to be sufficient to seal off a potential flow of the administered substance from the needle insertion path during administration of the delivered substance. The sealing force is minimized at the needle penetration site to avoid compression of the tissue of a normally closed or nearly closed space such as the suprachoroidal space or the supra-ciliary body space, and to prevent an increase in intraocular pressure that restricts cannulation into the space or the movement of the administered substance into a normally closed or nearly closed space. In one embodiment, the distal element maintains contact with the tissue surface but maintains a seal on the eye surface without applying a sealing force in the distal direction to the tissue surface. In one embodiment, the distal element contacts the eye surface while the tip of the needle penetrates the distal seal of the distal element, but does not maintain contact with the eye surface after the needle passes through the distal seal and penetrates into the eye tissue.

[0045] In embodiments comprising a tissue contact and a distal seal, the tissue contact and the distal seal may include a soft polymer, rubber, or other material that allows the needle to penetrate without punching out the sealing material. The tissue contact and distal seal material can be selected to provide physical flexibility to the eye surface during insertion of the needle into the eye tissue and to seal the deployment path from the needle until the needle advances through the distal seal. When the needle penetrates the distal seal, the needle advances through the outside of the eye tissue and reaches the desired cannulation site. The tissue contact and distal seal remain on the surface of the eye. The distal seal is sufficiently elastic to prevent rupture by the cannula under the deployment force before the needle advances through the distal seal. The distal seal portion in the path of the needle is also sufficiently thin to allow the needle to penetrate without the application of excessive force. The distal seal typically has a thickness in the range of 250 (0.01 inches) to 1500 microns (0.06 inches) in the region where the needle penetrates.

[0046] In one embodiment, the sealing force is imparted by a compressible or foldable element between the body of the device and the proximal end of the distal element or distal housing. In one embodiment, the tissue contact imparts the sealing force by compression of an elastically compressible element at the tissue contact or distal element. In one embodiment, the distal element is configured to elastically decrease in length during advancement of the needle and add sealing force. In one embodiment, a friction element disposed within or around the distal element increases the force required to move the distal element proximally, thereby facilitating contact between the tissue contact and the ocular surface and maintaining a seal against the ocular surface during advancement of the needle. The friction of the distal element with respect to the needle may be adjusted in relation to proximal movement of the distal element during advancement of the needle. The increase in friction is obtained by an increase in contact or surface roughness between the distal element and the outer surface of the needle, or by a decrease in the durometer of the distal element, and adjusts the amount of force applied by the tissue contact during proximal movement of the tissue contact along the needle length. The friction can be varied along the path of movement of the distal element along the needle. For example, low friction may be provided in the initial path of movement of the distal element to facilitate insertion of the needle into the ocular tissue, and the friction may be increased after the length of the needle corresponding to the length of the needle bevel has been inserted into the ocular tissue. The length of movement of the distal element under the influence of the high friction region ranges from 0.3 mm (0.01 inch) to 2 mm (0.08 inch).

[0047] The distal element incorporates a distal seal having a distal end attached to the body of the device by one or more foldable elements. The foldable elements are configured to not allow an increase in length to prevent the distal seal from slipping off the tip of the needle when a deployment force is applied to the cannula prior to needle penetration. The foldable elements allow a decrease in length, thereby allowing proximal movement of the distal element while the needle advances through the tissue. In one embodiment, the foldable element comprises one or more elongated struts that can deform, bend, or flex away from the needle during proximal movement of the distal element. In one embodiment, the foldable element comprises a cannula-concentric tube portion cut to form an opening along the axial length of the tube to form foldable struts. The shape and configuration of the foldable struts can be adjusted to provide the desired force-displacement characteristics of the foldable element. The force vs. displacement can be linear or non-linear. In one embodiment, the foldable element provides a force that transitions from an increasing spring-like force per unit displacement to a constant force that is independent of displacement, maintaining the tissue contact and distal seal in contact with the eye surface without applying excessive force associated with further advancement of the needle into the eye. In another embodiment, the foldable element provides a very low force per unit displacement to facilitate insertion of the needle into the tissue and increases the force after the needle bevel is inserted into the tissue. Application of a force exceeding 80 grams force (0.18 pound force) to 100 grams force (0.22 pound force) can limit the force for the cannula to enter a closed space such as the suprachoroidal space or the supra-ciliary body cavity. In one embodiment, the tissue contact applies a force in the range of 40 grams force (0.09 pound force) to 80 grams force (0.18 pound force). The transition in the amount of force is designed to occur after the bevel length of the needle is inserted into the eye tissue, which corresponds to a compression or collapse of the foldable element of 0.3 mm (0.01 inch) to 2 mm (0.08 inch). In one embodiment, the foldable element contacts the tissue contact to the eye surface during the initial insertion of the needle into the eye tissue, but collapses such that there is little or no resistance to the proximal movement of the distal element along the needle after the needle bevel is fully inserted into the tissue.The foldable element may be assembled from components of a tubular structure or may be cut from a portion of a tube such as a laser machined nickel titanium alloy (e.g., Nitinol) tube or a polyimide tube. Materials suitable for the distal foldable element include, but are not limited to, stainless steel, spring temper steel, superelastic nickel titanium alloy, cobalt chromium alloy, oil tempered chromium silicon, polyimide, and polyetherimide. The foldable element can be disposed between the elongated body and the distal element, such as between the cannula and the housing (if any) of the distal element. The foldable element may be fixed to the body and the distal element of the device such that the distal element is slidable proximally over the needle but does not move distally from its initial position.

[0048] In some embodiments of the device incorporating the distal seal and tissue contact, the tissue contact has a sealing function. The sealing force imparted by the tissue contact is within the range that provides sealing of the needle path but is not sufficient to close the tissue space and prevent the cannula from moving into the suprachoroidal or supra ciliary space. 0.45 mm 2 (0.0007 in 2 )~5.07 mm 2 (0.008 in 2) having a tissue contact surface area within the range is suitable for sealing the path of the needle. Suitable materials for the tissue contact and the distal seal include, but are not limited to, thermoplastic elastomers such as natural rubber, silicone rubber, and polyurethane. The stiffness of the rubber or elastomer can be selected to provide an appropriate combination of conformity to the tissue surface and sealing of the distal lumen of the needle. The selection of the material for the tissue contact also minimizes the sealing force that hinders the cannula from moving into the tissue space. Also, the rubber or elastomer must be penetrable or deformable by the tip of the needle to cause the release of the cannula. Rubbers or elastomers with a Shore A durometer of 10 to 70, 10 to 50, or 10 to 30 are suitable for use as the 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.

[0049] In one embodiment, the body or barrel of the device comprises a container and provides an external surface for holding the device during use. The container can comprise a tubular cylinder attached at its distal end towards the proximal end of the needle, together with a plunger slidably disposed within the lumen of the tubular body. The container is also provided for insertion of a cartridge containing the substance for administration, where the plunger of the device moves a slidable seal at the proximal end of the cartridge to deliver the substance. The body of the device can be manufactured from a variety of thermoplastic materials suitable for medical use, such as polypropylene, polyamide, polycarbonate, polysulfone, polyethylene, cyclic polyolefin, polystyrene and polymethyl methacrylate. The body can incorporate external features such as a texture or finger indentations to enable the user to grip and use the device more ergonomically. The body can incorporate indicators or measurement markings to display the amount of substance being delivered. The body can incorporate a transparent material or a portion of a transparent material to visualize the movement of the plunger for visually indicating the substance for administration or delivery event within the container. The plunger can have markings to assist in visualizing the filling of the container and the release of the substance for administration. The device body can incorporate a label or indicator, for example, a needle bevel orientation confirmation or a deflection element that indicates the direction in which the tip of the cannula is deflected during deployment, so that the user can confirm the orientation of the cannulation.

[0050] In some embodiments of the present invention, the device comprises means for applying a deployment force to the cannula. In some embodiments of the present invention, the device comprises means for providing a force to deliver the administered substance from a container within the device. The means for applying a deployment force to the cannula can be manually actuated by any suitable actuator, such as a button or lever incorporated into the device, or by a trigger mechanism at the distal end of the device against tissue penetration of the needle. The means for providing a force to deliver the administered substance from a container within the device can be manually actuated by a suitable actuator, such as a button or lever incorporated into the device, or by a trigger mechanism coupled to the deployment of the cannula. The means described herein can be, for example, a compressible container or lever that can be "pushed" or compressed (directly or indirectly) by the user to achieve, for example, deployment of the cannula or delivery of the administered substance. Alternatively, in one embodiment, the means is a mechanism having a biasing means or force element (such as a compression spring or pressurized gas).

[0051] The device may be disposable and / or single-use. Alternatively, the device can be reused. In some embodiments, the device incorporates a distal seal that functions to prevent cannula withdrawal from the needle when the device is primed by activation of a force element prior to contact of the eye with the needle. This is achieved by a seal between the needle lumen and the outside of the device. This seal may be achieved by the seal directly contacting the needle tip, or may be achieved by use of a distal element housing appropriately formed to provide a seal around the needle shaft when disposed over the needle tip. For example, the outer diameter of the needle may be complementary to the inner diameter of the housing to provide a seal. In embodiments of the present invention, the seal need only sufficiently close the needle lumen such that the cannula is not deployed until the seal moves proximally and thereby fully exposes the opening of the lumen. In such embodiments, the distal seal is a partial seal and does not cover the entire needle lumen at the distal end of the needle. Thus, the seal can comprise a deformable protrusion extending into the lumen at the distal end of the needle, or a deformable protrusion extending from the distal end into the end protrusion of the lumen sufficient to prevent cannula deployment. Needle penetration through such an embodiment of the distal seal can be achieved by deformation of the protrusion by the tip of the needle as the needle passes through the protrusion. Also, embodiments of the present invention that describe needle penetration of the distal seal are applicable to the use of a partial seal formed by a protrusion extending towards or across the lumen at the distal end of the needle.

[0052] Generally speaking, and as described above, some embodiments of the device provide for self-actuating deployment of a cannula such that the cannula automatically deploys when the needle reaches a desired delivery site within the eye (such as the suprachoroidal space or the supra-ciliary body space). Self-actuation may be performed by a device with a distal seal to prevent deployment of the cannula in conjunction with a deployment force that actuates before or simultaneously with insertion of the needle tip into tissue. Self-actuation may also be performed by a device with a trigger at the distal end that actuates the deployment force simultaneously with or immediately after insertion of the needle tip into tissue. In this way, the device can be actuated with one hand. With regard to needle insertion, the effective needle length and angle can be appropriately designed to target a specific cannulation site at a specific depth within the eye. In some embodiments, the device can comprise retaining means for holding a distal element on the needle when the device is prepared.

[0053] In embodiments of the device with a needle exposed at the tip and no distal element or distal seal, the maximum needle depth is the length of the needle from the tip of the needle to the distal end of the device body or a stop placed between the needle and the body. In embodiments of the device with a distal element and a distal seal, the distance between the proximal end of the distal element and the distal end of the elongated body or barrel (and the arrangement of any compressible or foldable elements that may be present) can be arranged to determine the maximum depth of needle penetration. The distance between the proximal end of the distal element and the distal end of the elongated body or barrel may be equal to the maximum depth of needle penetration, taking into account any distance between the needle tip and the distal seal / tissue contact or the use of any compressible or foldable elements. In this way, the position and size of the needle as the distal element, and the distance between the needle tip and the distal seal / tissue contact (if any) can be configured to determine the maximum needle penetration depth. One of ordinary skill in the art can appropriately design the device based on the present disclosure.

[0054] In this way, the device can comprise means for determining a maximum needle penetration depth for controlling the maximum insertion tube depth into the eye. The needle can comprise a separate element, such as an annular ridge, a stopper or a clamp, for stopping the forward movement of the needle. In some embodiments, this element for preventing further forward movement of the needle during operation may be movable so that the user can determine the maximum needle penetration depth. In such an embodiment, the needle can comprise markings that enable the user to select an appropriate maximum penetration depth. In another embodiment, the depth of needle penetration can be determined by a compressible element. For example, the compressible element can allow the desired forward movement of the needle by increasing its rigidity as the element is compressed, or by other mechanical means. Thus, the present invention provides a device having a fixed maximum needle penetration depth suitable for targeting the tissue of interest. Appropriate designs for achieving a fixed maximum needle penetration depth will be apparent to those skilled in the art based on the present disclosure. Of course, the maximum depth of needle penetration can be within a certain tolerance range. The maximum needle penetration depth is also referred to herein as the effective needle length.

[0055] In one embodiment, the substance for administration, such as an active ingredient-containing composition, is pre-filled in the intubation device, whereby the device functions as a storage container for the substance for administration before use. In one embodiment, the pre-filled device has the substance for administration disposed therein, and after being sealed, is sterilized for use. Sterilization can be performed by existing sterilization methods such as heat or ionizing radiation. In one embodiment, the substance for administration is pre-filled in the device as a dry substance. The dry substance is reconstituted by a liquid and introduced into the device before use. The intubation device may be provided with a port or connector that is in liquid communication with the device container to facilitate reconstitution of the substance for administration within the intubation device. In another embodiment, the substance for administration is placed in a container such as a cartridge vial and sterilized or aseptically prepared separately from the intubation device. The cartridge vial and the intubation device are designed to allow insertion of the cartridge vial of the intubation device by the user before use. In another embodiment, the substance for administration is placed in a container such as a cartridge vial having two container compartments, one for the lyophilized substance for administration and one for the reconstitution liquid. Before administration, the reconstitution liquid is transferred to the substance compartment to reconstitute the lyophilized substance.

[0056] One embodiment of the intubation device is shown in FIG. 1. The device includes a hollow cylinder 1 having a proximal cylinder end cap 2. A plunger 3 slidably passes through the cylinder end cap. The plunger has a lumen 4 to which a flexible cannula tubular element 5 is attached. The flexible cannula 5 is fixed at a predetermined position of the plunger 3. The tip of the flexible cannula has a rounded non-invasive tip 6. A plunger compression spring 7 applies a distal force to the plunger 3 and the flexible cannula 5. An angled needle 8 is attached and fixed to the distal end of the cylinder 1 so that the position of the needle tip can be directly controlled when operating the position of the cylinder 1, and the needle 8 does not move relative to the cylinder 1. The flexible cannula 5 moves distally under the force of the plunger compression spring 7. The proximal end of the plunger 3 ends at a connection point such as a Luer fitting 9 to enable delivery of the substance for administration through the plunger lumen 4 and the flexible cannula 5.

[0057] Two embodiments of the distal end of the flexible cannula are shown in FIGS. 2, 2A, and 2B. In FIG. 2, it is shown that the flexible cannula 5 is deployed beyond the tip of the beveled needle 8 attached to the hollow cylinder 10. In the embodiment shown in FIG. 2A, the tip of the flexible cannula 5 is straight, and in the second embodiment shown in FIG. 2B, the tip of the flexible cannula 5 is incorporated into the curved tip 11. Both embodiments are shown with illumination 12 emanating from the tip of the flexible cannula 5.

[0058] One embodiment of the device is shown in FIG. 3. The device incorporates a spindle 13 slidably disposed within a housing assembly 14. The spindle incorporates a distal flexible cannula assembly 15, a connector assembly 16, an internal fluid path 17, and an optical fiber 18. Proximally, the internal fluid path 17 connects to a female Luer connector 9 via an external fluid path 36, and the optical fiber terminates at an optical connector 19.

[0059] The housing assembly includes left and right main housing elements 20 and 21, a proximal end cap 2, and a distal nose cone 22. The tip beveled hollow needle 8 is adhesively bonded within the lumen of the distal nose cone. The tip of the needle 8 may be configured with a subcutaneous or lancet-type multi-faceted bevel or another bevel shape suitable for the application.

[0060] The main shaft 13 is advanced by a main shaft compression spring 7 that functions as a force element. This advancement is initiated by the actuation of a trigger 23, as shown in FIG. 3A. The trigger incorporates a lifting tip 24 that interlocks with a connector assembly 16 for holding the main shaft 13 in a retracted position prior to use. When the trigger 23 is actuated, the trigger lifting tip 24 moves upward, disengaging the trigger lifting tip from the connector assembly 16, allowing the main shaft 13 to move forward under the force of the main shaft compression spring 7. The trigger 23 can be manufactured from a rigid or semi-rigid material such as acrylonitrile butadiene styrene, high density polyethylene, or polycarbonate. The trigger 23 can be machined, molded, or three-dimensionally printed. The force required to actuate the trigger 23 depends on the material properties of the trigger as well as the thickness and length of the flexible portion of the trigger body. As the material becomes thinner, the force required to deflect the actuated trigger and thus the force required to operate the device becomes weaker. The main shaft compression spring 7 can be manufactured from piano wire, stainless steel wire, Elgiloy alloy, or similar materials. The main shaft compression spring 7 has a length in the range of 63.5 mm (2.5 inches) to 127 mm (5.0 inches), the diameter of the spring wire is in the range of 0.23 mm (0.009 inches) to 0.51 mm (0.020 inches), and a spring force in the range of 0.007 N / mm (0.04 pounds / inch) to 0.044 N / mm (0.25 pounds / inch), preferably in the range of 0.011 N / mm (0.06 pounds / inch) to 0.018 N / mm (0.10 pounds / inch). The housing assembly 14 can be machined, molded, or three-dimensionally printed from plastics such as acrylonitrile butadiene styrene, glass filled acrylonitrile butadiene styrene, styrene, polycarbonate, nylon, glass filled nylon, or from metals such as stainless steel, titanium, aluminum, or similar materials.

[0061] The feature of the actuating trigger 23 is that when it is actuated, first the spindle 13 moves proximally a short distance to break the static friction force of the system before causing the trigger lifting tip 24, enabling the spindle 13 to move distally. The distal portion of the spindle is composed of the coupler assembly 16 and the flexible cannula assembly 15. When actuated, the flexible cannula assembly 15 advances distally outward through the lumen of the bevel needle 8. The flexible cannula assembly 15 is sized such that the flexible cannula can slide freely within the lumen of the needle 8. The bevel needle can be in the range of sizes from 21 to 31 gauge.

[0062] The moving speed of the spindle 13 is controlled by an adjustable friction speed attenuation assembly 25 as shown in Figure 3B. The adjustable friction speed attenuation assembly 25 is composed of a swivel arm 26, on which a speed attenuation wheel 27 using a wheel axle 28, a proximal bearing cylinder 29, a distal bearing cylinder 30, a speed control adjustment screw 31 and a speed control compression spring 32 are mounted. The swivel arm 26 rotates freely on a swivel arm axle 33 mounted inside the housing 14. The degree control spring is a torsion spring or a compression spring and acts to apply a compressive force to the swivel arm 26. The degree control spring can be manufactured from materials such as piano wire, stainless steel wire or similar materials. The speed attenuation wheel 27 can be made from various elastic materials such as Buna N, silicone, Viton (registered trademark), EPDM, or rigid materials such as polycarbonate, nylon or ABS or similar materials. The speed attenuation wheel axle 28 and the swivel arm axle 33 can be made from smooth rigid materials such as stainless steel, titanium, copper, aluminum or similar materials. The swivel arm 26 can be molded, machined or three-dimensionally printed from rigid materials such as polycarbonate, acrylonitrile butadiene styrene, Ultem (registered trademark), nylon, acetal, polysulfone or similar materials. The swivel arm adjustment screw is threaded in the range of 1 to 5 threads per millimeter (24 to 120 threads per inch) so as to enable fine adjustment of the spindle forward speed.

[0063] The forward speed of the main shaft 13 is controlled by the force of the damping wheel on the main shaft and the friction generated in the bearing cylinders 29 and 30. The forward speed is controlled by the degree of compression of the speed control compression spring 32 against the swivel arm 26, and then the force is transferred to the polymer wheel 27 in frictional contact with the main shaft 13. The speed control adjustment screw 31 is inserted and removed to change the compression of the spring. The main shaft 13 is slidably disposed within the proximal and distal bearing cylinders 29 and 30. The proximal and distal bearing cylinders 29 and 30 can be machined or molded and are preferably made of a low friction polymer material such as polytetrafluoroethylene, fluorinated ethylene, polyethylene, ultra-high molecular weight polyethylene, Ultem®, acrylonitrile butadiene styrene or similar materials. The proximal and distal bearing cylinders can also be incorporated into the housing assembly portions on the left and right sides of the assembly.

[0064] The tubular main shaft 13 is hollow and can be made of a rigid material such as stainless steel, titanium, aluminum, acrylonitrile butadiene styrene, polycarbonate, glass filled nylon or similar materials and preferably has a smooth outer surface with low friction. The lumen diameter of the main shaft 13 is sized such that the internal fluid passage 17 and the fiber optic cable 18 are disposed within the lumen.

[0065] As shown in FIG. 3C, the flexible cannula assembly 15 includes a distal cannula flexible tip 34, a flexible cannula body 35, and a flexible cannula proximal support 37. The flexible cannula assembly is sized to slide freely through the lumen of the bevel needle 8. The distal flexible tip 34 is composed of a polymer with a lower durometer than the flexible cannula body 35. The distal end of the flexible tip is composed of a non-invasive tip 6 configured with an arcuation, chamfer, or spherical tip. The flexible tip and the spindle should ideally be made of the same type of polymer. The flexible tip is preferably attached to the body by thermal means, but adhesives, ultrasonic, or other means may be used to connect the tip to the body. The body and the flexible tip may be made of an elastomer such as polyurethane, polyurethane copolymer, polysiloxane, polysiloxane copolymer, polyether block amide, or similar materials. The flexible cannula may be sized with an outer diameter in the range of 0.18 mm (0.007 inches) to 0.51 mm (0.020 inches) and an inner diameter in the range of 0.08 mm (0.003 inches) to 0.46 mm (0.018 inches).

[0066] The flexible cannula assembly 15 is supported by a thin tubular flexible cannula proximal support 37. Since the cannula is advanced under the force of the main compression spring, the proximal support helps prevent the cannula assembly from twisting within the device. The proximal support may be made of a material such as stainless steel, titanium, polyimide, polytetrafluoroethylene, polycarbonate, or similar materials. The flexible cannula proximal support 36 is sized to fit outside the flexible cannula assembly 15 and to fit within the lumen of the bevel needle 8.

[0067] The optical fiber cable 18 is arranged centrally and is very close to the proximal end of the flexible cannula assembly 15. The optical fiber cable 18 sends light from a light source (not shown) to the proximal end of the flexible cannula assembly 15, thereby illuminating the entire cannula. The illuminated cannula allows the user to see the cannula through the scleral tissue so that the position of the cannula can be searched for and confirmed during the examination. The optical fiber cable 18 is made of plastic optical fibers to ensure flexibility, and the fiber diameter may range from 0.25 mm (0.010 inches) to 2 mm (0.08 inches). The gap or clearance between the distal end of the optical fiber cable 18 and the proximal end of the flexible cannula assembly 15 may be configured to attenuate the intensity of the light sent to the flexible cannula assembly 15 and the light output of the cannula. Alternatively, an attenuator for adjusting the light output of the cannula may be disposed between the distal end of the optical fiber cable 18 and the proximal end of the flexible cannula assembly 15. The device is configured to provide a light output of typically 100 to 700 μW.

[0068] The internal fluid path 17 is disposed within the main shaft 13 and is placed separately from the optical fiber cable 18. The internal fluid path 17 enables liquids and flowable semi-solid materials to enter the connector assembly 16 and enter the lumen of the flexible cannula assembly 15. The internal fluid path 17 passes through the main shaft 13 and is connected in proximity to the external fluid path 36. The proximal end of the external fluid path 36 terminates at the female Luer fitting 9 for connection to an external device such as a syringe for delivering a therapeutic agent. The internal fluid path 17 is composed of a rigid tube having an outer diameter in the range of 0.25 mm (0.010 inches) to 1.5 mm (0.060 inches) and an inner diameter in the range of 0.13 mm (0.005 inches) to 1.4 mm (0.055 inches), and may be made of a material such as stainless steel, titanium, polyimide, polytetrafluoroethylene, polycarbonate or a similar material. The external fluid path 36 is composed of a flexible tube having an outer diameter in the range of 0.5 mm (0.020 inches) to 3.2 mm (0.125 inches) and an inner diameter in the range of 0.25 mm (0.010 inches) to 2.54 mm (0.10 inches), and may be made of an elastomer such as polyurethane, polyurethane copolymer, polysiloxane, polysiloxane copolymer, polyether block amide, polyvinyl chloride or a similar material.

[0069] The device can be used to deliver a very small amount of a therapeutic agent in the range of 10 to 250 microliters. In some embodiments, the device can be used to deliver expensive pharmaceuticals where the amount used for treatment must be carefully controlled and losses minimized. To deliver a small amount, it is necessary to control and minimize the dead space within the fluid paths of the device. The device can be configured with a dead volume of less than 75 microliters, less than 50 microliters or less than 25 microliters.

[0070] An embodiment of the cannulation device is shown in FIG. 4. The device comprises a hollow cylinder 1 having a proximal cylinder end cap 2. A plunger 3 passes slidably through the cylinder end cap. The plunger has a lumen 4 through which a flexible cannula tubular element 5 passes. The flexible cannula 5 is fixed at a predetermined position of the plunger 3. The distal end of the flexible cannula has a rounded non-invasive tip 6. A plunger compression spring 7 applies a distal force to the plunger 3 and the flexible cannula 5. An angled needle 8 is attached and fixed to the distal end of the hollow cylinder 1, and in order to directly control the position of the needle tip when operating the position of the cylinder 1, the needle 8 is made immovable relative to the cylinder 1.

[0071] When the tissue contact and the end seal 38 are opened by the tip of the needle 8, the flexible cannula 5 moves distally under the force of the plunger compression spring 7. The tissue contact and the end seal 38 are attached to the distal end of a foldable element 39. The foldable element 39 is attached to the distal end of the cylinder 37 and applies a distal force to the tissue contact and the end seal 38, thereby pressing the tissue contact and the end seal 38 against the tissue surface. The proximal end of the flexible cannula 5 ends at a connection such as a Luer fitting 9, allowing the delivery of the administered substance through the flexible cannula 5.

[0072] An embodiment of the cannulation device is shown in FIG. 5. The device is configured as a hollow cylinder 13, within which a hollow body 40 is slidably mounted and includes a container for the substance to be administered. The distal end of the container body 40 is connected to a flexible cannula tubular element 5. A tubular container plunger 42 is slidably mounted inside the container, and a connector such as a Luer fitting 9 is attached to the proximal end of the container plunger to enable filling of the container. The connector incorporates a one-way valve 43 to prevent backflow of the administered substance. A container plunger compression spring 44 applies a force to release the administered substance.

[0073] The container body 40 operates as a plunger within the hollow cylinder for the deployment of the flexible tubular cannula 5. A container compression spring 44 is present on top of the hollow body 40. The container compression spring 44 provides the force to deploy the flexible cannula 5.

[0074] The beveled needle 8 is attached and fixed to the distal end of the barrel 13 so that when operating the position of the barrel 13, the position of the needle tip can be directly controlled, preventing the needle 8 from moving relative to the barrel 13. The distal end of the flexible cannula assembly 15 is configured within the lumen of the beveled needle 8. The flexible cannula 5 moves distally under the force of the container compression spring 44 when the tissue contact and terminal seal 38 are opened by the tip of the needle 8.

[0075] In one embodiment, the tip of the device comprises a foldable element. Referring to the device shown in FIG. 6 and the enlarged device tip detail of FIG. 7, the tip is composed of a distal portion, a central foldable portion, and a proximal portion. The tissue contact and terminal seal 38 are disposed around the distal tubular shaft 45. The lumen of the distal tubular shaft 45 includes an internal seal 46 that seals the space between the distal tubular shaft 45 and the beveled needle 8. The central portion is composed of one or more portions 47 that function as foldable elements. The foldable element 47 is attached to or integral with the distal tubular shaft 45 and the proximal tubular shaft 48. The proximal tubular shaft 48 provides a fixed point for the foldable element and is connected to the barrel 1 of the device to prevent distal movement of the tissue contact and terminal seal 38. FIG. 8 shows the distal portion of the device in an uncrushed state. The tissue contact along with the terminal seal 38 and the distal tubular shaft 45 are disposed at the ends of the foldable element 47. The proximal tubular shaft 48 is fixed to the barrel 1.

[0076] FIG. 9 shows the distal portion of the device in a folded state. The force advancing the device into the tissue deforms the foldable element 47, enabling the distal tubular shaft 45 along with the tissue contact and terminal seal 38 to slide proximally along the needle 8 towards the distal end of the barrel 1. The tip of the needle 8 penetrates the tissue contact and terminal seal 38.

[0077] In some embodiments, the tip of the needle is configured to direct the tubular element obliquely from the longitudinal axis of the needle. With respect to the tip of the needle shown in FIG. 10, the tip 49 of the needle may be curved to direct the tubular element. With respect to the tip of the needle shown in FIG. 11, the tip of the needle 50 can have an internal deflection element 51 within the needle lumen in the needle bevel region. With respect to the tip of the needle shown in FIG. 12, the tip of the needle 50 can have a local internal deflection element 52 within the needle lumen in the needle bevel region.

[0078] The embodiments described for the cannulation device can be used in combination to insert a cannula into the tissue space for administering a liquid, semi-solid or solid. In one embodiment, the configuration of the distal portion of the cannulation device comprises a distal element on the distal end of the needle that functions as a tissue contact and a terminal seal. The cannula and container for the delivery substance are configured to administer a liquid, semi-solid, solid or implant from the cannula. In some embodiments, the lumen of the cannula functions as a container or part of a container for the substance to be administered.

[0079] For use in an intubation device, a lubricant or lubricious coating may be used to assist intubation. For use in the device and deployment into the eye, the coating should provide lubricity immediately upon tissue contact. Some lubricants, such as polyvinylpyrrolidone coatings commonly used on vascular catheters, require 1 - 5 minutes of water contact to provide lubricity and are not suitable for use in intubation devices. Suitable lubricants for the 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 polymeric lubricants such as polysiloxane. Polymer solvent mixtures include, but are not limited to, aqueous formulations of water-soluble polymers such as polyethylene oxide, polyethylene glycol, and glycosaminoglycan. Also included as polymer solvent mixtures are silicone fluids or organic solvent formulations of polyethylene glycol. The polymer solvent mixture can be formulated using both high molecular weight forms of the polymer that provide durability and low molecular weight forms of the polymer that provide high lubricity. The lubricant can be applied to the entire cannula or its distal portion. The lubricant may be applied to the cannula by spraying or dipping. The lubricant may be non-bonded to the cannula surface, covalently bonded to the cannula surface, or both non-bonded and covalently bonded to the cannula surface. Suitable covalent binders include silanes, isocyanates, polyisocyanates, epoxides, photoinitiators, and photoreactive groups bonded to the lubricant. Also, the lubricant may be mechanically bonded to the cannula surface by contact with the lubricant in high molecular form in a solvent of the cannula material so that a penetrating polymer composition is formed on the cannula surface. The distal end of the needle lumen can also function as a small container for the lubricant that coats the cannula during deployment.

[0080] The administered substance may be a liquid, semi-solid or solid composition of the active ingredient for delivery to other spaces of the eye such as the suprachoroidal space, the supra-ciliary body space or the vitreous cavity, the subconjunctival space, the sub-Tenon's space and the subretinal space. The active ingredient may be dissolved, dispersed or suspended in a liquid or semi-solid formulation. Alternatively, the active ingredient may be formulated as an individual composition. The active ingredient may be distributed in the composition as particles. In one embodiment, the composition includes a plurality of drug-containing particles 53 formed in a semi-solid 54, as schematically shown in FIG. 13.

[0081] For delivery of the semi-solid to the suprachoroidal space or the supra-ciliary body space, the composition is placed into the eye from the outer surface of the eye through a cannula, and the substance is selectively placed in the suprachoroidal space or the supra-ciliary body space near the distal end of the cannula. After placement in the suprachoroidal space or the supra-ciliary body space, the semi-solid composition is converted, decomposed or dissolved into individual drug-containing particles that can move through the space and distribute the active ingredient. The semi-solid mass of drug particles allows a large amount of drug to be injected in a very small volume, preventing a sharp increase in intraocular pressure associated with the administration of an equivalent amount of drug suspended in a liquid. The semi-solid formulation allows an effective amount of drug to be delivered in the range of 5 to 100 microliters, 10 to 50 microliters or 15 to 40 microliters.

[0082] In one embodiment, the composition includes a plurality of drug-containing particles 53 shaped into a solid 55, as schematically shown in FIGS. 14 and 14A. The shaped solid 55 containing the plurality of drug-containing particles 53 may be in the shape of a plug, tube or cylinder. In one embodiment, the shaped solid is an elongated body having a diameter approximating the inner diameter of a cannula used for placement of the shaped solid in the tissue space. This diameter may vary in the range from 0.60 mm (0.02 inches) to 0.159 mm (0.006 inches). The shaped solid may have a length in the range of 1 mm (0.04 inches) to 50 mm (2 inches), or for example 1 mm (0.04 inches) to 25 mm (1 inch), depending on the dosage of the active ingredient and the active ingredient content of the particles. The shaped solid is present in the lumen of the cannula and is delivered from the cannula by hydraulic, pneumatic or mechanical forces from the device. The shaped solid composition is converted, decomposed or dissolved into individual active ingredient-containing particles that can move within the space after being placed in the suprachoroidal space or supra-ciliary body space. The semi-solid mass of shaped particles allows for the injection of a large amount of the active ingredient in a very small volume and prevents a sharp increase in intraocular pressure associated with the administration of an equivalent amount of the active ingredient suspended in a liquid. The volume of the shaped solid injected may vary in the range from 0.1 microliter to 10 microliters, or for example 0.1 to 5 microliters.

[0083] The particles of the active ingredient may be in the form of a selected size range of crystals of the active ingredient. The particles of the active ingredient may be in the form of fine particles by producing the active ingredient in the form of spherical particles, or may be in the form of fine particles by formulating the active ingredient together with a polymer and producing fine particles from this combination. The fine particles containing the active ingredient can be produced by known methods for the production of fine particles, such as spray drying, emulsification or coacervation. The use of a non-toxic polymer to retain the active ingredient within the fine particles enables adjustment of the active ingredient release rate depending on the polymer composition, active ingredient content and fine particle size. Fine particles with an active ingredient content of 10 to 50% by weight provide appropriate release. The use of a polymer with a selected solubility enables both water-soluble and water-insoluble active ingredients to be incorporated into the fine particles. Suitable polymers include polyvinylpyrrolidone, polyvinylpyrrolidone-co-vinyl acetate, polyvinyl alcohol, polyethylene glycol and polyethylene oxide as non-toxic water-soluble polymers, polyhydroxybutyric acid, polydioxanone, polyorthoesters, polycaprolactone, polycaprolactone copolymers, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymers and polylactic acid-glycolic acid-ethylene oxide copolymers as biodegradable polymers, and gelatin, collagen, glycosaminoglycan, cellulose, chemically modified cellulose, dextran, alginate, chitin and chemically modified chitin as biopolymers, but are not limited thereto.

[0084] In particular, in the case of a hydrophobic active ingredient, fine particles having an average volume diameter in the range of 3 to 14 microns and composed of a polylactic acid-glycolic acid copolymer having a lactic acid-glycolic acid fixed ratio (L-G) of 75:25 and 85:15 were found to give a release half-life in the range of 12 to 80 weeks in laboratory tests. The small diameter of the fine particles enables injection through small-gauge needles and cannulas for minimally invasive administration of the active ingredient.

[0085] For example, using fine particles with a relatively narrow size distribution where the coefficient of variation is in the range of 10% to 25%, the drug release rate can be adjusted according to the average size of the fine particles. The selection of the polymer in the fine particles and the form of the active ingredient such as crystalline or amorphous solid dispersions result in a general range of release that can be effectively adjusted by the use of size selection of the fine particles.

[0086] Alternatively, approximately spherical or other uniformly shaped active ingredient-containing particles can be produced by milling large active ingredients or by controlled crystallization. The active ingredient particles and the active ingredient-containing fine particles may be individually coated with a polymer layer to form outer-coated or protected active ingredient particles. The coating may include, but is not limited to, polyvinylpyrrolidone, polyvinylpyrrolidone-co-vinyl acetate, polyvinyl alcohol, polyethylene glycol, and polyethylene oxide as non-toxic water-soluble polymers, polyhydroxybutyric acid, 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 as biodegradable polymers, and gelatin, collagen, glycosaminoglycan, cellulose, chemically modified cellulose, dextran, alginate, chitin, and chemically modified chitin, lipids, fatty acids, and sterols as biomaterials.

[0087] In one embodiment, the plurality of active ingredient-containing particles flow upon the application of an injection pressure, but once administered into the tissue, they are formed into a semi-solid composition that forms a semi-solid substance at the delivery site. The semi-solid form with a high concentration of active ingredient-containing particles, i.e., in the range of 70 to 200 mg / mL, confers the ability to deliver an amount of active ingredient sufficient to provide a sustained delivery at a therapeutic level. The ability to inject the composition is assisted by the use of microparticles or spherical particles to minimize aggregation during injection. The ability to inject a semi-solid at a high particle concentration is made possible by the use of excipients that suspend the particles in an aqueous formulation, but also confers viscoelastic properties that facilitate the flow of the particles during injection. Suitable viscoelastic excipients include polyethylene glycol, polyethylene oxide, high molecular weight polyvinylpyrrolidone, and biopolymers such as hyaluronic acid and chondroitin sulfate. In one embodiment, the semi-solid is formulated using an excipient mixture containing microparticles in the range of 70 to 200 mg / mL, as well as a viscoelastic excipient and a physiological buffer.

[0088] In one embodiment, the plurality of active ingredient-containing particles are shaped into a solid or semi-solid together with an excipient. Suitable excipients include non-toxic water-soluble polymers such as polyvinylpyrrolidone, polyvinylpyrrolidone-co-vinyl acetate, polyvinyl alcohol, polyethylene glycol, and polyethylene oxide; biodegradable polymers such as polyhydroxybutyric acid, polydioxanone, polyorthoester, polycaprolactone, polycaprolactone copolymer, polylactic acid, polyglycolic acid, polylactic acid-glycolic acid copolymer, and polylactic acid-glycolic acid-ethylene oxide copolymer; and biomaterials such as gelatin, collagen, glycosaminoglycan, cellulose, chemically modified cellulose, dextran, alginate, chitin, and chemically modified chitin, but are not limited thereto. The solid or semi-solid composition can be formulated using a mixture of different excipients. The particles containing the active ingredient are mixed with the excipient in a suitable solvent or diluent that dissolves the excipient or forms a dispersion system with 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 with a solvent. In one embodiment, the solid or semi-solid composition is placed in a mold and shaped, or extruded and dried to form a solid of a desired size for administration. The ideal one for administering the formed solid or semi-solid composition has an elongated shape with an outer diameter that fits within the lumen of a cannula or needle with a small diameter, 20 gauge or less, corresponding to 0.60 mm (0.02 inches) or less in diameter. In one embodiment, the formed solid or semi-solid composition has an outer diameter that fits within the lumen of a cannula or needle 25 gauge or less, corresponding to 0.26 mm (0.01 inches) or less in diameter. In one embodiment, the formed solid or semi-solid composition has an outer diameter that fits within the lumen of a cannula or needle 27 gauge or less, corresponding to 0.20 mm (0.008 inches) or less in diameter.

[0089] In one embodiment, the semi-solid composition is dried, such as by lyophilization or air drying, and rehydrated before administration. The semi-solid composition may contain excipients such as salts, sugars, water-soluble polymers, and surfactants to assist in reconstitution. In the case of lyophilized formulations, the use of bulking agents such as sucrose, mannitol, glycine, povidone, or dextran assists in the production of a loose lyophilizate having large channels or pores for increasing the reconstitution rate. Excipients that act as reconstitution aids for increasing the reconstitution rate of the lyophilized composition, such as surfactants, salts, sugars, or trehalose, can be added before freezing and lyophilization. In one embodiment, the semi-solid composition contains microparticles containing an active ingredient, viscoelastic polymers, bulking agents, and physiological buffers, which are lyophilized to produce a dried product for enhancing stability during storage. The composition can be reconstituted with water immediately before use. In one embodiment, the composition may further contain an excipient that accelerates reconstitution, such as trehalose. The combination of components must be carefully coordinated to provide physical stability for lyophilizing a composition without particle aggregation, rapid rehydration, physical properties providing reconstitution stability without particle aggregation, flow properties for administration through a narrow lumen, and at the same time a physiologically compatible osmotic pressure and pH.

[0090] In one embodiment, the active ingredient-containing particles are of a size smaller than the inner diameter of the cannula, enabling the closest packing of the particles in the formed solid or semi-solid and enhancing the mechanical properties. Such active ingredient-containing particles have an average diameter in the range of 5 to 100 microns, for example 10 microns (0.0004 inches) to 50 microns (0.002 inches), and may include a mixture of diameters that facilitate closest packing. The average value or median value of the diameter of the particles is in the range of 5 microns (0.0002 inches) to 100 microns (0.004 inches), for example, in the range of 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).

[0091] The dispersion and movement of the particles containing the active ingredient are desirable to promote a uniform distribution of the particles within the eye. The dissolution of the excipient and the resulting release of the active ingredient-containing particles can be caused, for example, by the ionic environment, the dissolution of the excipient or the absorption of liquid from the tissue space due to the temperature of the environment. In one embodiment, the excipient includes a lipid or fatty acid having a melting temperature between room temperature and the temperature of the eye tissue space, and this melting temperature is about 37 °C (for example, a melting temperature between 21 and 37 °C, between 25 and 37 °C, or between 30 and 35 °C). The release rate of the individual active ingredient-containing particles from the solid or semi-solid composition can be adjusted by the addition of a hydrophilic or amphiphilic agent that increases the dissolution rate of the excipient of the solid or semi-solid composition. The release of the active ingredient-containing particles can occur over several hours, days or weeks, depending on the amount and composition of the administered substance. For example, up to (or, depending on the formulation, down to) 50% of the active ingredient-containing particles can be released after 1 hour, 6 hours, 12 hours, 1 day, 3 days or 1 week.

[0092] The solid or semi-solid composition may be operable by the ionic environment of the tissue space and may dissolve, as brought about by a polymer cross-linked with ions such as alginate. When the solid or semi-solid composition uses lipids, fatty acids, etc. having a melting transition temperature above room temperature of about 20°C and below about 37°C, which is the temperature within the eye tissue space, dissolution begins due to temperature in the tissue space. Such lipids and fatty acids include, but are not limited to, capric acid, erucic acid, 1,2-dinerubonoyl-sn-glycero-3-phosphocholine, 1,2-dimyristoyl-sn-glycero-3-phosphocholine, and 1,2-dipentadecanoyl-sn-glycero-3-phosphocholine, and mixtures thereof.

[0093] Since the active ingredient-containing particles have a small size, the release of the active ingredient from the particles may be too rapid, and it may not be possible to provide a sustained release effect of the active ingredient after administration to the eye. The object of the present invention is to provide active ingredient-containing particles having a sustained release kinetics (i.e., a release-controlled formulation). In one embodiment, the active ingredient is incorporated into a polymer matrix, creating a path through which the drug diffuses less easily. Thereby, the release of the active ingredient is slower compared to the active ingredient without the polymer matrix. In one embodiment, the active ingredient-containing particles are coated with a protective film such as a polymer or other compound. The protective material usually has different chemical properties from the active ingredient. As a result, the active ingredient does not easily dissolve through the protective coating, and the release of the active ingredient is slower compared to the active ingredient particles without the protective coating. One way to select the protective coating is a material with a partition coefficient or logP different from that of the active ingredient and with a large difference such that it provides a large barrier to the release of the active ingredient. In one embodiment, the individual particles of the active ingredient are coated with a protective coating having an increased water solubility or a decreased logP compared to the active ingredient, and a protective coating is formed on each particle. Examples of the protective material include non-toxic water-soluble polymers such as polyvinylpyrrolidone, polyvinylpyrrolidone-co-vinyl acetate, polyvinyl alcohol, polyethylene glycol, and polyethylene oxide, polyorthoester-ethylene oxide copolymers, acid-terminated poly(lactic acid-glycolic acid) copolymers, poly(lactic acid-glycolic acid-ethylene oxide) copolymers, poly(lactic acid-polyethylene glycol) copolymers, and poly(caprolactone-polyethylene glycol) copolymers, biodegradable polymers, and biomaterials such as gelatin, collagen, glycosaminoglycan, cellulose, chemically modified cellulose, dextran, alginate, chitin, and chemically modified chitin, but are not limited thereto. In one embodiment, the individual particles of the active ingredient are coated with a protective coating having a decreased water solubility or an increased logP compared to the active ingredient, and a protective coating is formed on each particle.Examples of such protective coatings include, but are not limited to, biodegradable polymers such as polyhydroxybutyric acid, 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, as well as biopolymers such as chemically modified chitin, lipids, fatty acids, and sterols. The active ingredient particles may be coated by known methods for any particle coating, such as spray drying, electrostatic spraying, or chemical precipitation. In one embodiment, as schematically shown in FIGS. 14 and 14A, the shaped solid or semi-solid material 54 comprises a plurality of active ingredient-containing particles 53 encapsulated or coated with a protective material 54 such as a soluble polymer or other coating material to modify the active ingredient release characteristics and / or mechanical properties.

[0094] The active ingredient of the composition is mainly contained in a plurality of particles, but a certain amount of the active ingredient may also be formulated in the excipient. The active ingredient in the excipient can act to prevent extraction or diffusion of the active ingredient from the particles during manufacture or storage. The active ingredient in the excipient can initiate the therapeutic effect of the active ingredient, but can also serve to provide a rapid release component to the active ingredient formulation that gives sustained release to the active ingredient in the particles to maintain the therapeutic effect.

[0095] In one embodiment, the active ingredient composition includes an active ingredient and an excipient composed of a biodegradable or bioerodible substance. Examples of the biodegradable or bioerodible substance include, but are not limited to, polyhydroxybutyric acid, 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 ingredient may be dispersed in the biodegradable or bioerodible substance as an amorphous solid dispersion. The active ingredient may be dispersed in the biodegradable or bioerodible substance as a plurality of crystals. The active ingredient may be dispersed in the biodegradable or bioerodible substance as both an amorphous solid dispersion and crystals. The active ingredient composition can be formed as a solid elongated body or a semi - solid for administration to the ocular tissue space. After placement in the tissue, the release of the active ingredient from the composition allows the active ingredient to diffuse into the ocular tissue, and the flow of liquid within the tissue space aids this. When the active ingredient is in the form of a solid amorphous dispersion, the biodegradable or bioerodible substance is selected to provide the desired filling and release characteristics of the active ingredient. When the active ingredient is in the form of dispersed crystals, the amount of the active ingredient, the properties of the biodegradable or bioerodible substance, and the crystal form of the active ingredient are selected to provide the desired filling and release characteristics of the active ingredient. The crystals of the active ingredient can also be coated with an excipient that reduces the active ingredient release rate of the composition. When the active ingredient release is initiated by contact with moisture in the hydrated tissue environment, the active ingredient composition is administered as a dry solid composition or a lyophilized formulation that is reconstituted immediately before use. In one embodiment, the composition has a sustained release of the active ingredient. The elution of the active ingredient from the composition can have a half - life in the range of 14 to 360 days, 21 to 270 days, 30 to 180 days, or 60 to 90 days.

[0096] According to the present invention, various drugs can be delivered to the eye as active ingredients for the treatment of eye 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, non-steroidal anti-inflammatory drugs, antibiotics, VEGF inhibitors, PDGF inhibitors, anti-TNFα agents, mTOR inhibitors, prostaglandin derivatives, cell therapy agents, neuroprotective drugs, antihypertensive drugs, antihistamines, aminosterols and nucleic acid-based therapeutic agents. The drug may be in the form of a soluble solution, suspension, gel, semi-solid, microspheres, shaped solid or implant.

[0097] In one embodiment, the active ingredient is pre-filled into the device before use during manufacture. The force source that applies the deployment force to the cannula can be actuated immediately before use or simultaneously with use. In one embodiment, actuation is achieved by a mechanism that pre-loads a force element, such as by compressing a spring from outside the device using a movable proximity handle attached to the plunger. In one embodiment, the force source is pre-loaded during manufacture and the pre-loaded force is stabilized by a stop mechanism. The stop mechanism is released before use or simultaneously with use, thereby applying a deployment force to the cannula before contact with or penetration of the eye, and cannula deployment is initiated by the forward movement of the needle into the eye, as in the previous embodiments of the invention.

[0098] As described above, according to the present invention, various drugs can be delivered to the eye as active ingredients for the treatment of various eye diseases and symptoms including inflammation, cancer, infection, macular degeneration, retinal degeneration, angiogenesis, proliferative vitreoretinopathy, glaucoma and edema. Useful drugs include steroids such as corticosteroids including dexamethasone, fluocinolone, loteprednol, difluprednate, fluorometholone, prednisolone, medrysone, triamcinolone, betamethasone and rimexolone; non-steroidal anti-inflammatory drugs such as salicylic acid-, indoleacetic acid-, arylacetic acid-, arylpropionic acid- and enolic acid derivatives including bromfenac, diclofenac, flurbiprofen, ketorolac tromethamine and nepafenac; antibiotics including azithromycin, bacitracin, besifloxacin, ciprofloxacin, erythromycin, gatifloxacin, gentamicin, levofloxacin, moxifloxacin, ofloxacin, sulfacetamide and tobramycin; VEGF inhibitors such as tyrosine kinase inhibitors, antibodies against VEGF, antibody fragments against VEGF, VEGF-binding fusion proteins; PDGF inhibitors such as antibodies against PDGF, antibody fragments against PDGF, PDGF-binding fusion proteins; anti-TNFα agents such as antibodies against TNFα, antibody fragments against TNFα and TNF-binding fusion proteins including infliximab, etanercept, adalimumab, certolizumab and golimumab; mTOR inhibitors such as sirolimus, sirolimus analogs, everolimus, temsirolimus and mTOR kinase inhibitors; cell therapy agents such as mesenchymal cells or cells genetically engineered to produce therapeutic agents; glaucoma drugs such as prostaglandin derivatives, β-blockers, α-agonists, carbonic anhydrase inhibitors, and rho kinase inhibitors; anticancer agents such as melphalan, topotecan, methotrexate, rituximab, carboplatin and 5-FU; neuroprotective agents such as antioxidants, calcineurin inhibitors, NOS inhibitors, sigma-1 modifiers, AMPA antagonists, calcium channel blockers, DNA gyrase inhibitors, DNA polymerase inhibitors, RNA polymerase inhibitors and histone deacetylase inhibitors;Antihypertensive drugs such as prostaglandin derivatives, β-blockers, α-agonists, and carbonic anhydrase inhibitors; amino steroids such as squalamine; antihistamines such as H1 receptor antagonists and histamine H2 receptor antagonists; therapeutic proteins and nucleic acid-based therapeutic agents such as gene vectors, gene editing therapeutic agents, plasmids, therapeutic mRNAs, guide RNAs, and siRNAs, but not limited thereto.;

[0099] In one embodiment of the present invention, for pharmaceutical use, specifically for ophthalmic pharmaceutical use, the drug composition of the present invention is provided. In a further embodiment of the present invention, the drug composition of the present invention is provided for use in the treatment of eye diseases or conditions. Examples of eye diseases or conditions include inflammation, infection, macular degeneration, retinal degeneration, angiogenesis, proliferative vitreoretinopathy, glaucoma, uveitis, eye tumors, and edema. In some embodiments, the drug composition is administered by delivery through a cannula, specifically through a cannula disposed by the cannulation device of the present invention.;

[0100] In one embodiment, the distal end of the cannulation device according to any one of claims 1 to 40 is placed on the surface of the affected area, and the needle of the device is advanced into the affected area; while illuminating the proximal end of the tubular element to illuminate the tip of the tubular element, the tubular element is advanced; the tip of the tubular element is advanced into the affected area; and delivering a substance for administration into the space: A method for treating a disease or condition by delivering a liquid or semi-solid substance to the affected area is provided.;

[0101] In another embodiment, the disease or condition is inflammation or infection. In another embodiment, the inflammation is selected from the group consisting of rhinosinusitis, osteoarthritis, rheumatoid arthritis, arthritis, rhinitis, and postoperative inflammation, and combinations thereof.;

[0102] In another embodiment, the disease or condition is an eye disease or condition. In another embodiment, the eye disease or condition is selected from the group consisting of blepharitis, allergic conjunctivitis, macular degeneration, retinal degeneration, angiogenesis, proliferative vitreoretinopathy, glaucoma, eye tumors, uveitis and edema, and combinations thereof.

[0103] In one embodiment, a method for treating an eye disease or condition is provided by administering a drug composition to the eye, for example, to the suprachoroidal space or the supra-ciliary body cavity, using the intubation device of the present invention. The drug composition can be dissolved or converted into a plurality of drug-containing particles that move from the administration site (e.g., the suprachoroidal space or the supra-ciliary body cavity) after administration. Examples of the eye disease or condition include inflammation, infection, macular degeneration, retinal degeneration, angiogenesis, proliferative vitreoretinopathy, glaucoma, eye tumors or edema.

[0104] In another embodiment of the present invention, there are provided parts of a kit comprising the intubation device described herein and the drug composition of the present invention. The drug composition is provided pre-filled in the delivery device. Alternatively, the drug composition is provided as a plurality of individual dosage forms suitable for insertion into the delivery device. Thus, the kit can also provide the drug composition of the present invention in the form of a plurality of individual dosage forms, together with the intubation device.

[0105] In other embodiments, the administered substance includes a steroid, a non-steroidal anti-inflammatory drug, an antibiotic, a VEGF inhibitor, an anti-TNFα agent, an mTOR inhibitor, a cell therapy agent, an antihypertensive drug, an antihistamine, an aminosteroid, a neuroprotective agent, or a nucleic acid-based therapeutic agent. The steroid includes dexamethasone, dexamethasone acetate, fluocinolone, loteprednol, difluprednate, fluorometholone, prednisolone, medrysone, triamcinolone, betamethasone, rimexolone, beclomethasone dipropionate, budesonide, fluticasone dipropionate, mometasone furoate, or ciclesonide. The non-steroidal anti-inflammatory drug includes bromfenac, diclofenac, flurbiprofen, ketorolac tromethamine, and nepafenac. The antihistamine includes cetirizine, loratadine, fexofenadine hydrochloride, olopatadine, alcaftadine, epinastine, or ketotifen. The anti-TNFα agent includes infliximab, etanercept, adalimumab, certolizumab, or golimumab. The mTOR inhibitor includes sirolimus, everolimus, temsirolimus, or an mTOR kinase inhibitor. The cell therapy agent includes mesenchymal cells or cells transfected to produce a therapeutic agent. The neuroprotective agent includes an antioxidant, a calcineurin inhibitor, an NOS inhibitor, a sigma-1 modifier, an AMPA antagonist, a calcium channel blocker, a DNA gyrase inhibitor, a DNA polymerase inhibitor, an RNA polymerase inhibitor, and a histone deacetylase inhibitor. The nucleic acid-based therapeutic agent includes a gene vector, a gene editing therapeutic agent, a plasmid, a guide RNA, or siRNA.

[0106] The present invention is described with reference to numerous examples provided for illustrative purposes and should not be construed as limiting the scope of the present invention.

Example

[0107] 〔Manufacture of an intubation device for placement of an illuminated flexible cannula in the ocular tissue space〕 An apparatus was manufactured according to an embodiment of the present invention. The apparatus consisted of a body with a 27-gauge distal needle and an illuminated flexible cannula designed to slideably deploy through the needle. The body included a housing and a drive mechanism for semi-automatically advancing the cannula. The cannula was connected to a syringe for liquid delivery. Illumination of the cannula was provided by a 532 nm green laser.

[0108] The cannula was made from a Shore 55D durometer polyurethane tube with an inner diameter of 0.13 mm, an outer diameter of 0.25 mm, and a length of 30 mm. A polyimide reinforcing tube with an inner diameter of 0.25 mm, an outer diameter of 0.28 mm, and a length of 20 mm was placed over the proximal end of the polyurethane tube, leaving 10 mm of polyurethane as the distal flexible cannula portion.

[0109] The housing of the body was made from a 0.5 cc insulin syringe. The syringe plunger was discarded and the injection needle was removed from the distal end of the barrel. The proximal lumen of the barrel was threaded with 8 - 32 threads and a proximal stop screw was accommodated. A 27-gauge extra-thin wall subcutaneous needle with an inner diameter of 0.3 mm, an outer diameter of 0.41 mm, and a length of 20 mm was joined to the injection barrel. The needle was positioned such that 2.5 mm of the needle extended distally from the barrel end and 14 mm extended proximally into the cavity of the injection barrel. An "L"-shaped groove was machined on the side of the barrel to accommodate a tube element for liquid delivery and to function as a trigger for cannula deployment.

[0110] The drive mechanism was fabricated from a shaft assembly that functions as a force element for deploying the cannula and a compression spring. The shaft assembly included a proximal tube, a central connector, and a distal attachment sub-assembly. The proximal tube was fabricated from a 17-gauge thin-walled subcutaneous 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 was fabricated from 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. Side holes with a diameter of 0.36 mm were drilled in the central connector 7.3 mm from the distal end. The distal attachment sub-assembly was fabricated from two portions of a polyether ether ketone (PEEK) tube with an outer diameter of 1.58 mm. The proximal portion had an inner diameter of 0.35 mm for attachment to the cannula. The distal portion had an inner diameter of 0.65 mm for attachment to the support tube. The support tube was fabricated from a 23-gauge thin-walled subcutaneous tube 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 joined to the distal portion provided support to prevent buckling of the cannula during deployment. The support tube was slidably disposed over the proximal end of a 27-gauge needle within a syringe, thereby positioning the distal end of the cannula within the proximal end of the lumen of the 27-gauge needle.

[0111] The proximal end of the cannula was joined to the proximal PEEK portion of the attachment sub-assembly. The distal PEEK portion to which the support tube was joined at a predetermined position slid on the cannula, and the two portions were joined to each other. The sub-assembly was press-fitted into the distal end of the central connector until the proximal end of the sub-assembly was distal to the side hole of the central connector. The proximal tube was inserted into the central connector until its distal end was proximal to the side hole and then joined at a predetermined position. The gap between the attachment assembly and the proximal tube enabled liquid to flow from the side hole into the central connector and then into the cannula lumen. A portion of a plastic optical fiber (POF) was inserted into the proximal tube and advanced until it exactly overlapped the distal end of the tube. The assembly enabled light from the POF to strike the end of the polyurethane cannula. The POF was composed of a polymethyl methacrylate core with a diameter of 0.46 mm, coated with a fluorinated polymer, and then covered with polyethylene with an outer diameter of 1 mm. The POF was cut to a length of 700 mm. The proximal end of the POF was inserted into a machined connector joint attached to a green laser. When the laser was activated, light was transmitted through the POF to the proximal end of the cannula. The light passed through the cannula with sufficient light escaping from the wall of the cannula to illuminate the entire length of the cannula and provided sufficient light transmission to give a brightly illuminated tip.

[0112] The compression spring provided a force element for deploying the cannula. The spring was made of stainless steel wire with a diameter of 0.22 mm, had an outer diameter of 2.6 mm and a length of 33 mm. The spring was disposed on the proximal tube that protruded distally relative to the central connector. The proximal stopper was made from an 8 - 23 thread nylon - headed screw with a length of 16 mm. A hole with a diameter of 1.5 mm was drilled along the axis of the screw and slidably fitted onto the proximal tube. The screw was screwed into the proximal end of the syringe barrel to provide the proximal stopper for the compression spring. A silicone O - ring with an inner diameter of 1.1 mm and an outer diameter of 3.6 mm and a Shore 50A durometer was placed on the proximal tube proximal to the stopper. The O - ring functioned as a friction element to slow down the deployment speed of the cannula.

[0113] The fluid connection was made to the cannula via a side tube. The side tube was part of a 27 - gauge stainless - steel subcutaneous tube with an inner diameter of 0.20 mm and an outer diameter of 0.41 mm and bent 90 degrees. One end of the tube was inserted through a groove in the syringe barrel into the side hole of the central connector. A portion of a polyurethane tube with an inner diameter of 0.25 mm, an outer diameter of 0.51 mm and a length of 120 mm was attached to the open end of the subcutaneous tube. A 30 - gauge smooth - ended Luer needle adapter was inserted into the proximal end of the polyurethane tube for attachment of a syringe or other liquid - delivery element. The drive mechanism with the cannula attached was retracted and rotated so that the side tube was placed in the short leg of the "L" - shaped groove. In this configuration, the device was in a locked state and the cannula could not be deployed. During use, the device was prepared for deployment by manually pressing the side tube onto the groove to a ready or operating state. By pushing the side tube out of the groove, it was observed that the cannula advanced outward from the tip of the needle and deployed by the drive mechanism.

Example

[0114] 〔Insertion device for placement of an illuminated flexible cannula in the suprachoroidal space〕 The device was manufactured according to Example 1. The drive device was retracted, and the side tube was placed on the short leg of the cylindrical groove that holds the device in a locked state. A 0.25 cc syringe was filled with a 0.1% fluorescein solution and attached to the Luer connector at the end of the fluid connection tube. The power of the green laser was turned on to illuminate the cannula. A porcine cadaver eye was prepared. The 27-gauge needle of the device was inserted into the sclera of the pars plana at an acute angle towards the posterior part of the eye and advanced until the bevel was well within the sclera. The side tube was pushed along the side into the groove to prepare the device. The cannula was blocked from advancing because its tip was within the scleral tissue. The needle advanced further into the eye. When the tip of the needle entered the suprachoroidal space, the cannula automatically deployed by the force of the compression spring. The illuminated cannula could be visually observed under the sclera as a green gland extending posteriorly from the entry position of the needle.

[0115] The injection of 0.1 cc of fluorescein was performed via the cannula. The cannula was withdrawn from the eye. A scleral incision was made at the administration site, and when entering the suprachoroidal space, a fluorescein jet was observed and the placement of the injected fluid in the suprachoroidal space was confirmed.

Example

[0116] 〔Insertion device for the placement of an illuminated flexible cannula in the vitreous cavity〕 The device according to Example 1 was manufactured as in Example 2. A porcine cadaver eye was prepared. The 27-gauge needle was inserted perpendicularly to the eye surface at the pars plana. The cannula deployed as in Example 2. The cannula illuminated under the sclera was not observed, but it was observed that the placement within the vitreous cavity was shown through the cornea.

Example

[0117] 〔Manufacture of an insertion device with a curved flexible cannula for cannula placement in the eye tissue space〕 An apparatus similar to that described in Example 1 was manufactured. The distal 2 mm of the cannula was formed at an angle of approximately 45 degrees. The cannula was placed on the forming wire and heated at 90 degrees Celsius for 30 seconds. The cannula was incorporated into the device with a curved portion directed towards the needle bevel angle. The device and the porcine cadaver eye were prepared as described in Example 2. The needle was inserted obliquely into the eye with respect to the surface, and the bevel angle of the needle was directed outside the eye. The device was activated and the needle advanced. The cannula was deployed and the sclera was incised in the region distal from the needle. The cannula was observed in the suprachoroidal space.

Example

[0118] An apparatus according to one embodiment of the present invention was assembled for injecting a liquid substance into the suprachoroidal space of the eye. The tubular main shaft was made from a 12-gauge thin-walled stainless steel subcutaneous tube with an outer diameter of 0.109 inches (2.77 mm), an inner diameter of 0.091 inches (2.31 mm), and a length of 5.5 inches (139.7 mm), the outer surface of which was electrically polished. The main shaft compression spring was made from a stainless steel wire with 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 had a spring constant of 0.119 pounds (0.53 N) at a spring height of 2.040 inches (51.82 mm) per inch (25.4 mm) and 0.146 pound force (0.65 N) at a spring height of 1.683 inches (42.75 mm). The connector assembly was made from polycarbonate and had functions that interacted with a central optical fiber cable, an internal fluid path offset from the center line, and a trigger lifting tip and hole that were compatible with the tubular main shaft.

[0119] The optical fiber cable was fabricated from ESKA fiber SH-2001-J, had a 0.020 inch (0.51 mm) fiber and a coated outer diameter of 0.040 inch (1.02 mm), and had the insulation stripped 1.5 inches (38.1 mm) at the distal end and was cut to a length of 84 inches (213.4 cm). The internal fluid path was fabricated from a 25G thin-wall subcutaneous tube 5.03 inches (127.76 mm) in length and both ends were grit blasted at a length of 0.25 inch (6.35 mm) to enhance the adhesive bonding. The stripped ends of the internal fluid path and the optical fiber cable were both adhesively bonded to the connector assembly. The spindle slid over the proximal end of the optical fiber cable and the internal fluid path and was adhesively bonded to the connector assembly.

[0120] The external fluid path was fabricated from 80A durometer polyurethane with an inner diameter of 0.014 inch (0.36 mm), a thickness of 0.019 inch (0.48 mm) and a length of 11.0 inches (279.4 mm). The external fluid path was adhesively bonded to the proximal end of the internal fluid path.

[0121] The proximal and distal bearing tubes were fabricated from UHMWPE with an inner diameter of 0.112 inch (2.84 mm) and an outer diameter of 0.25 inch (6.35 mm). The spindle compression spring and bearing tubes slid over the optical fiber cable, external fluid path and spindle and then to the connector assembly. The end cap was fabricated from polycarbonate and slid over the proximal ends of the optical fiber cable and internal fluid path for attachment to the proximal end of the housing body. A special order female luer fitting manufactured with a 5 microliter internal dead volume was adhesively bonded to the proximal end of the external fluid path. The optical connector for attachment to an external light source was created with an inner diameter of 0.042 inch (1.07 mm) and was adhesively bonded to the end of the optical fiber cable.

[0122] The flexible cannula assembly was made from a 55D durometer polyurethane tube for the body with an inner diameter of 0.005 inches (0.13 mm) and an outer diameter of 0.0098 inches (0.25 mm), and an 80A durometer polyurethane tube for the flexible cannula flexible tip with an inner diameter of 0.005 inches (0.13 mm) and an outer diameter of 0.0098 inches (0.25 mm). The flexible tip with a length of 0.070 inches (1.78 mm) was heat fused to the body, and the distal end of the flexible tip was polished and rounded at the edge of the distal end of the flexible tip.

[0123] The flexible cannula proximal support was made from a polyimide tube with an inner diameter of 0.0102 inches (0.26 mm) and a wall thickness of 0.0005 inches (0.013 mm) and a length of 0.86 inches (21.84 mm). The cannula proximal support slid over the cannula assembly and was joined at a predetermined position. Next, the flexible cannula proximal support was adhesively joined to the distal end of the connector assembly.

[0124] The speed control compression spring was made from a stainless steel spring wire with a diameter of 0.015 inches (0.38 mm), having a free length of 0.175 inches (4.45 mm), an outer diameter of 0.106 inches (2.69 mm), and a spring constant of 28.75 pounds (127.9 N) per inch (25.4 mm). The spring had three active coils and two inactive coils with a closed end and a grounded end. Four O-rings sized AS568-004 in Buna N were used as speed control wheels. A stainless steel retaining pin with a diameter of 0.078 inches (1.98 mm) and a length of 0.187 inches (4.75 mm) was used for the speed control wheel axle, and a stainless steel retaining pin with a diameter of 0.063 inches (1.60 mm) and a length of 0.375 inches (9.53 mm) was used for the swivel arm axle.

[0125] The swivel arm is machined from polycarbonate. The speed control adjustment screw is made of 304 stainless steel with 4-40 threads, and one end is machined to a diameter of 0.072 inches (1.83 mm). The speed control wheel axle passes through the swivel arm and the speed control wheel and is held in place by friction with the inside of the speed control wheel.

[0126] The housing assembly is machined from polycarbonate and has a 4-40 threaded hole for the speed control adjustment screw and a hole drilled for the swivel arm axle at the proximal end. The swivel arm axle retaining pin is press-fitted onto one side of the housing. The speed control adjustment screw is threaded into the hole in the housing. The swivel arm with the speed control wheel is mounted on the press-fitted swivel arm axle, and the speed control compression spring is placed between the swivel arm and the speed control adjustment screw.

[0127] The trigger is machined from polycarbonate, and the thickness of the flexible part of the trigger is 0.028 inches (0.71 mm). The trigger is placed between the two housing halves, and the assembled spindle is placed under the speed control polymer wheel. Also, the bearing cylinder is placed in the cavity within the housing part, and the two halves of the housing assembly are adhered to each other.

[0128] The bevel needle is made from a 27-gauge 304 stainless steel extra-thin-wall hypodermic tube. The tube had an inner diameter of 0.0115 inches (0.292 mm), an outer diameter of 0.0165 inches (0.42 mm), and a length of 0.80 inches (20.32 mm). The tip was ground to a lancet-type bevel, and the angle of the main bevel was 15 degrees. The nose cone is made from polycarbonate, and the bevel needle is adhesively bonded to the nose cone such that the needle extends 3 mm from the distal surface of the nose cone and is oriented horizontally relative to the centerline of the housing. The nose cone is adhesively bonded to the distal end of the housing assembly, and the distal end of the cannula is inserted into the proximal end of the needle such that the distal end of the cannula is approximately 0.5 - 1 mm proximal to the proximal end of the needle bevel.

Example

[0129] [Insertion device with a distal element and a deflecting needle for the placement of a flexible cannula in the suprachoroidal space] The device according to one embodiment of the present invention was manufactured for deploying a flexible cannula into the suprachoroidal space and the supra-ciliary body cavity of the eye. The barrel element was made by cutting the proximal end of a 0.5 mL insulin syringe to a barrel length of 30 mm. The integral needle was removed from the barrel to enable the attachment of a standard Luer hub needle. The tip of the barrel was cut leaving the remaining part of the Luer taper that could securely hold the Luer hub needle. The barrel end cap was made from a nylon 10-32 threaded hole with a 4.5 mm thread length. A through hole with a diameter of 1.86 mm was drilled through the barrel end cap so that the plunger could slide freely through the barrel end cap. The plunger shaft was made from a tubular Teflon®-coated 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 was tapered 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 was press-fitted onto the rod to provide a terminal stop for the plunger spring. The proximal end of the rod was drilled 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 was placed on the plunger shaft, and then the barrel end cap was slid onto the plunger shaft proximal to the spring. The plunger assembly was placed inside the barrel housing, and the terminal cap was press-fitted into the proximal end of the barrel to fix the plunger assembly inside the barrel.

[0130] The deflecting needle was made from a 27-gauge × 13 mm thin-walled hypodermic needle. The tip of the needle was bent at an oblique angle to form an inclined path-like inner surface. The back of the needle, which is opposite to the first oblique angle, was polished in the same way as the tip of a standard needle lancet with first and second oblique angles to create a sharp tip for tissue penetration. A 24-gauge thin-walled tube with a length of 3 cm was press-fitted into the needle hub to join with the proximal end of the 27-gauge needle. The 24-gauge tube served as a support tube to prevent the flexible cannula from twisting during deployment. The needle assembly was attached to the barrel assembly.

[0131] A flexible cannula was fabricated. The cannula shaft was composed of the proximal portion of a PEBAX polymer tube with an inner diameter of 0.30 mm, an outer diameter of 0.38 mm, and a length of 50 mm of a Shore 72D durometer. The proximal end of the proximal portion was attached to a 30-gauge smooth-ended Luer tube adapter. The distal end portion of a polyolefin polymer tube with an inner diameter of 0.12 mm, an outer diameter of 0.20 mm, and a length of 75 mm was adhesively bonded to the distal end of the proximal portion. A nickel-titanium (Nitinol) rigid wire with a diameter of 0.75 mm was inserted into the flexible cannula to provide pushability against the thin-walled distal cannula tube. The distal end of the cannula was shaped into a rounded non-invasive tip using a cyanoacrylate adhesive. The flexible cannula was inserted through a plunger and needle assembly and then fixed in place at the proximal end of the plunger shaft. When fully deployed, the flexible cannula extended 15 mm beyond the tip of the needle.

[0132] A safety mechanism was incorporated into the device to prevent premature activation of the plunger due to the plunger spring force. Two shallow grooves were made in the plunger at a distance of 19 mm from the tip, 180 degrees apart, and perpendicular to the axis of the plunger. The distance between the groove surfaces was 1.5 mm. The fixed clip was made from a brass sheet with a width of 6.3 mm and a length of 18 mm. A groove with a width of 1.6 mm and a length of 8.8 mm was machined into the fixed clip. The groove was cut at the center of the short side of the fixed clip and transversely across the long axis.

[0133] The formed cylindrical tissue contact and distal sealing element were made from 70 Shore A durometer silicone rubber. The distal element was 3.7 mm in length and 1.75 mm in diameter. The distal element had a lumen 2.7 mm in length and 0.38 mm in diameter. The distal end of the lumen of the distal element was configured in an angled shape that corresponded to the distal end of the needle. The distal sealing element was attached to the tip of the needle such that the needle bevel contacted the lumen bevel and sealed the tip of the needle. The non-angled portion of the lumen functioned as a seal slidable on the axis of the needle, imparting sufficient frictional force to the needle shaft to hold the tip against the ocular surface while the needle advanced through the 1 mm thick distal seal.

[0134] The plunger was retracted for use, thereby compressing the plunger spring and pulling out the flexible cannula until the plunger groove was exposed near the distal cap. A fixed clip was placed over the plunger such that the groove on the fixed clip engaged the groove on the plunger shaft. Next, the fixed clip was held against the proximal end surface of the distal cap by spring force, preventing movement of the plunger.

[0135] A 1 cc syringe was filled with 0.5 mL of 0.01% fluorescein solution. This syringe was attached to the female Luer fitting on the proximal end of the cannula. The porcine cadaver eye was prepared by inflating the posterior chamber to a pressure of approximately 20 mmHg. A target penetration position 4 mm posterior to the limbus was selected for insertion of the device needle for deployment of the flexible cannula. The fixation clip was removed from the plunger shaft. After placing the tissue contact and the end seal against the scleral surface, the needle tip was advanced through the end seal into the tissue while orienting the needle bevel towards the posterior part of the eye. When the needle lumen reached the suprachoroidal space, the cannula was able to freely exit the needle and was deployed by a push rod under the plunger spring force. When the plunger was considered to have actuated, 0.05 mL of fluorescein was injected into the suprachoroidal space through the flexible cannula. A radial incision was made over the position of the flexible cannula, exposing the suprachoroidal space through the sclera. When entering the cavity, leakage of the fluorescein solution from the cavity was observed, and upon further dissection, the axis of the flexible cannula in the suprachoroidal space could be directly visualized.

Example

[0136] 〔Insertion device with end seal for placement of flexible cannula in suprachoroidal space〕 An apparatus according to an embodiment of the present invention was fabricated. The apparatus comprised a cannula element, a needle with an end seal, a cannula support element, a force element and a housing body.

[0137] The cannula element was fabricated to consist of a flexible tubular portion at the distal end, a connecting tube, and a proximal Luer adapter, completing a flow path for the substance to be administered. The flexible tubular element at the distal end was made from a 72D durometer PEBAX tube with an inner diameter of 0.12 mm, an outer diameter of 0.18 mm, and a length of 75 mm. The proximal end of the flexible cannula was drawn through a polyimide support tube with an inner diameter of 0.18 mm, an outer diameter of 1.59 mm, and a length of 25 mm, extending the flexible cannula 20 mm proximally from the support tube. The support spring was made from a nickel-titanium alloy (nitinol) wire with a diameter of 0.1 mm. The support spring had a length of 25 mm and an inner diameter of 0.2 mm. The spring was wound with a pitch of 0.48 mm and had a closed end. The nitinol spring was shaped by applying hot air at 480 °C. The support spring was placed on the polyimide support tube. The support tube and the support spring prevented the flexible cannula from collapsing or twisting within the cannula support element. The proximal end of the flexible cannula was joined inside a polyether ether ketone (PEEK) tube with an inner diameter of 0.17 mm, an outer diameter of 1.59 mm, and a length of 10 mm, extending the flexible tube 10 mm proximally from the PEEK tube. The connecting tube made of polyethylene with an inner diameter of 0.28 mm, an outer diameter of 0.61 mm, and a length of 250 mm was placed over the exposed distal end of the flexible cannula and joined to the PEEK tube.

[0138] The needle was made from a 27-gauge thin-walled needle with a length of 32 mm. The needle was adhesively bonded within a polyethylene Luer hub, extending the beveled tip of the needle 3 mm from the distal end of the hub. The distal seal was made from a molded 50A durometer silicone elastomer with a length of 3 mm and an outer diameter of 0.75 mm. The proximal end consisted of a blind hole with a length of 2.1 mm and a diameter of 0.3 mm and a flat distal end. The distal seal was placed over the needle at the final stage of device assembly.

[0139] The cannula support element was fabricated from a distal tube, a connecting tube, and a proximal tube. The distal tube was fabricated from a PEEK tube with an inner diameter of 0.5 mm, an outer diameter of 1.59 mm, and a length of 30 mm. The proximal support element tube was fabricated from a stainless steel tube with an inner diameter of 1.32 mm, an outer diameter of 1.57 mm, and a length of 110 mm. The support element connecting tube was fabricated from an acetal (Delrin®, a registered trademark) tube with an inner diameter of 1.59 mm, an outer diameter of 3.2 mm, and a length of 25 mm. A hole with a diameter of 1.9 mm was drilled at 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 was placed over the flexible cannula and joined to the cannula PEEK tube to cover the portion including the support tube and the support spring. The proximal support tube was placed over the cannula connecting tube and adhesively bonded to the cannula PEEK tube. The support element connecting tube was placed over the distal tube, the cannula PEEK tube, and the proximal support tube junction point, thereby holding the assembly together.

[0140] The force element was fabricated from a spring support tube, a compression spring, and a proximal adjustable stopper. The force element spring support tube was fabricated from a stainless steel tube with an inner diameter of 1.6 mm, an outer diameter of 2 mm, and a length of 140 mm. The compression spring was fabricated from a stainless steel spring temper wire with a diameter of 0.26 mm. The compression spring had a closed end, an inner diameter of 2.6 mm, a pitch of 1.4 mm, and a length of 100 mm. The adjustable stopper was fabricated from a 10-32 nylon tapped screw with a length of 38 mm and a hole with a diameter of 2.2 mm drilled through the shaft. The spring support tube was placed over the polyethylene cannula connecting tube and press-fitted into the proximal end of the Delrin® cannula support element connecting tube, thereby completing the partial assembly consisting of the cannula element, the cannula support element, and the spring support tube.

[0141] The housing body was assembled from a distal body and a proximal body made from a modified polycarbonate 1 mL syringe body. The distal body was modified by cutting off the finger flange, drilling the proximal end, and creating a 5 / 16 - 18 thread and a hole with a depth of 8 mm. A syringe tip Luer lock connector was retained. The proximal body was modified by cutting off the finger flange, drilling the proximal end, and creating a 10 - 32 thread and a hole with a depth of 19 mm. The distal end of the proximal body was machined and had a 5 / 16 - 18 thread with a length of 7.6 mm. In this way, the distal body and the proximal body were attached via the 5 / 16 - 18 thread portion for assembly of the device.

[0142] The device was assembled by placing a sub - assembly of a cannula element, a cannula support element, and a force element spring support tube in the distal housing. The compression spring was placed on the spring support tube, and the proximal housing was attached to the distal housing. The distal end of the flexible cannula was inserted into the needle lumen, and the needle and the needle Luer hub were attached to the distal housing Luer connector. The proximal end of the needle was slidably disposed within the distal PEEK tube of the cannula support element. The proximal end of the needle was in contact with the cannula support spring. The force element adjustable stopper was placed on the cannula connecting tube and attached to the proximal end of the proximal housing. A 30 - gauge Luer needle adapter was inserted into the proximal end of the cannula connecting tube to enable connection of a syringe for delivery of the substance to be administered.

[0143] With the mechanism in the deployed configuration, the flexible cannula was configured to extend 12 mm from the tip of the needle. An adjustable stopper was threaded into the assembly so that the force element compression spring had sufficient force to overcome the compression of the cannula support spring and allow deployment of the cannula when the device was actuated. The proximal end of the force element support rod protruded from the proximal end of the adjustable stopper. A silicone O-ring that fit snugly on the force element support rod was temporarily placed on the support rod. The distal seal was placed on the needle tip, but the O-ring was used to hold the mechanism in the stored configuration. The O-ring was removed, thereby setting the device to the deployable state.

[0144] A 0.25 mL syringe was filled with 100 microliters of 0.1% fluorescein solution and attached to the proximal luer fitting of the device. Porcine cadaver eyes were prepared by inflating them 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 bent approximately 30 degrees from the surface of the eye with the needle bevel facing posteriorly. The device was advanced so that the needle tip penetrated the distal seal and entered the scleral tissue. When the needle tip reached the suprachoroidal space, the flexible cannula advanced under the force of the force element compression spring. After deployment, the fluorescein solution was injected through the device. The device was withdrawn and placed horizontally. An incision in the sclera was created from the needle penetration area and extended posteriorly towards the target area at the distal end of the deployed cannula. When the incision was made, fluorescein solution was seen in the suprachoroidal space.

Example

[0145] 〔Low-sealing-force tissue contact〕 Tissue contacts were fabricated in a manner similar to the method described in Example 5. Two tissue contacts with outer diameters different from 1.75 mm and 2.50 mm in diameter were fabricated. Samples of tissue contacts of each diameter were fabricated using four different durometer liquid silicone elastomers of Shore 10A, 30A, 50A, and 70A.

[0146] A test procedure for measuring the sealing force of various tissue contact samples was prepared. A portion of an 8.3 mm long PEEK tube was attached onto a 27-gauge × 13 mm thin-walled hypodermic needle that served as a stopper to prevent the tissue seal from moving proximally during the test. Next, the tissue seal to be tested was attached onto the needle tip. The length of the PEEK tube was such that approximately half of the beveled portion of the needle protruded through the end face of the tissue contact. The test surface used was composed of a Shore 50A durometer and a 3.2 mm thick silicone elastomer pad. The needle was attached to a T-shaped connector. Next, this connector was attached to the shaft of a 250 N digital force gauge mounted on an electric test stand. The side legs of the T-shaped connector were attached to a long tube, which was then attached to a luer fitting and a three-way valve. A 10 cc syringe filled with water was attached to the valve. The syringe was held vertically using a ring stand. The test was carried out using two different constant pressures, which were generated by applying fixed weights of 1030 grams and 1656 grams respectively to the finger flange of the syringe plunger. The interior of the syringe had a cross-sectional area of 1.64×10 -4 m 2 which corresponded to flow pressures of 6.18×10 4 Pa and 9.93×10 4 Pa respectively.

[0147] To conduct the test, the needle tip was moved downward until the tissue contact point almost touched the silicone test pad. The test bench motor was slowly moved downward until a pressure of about 30 grams was applied to the tissue contact point. When the three-way valve was opened, water leakage was observed on the surface of the tissue contact point. When the valve was closed, the needle moved downward until a pressure of about 35 grams was applied. When the valve was opened, leakage was observed at the tissue contact point. The tissue contact pressure on the test pad was increased in 5-gram pressure increments until leakage was no longer observed, for example, until sealing was achieved and the force was recorded. The test was repeated using a second syringe pressure weight. The test was conducted on tissue contact points of two different diameters and 4 different durometers (Table 1 and Figure 15). Each of the two samples of each tissue contact point was tested 3 times, and a total of 6 data points were obtained for each test condition. The silicone test pad was moved after each test so that each needle penetration was performed at a new site.

[0148] Table 1: Minimum sealing force (mean and standard deviation) in gram force for tissue contact test samples. Classified by tissue contact diameter and flow pressure as a function of durometer.

[0149]

Table 1

Example

[0150] 〔Semisolid drug composition〕 A semisolid drug composition was prepared. Polyethylene oxide (PolyOx®, WSR-303) with an average molecular weight of 7 million daltons was dispersed in deionized water at 1.5% by weight. Dexamethasone crystals with an average diameter of about 2 microns were mixed in the polyethylene oxide dispersion at a concentration of 8% by weight. The semisolid composition was opaque due to the dispersed dexamethasone crystals.

[0151] The cannulation device described in Example 7 was manufactured for injecting a semi-solid composition into the suprachoroidal space of the eye. The cannula was configured with a deployment length of 10 mm. Prior to use, the distal 3 - 5 mm of the cannula was coated with a lubricating polymer composition containing 50 wt% polyethylene glycol with a molecular weight (MW) of 100,000 daltons and 50 wt% polyethylene glycol with a molecular weight of 20,000 daltons.

[0152] The excised porcine eye was prepared by injecting it to 17 mmHg. The tip of the cannulation device was placed over the pars plana region of the eye and advanced into the eye with the bevel facing posteriorly. When the tip of the needle reached an appropriate depth for approaching the suprachoroidal space, self-actuated deployment of the cannula was observed to occur. Approximately 100 microliters of the semi-solid drug composition was administered to the proximal end of the cannula through the female Luer lock connector. After administration, a scleral incision was made posteriorly to the cannula from the needle penetration site to a region 10 mm from the needle penetration site. When the suprachoroidal space was incised, the semi-solid composition was seen in the posterior part of the suprachoroidal space. No perforation into the vitreous cavity was observed.

Example

[0153] 〔Sustained-release microparticles of corticosteroid〕 The microparticles containing the active ingredient were manufactured to provide controlled sustained-release of the ingredient after administration. A biodegradable polymer was used to manufacture the microparticles and encapsulate the active ingredient. The polymer includes poly(lactic-co-glycolic acid) (PLGA) having various molecular weights represented by various lactic acid - glycolic acid (L - G) ratios and intrinsic viscosities and having ester end groups. Table 2 shows the polymers used for microparticle manufacture.

[0154] Table 2: Microparticle biodegradable polymers

[0155]

Table 2

[0156] The polymer was dispersed in a mixed organic solvent containing solvents for the polymer such as dichloromethane (DCM), chloroform, ethyl acetate, and isopropyl acetate, and mixed with a solvent such as tetrahydrofuran (THF) or methanol (MeOH) to assist in solubilizing the active ingredient. In some productions, multiple solvents were used to assist in solubilizing the active ingredient. The polymer was dispersed at a solids concentration of about 3.2 - 4.3 wt%, and the polymer in the solvent system was mixed for about 4 - 24 hours until it was well dispersed. Dexamethasone acetate was added to the dispersion as the active ingredient at a concentration of about 20 - 50 wt% of the total solids (polymer and drug).

[0157] The polymer and drug dispersion was emulsified in an aqueous dispersion of polyvinyl alcohol at a concentration of about 2.5 - 6 wt%, where the dispersion formed the discontinuous phase of the emulsion. The emulsification was carried out at 25 °C. After mixing for about 8 - 30 hours to form and harden the microparticles, the resulting microparticle suspension was recovered by filtration. The microparticles were washed and suspended in water with 0.01 - 0.05 wt% of polysorbate 20 to prevent aggregation. The suspension was centrifuged at 2,500 rpm to collect the microparticles. It was washed repeatedly to remove the remaining polyvinyl alcohol. The collected microparticles were suspended in water, frozen, and further lyophilized to produce a dry, free-flowing powder.

[0158] Microscopic observation of the microparticle powder sample showed an aggregation of spherical microparticles. The microparticle sample was suspended in a 0.1 wt% aqueous solution of the polysorbate 20 surfactant and analyzed with a Coulter (registered trademark) LS200 laser diffraction particle size analyzer. The resulting particle size distribution showed that the volume average particle size range was about 3.9 - 14.3 microns and the coefficient of variation was about 10.4% - 19.2%. By repeating the production of the microparticles and varying the polymer, polymer solids concentration, solvent conditions, and emulsification conditions, the ability to control the average particle size to about 3 microns - 14 microns was demonstrated.

[0159] A sample of the microparticles containing dexamethasone acetate was dissolved in acetonitrile to extract the active ingredient from the microparticles. The acetonitrile extract was filtered through a 0.2 micron filter and analyzed using reverse-phase high performance liquid chromatography (RP-HPLC). The peak obtained for dexamethasone acetate was used to calculate the concentration of the active ingredient in the extract based on the response coefficient obtained from the analysis of the dexamethasone acetate standard solution. The active ingredient content of the microparticles was determined from the concentration of the active ingredient relative to the amount of microparticles extracted. It was found that the active ingredient content of the microparticles was controlled by adjusting the concentration of the active ingredient in the polymer dispersion. It was possible to produce microparticles having an active ingredient content in the range of 16.1 to 42% by weight. The resulting microparticles had different average particle sizes and active ingredient contents and were used to provide a family of microparticle formulations. Table 3 shows the manufacturing conditions of the active ingredient-containing microparticles and the resulting volume average particle size and active ingredient content.

[0160] Table 3: Production of Drug-Containing Microparticles

[0161]

Table 3

[0162] In the polarized light microscopic observation of the dry microparticle powder, no significant amount of free crystals of the active ingredient was shown. Differential scanning calorimetry was performed on a sample of the dry microparticle powder. A temperature profile at a rate of 10 to 15 degrees per minute was executed to characterize the microparticles. A heat transition due to the polymer was observed in the range of 50 to 60 °C. An exothermic peak due to the recrystallization of the active ingredient was observed in the range of 143 to 163 °C. An endothermic peak due to the melting of the active ingredient was observed in the range of 203 to 221 °C. The enthalpy of active ingredient recrystallization was calculated to be in the range of about 88.5% to 94.0% of the enthalpy of active ingredient melting, indicating that the active ingredient was mainly in the form of an amorphous solid dispersion in the polymer.

[0163] Weighed samples from the manufactured microparticles were placed in vials containing physiological buffer at an active ingredient concentration of 0.1 microgram per milliliter. The vials were placed in an incubator at 37 °C on a rotating platform at 200 rpm to promote mixing. Samples of the buffer were periodically taken out and the active ingredient concentration was measured by RP-HPLC. The obtained data were used to determine the active ingredient (drug) dissolution profile of the microparticles and to determine the release rate of each microparticle formulation. The dissolution data were fitted to the Korsmeyer-Peppas model equation for drug release. Dissolution tests were performed on various microparticle formulations having different average particle sizes, active ingredient fillings, and polymers. Figure 16 shows the dissolution profiles of PLGA microparticles having an L-G ratio different from the modeled data. The microparticles showed faster release when the L-G ratio of the polymer in the microparticle formulation was decreased. Figure 17 shows the dissolution profiles of PLGA microparticles having a 75:25 L-G ratio and different average diameters from the data. The microparticles showed faster release when the average diameter of the microparticles was decreased. Figure 18 shows the dissolution profiles of PLGA microparticles having an 85:15 L-G ratio and different average diameters from the data. The microparticles showed faster release when the average diameter of the microparticles was decreased. Although the actual release in vivo may be different from the laboratory characteristics of drug dissolution, the modeled data showed drug half-lives in the range of 5 weeks to 80 weeks, demonstrating a wide range of release profiles that can be designed for the microparticles.

Example

[0164] 〔Semisolid drug composition using microparticles containing an active ingredient〕 Various semi-solid formulations for an injectable substance containing the microparticles of Example 10 were produced. The formulations were designed to enable lyophilization and to facilitate rapid reconstitution with sterile water for stability and administration. Mannitol at a concentration of 1 wt% to 10 wt%, trehalose at a concentration of 1 wt% to 3 wt%, and sodium hyaluronate (HA) at a concentration of 0.3 to 1.0 wt% that function as an excipient mixture for the microparticles were dissolved in 10 to 25 millimolar sodium phosphate buffer. In one formulation, the mannitol concentration was 4 wt%, the trehalose concentration was 1 wt%, and the sodium hyaluronate concentration was 0.75 wt%, and two different molecular weights of sodium hyaluronate were used. Sodium phosphate was prepared in deionized water using monobasic sodium phosphate and dibasic sodium phosphate in a ratio such that the final pH was 7.4. The excipient mixture was filter sterilized by passing through a 0.2 micron sterile filter. Also, the excipient formulation was characterized by the viscosity of a Brookfield viscometer, showing a zero shear viscosity of 726 mPas for the formulation using hyaluronic acid with a molecular weight of 700K and 1,585 mPas for the formulation using hyaluronic acid with a molecular weight of 1.5M.

[0165] PLGA microparticles encapsulating dexamethasone acetate were mixed with the excipient mixture in the range of 50 mg / mL to 150 mg / mL after being sterilized by ionizing radiation. Formulations with good suspension stability were produced at a microparticle concentration of 62 mg / mL to 125 mg / mL.

[0166] The microparticle suspension was mixed and created in the excipient mixture using a tip-to-tip syringe mixing technique. The final mixed formulation was filled into vials and frozen at -70 °C for at least 30 minutes. The frozen vials were placed in a lyophilizer and lyophilized until dry.

[0167] For administration, the lyophilized formulation was reconstituted to a microparticle concentration of 125 mg / mL by adding sterile water for injection. The reconstituted formulation was tested with a cryoscopic osmometer and shown to have an osmotic pressure in the range of 300 - 850 mOsM. Table 4 shows the formulations that were manufactured and characterized. All formulations showed appropriate suspension stability prior to lyophilization to enable freezing and lyophilization. All formulations were shown to be reconstituted into a uniform semi-solid for administration.

[0168] Table 4: Semi-Solid Microparticle Formulations

[0169]

Table 4

[0170] The reconstituted formulation was injected using the apparatus of Example 1, which showed good injectability and visual homogeneity for the injected substance. Also, the injectable formulation could be injected through a 31-gauge needle 0.5 inches in length using a 1 mL syringe. All injectable substance formulations in Table 4 showed good suspension stability and had the ability to be injected for at least 30 minutes without additional mixing after reconstitution.

Example

[0171] 〔Soft-Tip Cannula for Insertion into Narrow Tissue Spaces〕 To compare the deflection and penetration characteristics of soft tips of various lengths, a test was conducted in which soft tips of different lengths on the cannula of Example 5 were advanced toward a tissue model (7 wt% hi-bloom gelatin) at various angles. Soft tips with lengths of 0.85 mm, 1.5 mm, 2.0 mm, 2.5 mm, and 3 mm, manufactured from 80A durometer polyurethane tubing, were tested on the distal end of a 55D durometer polyurethane cannula. The distal ends of the soft tips were polished to minimize sharp edges. The cannula was advanced toward the gel surface at a speed of 270 mm / min. The catheter was advanced through a 27-gauge extra-thin-wall needle while positioning the distal edge of the needle bevel to touch the gelatin surface or while inserting it into the gelatin at various degrees. The beveled opening of the needle was covered with a 50 Shore A silicone elastomer sheet to mimic a strong membrane. The catheter was advanced 4.5 mm, and the deflection from the gelatin surface or penetration into the gel was visually observed. The tests were conducted at needle bevel angles of 90 degrees (perpendicular), 45 degrees, and 60 degrees with respect to the surface of the gel. The results of the tests showed that a soft tip length of 0.85 mm had insufficient deflection, with the minimum tightness at which the injection needle contacted the gelatin surface, and penetrated the gelatin at an angle of 45 degrees. The cannula with a 1.5-mm soft tip deflected at an angle of 45 degrees from the surface where the needle contacted the gelatin. The cannula with a 2.0-mm soft tip deflected at an angle of 90 degrees from the surface where the needle contacted the gel, and deflected from the surface where there was a buried or deeply buried needle at a needle angle of 45 degrees. The cannula with a 2.5-mm soft tip deflected at all angles, together with the needle contacting the gelatin surface and with the needle buried or deeply buried in the gelatin at 45 degrees. The cannula with a 3.0-mm soft tip deflected away from the gelatin under all conditions and angles. The test results show the deflection characteristics of soft tip cannulas with soft tip lengths exceeding 0.85 mm, and very good deflection characteristics for soft tip lengths of at least 1.5 mm.

Example

[0172] 〔Insertion into a living pig eye by an intubation device〕 The device manufactured in Example 5 was tested in a porcine animal model. Before use, the distal tip of the cannula was coated with a silicone fluid lubricant for the distal 3 - 5 mm that acts as a lubricant. The animal was anesthetized and placed on its side. A sterile drape was placed over the eye and fenestrated. A speculum was placed to keep the eyelids open. A 5 - 0 Vicryl (registered trademark) suture was placed at the limbus at the selected clock - hour injection site to provide traction. This procedure was performed under direct visual observation using a surgical loupe used by the observer without using a microscope. The test device was attached 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 light intensity meter (PM100D with S140C / S120 - FC sensor), and it was shown that the light output range was 165 - 700 mW.

[0173] The cannula approached the ocular surface at a 45 - degree angle, and the needle tip was inserted into the eye in the pars plana region. When the illuminated cannula provided a "headlight" through the needle, directly illuminating the tissue surface in front of the needle, the needle advanced through the tissue until the headlight disappeared, giving a visual indication that the needle bevel was in the scleral tissue. After the trigger button of the device was activated, the device advanced slowly and steadily until the cannula automatically deployed. Observation of the illumination across the sclera from the cannula shaft and tip was performed to determine the position of the cannula and the placement of the cannula in situ.

[0174] The device was tested at 28 sites in the eye, and 27 cannulas observed through the overlying sclera and conjunctiva were found to be located in the suprachoroidal space, as illumination lines starting near the needle insertion site in the anterior part of the suprachoroidal or supra-ciliary space and, in the suprachoroidal space, as illumination lines extending posteriorly to a glowing tip. Illumination from the cannula axis clarified that the cannula was directed posteriorly from the needle insertion site. Tests were conducted to intentionally place the cannula in the vitreous cavity. As a result, there was no visible illumination through the sclera, but light was visible through the pupil aperture, indicating that the device was not placed in the suprachoroidal or supra-ciliary space but instead in the intraocular space.

[0175] The device was manufactured using a 0.25 mL syringe filled with the semi-solid microparticle formulation of Example 10 (25 mM sodium phosphate, 4 wt% mannitol, 1 wt% trehalose, 0.75 wt% high molecular weight sodium hyaluronate). The needle of the device was inserted into the sclera, and after the cannula was deployed into the suprachoroidal space observed by illumination across the sclera, 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 the injected substance was observed at the needle injection site during removal of the cannula. As a result of performing indirect ophthalmoscopy, no injected substance was observed in the vitreous, indicating successful administration of the injected substance into the suprachoroidal space.

Example

[0176] 〔Pharmacokinetics of a Semi-Solid Drug Composition Using Drug-Releasing Microparticles〕 The microparticle preparation with an average diameter of 9.7 microns and loaded with 35% by weight of dexamethasone acetate drug was produced from a PLGA polymer with a 75:25 L-G fixed ratio and an intrinsic viscosity of 0.75 dL / g as described in Example 10. The microparticles were produced to have a concentration of 70 mg / mL in the injection substance preparation of Example 11. A second microparticle preparation with an average diameter of 9.7 microns and loaded with 35% by weight of dexamethasone acetate drug was produced from a PLGA polymer with an 85:15 L-G fixed ratio and an intrinsic viscosity of 0.78 dL / g as described in Example 10. The microparticles were produced to have a concentration of 70 mg / mL in the Example 11 injection substance preparation.

[0177] Two injectable substance formulations were the test articles, and these were administered into the suprachoroidal space of rabbits (New Zealand White) to determine the ophthalmic pharmacokinetic characteristics of the formulations. The animals were anesthetized and placed on their sides, with their heads covered over the eye openings. An eyelid speculum was placed on the eyes. The test article was rotated and withdrawn into a syringe calibrated in microliters. The site of the eye between the rectus muscles was used for introduction of the cannula portion of the cannula of Example 12 attached to a female Luer connector. A 5-0 Vicryl control suture was placed near the site to prevent excessive movement of the eye. An optical fiber was fabricated on a male Luer adapter to fit within the female Luer connector. When the Luer adapters were connected together, the distal end of the optical fiber contacted the proximal end of the cannula, providing an optical path from the light source to the cannula. The proximal end of the optical fiber was terminated with an optical connector attached to the light source of Example 12. The conjunctiva and underlying sclera were cut at the pars plana by a 2-3 mm radial incision to expose the suprachoroidal space and underlying choroid. The illuminated cannula was placed in the incision and the cannula was directed 4-5 mm posteriorly. Placement of the cannula in the suprachoroidal space was confirmed by the position of the illumination across the sclera. The optical fiber was disconnected from the cannula female Luer connector and removed from the cannula and syringe containing the injectable substance. The incision was sutured around the cannula using horizontal mattress sutures to stabilize the site. The injectable substance was administered through the cannula by depressing the syringe plunger, delivering 40 microliters of the injectable substance into the suprachoroidal space. The cannula was removed and the conjunctiva was returned to its normal position. Ophthalmoscopic examination of the eye was performed and it was confirmed that the drug test article had not been injected into the vitreous. The control suture and the speculum were removed, the eye was irrigated, and an antibiotic ointment was applied according to the regulatory guidelines. Each test article was administered to 6 eyes.

[0178] The eyes were harvested at 7, 14, 30, 60, 90 and 120 days after administration of each test article. The eyes were dissected to separate the choroid, retina and vitreous tissues. The drug concentration in the said tissues was quantified by LC-MS. The test results showed the concentration of dexamethasone acetate and the concentration of dexamethasone formed from the hydrolysis of dexamethasone acetate in vivo. The total of both forms of dexamethasone during the test period is shown in the pharmacokinetic profile charts of Figures 19, 20 and 21. Figure 19 shows the drug concentration in the vitreous tissue by administration of both test articles. Both test articles showed that due to suprachoroidal cavity administration and the slow sustained release characteristics of the test article formulation, the total drug concentration in the vitreous was low. Figure 20 shows the drug concentration in the choroid tissue resulting from the administration of both test articles. Figure 21 shows the drug concentration in the retina tissue resulting from the administration of both test articles. The 85:15 PLGA microparticle formulation showed a high sustained release level of total dexamethasone in both the retina and choroid over 120 days. The 75:25 PLGA microparticle formulation showed that total dexamethasone was at a high level in both the retina and choroid over 60 days, and the tissue drug concentration decreased significantly at 90 and 120 days.

[0179] The technical idea that can be grasped from the above embodiments is described below as an appended note. [Appended Note 1] An intubation device for administering an active ingredient-containing composition to the eye, An elongated body having a hollow needle at its distal end; A cannula comprising an elongated tubular element having a non-invasive tip, wherein the elongated tubular element is configured to transmit light from a proximal portion of the elongated tubular element to the tip of the elongated tubular element, and at least a part of the tubular element is a cannula contained in the needle lumen before deployment; A mechanism for advancing the elongated tubular element through the needle; A mechanical connection element from the said mechanism for advancing the elongated tubular element into the tubular element; and, A connector or injection port communicating with the proximal end of the tubular element for delivering the active ingredient-containing composition; comprising, The mechanism for advancing the elongated tubular element operates simultaneously with, or after, the placement of the needle tip into the eye; and, The mechanism for advancing the elongated tubular element functions to extend the tubular element out of the distal end of the needle and advance it into the suprachoroidal space or supra-ciliary body space; Device.

[0180] [Appendix 2] An intubation device for administering an active ingredient-containing composition to the eye, comprising: An elongated body having a hollow needle at its distal end; A cannula comprising an elongated tubular element having a non-invasive tip, the elongated tubular element being configured to transmit light from a proximal portion of the elongated tubular element to the tip of the elongated tubular element, at least a portion of the tubular element being contained within the needle lumen prior to deployment; A mechanism for advancing the elongated tubular element through the needle; A mechanical connection element from the mechanism for advancing the elongated tubular element to the tubular element; and, A container for containing an active ingredient-containing composition for administration, communicating with the proximal end of the tubular element; Comprising: The mechanism for advancing the elongated tubular element operates simultaneously with, or after, the placement of the needle tip into the eye; and, The mechanism for advancing the elongated tubular element functions to extend the tubular element out of the distal end of the needle and advance it into the suprachoroidal space or supra-ciliary body space; Device.

[0181] [Appendix 3] An intubation device for administering an active ingredient-containing composition to the eye, comprising: An elongated body having a hollow needle at its distal end; A cannula comprising an elongated tubular element having a non-invasive tip, the elongated tubular element being configured to transmit light from a proximal portion of the elongated tubular element to the tip of the elongated tubular element, at least a portion of the tubular element being contained within the needle lumen prior to deployment; A mechanism for advancing the elongated tubular element through the needle; A mechanical connection element from said mechanism for advancing said elongate tubular element into said tubular element; A distal element having a distal seal attached to the distal end of said device, said distal element sealing or occluding said needle lumen from the advancement of said tubular element exiting said needle; and, A connector or injection port in communication with the proximal end of said tubular element for delivering an active ingredient-containing composition; comprising The mechanism for advancing said elongate tubular element operates simultaneously with, or prior to, the placement of the needle tip into the eye; Said distal seal functions as a tissue contact and is penetrated by said needle tip by applying pressure to the eye surface at the distal end of said device; Said penetrated distal element is slidable over said needle, enabling the advancement of said needle into tissue; Said penetrated distal seal opens the advancement path of said tubular element from the distal end of said needle; and, The mechanism for advancing said elongate tubular element functions to advance said tubular element from the distal end of said needle into the suprachoroidal space or supra-ciliary body space; A device.

[0182] [Appendix 4] An intubation device for administering an active ingredient-containing composition to the eye, An elongate body having a hollow needle at the distal end; A cannula comprising an elongate tubular element having a non-invasive tip, said elongate tubular element being configured to transmit light from the proximal portion of said elongate tubular element to the tip of said elongate tubular element, at least a portion of said tubular element being contained within the needle lumen prior to deployment; A mechanism for advancing said elongate tubular element through the needle; A mechanical connection element from said mechanism for advancing said elongate tubular element into said tubular element; A distal element having a distal seal attached to the distal end of said device, said distal element sealing or occluding said needle lumen from the advancement of said tubular element exiting said needle; and, A container for containing a composition containing an active ingredient for administration, which communicates with the proximal end of the tubular element; comprising a mechanism for advancing the elongated tubular element operates simultaneously with, or prior to, the placement of the needle tip into the eye; the end seal functions as a tissue contact and is penetrated by the needle tip by applying pressure to the eye surface at the distal end of the device; the penetrated distal element is slidable over the needle, enabling the needle to advance into the tissue; the penetrated end seal opens the advancing path of the tubular element from the distal end of the needle; and the mechanism for advancing the elongated tubular element functions to advance the tubular element from the distal end of the needle into the suprachoroidal space or the supra-ciliary body cavity; a device.

[0183] [Appendix 5] The device according to any one of Appendices 1 to 4, wherein the elongated tubular element is configured to transmit light by incorporating an optical fiber into the tubular element.

[0184] [Appendix 6] The device according to any one of Appendices 1 to 4, wherein the elongated tubular element is configured to transmit light along the wall of the elongated tubular element.

[0185] [Appendix 7] The device according to any one of Appendices 1 to 6, wherein the elongated tubular element has a curved shape in an unconstrained state and returns to the curved shape when deployed from the distal end of the needle.

[0186] [Appendix 8] The device according to any one of Appendices 1 to 7, wherein the mechanism for advancing the elongated tubular element is configured for manual advancement.

[0187] [Appendix 9] The device according to any one of appendices 1 to 7, wherein the mechanism for advancing the elongated tubular element comprises a force element that provides a deployment force for advancing the tubular element through the needle lumen.

[0188] [Appendix 10] The device according to appendix 3 or 4, wherein the end seal comprises a deformable protrusion that extends into the lumen at the distal end of the needle or extends from the distal end into the end protrusion of the lumen to prevent deployment of the tubular element under the deployment force.

[0189] [Appendix 11] The device according to appendix 3 or 4, further comprising a foldable element between the body of the device and the end element, the foldable element being configured to prevent distal movement of the end element.

[0190] [Appendix 12] The device according to appendix 11, wherein the foldable element comprises an elongated strut. [Appendix 13] The device according to appendix 11, wherein the foldable element comprises nitinol or polyimide.

[0191] [Appendix 14] The device according to any one of appendices 11 to 13, wherein the foldable element is configured to apply a forward force to the end element while the tip of the needle penetrates the end seal.

[0192] [Appendix 15] The device according to appendix 14, wherein the forward force is in the range of 40 to 82 grams of force. [Appendix 16] The device according to appendix 14, wherein the foldable element is configured to apply a constant force after an initial force, the initial force being applied during the first 0.5 mm of proximal movement of the end element along the needle.

[0193] [Appendix 17] The device according to appendix 3 or 4, wherein the end seal functions as a tissue contact, and the end seal comprises an elastomer having a Shore A hardness of 10 to 30.

[0194] [Appendix 18] The device according to appendix 3 or 4, wherein the end seal is attached to a tubular end housing. [Appendix 19] The device according to appendix 9, wherein the force element for applying a deployment force to advance the tubular element is a spring mechanically connected to a plunger.

[0195] [Appendix 20] The device according to appendix 9, wherein the force element is pressurized gas. [Appendix 21] Furthermore, the device according to appendix 19 or 20, comprising a braking mechanism or a friction element for limiting the deployment speed of the cannula.

[0196] [Appendix 22] The cannulation device according to any one of appendices 19 to 21, wherein the deployment force is actuated by a mechanism that compresses a force element from outside the device.

[0197] [Appendix 23] The cannulation device according to any one of appendices 19 to 21, wherein the force element is restrained before use, and the deployment force is actuated by mechanically releasing the restrained force element.

[0198] [Appendix 24] The device according to any one of appendices 1 to 23, wherein the needle has a curved tip for directing the tubular element obliquely from the long axis of the needle.

[0199] [Appendix 25] The device according to any one of appendices 1 to 24, wherein the needle comprises an internal deflection element within the lumen of the needle at a needle bevel angle for directing the tubular element obliquely from the long axis of the needle.

[0200] [Appendix 26] An intubation device according to any one of Appendices 1 to 25 for delivering an active ingredient-containing composition having an effective needle total length of 1 to 5 mm to the suprachoroidal space or the supra-ciliary body cavity.

[0201] [Appendix 27] An intubation device according to any one of Appendices 1 to 26 for delivering an active ingredient-containing composition having an effective needle total length of 5 to 15 mm to the vitreous cavity.

[0202] [Appendix 28] An intubation device according to any one of Appendices 1 to 27 for delivering an active ingredient-containing composition having an effective needle total length of 0.35 to 2 mm to the subconjunctival space or the sub-Tenon's space.

[0203] [Appendix 29] Furthermore, the device according to Appendix 2 or 4, wherein the container contains an administration substance, and the administration substance is a liquid or a semi-solid.

[0204] [Appendix 30] An elongate body having a hollow needle at its distal end; An elongate tubular element having a lumen, which is deployed through the needle; A path for the movement of a liquid or semi-solid substance from the elongate body to the proximal lumen of the tubular element; and, A mechanism for advancing the elongate tubular element through the needle; Comprising The tubular element is configured to transmit light from a proximal portion of the tubular element to the tip of the tubular element; Intubation device.

[0205] [Appendix 31] Furthermore, the intubation device according to Appendix 30, comprising a force element configured to apply a forward deployment force to the tubular element to advance the tubular element through the needle lumen, and an actuator for actuating the force element.

[0206] [Appendix 32] The apparatus according to appendix 30 or 31, wherein the tubular element is configured to transmit light along the wall of the tubular element.

[0207] [Appendix 33] The apparatus according to appendix 32, wherein the tubular element comprises a polymer and a low refractive index coating.

[0208] [Appendix 34] The apparatus according to any one of appendices 30 to 33, wherein the needle has a curved tip for directing the tubular element obliquely from the long axis of the needle towards the posterior region of the eye.

[0209] [Appendix 35] The apparatus according to any one of appendices 30 to 34, wherein the needle comprises an internal deflection element in the lumen of the needle at a needle bevel angle for directing the tubular element obliquely from the long axis of the needle towards the posterior region of the eye.

[0210] [Appendix 36] The apparatus according to any one of appendices 30 to 35, wherein the tip of the cannula comprises a material having a greater flexibility than the proximal portion of the cannula.

[0211] [Appendix 37] The apparatus according to appendix 36, wherein the tip of the cannula comprises a material having a greater flexibility and a length of at least 1 mm.

[0212] [Appendix 38] The apparatus according to any one of appendices 30 to 37, wherein the tubular element has a curved shape in an unconstrained state and returns to the curved shape when deployed from the distal end of the needle.

[0213] [Appendix 39] The apparatus according to any one of appendices 30 to 38, further comprising a connector or port provided in the elongated body for providing a path for the movement of a liquid or semi-solid substance into the proximal lumen of the tubular element.

[0214] [Appendix 40] Furthermore, the device according to any one of Appendices 30 to 39, comprising a container for an active ingredient-containing substance within the elongated body and a path for the transfer of the active ingredient-containing substance from the container to the proximal lumen of the tubular element.

[0215] [Appendix 41] The device according to any one of Appendices 1 to 40, wherein light transmitted from the proximal portion of the tubular element provides illumination at the tip of the tubular element.

[0216] [Appendix 42] A method for treating a disease or condition by delivering a liquid or semi-solid substance to an affected area, comprising: placing the distal end of an intubation device according to any one of Appendices 1 to 41 on the surface of the affected area and advancing the needle of the device into the affected area; advancing the tubular element while providing illumination to the proximal end of the tubular element to illuminate the tip of the tubular element; advancing the tip of the tubular element into the affected area; and delivering a substance for administration into the space. A method comprising the above.

[0217] [Appendix 43] The method according to Appendix 42, wherein the disease or condition is inflammation or infection. [Appendix 44] The method according to Appendix 43, wherein the inflammation is selected from the group consisting of rhinosinusitis, osteoarthritis, rheumatoid arthritis, arthritis, rhinitis, and postoperative inflammation, and combinations thereof.

[0218] [Appendix 45] The method according to Appendix 42, wherein the disease or condition is an eye disease or condition. [Appendix 46] The method according to Appendix 45, wherein the eye disease or condition is selected from the group consisting of blepharitis, allergic conjunctivitis, macular degeneration, retinal degeneration, angiogenesis, proliferative vitreoretinopathy, glaucoma, eye tumors, uveitis, and edema, and combinations thereof.

[0219] [Appendix 47] A method for treating an eye disease or condition by delivering a liquid or semi-solid substance to the suprachoroidal space or the supra-ciliary body cavity of the eye, placing the distal end of the cannulation device according to any one of Appendices 1 to 41 on the eye surface and advancing the needle of the device into the eye; while illuminating the proximal end of the tubular element to illuminate the tip of the tubular element, advancing the tubular element; advancing the tip of the tubular element into the suprachoroidal space or the supra-ciliary body cavity; and, delivering the substance to the cavity; A method comprising the above.

[0220] [Appendix 48] A method for treating an eye disease or condition by injecting a solid or semi-solid substance into the suprachoroidal space or the supra-ciliary body cavity, filling the container of the cannulation device according to Appendix 2 or 4 with the substance; placing the distal end of the device on the eye surface and advancing the needle of the device into the eye; advancing the cannula; and, delivering the substance to the cavity; A method comprising the above.

[0221] [Appendix 49] A method for injecting a substance into the suprachoroidal space or the supra-ciliary body cavity using the device according to Appendix 3 or 4, wherein the cannula receives a deployment force from the force element before introduction into the tissue at the tip of the device; advancing the needle through the end seal opens the delivery path of the cannula from the tip, enabling one-handed use of the device without the need for actuation for injection by a valve or trigger on the body of the cannulation device; A method.

[0222] [Appendix 50] The method according to any one of Appendices 42 to 49, wherein the administration substance includes a steroid, a non-steroidal anti-inflammatory drug, an antibiotic, a VEGF inhibitor, an anti-TNFα agent, an mTOR inhibitor, a cell therapy agent, an antihypertensive drug, an antihistamine, an aminosteroid, a neuroprotective drug, or a therapeutic drug based on nucleic acid.

[0223] [Appendix 51] The method according to Appendix 50, wherein the steroid includes dexamethasone, dexamethasone acetate, fluocinolone, loteprednol, difluprednate, fluorometholone, prednisolone, medrysone, triamcinolone, betamethasone, rimexolone, beclomethasone dipropionate, budesonide, fluticasone dipropionate, mometasone furoate, or ciclesonide.

[0224] [Appendix 52] The method according to Appendix 50, wherein the non-steroidal anti-inflammatory drug includes bromfenac, diclofenac, flurbiprofen, ketorolac tromethamine, or nepafenac.

[0225] [Appendix 53] The method according to Appendix 50, wherein the antihistamine includes cetirizine, loratadine, fexofenadine hydrochloride, olopatadine, alcaftadine, epinastine, or ketotifen.

[0226] [Appendix 54] The method according to Appendix 50, wherein the anti-TNFα agent includes infliximab, etanercept, adalimumab, certolizumab, or golimumab.

[0227] [Appendix 55] The method according to Appendix 50, wherein the mTOR inhibitor includes sirolimus, everolimus, temsirolimus, or an mTOR kinase inhibitor.

[0228] [Appendix 56] The method according to Appendix 50, wherein the cell therapy agent includes mesenchymal cells or cells transfected with a gene to produce a therapeutic drug.

[0229] [Appendix 57] The neuroprotective agent is an antioxidant, a calcineurin inhibitor, a NOS inhibitor, a sigma-1 modifier, an AMPA antagonist, a calcium channel blocker, a DNA gyrase inhibitor, a DNA polymerase inhibitor, an RNA polymerase inhibitor, or a histone deacetylase inhibitor, and the method according to Appendix 50.

[0230] [Appendix 58] The therapeutic agent based on the nucleic acid is a gene vector, a gene editing therapeutic agent, a plasmid, a guide RNA, or an siRNA, and the method according to Appendix 50.

Claims

**Claim 1** An intubation device for administering an active ingredient-containing composition into the suprachoroidal cavity or the supra-ciliary body cavity of the eye, comprising: An elongate body having a proximal end and a distal end; A needle having a proximal end, a distal end and a lumen, wherein the proximal end of the needle is fixed to the distal end of the elongate body, and the distal end of the needle is chamfered or sharpened for penetrating the scleral tissue; A flexible cannula comprising an elongate tubular element having a proximal end, a distal end, a lumen, and a rounded non-invasive tip, and configured with a deployment length deployed through the needle; The distal portion of the elongate tubular element is housed within the lumen of the needle prior to deployment of the elongate tubular element; A path for transferring a liquid or semi-solid material from the elongate body to the proximal lumen of the elongate tubular element; and An auto-actuating deployment mechanism configured to deploy the elongate tubular element from the distal end of the needle into the suprachoroidal cavity or the supra-ciliary body cavity of the eye; the mechanism comprising: A force element configured to apply a deployment force for advancing the elongate tubular element through the lumen of the needle; A mechanical connection element from the force element to the elongate tubular element; A mechanism configured to pre-load the force element; and A trigger for releasing the pre-loaded force element before, simultaneously with, or after placing the distal end of the needle on the sclera of the eye; The elongate tubular element is configured to be illuminated by transmitting light from the proximal portion of the elongate tubular element to the distal tip of the elongate tubular element; and The deployment force from the released force element acts to automatically deploy the deployment length of the elongate tubular element from the distal end of the needle into the suprachoroidal cavity or the supra-ciliary body cavity. The intubation device. **Claim 2** The intubation device according to claim 1, wherein the liquid path from the proximal end of the elongate tubular element is connected to an injection port or a luer connector. **Claim 3** The intubation device according to claim 1, wherein the liquid path from the proximal end of the elongate tubular element is connected to a container within the body of the device. **Claim 4** The intubation device according to any one of claims 1 to 3, further comprising a braking mechanism or a friction element for limiting the deployment speed of the cannula. **Claim 5** The intubation device according to any one of claims 1 to 4, wherein the elongate tubular element is configured to conduct light by using the wall of the elongate tubular element for light conduction. **Claim 6** The intubation device according to any one of claims 1 to 5, wherein the elongate tubular element is configured to totally reflect or partially internally reflect light. **Claim 7** The insertion device according to any one of claims 1 to 6, wherein the elongated tubular element is illuminated along its deployed length.

8. The insertion device according to any one of claims 1 to 7, wherein light transmitted from a proximal portion of the elongated tubular element provides illumination at a distal tip of the elongated tubular element.

9. The insertion device according to any one of claims 6 to 8, wherein the elongated tubular element comprises a polymer and a low refractive index coating.

10. The insertion device according to any one of claims 1 to 9, wherein the needle comprises a curved distal tip that directs the elongated tubular element at an angle from the longitudinal axis of the needle towards a posterior region of the eye.

11. The insertion device according to any one of claims 1 to 10, wherein the needle comprises an internal deflection element within the lumen of the needle at the bevel angle of the needle to direct the elongated tubular element at an angle from the longitudinal axis of the needle towards the posterior region of the eye.

12. The insertion device according to any one of claims 1 to 11, wherein a distal tip of the elongated tubular element comprises a material having a greater flexibility than a proximal major axis of the elongated tubular element.

13. The insertion device according to claim 12, wherein the distal tip of the elongated tubular element comprises a material having a greater flexibility and having a length of at least 1 mm.

14. The insertion device according to claim 12 or 13, wherein the distal tip and the major axis of the elongated tubular element comprise polyurethane, a polyurethane copolymer, polysiloxane, a polysiloxane copolymer, or a polyether block amide.

15. The insertion device according to any one of claims 1 to 14, wherein the elongated tubular element has a curved shape in an unconstrained state and returns to the curved shape when deployed from a distal end of the needle.

16. The insertion device according to any one of claims 1 to 15, wherein the elongated tubular element further comprises a lubricious coating.

17. The insertion device according to claim 3, further comprising a material for administration within the container, wherein the material for administration is a fluid, a semi-solid, or a dry composition that is rehydrated to a semi-solid.

18. Furthermore, a terminal element having a terminal seal attached to a distal end of the device, the terminal element sealing or blocking the needle lumen from a forward movement of the elongated tubular element exiting the needle, wherein the terminal seal functions as a tissue contact and is penetrated by a distal end of the needle by applying pressure to the eye surface at a distal end of the device; The penetrated distal element is slidable over the needle and enables advancement of the needle into tissue; and, The penetrated distal seal opens the advancement path of the elongated tubular element from the distal end of the needle. The cannulation device according to any one of claims 1 to 17. **Claim 19** Furthermore, a foldable element is provided between the main body of the device and the distal element, and the foldable element is configured to prevent movement of the distal element in the distal direction. The cannulation device according to claim 18. **Claim 20** The foldable element according to claim 19, comprising an elongated support pillar. **Claim 21** The cannulation device according to claim 20, wherein the foldable element contains nitinol or polyimide. **Claim 22** The foldable element according to any one of claims 19 to 21, wherein the foldable element is configured to apply a forward force to the distal element during penetration of the distal seal by the distal tip of the needle. **Claim 23** The cannulation device according to claim 22, wherein the forward force is in the range of 40 to 82 gram-forces. **Claim 24** The foldable element according to claim 22 or 23, wherein the foldable element is configured to apply a constant force after an initial force, and the initial force is applied during the first 0.5 mm of proximal movement of the distal element along the needle. **Claim 25** The cannulation device according to claim 18, wherein the distal seal functions as a tissue interface, and the distal seal contains an elastomer having a hardness of 10 to 30 Shore A. **Claim 26** The cannulation device according to claim 18, wherein the distal seal is attached to a tubular distal housing. **Claim 27** The cannulation device according to any one of claims 1 to 26, wherein the force element for applying a deployment force to advance the elongated tubular element is a spring. **Claim 28** The cannulation device according to any one of claims 1 to 26, wherein the force element is pressurized gas. **Claim 29** The cannulation device according to any one of claims 1 to 26 for delivering an active ingredient-containing composition having an effective total needle length of 1 to 5 mm to the suprachoroidal space or the supra-ciliary body cavity.

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