Devices and methods for corneal treatment

Abstract

A medical device and a method of using the same are described. The device may include a body having a housing defining a lumen, a piston within the housing, and an actuator operably coupled to the piston, the piston being movable along the lumen by operating the actuator. The device may also include a cartridge insertable into the body and / or a flexible fitting configured for direct application to the subject's eye.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Patent Application No. 18 / 072,163, filed November 30, 2022, which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to devices for delivering compositions to the eye of a subject, for example, devices for use in preparation for, during, and / or after a medical procedure. [Background technology]

[0003] The corneal epithelium is the outermost layer of tissue in the cornea and serves to protect the eye from foreign bodies entering the underlying tissue structures. The epithelium is 4-5 cell layers thick, with tightly connected junctions between the cells in each layer. The epithelium's tight protective shield makes it difficult to deliver desired medications to the cornea, such as antibiotics to fight infection, mydriatics to dilate the pupil to allow for retinal examination, or other therapeutic or pharmaceutical agents.

[0004] Treatment of many ocular diseases and postoperative conditions requires frequent drug administration to ocular tissues. Many medications must be applied topically to the eye, and one common treatment is the use of eye drops or ointments. Topical formulations are administered by the patient or caregiver using an eye dropper or dispenser. However, a substantial drawback of this drug delivery method is that the medication can be rapidly drained from the ocular surface into the lacrimal system through openings in the eyelids called puncta. Furthermore, medications can be rapidly diluted by tears secreted by the lacrimal gland, and preservatives in multi-dose bottles can cause irritation or more serious complications to ocular tissues. Another approach for local drug delivery involves direct injection of the drug subconjunctivally or sub-Tenon's capsule, into the anterior chamber, or into the vitreous. This approach may require periodic injections of the drug to maintain effective concentrations at the target site and has many potential adverse effects. Current treatment methods such as these can result in sporadic drug delivery at the target tissue and unpredictable dosages. Intermittent administration can also lead to initial overdosing due to dilution and tear drainage, with concentrations rapidly decreasing to ineffective levels. Summary of the Invention [Means for solving the problem]

[0005] The present disclosure includes medical devices and methods of use useful, for example, in ophthalmic procedures for treating a subject. For example, the present disclosure includes a method and device comprising: a body containing a housing defining a lumen, a piston within the housing, and an actuator operably coupled to the piston, the piston being movable along the lumen by actuating the actuator; a cartridge insertable into the lumen, the distal end of the cartridge being sealed with a pierceable material; and a flexible fitting configured for direct application to the subject's eye, the fitting coupled to and removable from the distal end of the cartridge or body housing. The body may include a handle extending along an axis transverse to the lumen, the handle including the actuator. Additionally or alternatively, the body may include a slot communicating with the lumen, the cartridge being removable from the lumen through the slot. In some examples herein, the proximal end of the fitting includes a mating element complementary to a mating element of the cartridge or a mating element at the distal end of the housing. Optionally, the device may further include a motor near the lumen, the motor capable of vibrating the cartridge when the cartridge is disposed within the lumen. In some examples, the device does not include electronic components. The device may include a release button for resetting the starting position of the piston.

[0006] According to some aspects of the present disclosure, the puncturable material of the cartridge includes a metal foil or a polymeric film. Furthermore, for example, the proximal end of the cartridge can be sealed with an element including a puncturing tip extending toward the distal end of the cartridge. In some examples, the cartridge includes a first sub-cartridge adjacent to a second sub-cartridge, the distal end of the second sub-cartridge being sealed with the puncturable material. The distal end of the first sub-cartridge can be sealed with the puncturable material. Additionally or alternatively, the first sub-cartridge can contain a liquid and / or the second sub-cartridge can contain a powder.

[0007] An exemplary method of treating a subject using the device described above and / or elsewhere herein includes combining a liquid and a powder to prepare a composition by depressing an actuator to move a piston distally and establish fluid communication between a first sub-cartridge and a second sub-cartridge, where moving the piston distally ruptures a puncturable material between the first sub-cartridge and the second sub-cartridge, preparing a composition wherein the liquid comprises a buffer solution and the powder comprises an acylating agent; mixing the composition; applying the fitting to the subject's eye; and administering the composition to the eye by expelling the composition into the enclosed space between the fitting and the eye. According to some embodiments of the present disclosure, the first sub-cartridge further comprises an active agent mixed with the buffer solution, and the second active agent comprises a steroid, an anti-inflammatory agent, an antihistamine, a prostaglandin, an anesthetic, or an antibacterial agent.

[0008] The present disclosure also includes a medical device comprising a body, the body comprising a housing defining a lumen and a slot communicating with the lumen, the slot being (a) between the proximal end of the housing and the distal end of the housing or (b) at the distal end of the housing, a piston disposed within the lumen, and an actuator operably coupled to the piston, the piston being movable along the lumen by operating the actuator. In some examples, the device further comprises a cartridge insertable into the lumen through the slot. For example, the distal end of the cartridge can be sealed with a pierceable material, and the proximal end of the cartridge can be sealed with an element including a piercing tip extending toward the distal end of the cartridge. The cartridge can include a first subcartridge adjacent to a second subcartridge, the distal end of the second subcartridge being sealed with a pierceable material, and the proximal end of the first subcartridge being sealed with an element. In some examples, the first subcartridge contains a buffer solution and / or the second subcartridge contains an acylating agent. Optionally, the device may further comprise a flexible fitting configured for direct application to the subject's eye. The fitting may be coupled to and detachable from the distal end of the cartridge or the distal end of the body housing via complementary mating elements. According to some embodiments, the proximal end of the cartridge includes at least one tab, and the slot in the housing includes at least one recess corresponding to each tab.

[0009] The present disclosure also includes a method of treating a subject using a medical device comprising a housing and a flexible fitting, the housing defining an internal cavity containing a cartridge and a piston operably coupled to an actuator, the cartridge including a first subcartridge containing a buffer solution and a second subcartridge containing an active agent. The method may include combining the buffer solution and the active agent to prepare a composition by depressing the actuator of the device to distally move the piston and establish fluid communication between the first subcartridge and the second subcartridge; mixing the composition; applying the fitting to the subject's eye, the fitting expanding radially outward to conform to the convex curvature of the eye; and administering the composition to the eye by expelling the composition into the enclosed space between the fitting and the eye. In some examples, the active agent is an acylating agent, and the composition is administered to the eye while having a pH range of about 8.4 to about 8.6. Further, for example, the active agent may be a first active agent, and the first sub-cartridge may further include a second active agent mixed with a buffer solution. For example, the second active agent may include a steroid, an anti-inflammatory agent, an antihistamine, a prostaglandin, an anesthetic, or an antibacterial agent. In some examples herein, the composition does not include a preservative. Establishing fluid communication between the first sub-cartridge and the second sub-cartridge may include puncturing a thin foil or polymer film between the first sub-cartridge and the second sub-cartridge. The method may further include inserting a cartridge into the lumen before preparing the composition, and removing the cartridge from the lumen after administering the composition to the eye.

[0010] The present disclosure also includes a medical device comprising: a body including a housing defining a lumen, a piston within the housing, and an actuator operably coupled to the piston, the piston being movable along the lumen by operating the actuator; a cartridge insertable into the lumen, the distal end of the cartridge sealed with a pierceable material, optionally comprising a metal foil or a polymeric film; and a flexible fitting configured for direct application to a subject's eye, the fitting coupled to and detachable from the distal end of the cartridge or the housing of the body, the body including a slot communicating with the lumen, the cartridge being detachable from the lumen through the slot. In some embodiments, the proximal end of the fitting includes a mating element complementary to a mating element of the cartridge or a mating element at the distal end of the housing. Further, for example, the device may include a release button for resetting the starting position of the piston, optionally coupled to an extension with at least one arm insertable into each pocket of the piston. The at least one arm may include, for example, two arms. In some embodiments, pressing the release button while at least one arm of the extension is inserted into a respective pocket of the piston moves the arm(s) of the extension away from the piston, releasing the arm(s) of the extension from the pocket(s). The piston may include at least one notch near the pocket(s), and the device may further include a cam insertable into the at least one notch while the arm(s) of the extension are inserted into the pocket(s). In some embodiments, the at least one notch of the piston includes two notches. In some embodiments, the extension includes two arms, the piston includes two pockets on opposite sides of the piston, and the arms of the extension are located on opposite sides of the piston below the release button. Additionally or alternatively, the proximal end of the cartridge may be sealed with an element including a piercing tip extending toward the distal end of the cartridge.The cartridge may include a first sub-cartridge adjacent to the second sub-cartridge, the distal end of which is sealed with a puncturable material. Optionally, the distal end of the first sub-cartridge is sealed with a puncturable material, and / or the cartridge includes at least one vent hole for releasing gas from the cartridge during use of the device. In some examples, the cartridge includes multiple vent holes, each vent hole comprising a porous membrane or hole. The device may include a removable tab covering at least one vent hole of the cartridge, the tab configured to be removed prior to use of the device (e.g., prior to inserting the cartridge into the body of the device). In some embodiments of the present disclosure, the first sub-cartridge contains a liquid such as a buffer solution, and the second sub-cartridge contains a powder such as an acylating agent. Optionally, the first sub-cartridge may further include an active agent mixed with the buffer solution. In some examples, the active agent includes a steroid, an anti-inflammatory agent, an antihistamine, a prostaglandin, an anesthetic, or an antibacterial agent. In some embodiments, the proximal end of the cartridge includes at least one mating or engaging element, such as a tab, and the slot in the housing includes at least one complementary mating or engaging element, such as a recess, corresponding to each tab. In some examples, the body includes at least one indicator configured to emit light and / or sound after a predetermined amount of time has elapsed. For example, the indicator(s) can be configured to emit light and / or sound after a predetermined amount of time has elapsed since the pH-sensitive composition was prepared by establishing fluid communication between the contents of a first subcartridge of the cartridge and the contents of a second subcartridge of the cartridge, the indicator signaling that the composition has reached a pH suitable for application to the subject's eye. In some examples, the at least one indicator is configured to emit light and / or sound approximately 10-30 seconds (e.g., the predetermined amount of time is 10-30 seconds) after establishing fluid communication between the first subcartridge and the second subcartridge. The predetermined amount of time can be programmed into a processor, e.g., a processor on the circuit board of the device.The device may be used to administer a therapeutic composition to the eye of a subject, as discussed above and elsewhere herein.

[0011] It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the present disclosure, as claimed.

[0012] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate various exemplary embodiments and, together with the description, serve to explain the principles of the disclosed embodiments. [Brief explanation of the drawings]

[0013] [Figure 1] FIG. 1 is a perspective view of an exemplary medical device according to some aspects of the present disclosure. [Figure 2] 2 shows an exploded view of the components of the device of FIG. 1. [Figure 3] 2 shows an exploded view of the components of the device of FIG. 1. [Figure 4A] 2 shows a partial cross-sectional view of parts of the device of FIG. 1. [Figure 4B] 2 shows a partial cross-sectional view of parts of the device of FIG. 1. [Figure 5] 2 shows a cartridge for the device of FIG. 1. [Figure 6] 2 shows a cartridge for the device of FIG. 1. [Figure 7] FIG. 1 is a perspective view of another exemplary medical device according to some aspects of the present disclosure. [Figure 8A] 8 is a side cross-sectional view of the device of FIG. 7 in a first position. [Figure 8B] 8 is a side cross-sectional view of the device of FIG. 7 in a first position. [Figure 9] 8 is a side cross-sectional view of the device of FIG. 7 in a second position. [Figure 10] 8 shows an exploded view of the components of the device of FIG. 7. [Figure 11] FIG. 8 is a side cross-sectional view of a portion of the device of FIG. 7. [Figure 12] FIG. 1 is a perspective view of another exemplary medical device according to some aspects of the present disclosure. [Figure 13] 13 shows a cartridge for the device of FIG. 12. [Figure 14] FIG. 13 is a side cross-sectional view of the device of FIG. 12. DETAILED DESCRIPTION OF THE INVENTION

[0014] The singular forms "a," "an," and "the" include plural referents unless the context dictates otherwise. The terms "approximately" and "about" refer to being nearly the same as a referenced numerical value or value. As used herein, the terms "approximately" and "about" should generally be understood to encompass ±5% of the specified amount or value. Any embodiment described herein as exemplary should not be construed as preferred or advantageous over other embodiments. Rather, the term "exemplary" is used in the sense of an example or illustration.

[0015] The devices herein can provide effective and controlled delivery of therapeutic agents, including pH-sensitive agents, to one or both eyes of a human subject, such as a patient. For example, the devices and methods described herein can be useful for delivering agents to a subject's eyes before, during, and / or after an eye examination or other procedure. The devices herein can be useful for agents prepared from multiple components that are mixed prior to application to the eye and applied to the eye within a desired pH range. Mixing the components in real time to achieve a composition within the desired pH range can help promote a safe and comfortable experience for the subject.

[0016] According to some examples herein, a device can be used to combine components or ingredients contained in a cartridge to prepare a therapeutic composition (which may include one or more active agents) and deliver the composition to a subject's eye(s). Generally, the device can include a body including a housing defining a lumen and a piston movable along the lumen by operating an actuator. The device can also include a cartridge insertable into and removable from the lumen. For example, the cartridge can be single-use and disposable, containing one or more therapeutic agents, such as one or more active agents. The device can also include a flexible fitting configured for direct application to the subject's eye; the fitting can be integral with the body or removably coupled to the body or cartridge. For example, the fitting can be single-use or otherwise replaceable / interchangeable. Different fittings can be used, for example, to accommodate different subjects. The distal end of the fitting can have a size and shape to fit the convex curvature of the eye. The fitting may comprise a suitable biocompatible material that can provide flexibility for the subject's comfort when the fitting contacts the eye. For example, the fitting may comprise silicone, rubber, plastic, or other polymers.

[0017] The body may include a handle. For example, the handle may have a shape that allows a user to grasp it to operate the actuator and / or position the device to deliver the composition to the subject's eye. In some embodiments of the present disclosure, the handle may extend along an axis transverse to the lumen of the body, e.g., approximately perpendicular to the lumen or forming an angle between about 90 degrees and about 135 degrees with the lumen. In other embodiments, the handle may extend along the same axis as the lumen. Optionally, the handle may include an electronic connector configured to receive power from a power source, such as a battery (e.g., a rechargeable battery), and / or an external power source. Further, for example, the handle may include a processor, e.g., included on a circuit board, to control one or more electronic components of the device, as discussed further below. However, in some examples, the device does not include electronic components.

[0018] An actuator of the device can engage a piston disposed with the lumen to move the piston along the lumen. When a cartridge is inserted into the lumen of the body, distal movement of the piston can similarly move the cartridge and / or parts thereof distally, ultimately delivering a composition (e.g., a therapeutic composition) from the cartridge through the fitting and out of the device. In some examples, the device includes a mechanism capable of providing a vibratory motion to agitate the lumen and a cartridge disposed within the lumen to promote mixing of the therapeutic agent(s) contained within the cartridge.

[0019] The piston can be configured to engage the cartridge and advance the cartridge distally to deliver the composition contained within the cartridge. In some examples, the composition may exit the device through one or more openings at or near the distal end of the body and through the fitting. For example, the distal end of the cartridge can include a pierceable material such as a thin foil or polymeric film. The material can be pierced by a sharp inner edge of the opening(s), allowing the composition (e.g., a liquid composition) to exit the device through the opening(s). In other examples, the composition can exit the cartridge through a fitting (e.g., the fitting is coupled to the cartridge, and both the fitting and the cartridge are located distally relative to the body). The distal end of the cartridge can include a pierceable material that can be pierced by a piercing tip of a pierceable element within the cartridge.

[0020] In some examples, the cartridge comprises a single chamber, for example, the cartridge may be provided as a sealed container with the composition therein.

[0021] In other examples, the cartridge may include two or more subcartridges with components of the composition to be mixed together using the device before the composition exits the device for administration to a subject. The piston may be configured to sequentially advance the two or more cartridges to mix the components together. The two or more subcartridges may contain different active agents and / or other components of the composition, and each subcartridge may be sealed before use to avoid contamination or exposure to other environments. For example, the subcartridges may have one or more openings sealed with a material such as a metal, metal alloy, or polymer. To combine the components, the material may be punctured or otherwise pierced, allowing the components to mix together. For example, a first movement of the piston relative to the cartridge may press a first proximal subcartridge against a second distal subcartridge, thereby piercing the distal seal of the first subcartridge and the proximal seal of the second subcartridge. Piercing the respective seals may allow the contents of the two subcartridges to mix within the cartridge.

[0022] Further movement of the piston can move both the first and second sub-cartridges relative to the device body. When the distal end of the cartridge (e.g., corresponding to the distal end of the second sub-cartridge) contacts a sharpened feature on the device body, the sharpened feature can puncture the material at the distal end of the cartridge, allowing the composition therein to exit the cartridge and the device. Alternatively, further movement of the piston can puncture the most distal end of the cartridge, allowing the composition to exit the cartridge.

[0023] As described above, the devices herein may optionally include a mechanism for promoting mixing of the cartridge contents when disposed within the lumen. The mechanism may be located near the lumen. For example, the mechanism may be housed in a chamber adjacent to the lumen, e.g., a chamber that shares a wall with the lumen. In some embodiments, the mechanism includes a motor, e.g., a vibration motor. The motor or other mechanism may be manually controlled by a user, activated based on a predetermined algorithm (e.g., an algorithm stored in the device's memory / circuitry), or engaged based on movement of the piston. For example, the piston may advance along the lumen a sufficient distance for two electrical contacts to touch each other and activate the motor. Further movement of the piston may separate the electrical contacts and stop the motor.

[0024] According to some aspects of the present disclosure, a device can be programmed to perform sequential steps upon activation of an actuator. For example, movement of a piston can be automated. A user may actuate the actuator, causing the piston to move to a first position. The device can then wait a predetermined amount of time and move the piston to a second position without a second actuation of the actuator by the user. Parameters of the automated method can be programmed into a processor, for example, a processor on the device's circuit board.

[0025] The device may include indicators to provide information regarding the status of the device during operation. For example, the device may provide one or more audio and / or visual indicators configured to communicate to the user when to perform different actions and / or when the composition is ready to be applied to the subject. In the case of a pH-sensitive composition, for example, the indicator may include a light source that illuminates when the composition reaches a pH appropriate for administration to the subject. The appropriate pH may be determined as a function of time based on the amount of time from when the components are mixed together until the pH begins to change. In at least one embodiment, the device includes a visual indicator in the form of a light source configured to emit and / or change color when mixing begins and / or ends and / or when the composition reaches a desired pH or pH range, if multiple components of the composition are being mixed. For example, the light source may emit a red light while the components are being mixed and then change to a green light after the components have been mixed for a sufficient amount of time.

[0026] The devices herein can be used to deliver various therapeutic compositions containing one or more active agents to a subject's eye(s). The desired active agent(s) and / or compositions containing one or more active agents can be provided in a cartridge and sealed therein, for example, to avoid exposure to contamination or other environments that could damage, inactivate, or otherwise impair the activity of the active agent(s) prior to administration to a subject. The active agent(s) and composition(s) containing the active agent(s) can be in liquid or solid form. The cartridges can be formulated for single-use applications without preservatives that could otherwise cause irritation and / or other harm to the eye.

[0027] In some examples, the device can be used to administer a composition prepared from two or more agents contained in separately sealed sub-cartridges of a cartridge. For example, a cartridge can include a first sub-cartridge containing a first agent (e.g., a buffer solution) and a second sub-cartridge containing a different second agent (e.g., an active agent). The first and second agents, when combined, can generate a composition for administration to a subject. Optionally, the first and / or second cartridges can contain multiple agents, including multiple active agents. For example, a cartridge can include a first sub-cartridge containing a buffer solution and an active agent, and a second sub-cartridge containing an active agent different from the active agent in the first sub-cartridge. When the contents of the two sub-cartridges are combined during use, the composition formed will include a buffer solution and two different active agents.

[0028] Exemplary active agents that can be delivered to a subject's eye include acylating agents, which, when applied to the cornea, can open tight epithelial junctions, allowing transcorneal penetration of pharmaceuticals and other therapeutic agents. The acylating agent can be combined with a buffer using the device to create a composition with a pH suitable for administration to the eye and for opening epithelial junctions. The acylating agent and buffer can be contained in separate subcartridges, and operation of the device can combine the acylating agent and buffer to create the composition.

[0029] Acylating agents useful in the present disclosure include anhydrides, acid chlorides, sulfonyl chlorides, and sulfonic acids. Suitable anhydrides include agents that change the net charge from positive to negative. Exemplary anhydrides suitable for the devices and methods herein include, but are not limited to, maleic anhydride, succinic anhydride, glutaric anhydride, citraconic anhydride, methylsuccinic anhydride, itaconic anhydride, methylglutaric anhydride, dimethylglutaric anhydride, phthalic anhydride, acetic anhydride, chloroacetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, isovaleric anhydride, and hexanoic anhydride. Anhydrides are susceptible to conversion to the corresponding acids (e.g., conversion of glutaric anhydride to glutaric acid) when exposed to and / or mixed with aqueous solutions. Such anhydrides are also reactive with deprotonated amines on protein molecules. Amine groups on protein molecules can be deprotonated, for example, by exposure to alkaline buffers. Exemplary acid chlorides suitable for the devices and methods herein include, but are not limited to, oxalyl chloride, malonyl chloride, acetyl chloride, propionyl chloride, dichloropropionyl chloride, butyryl chloride, isobutyryl chloride, and valeryl chloride. Exemplary sulfonyl chlorides suitable for the devices and methods herein include, but are not limited to, chlorosulfonylacetyl chloride, chlorosulfonylbenzoic acid, 4-chloro-3-(chlorosulfonyl)-5-nitrobenzoic acid, 3-(chlorosulfonyl)-p-anisic acid, ethanesulfonyl chloride, methanesulfonyl chloride, and 1-butanesulfonyl chloride.

[0030] Acylation reagents may preferentially react with deprotonated protein groups, such as lysine groups. These same reagents also have the potential to react with N-terminal amino groups, tyrosyl residues, and cysteinyl residues. Deprotonation of the ε-amino group on lysine can be achieved by raising the pH to alkaline levels. The pH level effective for deprotonating the ε-amino group on lysine is generally around pH 10.0. However, reactions with acylating agents typically occur between pH 8.0 and 9.0, with reactivity generally slower at pH 7.0. Active acylating agents may react with deprotonated protein(s) and alter the protein's solubility. Therefore, timing is a consideration for effective delivery of the acylating agent in alkaline buffer to a protein that is also exposed to alkaline buffer and deprotonated.

[0031] The acylation reaction rate may depend on (1) the reaction pH (e.g., at higher pH, such as up to pH 10.0, the reaction may occur faster), (2) the concentration of the acylating agent, and / or (3) the hydrolysis of the acylating agent to an inactive acid in aqueous solution (a time factor). As discussed above, the higher the pH, the higher the reactivity. It is understood that when proteins are acylated in solution, the pH is always adjusted to an alkaline pH, e.g., pH 9.0. The effectiveness of acylation may also depend on the concentration of the active acylating agent. The acylating agent may be rapidly hydrolyzed to an inactive acid upon a decrease in pH. Because the acidic form may be inactive, as the pH decreases, the rate of acylation also decreases due to the availability of less reactive acylating agents and the lower pH, which is unfavorable to reactivity.

[0032] The reaction involves a balance between pH and the concentration of the active acylating agent. For example, in the case of an anhydride, the ratio of inactive acylating agent (e.g., acid form) to active acylating agent (e.g., anhydride form) changes immediately when the anhydride form is mixed with an aqueous solution. The time required for complete hydrolysis of the anhydride to acid is relatively short, e.g., less than one minute. During this time, the pH decreases, reducing the reactivity of the active form. Therefore, both the reaction pH and the concentration of the active acylating agent are variables that must be controlled for effective treatment. The devices herein provide effective and controlled delivery of pH-sensitive drugs to a subject. For example, the devices and methods herein may be useful for creating transepithelial channels for effective delivery of desired therapeutic agents to the eye.

[0033] According to some examples herein, a composition formulated for ocular administration is prepared by mixing two components, each contained in a separate subcartridge: (1) an acylating agent (e.g., a powdered anhydrous form), which is sealed in the subcartridge prior to use to prevent moisture in the air from degrading the powder's properties before mixing, and (2) a buffer solution, which is also sealed in a separate airtight subcartridge prior to use. Exemplary buffer solutions include phosphate buffers, e.g., sodium dihydrogen phosphate, disodium hydrogen phosphate, and / or potassium dihydrogen phosphate, as well as other alkaline pH buffers, such as carbonate buffers. The buffer solution can have a pH ranging from about 7.5 to about 9.5, e.g., from about 8.0 to about 9.0, or from about 8.2 to about 8.5.

[0034] To prepare the composition, the acylating agent (e.g., in powder form) and the buffer solution can be mixed together by placing the two subcartridges in fluid communication with each other, such as by rupturing the puncturable material(s) between the two subcartridges. For example, the seal between the subcartridges can be punctured by sequential movement of a piston. A buffer solution, such as an alkaline phosphate buffer, can be contained in the first subcartridge. The volume of the buffer solution in the first subcartridge can range from about 250 mL to about 750 mL, e.g., about 500 mL. A second subcartridge adjacent to the first subcartridge contains the acylating agent in solid form, e.g., as a loose powder or as a solid film on the inner surface of the second subcartridge. The amount of the acylating agent can range from about 3 mg to about 10 mg, e.g., about 5 mg. In some examples, the acylating agent includes glutaric anhydride.

[0035] As described above, the devices herein can be used to administer various active agents to one or both eyes of a subject. Other exemplary active agents that can be administered using the devices herein include, but are not limited to, riboflavin, steroids, anti-inflammatory agents, antihistamines, prostaglandins, anesthetics, and antimicrobial agents (e.g., antifungal agents, antibiotics, antibacterial agents, antiviral agents, etc.). Exemplary active agents that can be delivered using the devices and methods herein include, but are not limited to, riboflavin, timolol, latanoprost (e.g., Xalatan), epinephrine, neosynephrine, phenylephrine, hydroxyamphetamine, tropicamide, cyclopentolate, atropine, homatropine, scopolamine, deflazacort, and prednisone (including prednisone acetate). For example, the cartridge may contain an active agent such as riboflavin, steroids, anti-inflammatory agents, antihistamines, prostaglandins, anesthetics, or antibacterial agents in a buffer solution. In some examples, the cartridge may include two sub-cartridges, a first sealed sub-cartridge containing a buffer and riboflavin, a steroid, an anti-inflammatory agent, an antihistamine, a prostaglandin, an anesthetic, or an antibacterial agent, and a second sealed sub-cartridge containing an acylating agent, and the device may be used to fluidly connect the first and second sub-cartridges to produce a composition of the acylating agent and the active agent in the buffer, which composition may then be administered to a subject.

[0036] To maintain sterility, multi-dose drug containers typically contain preservatives to kill pathogens that may be introduced when the container is opened and closed. However, these preservatives, such as benzalkonium chloride and other quaternary ammonium chemicals, can pose risks to sensitive ocular structures, such as corneal and conjunctival epithelial cells. Long-term exposure to preservatives can also roughen the surfaces of the cornea and conjunctiva. The device herein provides a method for delivering active agents to the eye without the use of preservatives.

[0037] As described above, the disclosed device can be used to administer compositions prepared from agents contained in separately sealed subcartridges of a cartridge. In some examples, the device can be used to administer compositions containing two different active agents. The first active agent can be, for example, an acylating agent, while the second active agent can be a pharmaceutical or other therapeutic agent other than the acylating agent, such as riboflavin, a steroid, an anti-inflammatory agent, an antihistamine, a prostaglandin, an anesthetic, or an antibacterial agent. As discussed above, the acylating agent can be contained in a subcartridge of the device that is different from the buffer, allowing the acylating agent and buffer to be combined immediately prior to administration to the eye, ensuring that the composition has the desired pH when applied to the subject. That is, the acylating agent can be contained in the first subcartridge and the buffer can be contained in the second subcartridge. When a second active agent is administered, the second active agent can be contained in the second subcartridge along with the buffer. For example, the second active agent may include riboflavin, a steroid, an anti-inflammatory agent, an antihistamine, a prostaglandin, an anesthetic, or an antibacterial agent.

[0038] As discussed above (and / or illustrated below with reference to the drawings), operation of the device herein may combine the contents of the first and second sub-cartridges to produce a composition comprising a buffer, a second active agent, and an acylating agent. When the composition is applied to the eye, the acylating agent opens the tight epithelial junctions of the cornea, allowing the second active agent to pass through the junctions and reach the intraocular tissue intended for treatment. In this manner, the device may enable the administration of various active agents without the use of preservatives using convenient, single-use cartridges pre-filled with the desired active agent(s). By administering the active agent(s) with the acylating agent, the subject receiving treatment may experience a more convenient and efficient procedure, avoiding lengthy hospital stays and wait times for the desired therapeutic agent to take effect.

[0039] The following describes exemplary devices shown in the figures that are used to prepare compositions prepared from two components (e.g., a powder and a liquid, or, e.g., two liquids), but the disclosure is not limited to these examples. Rather, the devices herein may include more or fewer components than those shown, as discussed herein, and may be used to deliver other compositions to the eye, including compositions formulated for administration to a subject with properties (e.g., viscosity, temperature, etc.) that change over time.

[0040] 1-6 depict an exemplary medical device 100 according to the present disclosure, which includes a body 102 defining a lumen 104 and including a handle 110 with an actuator 105. The lumen 104 communicates with a slot 108 providing access to the lumen 104 between the proximal and distal ends of the body 102. The lumen 104 may receive a cartridge 150 through the slot 108, which is removable and replaceable (see also FIGS. 5 and 6 ). As shown, the body 102 includes a chamber 140 near the lumen 104 that may house a motor 145, as discussed below. The device 100 also includes a fitting 130 at the distal end of the body 102. In this embodiment, the fitting 130 is removable from the body 102 via complementary engaging elements (engaging elements alternatively referred to herein as mating elements), although in other embodiments the fitting 130 may be integral with the body 102.

[0041] 2 and 3 show partially exploded views of the medical device 100, with the cartridge 150 and fitting 130 shown as removable components in this example. For example, the cartridge 150 and fitting 130 may each be single-use, replaceable components. The fitting 130 may have an engaging element 132 (see FIG. 3 ) complementary to an engaging element 129 on the body 102. As shown, the engaging elements 129, 132 include complementary threads (e.g., on the inner surface of the fitting and on the outer surface of the body 102, as shown, or vice versa), although other engaging elements, such as clips, tabs, friction fits, luer lock connections, magnets, etc., may also be used. The fitting 130 has a flared distal end 134 that can conform to the convex curvature of the subject's eye. The cartridge 150 has a generally cylindrical shape to fit within the similarly shaped lumen 104. For example, the cross-sectional dimension (diameter in this example) of cartridge 150 may be slightly smaller than the cross-sectional dimension (diameter in this example) of lumen 104 to ensure reliable placement of cartridge 150 within lumen 104 .

[0042] FIG. 3 shows the internal components of body 102, including piston 190, which is disposed toward the proximal end of lumen 104, i.e., toward handle 110. Piston 190 has a distal protrusion 192 such that the distal end of piston 190 has a stepped configuration. Piston 190 may be biased toward the proximal end of lumen 104 via spring 195. Piston 190 is coupled to actuator 105 and shaft 197, allowing actuator 105 to initiate and control the distal longitudinal movement of piston 190 and shaft 197 along lumen 104. While actuator 105 is shown in the form of a trigger, actuator 105 may be in any other suitable form, such as a button, a switch, or any other suitable actuator capable of engaging piston 190.

[0043] The medical device 100 may include electronic components for controlling various operations of the device 100, such as the operation of the motor 145 and / or the indicator 180. The medical device 100 may include a power source, such as a battery 170 (e.g., a rechargeable battery), and / or may include electrical connections 177 for receiving power from an external power source and / or for charging the battery 170. The device 100 may also include a circuit board 175 with a processor, memory, etc., programmed to control the motor 145 and / or the indicator 180, these electronic components being electrically connected via wires 147. If the device 100 is configured to operate automatically, the circuit board 175 may store (e.g., in memory) one or more algorithms for controlling the operation of the motor 145 and / or the indicator 180. In some examples, the algorithm(s) may control the movement of the piston 190 when actuated by the actuator 105.

[0044] As shown in FIGS. 3, 4A, and 4B, device 100 may include first electrical contact 125a and second electrical contact 125b. First electrical contact 125a may be coupled to body 102, e.g., an inner surface of bore 104 adjacent piston 190. Second electrical contact 125b may be coupled to piston 190. Piston 190 is movable along bore 104, such that electrical contacts 125a, 125b may selectively contact or separate from each other depending on the position of the piston. FIGS. 3 and 4A show an initial position of piston 190, in which second electrical contact 125b is separated from and located distally of first electrical contact 125a. As piston 190 moves distally, second electrical contact 125b may contact first electrical contact 125a, thereby completing a circuit, as shown in FIG. 4B. Once the circuit is complete, this may connect motor 145 to circuit board 175 and a power source (e.g., battery 170 and / or an external power source). Motor 145 may thus be activated to provide, for example, an oscillatory motion within chamber 140 and lumen 104, promoting mixing of the contents of cartridge 150 when the cartridge is placed within lumen 104. In some embodiments, motor 145 may be operated for a predetermined amount of time, such as from about 1 second to about 30 seconds, from about 5 seconds to about 20 seconds, or from about 10 seconds to about 15 seconds. Alternatively, a user may start and stop operation of motor 145 via an actuator, such as, for example, actuator 105 or a second actuator.

[0045] 3 , the body 102 may include one or more openings 128 near the distal end of the body 102. The opening(s) 128 may have a sharpened edge 138 facing toward the lumen 104. The cartridge 150 may interact with the sharpened edge 138 when the cartridge 150 is within the lumen 104 and moved to a distal position by the piston 190. When the piston 190 urges the cartridge 150 distally toward the opening(s) 128, the sharpened edge 138 may puncture the distal end of the cartridge 150, allowing the composition within the cartridge 150 to pass through the opening(s) 128 and out of the device 100 through the fitting 130.

[0046] 5 and 6 show components of cartridge 150, including first sub-cartridge 152, second sub-cartridge 154, outer container 156 around first sub-cartridge 152 and second sub-cartridge 154, and piercing element 151. Each of first sub-cartridge 152, second sub-cartridge 154, outer container 156, and piercing element may comprise a suitable material, such as a polymer or a metal.

[0047] Each of the first sub-cartridge 152 and the second sub-cartridge 154 has a generally cylindrical shape with sealed proximal and distal ends. The proximal end of the first sub-cartridge is closed by the piercing element 151, which provides a seal with the wall of the first sub-cartridge 152 via a sealing element 165. For example, the sealing element 165 may include an O-ring that fits into a groove in the piercing element 151 and abuts against the wall of the first sub-cartridge 152. The distal end 162 of the first sub-cartridge 152 is sealed with a pierceable or puncturable material. The material may include, for example, a metal, a metal alloy, or a thin film of a polymer. In at least one embodiment, the material includes a metal foil. The second sub-cartridge 154 may include a proximal end 164 and a distal end 166, each sealed with a pierceable or puncturable material. The material may include, for example, a metal, such as a metal foil, a metal alloy, or a thin film of a polymer. Once cartridge 150 is assembled and prior to use, first sub-cartridge 152 and second sub-cartridge 154 may be adjacent to one another, such that distal end 162 of first sub-cartridge 152 is adjacent proximal end 164 of second sub-cartridge 154. Distal end 166 of second sub-cartridge 154 may form the distal-most end of cartridge 150. Alternatively, in some embodiments, the distal end of outer container 156 may be sealed with a pierceable or puncturable material adjacent to the material of distal end 166 of second sub-cartridge 154. Puncture element 151 may have a distally-facing puncture tip 153 and one or more openings 155. Before the cartridge 150 is assembled and used, the puncturing element 151 can extend distally toward the distal end 162 of the first sub-cartridge 152, with the puncturing tip 153 near but not touching the distal end 162.

[0048] In an exemplary procedure, a user (e.g., a medical professional) may obtain cartridge 150, fitting 130, and device body 102 as separate components that can be assembled by coupling fitting 130 to body 102 and inserting cartridge 150 into slot 108 of body 102, as discussed above. For example, a user may select an appropriate cartridge 150 containing a desired composition and active agent(s) (including dosages of the active agent(s)), and a desired size and shape of fitting 130 to suit a particular subject. In other examples, the device may be obtained in an assembled form, with fitting 130 coupled to or integral with body 102 and cartridge 150 inserted into lumen 104 of body 102. In an initial position, the proximal end of cartridge 150 (corresponding to the proximal end of piercing element 151) may be adjacent to and in contact with protrusion 192 of piston 190. The stepped configuration of piston 190 allows protrusion 192 to contact piercing element 151 without contacting the wall of first sub-cartridge 152. This initial position of piston 190 is illustrated in Figure 4A, where first electrical contact 125a and second electrical contact 125b are separated from each other.

[0049] A user may press the actuator 105 to engage the shaft 197, moving the piston 190 distally and thereby moving the piercing element 151 relative to the first sub-cartridge 152 and the remainder of the cartridge 150. The body 102 includes an internal stop that prevents further movement of the piston 190 when the actuator 105 contacts the stopper. As the piercing element 151 moves, the piercing tip 153 may have a sharp surface that punctures or pierces the material at the distal end 162 of the first sub-cartridge 152. By breaking the seal of the first sub-cartridge 152, the first sub-cartridge 152 and the second sub-cartridge 154 may be in fluid communication with each other. For example, the first sub-cartridge 152 may contain a liquid, such as a buffer solution, that can flow into the second sub-cartridge 154 and combine with the agent(s) contained therein. 4B, where the first electrical contact 125a and the second electrical contact 125b are in contact. As a result, the motor 145 may operate for a predetermined or desired amount of time, vibrating the cartridge 150 to promote mixing of the liquid and the agent(s) to produce a composition ready for administration to the eye.

[0050] The user may depress actuator 105 a second time to engage shaft 197 a second time, moving piston 190 further distally. At this point, the stepped portion of piston 190 contacts the wall of cartridge 150, moving the entire cartridge 150 distally and against sharp edge 138 at the end of lumen 104. Sharp edge 138 punctures or pierces the material at distal end 166 of second cartridge 154 (as well as the material at the distal end of outer container 156, if present), allowing the composition therein to pass through opening(s) 128 and out of cartridge 150 through fitting 130. The user may depress actuator 105 a second time after placing fitting 130 on the subject's eye. When fitting 130 contacts the subject's eye, the subject may be facing upward, causing gravity to force the composition through opening(s) 128 and into contact with the cornea of ​​the eye. The composition is maintained in contact with the eye via the enclosed space provided by fitting 130 (between fitting 130 and the surface of the cornea). The volume provided by this enclosed space may range from about 0.5 mL to about 5 mL. For example, the amount of composition applied to the eye may range from about 0.5 mL to about 5 mL, or from about 1 mL to about 3 mL. The composition may be maintained in contact with the eye via device 100 for at least 30 seconds, e.g., 30 to 60 seconds, or 30 to 45 seconds. After the desired amount of time for delivery and / or exposure of the composition to the eye has elapsed, the user may remove the device and flush the subject's eye with a buffer solution or other suitable eyewash. If the user is treating both eyes of the subject, the user may remove the used cartridge 150, insert a new cartridge, and repeat the steps above to treat the other eye.

[0051] 7-11 illustrate another exemplary medical device 200 according to an embodiment of the present disclosure. Except for variations described below, device 200 may include any of the features of device 100. As shown in FIG. 7, device 200 includes a body 202 with a housing including a handle 210 and an actuator 205. Actuator 205 is shown in the form of a trigger, but may be in any other suitable form, such as a button, switch, or any other suitable actuator capable of causing movement of a piston 290, as discussed below. Body 202 defines a lumen that receives piston 290. Body 202 receives cartridge 250 (e.g., via a distal slot in communication with the lumen), which may include any of the features of cartridge 150 of FIGS. 1-6. Cartridge 250 may be, for example, removable and replaceable and may be pre-filled with one or more active agents.

[0052] The device 200 also includes a fitting 230, which may include any of the features of the fitting 130 of FIGS. 1-4B. For example, the fitting 230 may be flexible and may have a flared distal end 234 that can conform to the convex curvature of the subject's eye. The fitting 230 may include an engaging element 232, such as a clip, tab, friction fit, luer lock connection, or magnet, that is complementary to an engaging element 229 of the cartridge 250 and is located, for example, at or near the distal end of the cartridge 250. As shown in FIG. 10 , the engaging elements 229, 232 may provide a friction fit connection, with a groove 232 on the inner surface of the fitting 230 receiving a raised lip on the outer surface of the distal end of the cartridge 250. The fitting 230 may be flexible to allow for establishing a tight friction fit seal with the cartridge 250. In at least one embodiment, the fitting 230 includes a biocompatible rubber or flexible plastic.

[0053] As described above, cartridge 250 may have similar features to cartridge 150 of FIG. 1. For example, cartridge 250 may include first sub-cartridge 252, second sub-cartridge 254, and piercing element 251 (see FIG. 8A). First sub-cartridge 252, second sub-cartridge 254, and piercing element 251 may each include a suitable material, such as a polymer or a metal. Piercing element 251 includes a piercing tip similar to piercing tip 153 of cartridge 150. The proximal and distal ends of first sub-cartridge 252 and second sub-cartridge 254 may be sealed with a pierceable or pierceable material. The material may include, for example, a thin film of polymer, a metal, such as a metal foil, or a metal alloy.

[0054] Device 200 includes a mechanism for advancing piston 290 against the proximal end of cartridge 250 in sequential steps to mix the contents of sub-cartridges 252, 254 together to form a therapeutic composition, which is then expelled from cartridge 250 for administration to a subject (e.g., a patient). The mechanism includes piston 290 coupled to cam 280, with piston 290 biased proximally away from cartridge 250 via spring 295. Spring 295 may be wound around a portion of piston 290. In the start or ready position of device 200 (FIGS. 8A-8B), piston 290 is in its proximal-most position and is prevented from moving distally by cam 280 being positioned within first (distal) notch 291. The underside of piston 290 includes two notches 291, 293 for receiving cam 280, and each side of piston 290 includes two pockets 233, 235 for receiving arms of extension 243. Extension 243 may have a curved shape as shown, with the arms of extension 243 on opposite lateral sides of piston 290 below release button 242, described further below.

[0055] In an exemplary procedure, a user may couple fitting 230 to cartridge 250 and then insert cartridge 250 into body 202 such that two tabs 270 of cartridge 250 are received within corresponding recesses 219 of body 202, the recesses being defined in distal surface 218 that include slots for receiving cartridge 250. The user may rotate cartridge 250 to lock tabs 270 into position within recesses 219. Alternatively, the user may insert cartridge 250 into body 202, rotate cartridge 250 to lock it into position, and then couple fitting 230 to cartridge 250. When initially assembled, device 200 is in a first starting position with cam 280 resting within distal notch 291 of piston 290, with the distal end of the piston contacting the proximal sealed end of cartridge 250 adjacent first sub-cartridge 252.

[0056] Upon a first actuation of the actuator 205 by a user, the actuator 205 rotates, causing a corresponding rotation of the cam 280, which presses the cam 280 in the notch 291 against the piston 290. This moves the piston 209 distally until the cam 280 reaches its full longitudinal length and can no longer press the piston 290 further. At this point, each arm of the extension 243 is positioned to be received within a corresponding pocket 233. Because each pocket 233 has a closed distal end, when the respective arm is received within the pocket 233, the arm acts as an internal stop to prevent proximal movement of the piston 290. Thus, when the user releases the actuator 205, disengaging the cam 280 from the notch 291, the arm of the extension 243 fits within the pocket 233 to maintain the position of the piston 290 relative to the cartridge 250. At this point, the cam 280 fits into the second (proximal) notch 293 (see Figures 9 and 11).

[0057] This first longitudinal movement of piston 290 (via a first actuation of actuator 205) corresponds to a first distal movement of piercing element 251 of cartridge 250 relative to the remainder of cartridge 250. The piercing tip of piercing element 251 pierces the wall separating first and second sub-cartridges 252, 254. The agent(s) contained in first sub-cartridge 252 (e.g., a buffer, optionally one or more active agents combined with the buffer) may then be mixed with the agent(s) contained in second sub-cartridge 254 (e.g., an acylating agent and / or other active agents) to form a therapeutic composition. The arm of extension 243 disposed within pocket 233 acts as a stopper, preventing piston 290 from further moving piercing element 251. The distal-most end of cartridge 250 remains sealed, so that the composition remains contained within cartridge 250.

[0058] The user may wait a suitable amount of time sufficient to ensure proper mixing of the medications within the cartridge 250 to form the composition. For example, the user may wait a predetermined amount of time to allow the medications to mix and reach the appropriate pH. The user may then apply the fitting 230 to the subject's eye so that the flared distal end 234 of the fitting 230 contacts the eye. The user then actuates the actuator 205 a second time, again rotating the actuator 205 relative to the handle 210. This correspondingly rotates the cam 280, causing it to press against the piston 290 within the second notch 293. This moves the piston 209 distally until the cam 280 again reaches its full longitudinal length and can no longer press against the piston 290. At this point, each arm of the extension 243 is positioned to be received within a corresponding pocket 235. Because each proximal pocket 235, like distal pocket 233, has a closed distal end, when its respective arm is received within pocket 235, the arm acts as an internal stop to prevent proximal movement of piston 290. This second longitudinal movement of piston 290 (via a second actuation of actuator 205) corresponds to a second distal movement of puncturing element 251 relative to the remainder of cartridge 250. The puncturing tip of puncturing element 251 pierces the distal-most end of cartridge 250, allowing the composition to exit device 200. When fitting 230 contacts the subject's eye, the subject may be facing upward, such that gravity causes the composition to exit through fitting 230 and contact the cornea of ​​the eye, maintaining the composition in contact with the eye via the closed space provided by fitting 230 (between fitting 230 and the surface of the cornea). Once sufficient time has passed to allow the composition to treat the eye, the user may remove device 200 and optionally rinse the subject's eye with a buffer solution.

[0059] At this point, the unsealed cartridge 250 is used and can be removed from the device body 202 and discarded. The user can rotate the cartridge 250 to release the tabs 270 from the corresponding recesses 219 in the device body 202. To reset the position of the piston 290, the user can press the release button 242. The release button 242 is coupled to the extension 243 (see FIG. 11 , with a portion of the cam 280 omitted for illustrative purposes), and pressing the release button 242 pushes the extension 243 and its arm downward. Each pocket 235 has an open bottom, which releases the arm from the constraint of the pocket 235 and allows the piston 290 to move proximally under the biasing force provided by the spring 295. This returns the piston 290 to its starting position ( FIGS. 8A-8B ), allowing the device body 202 to accept a new cartridge.

[0060] 12-14 illustrate another exemplary medical device 300 according to an embodiment of the present disclosure. Except for variations described below, device 300 may include any of the features of device 100 and / or device 200. As shown in FIG. 12, device 300 includes a body 302 with a housing including a handle 310 and an actuator 305, such as, for example, a trigger, button, switch, or the like. Body 302 defines a lumen that receives a piston 390. Body 302 receives a cartridge 350 (e.g., via a distal slot in communication with the lumen), which may include any of the features of cartridge 150 and / or cartridge 250 discussed above. Cartridge 350 may be, for example, removable and replaceable and may be pre-filled with one or more active agents. Fitting 330 is coupled to body 302 and may include any of the features of fitting 130 and / or fitting 230. The fitting 330 may be flexible and may have a flared distal end 334 configured to contact the eye, e.g., to conform to the convex curvature of the subject's eye. The fitting 330 may include an engaging element 332, such as a clip, tab, friction fit, luer lock connection, magnet, or the like, that is complementary to an engaging element 329 of the cartridge 350, e.g., located at or near the distal end of the cartridge 350.

[0061] Similar to the cartridges discussed above, cartridge 350 may include a first sub-cartridge 352, a second sub-cartridge 354, an outer container 356 surrounding first sub-cartridge 352 and second sub-cartridge 354, and a piercing element (see, e.g., piercing element 151 in FIGS. 5 and 6 and piercing element 251 in FIG. 8A ). The proximal and distal ends of first sub-cartridge 352 and second sub-cartridge 354 may be sealed with a pierceable or pierceable material, e.g., a thin film of polymer, a metal such as a metal foil, or a metal alloy. Cartridge 350 may include at least one tab 370, e.g., two tabs 270, received in a corresponding recess 319 in body 302, the recess defined in distal surface 318 including a slot for receiving cartridge 350.

[0062] In this example, cartridge 350 includes features provided for venting air and / or other gas(es) within cartridge 350 during mixing of the medicament(s) within cartridge 350 by sequential movement of piston 390, as discussed in connection with device 100 and device 200. Outer container 356 includes at least one vent hole that aligns with a corresponding vent hole in the second sub-cartridge. In some examples, outer container 350 also includes multiple vent holes, which may have the same or different sizes and / or shapes. FIGS. 12-14 show an example in which outer container 356 includes two vent holes 355 located on opposite sides (one vent hole 355 is visible and the other vent hole 355 is distal in each of FIGS. 12-14 ) and another vent hole 359 between them, e.g., approximately 90 degrees from each vent hole 355. The second sub-cartridge includes two vent holes 357 (one vent hole 357 is visible and the other vent hole 357 is distal in FIG. 13 ) that align with the vent holes in the outer container 356. Each vent hole 355, 357, 359 may comprise, for example, a porous membrane (e.g., a filter) or a hole. Thus, the vent holes 355, 357 may be aligned to release gas from the cartridge 350 when the contents of the first sub-cartridge 352 are combined with the contents of the second sub-cartridge 354 by longitudinal movement of the piston 390. Other vent holes 359, if present, may similarly allow the release of gas. These venting features may prevent leakage of the cartridge 350 that might otherwise occur due to, for example, a pressure buildup within the cartridge 350. In some embodiments of the present disclosure, the cartridge 350 may include one or more removable tabs 369 that cover one or more corresponding vent holes prior to use. In this example, vent holes 355, 357 may each include a porous membrane, and vent hole 359 may include a hole with a removable tab 369 that covers vent hole 359 prior to use. The porous membrane may have a pore size small enough to limit or prevent environmental contamination from the passage of material(s) into cartridge 350 while allowing gas to exit cartridge 350.

[0063] Device 300 includes a mechanism similar to that of device 200 for combining the contents of sub-cartridges 352, 354 to prepare a therapeutic composition and resetting the position of piston 390 via release button 342. For example, piston 390 is coupled to cam 380 and biased away from cartridge 350 via spring 395. Cam 380 is receivable within one or more notches 391 in piston 390 (e.g., the two notches 391 shown in FIG. 14). Piston 390 also includes one or more pockets, e.g., a pair of pockets 333 and another pair of pockets 335 (e.g., adjacent pockets 333), for receiving corresponding arms of an extension coupled to release button 342. In FIG. 14, one pocket of each pair of pockets is visible; for example, the other pocket is on the opposite side of the piston. Pockets 333, 335 may be adjacent to one or more notches or may be distal to spring 395.

[0064] In this example, device 300 also includes a circuit board 375 and one or more indicators 380. The indicator(s) 380 may be coupled to circuit board 375 to receive power and / or instructions according to an algorithm. For example, device 300 may be coupled to circuit board 375 and powered by a battery, e.g., a rechargeable battery, contained within body 302, or may receive power from an external power source via electrical connections coupled to circuit board 375 to power indicator(s). Indicator(s) 380 may be configured to provide visual and / or audio information to signal a user before, after, and / or during mixing of the medications in cartridge 350. Indicator(s) 380 may operate according to parameters programmed into a processor, e.g., a processor of circuit board 375 of device 300. Such parameters may include instructions to emit a light and / or sound after a predetermined amount of time has elapsed, for example, after the actuator 305 has been used to move the piston 390 to establish fluid communication between the contents of the subcartridges 352, 354 of the cartridge 350. The indicator(s) 380 may signal to the user that the composition has reached a suitable pH for application to the subject's eye. The predetermined amount of time may correspond to a time sufficient to ensure proper mixing of the medication within the cartridge 350, for example, about 10-30 seconds, e.g., about 15 seconds, about 20 seconds, or about 25 seconds.

[0065] The indicator(s) 380 may include, for example, a light source (e.g., a light-emitting diode, LED) that illuminates and / or a speaker that emits a sound when the composition reaches a pH suitable for administration to a subject. The appropriate pH may be determined as a function of time based on the time from when the components are mixed together until the pH begins to change. In at least one embodiment, device 300 includes indicator 380 in the form of a light source configured to emit and / or change color when mixing of multiple components of the composition begins and / or ends and / or when the composition reaches a desired pH or pH range. For example, the light source may emit a red light while the components are mixing, and then change to a green light after the components have been mixed for a sufficient amount of time (e.g., about 10-30 seconds). In at least one embodiment, indicator 380 is in the form of a speaker that emits a sound, e.g., a pattern of sounds, when mixing of multiple components of the composition begins and / or ends and / or when the composition reaches a desired pH or pH range. For example, the speaker may emit a single tone while the components are mixing, and then emit a different tone and / or multiple tones after the components have been mixed for a sufficient amount of time (e.g., about 10-30 seconds). Audio indicators may be suitable for providing information to a user to enable them to self-administer the composition (e.g., when the device 300 is positioned relative to the user such that the user cannot easily see the visual indicator). The device 300 may include an indicator 380 configured to emit both light and sound, or may include two separate indicators 380, one configured to emit light and the other configured to emit sound. While the example shown in FIGS. 12-14 includes an indicator 380 at or near the proximal end of the body 302, it will be understood that the indicator(s) 380 may be located at any other suitable location or portion of the device 300.

[0066] The components of the devices herein may be provided in a kit. For example, a kit according to the present disclosure may include a device body (e.g., body 102, body 202, or body 302), one or more cartridges (e.g., cartridge 150, cartridge 250, or cartridge 350), and one or more fittings (e.g., fitting 130, fitting 230, or fitting 330). A kit according to the present disclosure may include multiple fittings of different sizes to accommodate different subjects. For example, an exemplary kit may include a device body, a cartridge, and two or more fittings of different sizes, each fitting including an engaging element complementary to an engaging element on the cartridge. In this way, a user may select an appropriate fitting or exchange for a different fitting depending on the size preferred for a given subject's eye. In some examples, a kit may include two or more cartridges. For example, an exemplary kit may include a device body, at least two cartridges insertable into and removable from the device body, where the at least two cartridges may be pre-filled with the same active agent(s) and / or different active agent(s). A user may treat both eyes of a subject using a single device, removing a used cartridge and replacing it with a new one to treat the first eye and then the second eye. In some examples, the kit may include cartridges containing different active agents to allow a user to treat the same eye or different eyes with different active agents using the same device.

[0067] The devices herein can provide effective and controlled delivery of therapeutic compositions to a subject's eye (one or both eyes). For example, the devices and methods herein can be useful for delivering pH-sensitive compositions to the eye to open transepithelial channels for effective delivery of other active agents. In some examples, the pH-sensitive composition can also include other active agent(s).

[0068] As discussed above, the cartridge contains two or more sub-cartridges, each sealed (optionally including one or more vent holes) prior to use to avoid exposure to environmental contamination or other conditions that could damage, inactivate, or otherwise impair the activity of the active agent(s) prior to administration to a subject. The cartridges may be configured for single use, with each sub-cartridge containing a desired amount of agent (e.g., buffer or active agent) for a single administration to the eye. In this manner, the devices herein may be used to administer therapeutic compositions without the use of preservatives that could irritate or even damage ocular tissue. Furthermore, the cartridges may be pre-filled with a desired amount of active agent for targeted delivery to the eye, avoiding overdosing and potentially harmful amounts of active agent that could otherwise occur with multiple-dose regimens.

[0069] As described above, various active agents can be administered simultaneously or substantially simultaneously with the opening of corneal tight epithelial junctions by delivering a composition comprising an acylating agent, a buffer, and an active agent. According to some aspects of the present disclosure, the active agent can include an ophthalmic drug, including, but not limited to, riboflavin, timolol, latanoprost, epinephrine, neosynephrine, phenylephrine, hydroxyamphetamine, tropicamide, cyclopentolate, atropine, homatropine, and scopolamine. For example, riboflavin can be administered to treat keratoconus by exposure to ultraviolet (UVA) light after riboflavin administration. In some examples, the active agent can include a steroid, an anti-inflammatory agent, an antihistamine, a prostaglandin, an anesthetic, or an antimicrobial agent (e.g., an antifungal, antibiotic, antibacterial, or antiviral agent).

[0070] In an exemplary treatment, a cartridge may be selected that includes a first subcartridge containing a buffer (e.g., sodium phosphate buffer) and an active agent (e.g., 1.0% tropicamide) and a second subcartridge containing an acylating agent, such as glutaric anhydride. For example, the second subcartridge may contain about 3 mg to about 10 mg, e.g., about 5 mg, of glutaric anhydride, either in powder form or as a solid layer on the inner surface of the second subcartridge. As discussed above, when the first and second subcartridges are placed in fluid communication by operating the device, the acylating agent may combine with the buffer and the active agent to produce a therapeutic composition containing the acylating agent and the active agent. Over time, for example, within the first few seconds to one minute, the pH of the composition may decrease. A pH of about 8.4 to 8.6 may be suitable for delivery to a subject's eye. The user may monitor the amount of time that has elapsed since the contents of the sub-cartridges were combined, and / or the user may use an indicator on the device (e.g., indicator 180 on device 100) to determine when the composition has reached the desired pH.

[0071] After the composition has been applied to the subject's eye, the user may remove and discard the cartridge. A new cartridge (pre-filled with the same buffer, acylating agent, and active agent) may be inserted into the device to treat the subject's other eye in the same manner, after which the second cartridge may also be removed and discarded in the same manner. The body of the device may be sterilized between uses and / or between treatments of different subjects.

[0072] The present application encompasses additional procedures for delivering therapeutic agents to the eye. For example, in cataract surgery, a medical professional may use the devices herein to administer antibiotics and / or anti-inflammatory agents (e.g., deflazacort or other anti-inflammatory agents) to a patient as a pre-operative treatment, instead of applying eye drops. Additionally or alternatively, after cataract surgery or other surgical procedures, a medical professional may use the devices herein to administer antibiotics and / or steroids (e.g., prednisone or other steroids) rather than by injection. The methods and devices herein may be used to saturate the cornea with antibiotics, steroids, and / or anti-inflammatory agents, optionally in a single dose, as part of pre-operative preparation, and then ensure that these active agents remain present at therapeutic levels post-operatively.

[0073] Aspects of the present disclosure include the following numbered clauses:

[0074] 1. A medical device comprising: a body including a housing defining a lumen, a piston within the housing, and an actuator operably connected to the piston, wherein the piston is movable along the lumen by operating the actuator; a cartridge insertable into the lumen, wherein a distal end of the cartridge is sealed with a puncturable material; and a flexible fitting configured for direct application to a subject's eye, wherein the fitting is coupled to and detachable from the distal end of the cartridge or body housing.

[0075] 2. The device described in clause 1, wherein the body includes a handle extending along an axis transverse to the lumen, the handle including the actuator.

[0076] 3. A device according to clause 1 or 2, wherein the body includes a slot in communication with the lumen, and the cartridge is removable from the lumen through the slot.

[0077] 4. A device described in any one of clauses 1 to 3, wherein the proximal end of the fitting includes a mating element that is complementary to a mating element on the cartridge or a mating element on the distal end of the housing.

[0078] 5. A device described in any one of clauses 1 to 4, wherein the device further comprises a motor in the vicinity of the lumen capable of vibrating the cartridge when the cartridge is disposed within the lumen.

[0079] 6. The device of any one of clauses 1 to 5, wherein the device includes a release button for resetting the starting position of the piston.

[0080] 7. The device of any one of clauses 1-6, wherein the puncturable material comprises a metal foil or a polymeric film.

[0081] 8. A device described in any one of clauses 1 to 7, wherein the proximal end of the cartridge is sealed with an element including a puncture tip extending toward the distal end of the cartridge.

[0082] 9. A device according to any one of clauses 1 to 8, wherein the cartridge comprises a first sub-cartridge adjacent to a second sub-cartridge, the distal end of the second sub-cartridge being sealed with a puncturable material.

[0083] 10. A device as described in clause 9, wherein the distal end of the first sub-cartridge is sealed with a puncturable material.

[0084] 11. A device according to clause 9 or 10, wherein the first sub-cartridge contains a liquid and the second sub-cartridge contains a powder.

[0085] 12. A method of treating a subject using the device of claim 11, comprising: combining a liquid and a powder to prepare a composition by pressing the actuator to move a piston distally to establish fluid communication between a first sub-cartridge and a second sub-cartridge, wherein moving the piston distally ruptures a puncturable material between the first sub-cartridge and the second sub-cartridge, wherein the liquid comprises a buffer and the powder comprises an acylating agent; mixing the composition; applying the fitting to the subject's eye; and administering the composition to the eye by expelling the composition into the enclosed space between the fitting and the eye.

[0086] 13. The method of clause 12, wherein the first sub-cartridge further comprises an active agent mixed with a buffer, and the second active agent comprises a steroid, an anti-inflammatory agent, an antihistamine, a prostaglandin, an anesthetic, or an antibacterial agent.

[0087] 14. A medical device comprising: a body, the body being a housing defining a lumen and a slot in communication with the lumen, the slot being either (a) between a proximal end of the housing and a distal end of the housing or (b) at the distal end of the housing; a piston disposed within the lumen; and an actuator operably coupled to the piston, the piston being movable along the lumen by operating the actuator.

[0088] 15. The device of clause 14, further comprising a cartridge insertable into the lumen through the slot, the distal end of the cartridge being sealed with a puncturable material and the proximal end of the cartridge being sealed with an element including a puncturing tip extending toward the distal end of the cartridge.

[0089] 16. A device as described in clause 15, wherein the cartridge includes a first sub-cartridge adjacent to a second sub-cartridge, the distal end of the second sub-cartridge being sealed with a puncturable material and the proximal end of the first sub-cartridge being sealed with an element.

[0090] 17. A device according to clause 16, wherein the first sub-cartridge contains a buffer and the second sub-cartridge contains an acylating agent.

[0091] 18. A device described in any one of clauses 15 to 17, further comprising a flexible fitting configured for direct application to the subject's eye, the fitting coupled to the distal end of the cartridge or the distal end of the main body housing via a complementary mating element and removable from the distal end of the cartridge or the distal end of the main body housing.

[0092] 19. A device described in any one of clauses 15-18, wherein the proximal end of the cartridge includes at least one tab and the slot in the housing includes at least one recess corresponding to each tab.

[0093] 20. A method of treating a subject using a medical device comprising a housing and a flexible fitting, the housing defining an internal cavity containing a cartridge and a piston operably connected to an actuator, the cartridge including a first sub-cartridge containing a buffer solution and a second sub-cartridge containing an active agent, the method comprising: preparing a composition by combining the buffer solution and the active agent by depressing the actuator of the device to move the piston distally and establish fluid communication between the first sub-cartridge and the second sub-cartridge; mixing the composition; applying the fitting to the subject's eye, the fitting expanding radially outward to conform to the convex curvature of the eye; and administering the composition to the eye by expelling the composition into the enclosed space between the fitting and the eye.

[0094] 21. The method of clause 20, wherein the active agent is an acylating agent and the composition is administered to the eye while having a pH in the range of about 8.4 to about 8.6.

[0095] 22. The method of clause 21, wherein the active agent is a first active agent and the first sub-cartridge further comprises a second active agent mixed with a buffer, the second active agent comprising a steroid, an anti-inflammatory agent, an antihistamine, a prostaglandin, an anesthetic, or an antibacterial agent.

[0096] 23. The method of any one of clauses 20 to 22, wherein the composition does not contain a preservative.

[0097] 24. The method of clause 20, wherein establishing fluid communication between the first subcartridge and the second subcartridge comprises puncturing a thin foil or polymeric film between the first subcartridge and the second subcartridge.

[0098] 25. The method of any one of clauses 20 to 24, further comprising inserting a cartridge into the lumen before preparing the composition, and removing the cartridge from the lumen after administering the composition to the eye.

[0099] It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the disclosure being indicated by the following claims.

Claims

1. A medical device comprising: a body including a housing defining a lumen, a piston within the housing, and an actuator operatively connected to the piston, the piston being movable along the lumen by operating the actuator; a cartridge insertable into the lumen, the distal end of the cartridge sealed with a pierceable material, optionally the pierceable material comprising a metal foil or a polymeric film; a flexible fitting configured for direct application to the subject's eye, the fitting coupled to and removable from a distal end of the cartridge or the housing of the body; the body includes a slot in communication with the lumen, the cartridge being removable from the lumen through the slot; Medical devices.

2. The device of claim 1 , wherein the body includes a handle extending along an axis transverse to the lumen, the handle including the actuator.

3. The device of claim 1 or 2, wherein the proximal end of the fitting includes a mating element that is complementary to a mating element on the cartridge or the distal end of the housing.

4. 10. A device according to any one of the preceding claims, wherein the device includes a release button for resetting the starting position of the piston, optionally the release button being connected to an extension with at least one arm insertable into a respective pocket of the piston.

5. 5. The device of claim 4, wherein pressing the release button while the at least one arm of the extension is inserted into the respective pocket of the piston moves the arm(s) of the extension away from the piston, releasing the arm(s) of the extension from the pocket(s).

6. 6. The device of claim 4 or 5, wherein the piston includes at least one notch adjacent the pocket(s), and the device further includes a cam insertable into the at least one notch while the arm(s) of the extension are inserted into the pocket(s).

7. 7. A device as claimed in any one of claims 4 to 6, wherein the extension includes two arms and the piston includes two pockets on opposite sides of the piston, the arms of the extension being located on opposite sides of the piston below the release button.

8. 10. A device according to any one of the preceding claims, wherein the proximal end of the cartridge is sealed with an element including a piercing tip extending towards the distal end of the cartridge.

9. 10. A device according to any one of the preceding claims, wherein the cartridge comprises a first sub-cartridge adjacent to a second sub-cartridge, the distal end of the second sub-cartridge being sealed with the puncturable material, and optionally the distal end of the first sub-cartridge being sealed with the puncturable material, and optionally the cartridge comprising at least one vent hole for releasing gas from the cartridge during use of the device.

10. 10. The device of claim 9, wherein the first sub-cartridge contains a liquid such as a buffer solution and the second sub-cartridge contains a powder such as an acylating agent.

11. 11. The device of claim 10, wherein the first sub-cartridge contains an active agent mixed with the buffer solution, the active agent further comprising a steroid, an anti-inflammatory agent, an antihistamine, a prostaglandin, an anesthetic, or an antibacterial agent.

12. 10. The device of claim 1, wherein the proximal end of the cartridge includes at least one tab, and the slot in the housing includes at least one recess corresponding to each tab.

13. 10. The device of any one of the preceding claims, wherein the body comprises at least one indicator configured to emit light and / or sound after a predetermined amount of time has elapsed since a pH-sensitive composition was prepared by establishing fluid communication between the contents of a first sub-cartridge of the cartridge and the contents of a second sub-cartridge of the cartridge, the indicator signaling that the composition has reached a pH suitable for application to the eye of the subject.

14. 10. The device of claim 1, wherein the at least one indicator is configured to emit light and / or sound approximately 10 to 30 seconds after establishing fluid communication between the first sub-cartridge and the second sub-cartridge.

15. 10. Use of a device according to any one of the preceding claims for administering a therapeutic composition to the eye of a subject.

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