Breathable multi-dose eye drop delivery system

Abstract

A device for delivering a precise amount of pharmaceutical fluid to the eye is provided. The device includes an ampoule for storing the liquid and an aperture through which the liquid is released. The device further includes a vibrating membrane comprising a needle protruding from the membrane and extending to the aperture to form a needle valve. The needle valve provides a hermetic closure of the aperture to enable preservative-free storage of the pharmaceutical fluid in the device. The system further includes an electromagnetic transducer to move the membrane back and forth to release the liquid through a nozzle. Finally, the system further includes a vent to allow air to enter the ampoule when the fluid is discharged from the ampoule. Preferably, this vent includes a filter to prevent the entry of microorganisms or other contaminants into the ampoule.

Description

Technology Field

[0001] The present invention relates to the local delivery of ophthalmic drugs to the eye. Background Technology

[0002] Currently, pharmaceutical fluids are typically delivered to the surface of the eye using droplet bottles. This method has several disadvantages: (1) patients cannot aim well and often miss the eye; (2) the volume of the droplet from the bottle is not well defined, and the tear film on the cornea is too large to absorb this droplet (approximately 50 L) — the tear film can be maintained at about 7 L or less —; (3) very often, patients blink during droplet delivery, so some of the droplet falls onto the eyelid and the rest is wiped off the cornea. Prior art literature

[65535] U.S. Patent Application Publication No. 2019 / 0314195 (Oct. 17, 2019) U.S. Patent Application Publication No. 2007 / 0102455 (May 10, 2007) International Publication WO2013 / 076682 (May 30, 2013) U.S. Patent Application Publication No. 2010 / 0147899 (June 17, 2010)

[0003] The inventors have developed a device that solves these problems by (1) delivering an accurate amount of fluid; (2) a micro-dose (< 10 uL) in which the tear film can be maintained; (3) delivering the fluid within a blink time (~100 ms); and (4) using optical aiming onto the cornea for accurate self-administration.

[0004] For convenient aiming, the fluid ejector should be positioned close to the eye, but should not come into contact with the eyelashes or eyebrows. Thus, referring to FIG. 1, the device (102) should be located approximately L = 1 cm to 10 cm, or more optimally 2 cm to 6 cm from the eye. In this figure, 102 is the fluid ejector, 104 is the ejected fluid stream, and 106 is the patient's eye.

[0005] The cornea has a diameter of approximately D=12 mm, i.e., a radius of 6 mm. To ensure that the fluid is delivered to approximately the middle of the cornea, the jet (104) must not be deflected under gravity by more than approximately half the radius of the cornea, i.e., less than or equal to h=3 mm. As illustrated in FIG. 1, the vertical deflection (h) of a projectile ejected horizontally at velocity (v) over a distance (L) is as follows: h = g*L / (2v 2 ). To ensure that the vertical deflection does not exceed h, the horizontal jet velocity is v = L*(g / 2h) 0.5 It must exceed. L=5cm, g= 9.8m / s 2 For h=3 mm, we obtain v=2 m / s. For L=5 cm and h=1 mm, the velocity should be approximately v=3.6 m / s, and for L=10 cm, h=1 mm, the velocity is (v=7.2 m / s). Therefore, overall, the jet velocity should be in the range of approximately 1 m / s to 10 m / s, and more optimally 2 m / s to 4 m / s. Velocities much higher than these can cause discomfort to the patient and even damage to the cornea.

[0006] The stream of fluid will reach the eye within a few milliseconds from the moment of distribution (t = L / v, in the range of 1 ms to 100 ms). As soon as the fluid touches the cornea, it will initiate the blink reflex, which typically takes about T = 100 ms. To prevent the drug from being blocked by the eyelids, the fluid must be delivered before the eye closes. For the required volume (V) to be delivered within time (T) at a jet velocity (v), the jet cross-sectional area must be S = V / (T * v). For a round aperture, S = π * d 2 / 4, his diameter(d) = (4V / (ΔT*v)) 0.5 This is because, for example, for v = 2 m / s, T = 100 ms, and V = 10 μL, we obtain d = 250 μm. For v = 1 m / s, d = 350 μm, and for v = 7 m / s, d = 130 μm. Therefore, the aperture diameter of the ejector should be in the range of approximately 200 μm to 600 μm, more optimally 400 μm to 550 μm. Alternatively, several apertures can be used to generate several parallel streams for faster delivery.

[0007] Another key property of the system is the prevention of microbial entry into the liquid held during storage or use. As in any closed system, as the liquid is discharged, air must be introduced (ventilation) to replace the discharged volume and thereby maintain pressure balance. To exclude microbial entry, air is preferably introduced through a special inlet equipped with a 0.2 µm filter. Ideally, the device should operate such that whenever the aperture is opened, the liquid is discharged through the aperture, thereby preventing air from entering through the aperture.

[0008] An exemplary embodiment is an array for storing and discharging liquid droplets, having a housing comprising a chamber for holding liquid inside and a suction port connected to an ampoule holding a pharmaceutical fluid to be dispensed. The chamber comprises a dispensing aperture plate comprising an aperture opening inside that defines a front closure to the chamber and discharges the liquid to the front of the housing. The chamber further comprises a vibrating membrane fixed to the housing in a pressure transfer relationship with the liquid in the chamber. The vibrating membrane has a needle formed therein that protrudes from the center of the vibrating membrane and extends to an aperture on the opposite side of the chamber, said needle closing the aperture to prevent leakage of liquid from the chamber and entry of bacteria.

[0009] The electromagnetic transducer is attached to the housing and, when power is supplied, pulls the membrane backward against the spring in the chamber. When the electromagnetic transducer is turned off, the spring returns the membrane to its original position with a closed valve. When a pulsatile or alternating current is supplied to the electromagnetic transducer, the membrane vibrates as a result, which eventually generates pressure in the liquid. At precise frequencies, the pressure is sufficient to discharge a stream of liquid from the aperture.

[0010] Typical ranges of frequencies are 10 Hz to 500 Hz, more optimally 50 Hz to 200 Hz. The nozzle diameter, fluid discharge velocity, and duration of the electromagnetic rupture are preferably optimized to deliver the required amount of fluid within the required amount of time, as described above. Preferably, the operating pulse duration is 250 ms or less, and more preferably, the operating pulse duration is 100 ms or less. Here, 'operating pulse duration' refers to the length of time the electromagnetic transducer is powered to pull the needle out of the aperture with a single operating pulse.

[0011] Other types of transducers, such as coin vibration motors, can also be used to drive fluid discharge with this configuration. Brief explanation of the drawing

[0012] Figure 1 illustrates a geometric shape for delivering fluid to a patient's eye. FIG. 2 is an external view of an exemplary embodiment of the present invention. FIG. 3a is a cross-sectional view of a first embodiment of the present invention. FIGS. 3B and FIGS. 3C illustrate the operation of the embodiment of FIG. 3A. Figures 4a and 4b illustrate examples of ventilation. FIG. 5 is a cross-sectional view of a second embodiment of the present invention. Figure 6 illustrates a conical spring. Specific details for implementing the invention

[0013] FIG. 2 illustrates a perspective view of a first embodiment of a liquid discharge unit. The fluid discharge unit (200) is suitable for use in delivering preservative-free pharmaceutical liquids to the surface of the eye, in particular, but not exclusively. The liquid discharge device (200) comprises a thermoplastic body (206) in which a liquid chamber is formed and connected to a fluid supply ampoule (202). The discharge unit comprises a nozzle (208) through which the liquid (210) is dispensed, as described in more detail below.

[0014] FIG. 3a illustrates a cross-sectional view of a fluid discharge device. As previously mentioned, the fluid discharge device comprises a thermoplastic body (206) defining a chamber (316) connected to a fluid supply ampoule (202) that holds fluid (302). The fluid discharge device comprises a nozzle (208) through which the liquid is discharged. The device further comprises a membrane (308) at the end opposite the nozzle to the chamber. The membrane (308) comprises an integral needle (306) such that the needles become a single component. The needle (306) and the membrane (308) are connected to an electromagnetic transducer (310) via a link member (318). When an electrical pulse is applied to the electromagnetic transducer (310), an electric current flows through the coil (312), and a magnetic force is generated that pulls the plunger (314) backward against the spring (320).

[0015] In FIG. 3a, 304 illustrates the direction of fluid flow from the ampoule (202) to the chamber (316). The ventilation tube (404) is described in more detail below.

[0016] FIG. 3b illustrates the device of FIG. 3a after an electric pulse has been applied to the electromagnetic transducer (310). As a result of the magnetic force, it can be seen that the plunger (314) is pulled into the electromagnetic transducer in the direction indicated by the arrow. The membrane (308) is connected to the plunger (314) by the linkage member (318) and is also pulled back. FIG. 3c illustrates the situation when the electromagnetic transducer (310) is de-energized. Here, the spring (320) pushes the membrane (308) back to its original position, so that the valve is closed and the chamber is sealed tightly and prevents the entry of microorganisms.

[0017] When the electromagnetic transducer (310) is powered by a pulsatile or alternating current (AC), the vibrating membrane generates pressure in the liquid, resulting in a stream being discharged from the aperture. Typically, the operating frequency is 10 Hz to 500 Hz and more specifically 50 Hz to 200 Hz. In an embodiment, the membrane (308) is made of silicone having a hardness durometer of 50 to 70 (Shore A), and the displacement of the plunger (314) is about 200 µm. Because the flow occurs only in the outward direction, this flow prevents microorganisms from entering even when the valve is open.

[0018] In the examples of FIGS. 4a and 4b, the liquid discharge device includes a venting arrangement to equalize the pressure inside the ampoule (202) with the ambient atmospheric pressure. Here, FIG. 4a is a cross-sectional view along line (EE) of FIG. 4b.

[0019] The ventilation system of this example includes an air inlet ventilation tube (404) extending beyond the liquid level of the fluid (302) in the ampoule (202). It should be noted that the ventilation tube (404) is above the liquid level in any orientation of the device of FIG. 4a and FIG. 4b. The ventilation tube (404) is connected to a ventilation outlet (406) that is open to the atmosphere. In one embodiment, a filter (408) is placed at the ventilation outlet (406) so that the vented air flowing into the ampoule is filtered to prevent the penetration of potential airborne contaminants, such as microorganisms. The filter (408) will filter particles having a size of > 1 µm (more preferably > 0.5 µm, much more preferably > 0.2 µm). In this way, although air (402) enters the ampoule (202) when the fluid is discharged, the system can be isolated from microbial contamination.

[0020] In previous examples, the diaphragm (308) is driven by a solenoid. In the example of FIG. 5, the diaphragm is driven by using a coin vibrator motor. More specifically, 306 is a needle connected to the diaphragm (308) as described above. This assembly is overmolded with a magnetic steel pin (510). 502 is a coin vibrator motor (e.g., JINLONG MACHINERY & ELECTRONICS CO., LTD. Model # C1026B002F). 504 is a plastic molded component that holds the motor (502) so that the plastic molded component can slide along the rails (i.e., the plastic molded component is a motor holder). 506 is a plastic molded component that provides the aforementioned rail guides for the motor holder (504) sliding therein. 510 is a ferromagnetic pin formed into a membrane / needle assembly (308 / 306). 512 is a housing that holds all the components together.

[0021] The needle (306), as described in more detail above, generally seals the aperture (i.e., the aperture is sealed except when the fluid is discharged). The coin vibrator has an eccentric weight that is off-axis (the axis of rotation is perpendicular to the plane of FIG. 5). Because the weight is off-axis, when the motor rotates, the unbalanced weight causes the motor to vibrate mainly in the plane of FIG. 5. By placing the coin vibrator (502) in a plastic motor holder (504) that fits into corresponding rails (within member (506)), the coin vibrator is restricted so that the coin vibrator moves only linearly (e.g., from left to right in FIG. 5). As a result of this physical restriction, when the motor rotates, the motor is allowed to vibrate only from left to right rather than vibrate in the plane. A coin vibration motor is coupled to a diaphragm (308), and as a result, as the motor vibrates from left to right, the diaphragm also vibrates from left to right. The discharged fluid stream is generated in the same manner as described above, namely, the needle (306) moves back and forth in the aperture to discharge the liquid.

[0022] In an alternative embodiment, the coin vibrator motor (502) can be coupled to the diaphragm via an optional magnet (508). The magnet (508) is also secured to a motor holder (504) attached to the coin vibrator motor (502). When the magnet (508) comes into contact with the magnetic steel pin (510), the two are latched together, and the motor is thereby coupled to the diaphragm. This is an advantageous assembly feature because the motor can be easily added to the system without the need for tight tolerances and the motor can be added at several different stages of the assembly process.

[0023] The example of FIG. 5 includes a disc-shaped spring (320). The spring is slightly deformed out of plane during assembly, serving to transmit force to the needle (306). This force or load keeps the needle (306) pressed upward against the orifice to close the flow path. Without the spring, the force required to push the needle open is very low, and the device would easily leak. Additionally, the spring has a significant spring constant to ensure the correct frequency and amplitude of the needle's vibration when the motor is powered. Furthermore, without the spring, it is important that the rigidity of the diaphragm (308) is the only factor applying the load to keep the needle (306) in a closed position. The diaphragm can be made of an elastomer. In the case of most elastomers, mechanical properties change significantly even with slight temperature variations. In the case of the spring (320), a significant portion of the load applied to the needle (306) comes from the spring (320) rather than the diaphragm (308). Because the mechanical properties of the spring steel (e.g., the material of the spring (320)) are much more constant for the same temperature change, adding the spring makes the system performance more consistent.

[0024] In an alternative embodiment, the disc spring (320) of FIG. 5 is replaced with a conical spring. The conical spring is similar to a conventional compression spring made of wire, but instead of being wound with a constant diameter, the diameter gradually decreases so that the spring has a conical shape rather than a cylinder. Refer to FIG. 6. When the conical spring is fully compressed, the coils may be thickened only by the diameter of the wire around which the spring is wound so that the spring can be flat. Thus, a fully compressed conical spring can be fitted into a form factor similar to that of the disc spring (320) of FIG. 5 and can provide the same function. Conical springs are cheaper and easier to obtain a wide range of spring constants and operating deflections compared to disc springs, which is a feature of the currently preferred embodiments.

[0025] The tip of the needle (306) and / or the aperture into which the needle engages may contain an antimicrobial material.

Claims

Claim 1 A device for delivering fluid to a patient's eye, the device comprising: a fluid package comprising a reservoir configured to hold said fluid, an aperture, and a needle configured to seal said aperture when said fluid is not being discharged through said aperture; said fluid package comprising a resilient diaphragm configured to provide a mechanical force to keep the tip of said needle engaged with said aperture when said fluid is not being discharged through said aperture; said resilient diaphragm connected to said needle; an actuator configured to discharge said fluid through said aperture by providing at least said needle with mechanical vibration; and a vent configured to allow air to enter said reservoir as said fluid leaves said reservoir. Claim 2 A device for delivering fluid to a patient's eye, further comprising a particle filter configured to remove particles larger than 0.2 μm from air entering the reservoir through the vent of claim 1. Claim 3 A device for delivering fluid to a patient's eye, wherein the actuator comprises an electromagnetic solenoid. Claim 4 A device for delivering fluid to a patient's eye, wherein the actuator comprises a coin vibration motor. Claim 5 A device for delivering fluid to a patient's eye, wherein the fluid package comprises an elastic spring configured to provide additional mechanical force to keep the tip of the needle engaged with the aperture when the fluid is not being discharged through the aperture. Claim 6 A device for delivering fluid to a patient's eye, wherein the device is configured to deliver a dose volume of 10 μl or less. Claim 7 A device for delivering fluid to a patient's eye, wherein the diameter of the aperture of the device is in the range of 200 μm to 600 μm. Claim 8 A device for delivering fluid to a patient's eye, wherein the velocity of the fluid discharged from the aperture in the range of 1 m / s to 10 m / s in claim 1. Claim 9 A device for delivering fluid to a patient's eye, wherein, in claim 1, the actuation pulse duration of the actuator is 250 ms or less. Claim 10 A device for delivering fluid to a patient's eye, wherein, in claim 1, the repetition rate of the actuation pulses of the actuator is in the range of 10 Hz to 500 Hz. Claim 11 A device for delivering fluid to a patient's eye, wherein the needle has a tip that engages with the aperture, and the tip comprises an antimicrobial material. Claim 12 In claim 1, the aperture is a device for delivering fluid to a patient's eye, comprising an antimicrobial material. Claim 13 A device for delivering fluid to a patient's eye, wherein, in claim 1, the aperture is located on the front wall of the reservoir and the diaphragm is located on the rear wall of the reservoir.

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