HK40037042A - Methods and devices for delivering atropine to the eye as a micro-dose stream of droplets - Google Patents

Description

Methods and devices for delivering atropine to the eye in microdose of droplet streams

Technical Field

The present disclosure relates to droplet delivery devices, methods of administration, and uses thereof, particularly to administering droplets to the eye.

Background

Atropine formulations have been used in ophthalmology for pupil dilation and treatment of amblyopia. Furthermore, recent studies suggest that atropine can be used to treat myopia. Recent academic studies have suggested that some of the side effects associated with the use of standard 1% concentrations can be avoided by using concentrations lower than active ingredients. These studies indicate that 1% atropine drops are less tolerant than low concentrations of atropine drops (e.g., 0.1% and 0.01%). Typically, low concentration formulations are prepared by simply diluting a 1% solution of atropine. However, these low volume solutions are generally not stable for long term use.

In addition, the amount of a typical medical drop dispensed by an eye drop bottle can vary depending on the viscosity and surface tension of the fluid. To control the amount of active ingredient administered as a single droplet, the concentration of the active ingredient is adjusted by volume. Once the concentration is determined, the correct dose may require one or more drops. However, since the human eye can typically only retain 7 μ l of liquid at a time, even a single drop of drug may cause some of the drug to spill and be lost from the eye. The problem of drug retention in the eye is often compounded by multiple drop volumes. Subjects typically apply all of the droplets required for dosing in one breath, which exacerbates the problem and can cause 50% to 90% of the drug to spill and escape from the eye.

In view of the above and other limitations of current ophthalmic drug delivery, there is a need for an effective delivery system for solutions delivered to the eye, including solutions containing drugs such as atropine.

Disclosure of Invention

In certain aspects, the present disclosure provides methods of delivering a composition comprising atropine to the eye of a subject in need thereof in a stream of microdroplet droplets. The method generally comprises: (a) generating a stream of microdose droplets via a piezoelectric droplet delivery device, the stream of microdose droplets comprising a composition comprising atropine, wherein the mean ejected droplet diameter of the stream of microdose droplets is greater than 15 microns; and (b) delivering a stream of microdose droplets to the eye of the subject. In certain embodiments, myopia, particularly progressive myopia (myopic eye) in adults and children, is treated by the method in a subject in need thereof.

In certain aspects, a piezoelectric droplet delivery device includes an ejector mechanism including a generator plate and a piezoelectric actuator, wherein the generator plate includes a plurality of openings formed through a thickness thereof; and wherein the piezoelectric actuator is operable to oscillate the generator plate, directly or indirectly, at a frequency to generate a directed stream of droplets of said low dose volume pharmaceutical composition.

In certain embodiments, the stream of microdose droplets delivered to the eye of the subject is less than 13 microliters, less than 10 microliters, less than 5 microliters, 3 to 7 microliters, or the like. In other embodiments, the average initial spray velocity of the stream of microdose droplets is at least about 3m/s, 4m/s to about 12m/s, etc. In other embodiments, the microdose droplet stream has an average ejected droplet diameter of at least 15 microns, 20 to 60 microns, and the like. In other embodiments, the stream of microdose droplets is delivered to the eye of the subject in less than 80 milliseconds.

In certain aspects, wherein the composition comprises atropine at a concentration of at least 0.5 wt.%, at least 0.8 wt.%, 1 wt.% or more, 0.5 to 1.2 wt.%, and the like.

In other aspects, during generation and delivery of the stream of microdose droplets, the piezoelectric droplet delivery device is oriented at an angle of less than 25 ° to the horizontal.

These and other features will become apparent from the following description of the preferred embodiments, the claims and the accompanying drawings.

Detailed Description

The present disclosure provides methods and devices that improve upon prior art methods and devices for delivering atropine to the eye. In particular, contrary to current trends, the present disclosure uses relatively higher concentrations of atropine in the solution to be administered, but delivers much smaller doses to the subject, thereby reducing or even preventing excess liquid from not being absorbed by the target tissue. Maintaining a higher concentration of atropine in the solution to be administered may also reduce or avoid the instability problem of low concentration solutions.

In certain aspects, the present disclosure provides methods of delivering a composition comprising atropine to the eye of a subject in need thereof in a stream of microdroplet droplets. The method generally comprises: (a) generating a stream of microdose droplets via a piezoelectric droplet delivery device, the stream of microdose droplets comprising a composition comprising atropine, wherein the mean ejected droplet diameter of the stream of microdose droplets is greater than 15 microns; and (b) delivering a stream of microdose droplets to the eye of the subject. In certain embodiments, myopia, particularly progressive myopia (nearsightedness) in adults and children, is treated by the method in a subject in need thereof.

In certain aspects, the methods and devices of the present invention utilize relatively high concentrations of atropine to avoid the stability problems of the currently preferred low concentration formulations.

In certain embodiments, the present disclosure provides a piezoelectric droplet delivery device configured to achieve many times more accurate micro-dosing than conventional eye droppers. In certain aspects, the microdosing delivers a dose of 6 to 8 μ Ι _ in a targeted manner, directly covering the corneal surface (where 80% of intraocular drug penetration occurs), rather than covering the conjunctiva of the subject's eye.

Without intending to be limited by theory, it is believed that concentrating the active agent to be administered to a substantial portion (i.e., more than 50%, 60%, 70%, 80%, etc.) of the subject's eye directly on the corneal surface rather than the conjunctiva reduces exposure of collateral tissue. In this regard, it is believed that direct administration to the corneal surface will reduce the potential systemic exposure of the active agent by more than 75%, thereby reducing toxicity and enabling potentially milder and more tolerable treatments. In other aspects, the micro-therapy methods of the present disclosure also reduce waste associated with conventional eye droppers.

In other aspects, advantages of the methods of microdosing of the present disclosure include:

dose reduction: microdosing achieves precise volume control at the microliter level to deliver 6 to 8 μ L, which is the physiological volume of the tear film, e.g., which can lead to overdosing, ocular toxicity, and systemic infiltration of plasma, as compared to 30 to 50 μ L bolus doses of an eye dropper pipette.

Targeted dose instillation: the piezoelectric droplet delivery devices described herein allow targeted delivery to the ocular surface and cornea, avoiding the conjunctival fornix. The jet of droplets produced by the piezoelectric vibration is focused and concentrated to provide precise delivery to the corneal surface where most ocular penetration occurs. Further, in certain embodiments, the device may include an LED targeting mechanism to allow for proper positioning and target alignment.

The delivery speed is as follows: unlike simple nebulizing mechanisms, piezoelectric droplet delivery devices provide micro-droplet ejection control, which results in rapid and targeted micro-jet delivery that provides ejected droplets to the ocular surface in less than 80 milliseconds, defeating the 100 millisecond transient reflections of the eye.

The intelligent electronic device: in certain embodiments, the piezoelectric droplet delivery device includes intelligent electronics and mobile electronic health technology designed to track as the patient undergoes treatment. This enables the physician to accurately monitor patient compliance. In certain aspects, this technique will improve compliance and improve chronic disease management by permitting patients and physicians access to dynamic, real-time monitoring and compliance data, thereby enabling a more intelligent and personalized treatment modality.

In other aspects, the present disclosure relates generally to piezoelectric droplet delivery devices, such as may be used to deliver a directed stream of droplets for ophthalmic use, and more particularly, for delivering ophthalmic fluid to the eye. Droplets may be formed by the ejector mechanism from a fluid contained in a reservoir coupled to the ejector mechanism. Unless otherwise described herein, the sprayer mechanism and reservoir may be disposable or reusable, and the assembly may be packaged in a housing of the sprayer device.

In certain embodiments, devices are provided and methods are described for reproducibly delivering a therapeutically effective small volume microdose composition to a desired target (e.g., the eye of a subject in need thereof, as opposed to using standard eye droppers and dose volumes). In certain aspects, the low volume microdose of the composition comprises atropine at a concentration of at least 0.5 wt.%, at least 0.7 wt.%, at least 0.8 wt.%, 1 wt.%, etc. In certain aspects, the devices and methods are used to treat myopia, particularly progressive myopia (nearsightedness) in adults and children. In certain aspects, a therapeutically effective low volume microdose of the composition may be delivered to the eye, for example, in 3/4, 1/2, 1/4, 1/6, 1/8 (e.g., about 0.02 to 0.75) volumes of standard eye dropper volume. By way of example, in certain embodiments, 0.5 μ Ι to 15 μ Ι, 3 μ Ι to 8 μ Ι, 7 μ Ι to 8 μ Ι, less than 15 μ Ι, less than 13 μ Ι, less than 10 μ Ι, less than 8 μ Ι, less than 5 μ Ι, etc., of a microdose composition can be delivered to the eye of a subject while achieving an equivalent or improved therapeutic effect as compared to delivering about 25 μ Ι to about 70 μ Ι of the microdose composition by a standard eyedropper.

The administration strategy may also include various methods to start treatment, stop treatment, switch treatment, and respond to different subject states. Examples of modes or strategies of administration include once daily, twice daily, three times daily, continuous, single (bolus dosing), weekly, monthly, gradual, on demand, and feedback dosing by a physician, human, subject, or home. In addition, the dosing regimen may include dosing per eye, as desired. Clinical protocols in which these methods may be employed include chronic diseases, exacerbations of diseases, need for inhibition therapy, need for relapse therapy, or treatment states such as drug tolerance.

One embodiment discloses a method of delivering a therapeutically effective low volume microdose composition to the eye of a subject in need thereof, compared to the dose volume of a standard eye dropper, for example for the treatment of myopia, in particular progressive myopia (myopic eye) in adults and children, comprising: (a) producing a directed stream of droplets of a low volume microdose composition, wherein the droplets have a desired average droplet size and average initial spray velocity; and (b) delivering a therapeutically effective amount of droplets of the low volume microdose composition to the eye of the subject, wherein the droplets deliver a desired percentage of droplet jets to the eye. Also, in certain aspects, the low volume microdose of the composition comprises atropine at a concentration of at least 0.5 wt.%, at least 0.7 wt.%, at least 0.8 wt.%, 1 wt.%, 0.5 to 1.2 wt.%, and the like.

Described herein are devices capable of providing and delivering therapeutically effective low volume microdose compositions to the eye. By way of example, a droplet delivery device may include a housing including a fluid reservoir in fluid communication with an ejector mechanism. The directed stream of droplets may be generated via an ejector mechanism comprising a generator plate and a piezoelectric actuator, wherein the generator plate comprises a plurality of openings formed through a thickness thereof. The piezoelectric actuator may be operable to oscillate the generator plate, directly or indirectly, at a frequency to generate a directed stream of droplets of the low volume microdosing composition.

Without limitation, the droplet delivery device may be as described in US 8,684,980 or WO 2018/227190, the entire contents of which are incorporated herein by reference.

In one embodiment, the device further comprises a fluid enclosure system to facilitate the ejection of the stream of droplets. In such embodiments, the fluid to be delivered to the eye is contained in a housing that retains the fluid to be dispensed in a chamber defined by the housing. The housing holds a dose of fluid in the vicinity of the opening of the generator plate of the ejector mechanism, so that the fluid can be ejected in a short time with little residual volume.

The housing has a lip positioned adjacent the generator plate. The lip may not be attached to the generator plate but still be in contact with the generator plate, or may be spaced a small distance such that surface tension holds the fluid in the chamber. When vibrating, the generator plate may have a relatively small maximum amplitude which is smaller than the average separation distance between the lip and the generator plate or smaller than the minimum separation distance between the lip and the generator plate.

The housing may be shaped to cooperate with the generator plate to avoid capillary feeding near the generator plate opening. To this end, the housing may be spaced from the generator plate such that at least 75%, at least 95%, or all of the openings are spaced from the proximal-most portion of the housing by at least 0.014. The housing may also be shaped so that all fluid can reach the generator plate openings in a short time. The housing may be configured to have an interior surface shape that is in contact with the fluid such that at least 75%, at least 95%, or even all of the interior surface is no more than 0.060 inches or no more than 0.040 inches from a nearest opening of the plurality of openings of the generator plate. In other words, the housing has an interior surface shaped such that the chamber is formed with at least 75%, at least 95%, or all of the interior surface having a direct line of sight to at least one of the openings of the generator plate. The interior surface of the housing may be hydrophobic over at least 70% of the interior surface in contact with the fluid.

The lip can be biased against the generator plate with moderate force to prevent fluid from escaping without over damping the vibration. The lip may exert a force on the vibratory element of no more than 3g-f, the force being measured in the direction of the central axis of the vibratory element. The lip may also apply a spring load to the generator plate so that minor displacements due to temperature, pressure or shock caused by an impact (drop) can be accommodated. The spring load may also help account for manufacturing tolerances that affect the load applied by the lip to the generator plate. The lip may exert a spring load on the generator plate, wherein the average spring constant does not exceed 60g-f/mm for displacements up to 0.050 mm. The housing itself may be resilient, with the walls of the housing having a tapered portion with relatively thin walls to provide flexibility. The ratio of radial displacement to longitudinal displacement of the tapered portion of the wall is at least 1 to 3, at least 1 to 2, and may be at least 1 to 1. In other words, the tapered portion also extends radially at least half the effective radius of the open end of the housing relative to the open end of the housing. The lip and/or the vibrating element may have PTFE coatings adjacent to each other to reduce friction therebetween. The coating may extend approximately at least 270 degrees when viewed along the central axis.

The housing may allow air to enter to replace the fluid ejected through the opening of the generator plate and/or between the lip and the generator plate, and may not include a dedicated exhaust opening. The maximum amplitude may be slightly smaller, which allows air to enter the chamber while still preventing fluid from escaping from the chamber. The envelope-to-generator-plate interface defines a closed boundary (which may be defined by the generator plate or envelope) that is slightly larger than the extent of the opening, with an additional area that extends radially outward at least 0.3 times the effective radius of the closed feed area.

The housing may include a wall opening through the wall that exposes the chamber through the wall. The wall is open. A wall opening extends through the wall to expose the chamber through the wall without allowing fluid to escape, while allowing air to enter when fluid is ejected. The wall opening has a longitudinal dimension measured from the lip in a direction of the central axis and a radial dimension measured in a radial direction relative to the central axis. The housing also has an inner wall, one side of which faces the opening in the generator plate. The longitudinal dimension of the wall opening is at least 80% of the separation distance between the generator plate and the side of the housing facing the opening. The radial dimension of the wall opening may be no more than 10% of the lip circumference, or no more than 5%.

The wall opening tapers as it extends proximally away from the lip. The wall opening extends proximally from the lip and the peripheral dimension of the wall opening decreases as the wall opening extends proximally from the lip. The wall opening is tapered such that the conical shape is oriented in the direction of the fluid inlet of the housing when viewed along the central axis. The wall opening may also extend through the frustoconical portion of the wall, and may extend proximally from the lip for at least 80% of the length of the frustoconical portion.

The fluid may be rapidly delivered at a relatively high velocity and pressure to encourage all of the fluid to collect in the chamber. The total downstream volume of the fluid path from the pump or valve of the isolation chamber may be sized slightly larger than the volume that allows the fluid to move slightly within the housing and coalesce into a single drop due to surface tension. The volume of fluid may be 40% to 70% of the total downstream volume.

The housing may also divide the fluid flow into at least two (and may be three, four or more) inlets to the chamber. Each of the inlets directs fluid at the sidewall before the fluid is directed to the plurality of openings of the generator plate. The housing has a main inlet that directs fluid in a direction within 30 degrees of the central axis, while the inlet to the chamber is oriented at 60 to 90 degrees from the central axis and directed to the sidewall. The housing may be an integrally formed structure defining the chamber.

The pump may have a first portion and a second portion that reciprocate in a single cycle between a storage position, a forward stroke position, and a return to storage position. A cavity is formed between the two parts, wherein fluid is drawn into the cavity and subsequently discharged into the chamber. The air make-up chamber may also be coupled to a pump to force air into the fluid reservoir during each cycle to actively vent the fluid reservoir.

It should be understood that the droplet delivery device can be divided into reusable and disposable portions in myriad different combinations. For example, the housing may form part of a reusable device with the ejector mechanism, or may be discarded with the reservoir, without departing from the scope of the invention.

In certain aspects, a stream of droplets can be generated by the apparatus described herein in a controlled size distribution, each distribution having an average droplet size. In certain embodiments, the average droplet size can range from at least about 15 microns, from about 15 microns to about 100 microns, from about 20 microns to about 100 microns, from greater than 20 microns to about 100 microns, from about 20 microns to about 80 microns, from about 25 microns to about 75 microns, from about 30 microns to about 60 microns, from about 35 microns to about 55 microns, and the like.

The device may also deliver fluid at a relatively high rate, which helps the fluid to "adhere" to the target tissue, in this case corneal tissue, thereby achieving direct coverage of the corneal surface with the fluid. Eye droppers, on the other hand, do not have the ability to target specific areas of the eye and deliver liquid at high speed. The ophthalmic drops are large enough to migrate and penetrate into undesired areas after delivery. In this regard, the average initial jetting velocity of the droplets can be from about 0.5m/s to about 20m/s, such as from about 0.5m/s to about 15m/s, from about 0.5m/s to about 10m/s, from about 1m/s to about 10m/s, from about 4m/s to about 12m/s, from about 1m/s to about 5m/s, from about 1m/s to about 4m/s, at least about 2m/s, at least about 3m/s, at least about 4m/s, at least about 5m/s, and the like. As used herein, the jet size and jet initiation velocity are the size and velocity of the droplet as it exits the ejector plate. A stream of droplets directed to the target will result in a certain mass percentage of the droplets (including their composition) being deposited at the desired location.

In certain aspects of the present disclosure, the ejector device will eject droplets without substantial evaporation, entrainment of air, or deviation from a target surface (e.g., the surface of the eye), which facilitates consistent dosing. The average ejected drop size and average initial ejection velocity depend on a number of factors, including fluid viscosity, surface tension, ejector plate characteristics, geometry and size, and the operating parameters of the piezoelectric actuator, including its drive frequency. In some embodiments, about 60% to about 100%, about 65% to about 100%, about 75% to about 100%, about 80% to about 100%, about 85% to about 100%, about 90% to about 100%, about 95% to about 100%, etc., of the droplet spray is deposited on the surface of the eye, such deposition being repeatable, regardless of operating and use conditions.

The direction of flow of the stream of droplets may be horizontal or any direction in which the user selects to aim the actuating mechanism during use. In certain aspects, the device may be oriented substantially horizontally, e.g., within 5 ° of horizontal, within 10 ° of horizontal, within 15 ° of horizontal, within 20 ° of horizontal, within 25 ° of horizontal, etc., and may assist a user in aiming the device. For example, light, mirrors or other visual alignment features known in the art may be used. Horizontal delivery with alignment assistance may also improve ease and repeatability compared to eye droppers that do not have a "targeting" mechanism and the droplets are too large to target only corneal tissue. In this regard, it has been found that the same amount of drug with horizontal targeted corneal delivery and coverage achieves a better pharmacodynamic effect than the same amount of drug administered in an eye dropper.

Droplet properties are generally related to particle diameter. Without intending to be limiting, the ejected droplets are decelerated to a stop (i.e., the stopping distance of the ejected droplets) by air resistance. The ejected droplets also fall vertically due to gravity. After a short acceleration time, the droplets reach a final velocity, at which point the resistance force equals gravity. The ejected droplets may carry air with themselves, creating an entrained air flow, which helps to then carry the ejected droplets beyond the calculated stopping distance. However, an increase in the level of entrained air may cause ejected droplets to flow across an impact surface (e.g., the eye surface) because the entrained airflow must turn 90 degrees at such a surface. The ejected droplets (e.g., droplets having an average diameter of less than about 17 microns, less than about 15 microns, etc.) are carried along the eye surface by the airflow and may not impact the surface. In contrast, larger jetted droplets produce less entrained air than smaller droplets of equal mass, and have sufficient momentum to impact a surface. The drop stopping distance of the jet is a measure of this effect.

Various factors, including those described herein, can affect the desired dosage. Once the desired dose and, if desired, the desired frequency are determined, such a dose can be delivered. The frequency of administration may vary depending on the number, period, or both.

The term "therapeutically effective" amount refers to an amount of an active agent that is used to treat, ameliorate, prevent or eliminate an identified ophthalmic condition (e.g., a disease or disorder) or to exhibit a detectable therapeutic or prophylactic effect. The effect may be detected by, for example, a chemical marker, antigen level, or time to a measurable event, such as morbidity or mortality. The precise effective amount of the subject will depend upon the weight, size and health of the subject; the nature and extent of the disorder; and selecting the therapeutic agent or combination of therapeutic agents for administration. The effective amount in a given situation may be determined by routine experimentation within the skill and judgment of the clinician. Any of the agents may be provided in an effective amount.

In one aspect, the concentration of the active ingredient in the medicament is measured as a percentage of the active ingredient in the solution. In one aspect, the concentration of the active ingredient ranges from about 0.0001% to about 5%. In another aspect, the concentration of the active ingredient in the medicament ranges from about 0.05% to about 1%. In other aspects, the concentration of the active ingredient ranges from about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.75%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 4%, and about 5% by weight of the solution. However, higher concentrations may be used depending on the intended use given the lower dosages provided by the methods of the present disclosure.

The present invention has been described with reference to certain embodiments, however, various modifications may be made without departing from the features and aspects of the present invention.

Claims (16)

1. A method of delivering a composition comprising atropine in a stream of microdroplet droplets to the eye of a subject in need thereof, the method comprising:

(a) generating a stream of microdose droplets via a piezoelectric droplet delivery device, the stream of microdose droplets comprising the composition comprising atropine, wherein the stream of microdose droplets has a mean jetted droplet diameter greater than 15 microns; and

(b) delivering the microdose stream of droplets to the eye of the subject.

2. The method of claim 1, wherein the method treats myopia in a subject in need thereof.

3. The method of claim 1, wherein the microdose stream of droplets delivered to the eye of the subject is less than 13 microliters.

4. The method of claim 1, wherein the stream of microdose droplets delivered to the eye of the subject is less than 10 microliters.

5. The method of claim 1, wherein the stream of microdose droplets delivered to the eye of the subject is less than 5 microliters.

6. The method of claim 1, wherein the stream of microdose droplets delivered to the eye of the subject is 3 to 7 microliters.

7. The method of claim 1, wherein the microdose stream of droplets has an average initial jet velocity of at least about 3 m/s.

8. The method of claim 1, wherein the microdose stream of droplets has an average initial jet velocity of about 4m/s to about 12 m/s.

9. The method of claim 1, wherein the composition comprises atropine at a concentration of at least 0.5% by weight.

10. The method of claim 1, wherein the composition comprises atropine at a concentration of at least 0.8% by weight.

11. The method of claim 1, wherein the composition comprises atropine at a concentration of 1% by weight or greater.

12. The method of claim 1, wherein the composition comprises atropine at a concentration of 0.5 to 1.2 weight percent.

13. The method of claim 1, wherein the microdose stream of droplets is delivered to the eye of the subject in less than 80 ms.

14. The method of claim 1, wherein the microdose droplet stream has an average jetted droplet diameter of 20 to 60 microns.

15. The method of claim 1, wherein during the generation and delivery of the stream of microdose droplets, the piezoelectric droplet delivery device is oriented at an angle of less than 25 ° to a horizontal plane.

16. The method of claim 1, wherein the piezoelectric droplet delivery device comprises an ejector mechanism comprising a generator plate and a piezoelectric actuator, wherein the generator plate comprises a plurality of openings formed through a thickness thereof; and wherein the piezoelectric actuator is operable to oscillate the generator plate, directly or indirectly, at a frequency to generate a directed stream of droplets of the low dose volume pharmaceutical composition.