阅读说明：本技术 用于以微剂量液滴流向眼睛递送毛果芸香碱的方法和装置 (Method and apparatus for delivering pilocarpine to the eye in a microdose droplet stream ) 是由 T·艾恩丘勒夫 L·克劳森 于 2020-03-02 设计创作，主要内容包括：本公开内容提供用于向眼睛递送毛果芸香碱的方法和装置。在某些方面,本公开内容提供用于以微剂量液滴流向有需要的受试者的眼睛递送包含毛果芸香碱的组合物的方法。在某些实施方案中,所述方法在有需要的受试者中治疗或缓解老视(特别是年龄40岁或更年长的成人的老视)的一个或多个症状。在某些实施方案中,本公开内容在待施用的溶液中使用相对高浓度的毛果芸香碱,且其作为单一活性剂。(The present disclosure provides methods and devices for delivering pilocarpine to the eye. In certain aspects, the present disclosure provides methods for delivering a composition comprising pilocarpine in a microdose droplet flow to the eye of a subject in need thereof. In certain embodiments, the methods treat or alleviate one or more symptoms of presbyopia (particularly presbyopia in adults 40 years of age or older) in a subject in need thereof. In certain embodiments, the present disclosure uses pilocarpine in a relatively high concentration in the solution to be administered, and as a single active agent.)

1. A method of delivering a composition comprising pilocarpine 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 comprising a pilocarpine-containing composition via a piezoelectric droplet delivery device, wherein the stream of microdose droplets has a mean spray droplet diameter of 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 composition comprises pilocarpine as the single active agent.

3. The method of claim 1, wherein the pilocarpine-containing composition is free of analgesic drugs, including non-steroidal anti-inflammatory drugs (NSAIDs), antihistamines, or decongestants.

4. The method of claim 1, wherein the method treats or alleviates one or more symptoms of presbyopia in the subject in need thereof.

5. The method of claim 1, wherein the method provides a temporary improvement in functional near vision in presbyopia as compared to placebo.

6. The method of claim 1 wherein said composition comprises pilocarpine at a concentration of at least about 0.5% by weight.

7. The method of claim 1 wherein the composition comprises pilocarpine at a concentration of at least about 1% by weight.

8. The method of claim 1, wherein the composition comprises pilocarpine at a concentration of about 1% to about 4% by weight.

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

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

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

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

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

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

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

16. The method of claim 1, wherein the stream of microdose droplets has a mean jetted droplet diameter of 20 to 60 microns.

17. The method of claim 1, wherein during the generating and delivering of the microdose droplet stream, the piezoelectric droplet delivery device is oriented within 25 ° of horizontal.

18. 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 that generates a directed stream of droplets of the low dose volume pharmaceutical composition.

Field of the invention

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

Background of the invention

Presbyopia typically affects patients in the late years (e.g., after about 40 years of age) and is characterized by loss of accommodative vision, which results in a reduction in quality of life. Current treatments for presbyopia are typically reading glasses or bifocal glasses. There is a great need for safe, non-invasive and reversible treatments that enhance reading vision and accommodation. In this regard, there is currently no approved drug therapy. However, in recent years, a drug solution for presbyopia has been proposed. Exemplary pharmaceutical methods as reported in the literature are provided in the following table, including examples of administration of pilocarpine mixtures and combinations for presbyopia treatment.

Typical drops of drug dispensed, such as through an eye drop bottle, can vary depending on the viscosity and surface tension of the fluid. In order to control the amount of active ingredient administered in a single drop, 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 retain only 7 μ l of fluid at a time, even a single drop of drug can result in some drug spillage and loss from the eye. The problem of drug retention in the eye is often exacerbated by multiple drop volumes. The subject will typically administer all of the droplets required for a dose once, which exacerbates the problem and can cause 50% -90% of the drug to spill and leak from the eye.

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

Disclosure of Invention

In certain aspects, the present disclosure provides methods of delivering a composition comprising pilocarpine in a stream of microdose droplets to the eye of a subject in need thereof. The method generally comprises: (a) generating a stream of microdose droplets comprising a pilocarpine-containing composition via a piezoelectric droplet delivery device, wherein the stream of microdose droplets has a mean spray droplet diameter of greater than 15 microns; and (b) delivering the stream of microdose droplets to the eye of the subject. In certain embodiments, the methods treat or alleviate one or more symptoms of presbyopia (particularly presbyopia in adults 40 years of age or older) in a subject in need thereof.

In certain embodiments, the methods and devices may use compositions comprising a relatively high concentration of pilocarpine as the single active agent. In certain embodiments, the pilocarpine-containing composition is free of analgesic drugs, including non-steroidal anti-inflammatory drugs (NSAIDs, such as nepafenac or diclofenac), antihistamines (such as pheniramine or decongestants (such as oxymetazoline, phenylephrine, or naphazoline), or other active agents.

In certain aspects, the small volume microdose of the composition comprises pilocarpine at the following concentrations: at least about 0.5% by weight, at least about 1% by weight, at least about 2% by weight, at least about 3% by weight, at least about 4% by weight, about 1% by weight, about 2% by weight, about 3% by weight, about 4% by weight, about 0.5 to about 1% by weight, about 0.5 to about 2% by weight, about 0.5 to about 3% by weight, about 0.5 to about 4% by weight, about 1 to about 2% by weight, about 1 to about 3% by weight, about 1 to about 4% by weight, and the like.

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 that generates a directed stream of droplets of the 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 stream of microdose droplets has an average initial spray velocity of at least about 3m/s, 4m/s to about 12m/s, etc. In other embodiments, the stream of microdose droplets has an average ejected droplet diameter of at least 15 microns, 20-60 microns, and the like. In still other embodiments, the stream of microdose droplets is delivered to the eye of the subject in less than 80 ms.

In still other aspects, during generation and delivery of the microdose stream of droplets, the piezoelectric droplet delivery device is oriented within 25 ° of 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 the prior art for methods and devices for delivering pilocarpine to the eye. Specifically, contrary to current trends, the present disclosure uses a relatively higher concentration of pilocarpine in the solution to be administered, but delivers a much smaller volume/dose to the subject, thereby reducing and even preventing excess fluid from being absorbed by the target tissue. Maintaining a higher concentration of pilocarpine in the solution to be administered may also reduce or avoid the instability problems of lower concentration solutions.

Furthermore, without intending to be limited by theory, previous attempts to use pilocarpine have focused on compositions comprising mixtures and combinations of active agents to mitigate the potential side effects of pilocarpine. Pilocarpine is effective in inducing miosis, and also can cause change in myopia due to accommodation spasm and migraine caused by stimulation of ciliary muscle by muscarinic. Pilocarpine can also cause chronic anterior ocular inflammation, adhesions, and pigment spread. Thus, previous methods have used additional active agents to relieve ciliary muscle spasm, vascular congestion, and congestion induced by pilocarpine in an attempt to avoid excessive pupil constriction. For example, NSAIDs may be co-administered to reduce inflammation, but these co-administered agents do not address the problem of near vision changes. In accordance with aspects of the present disclosure, it has surprisingly been found that relatively high concentrations of pilocarpine in solution can be administered in small volume microdoses without the need for mixed administration or combined administration.

In certain embodiments, the methods and devices may employ a composition comprising a relatively high concentration of pilocarpine as the single active agent. In certain embodiments, the pilocarpine-containing composition is free of analgesic drugs, including non-steroidal anti-inflammatory drugs (NSAIDs, such as nepafenac or diclofenac), antihistamines (such as pheniramine or decongestants (such as oxymetazoline, phenylephrine, or naphazoline), or other active agents.

In certain aspects, the present disclosure provides methods of delivering a composition comprising pilocarpine in a stream of microdose droplets to the eye of a subject in need thereof. The method generally comprises: (a) generating a stream of microdose droplets comprising a pilocarpine-containing composition via a piezoelectric droplet delivery device, wherein the stream of microdose droplets has a mean spray droplet diameter of greater than 15 microns; and (b) delivering the stream of microdose droplets to the eye of the subject. In certain embodiments, the methods treat or alleviate one or more symptoms of presbyopia (particularly presbyopia in adults 40 years of age or older) in a subject in need thereof. In some embodiments, the methods are used to temporarily treat or alleviate one or more symptoms of presbyopia. For example, the method may provide a temporary improvement in functional near vision in presbyopia as compared to placebo.

In certain aspects, the methods and apparatus of the present invention use relatively high concentrations of pilocarpine to avoid the stability problems of currently preferred low concentration formulations.

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

Without intending to be limited by theory, it is believed that concentrating the majority (i.e., more than 50%, 60%, 70%, 80%, etc.) of the active agent of the eye of the subject to be administered directly to the corneal surface rather than to the conjunctiva reduces exposure of lateral (cornea) 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 greater 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 still other aspects, advantages of the methods of microdosing of the present disclosure include:

dose reduction: for example, in contrast to 30-50 μ L dropper pipette bolus resulting in overdosing, ocular toxicity, and systemic infiltration of plasma, microdosing achieves precise volume control at the microliter level to deliver 6-8 μ L, which is the physiological volume of the tear film.

Targeted dose instillation: the piezoelectric droplet delivery devices described herein allow for targeted delivery to the ocular surface and cornea, avoiding the conjunctival fornix (conjectional cul-de-sac). The droplet microjets produced by the piezoelectric vibrations are 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 that produces rapid and targeted micro-jet delivery, providing 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 comprises intelligent electronics and mobile electronic health technology is designed to track as the patient administers therapy. This enables the physician to accurately monitor patient compliance. In certain aspects, the techniques will improve compliance and chronic disease management by allowing patients and physicians access to dynamic, real-time monitoring and compliance data to achieve a more intelligent and personalized treatment paradigm.

In other aspects, the present disclosure relates generally to piezoelectric droplet delivery devices, for example, for delivering a directed droplet stream for ophthalmic use, and more particularly, for delivering ophthalmic fluids to the eye. Droplets may be formed by an 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 of a composition to a desired target (e.g., the eye of a subject in need thereof, as compared to using standard eye droppers and dose volumes). In certain aspects, the small volume microdose of the composition comprises pilocarpine at the following concentrations: at least about 0.5% by weight, at least about 0.7% by weight, at least about 0.8% by weight, at least about 1% by weight, at least about 2% by weight, at least about 3% by weight, at least about 4% by weight, and the like. In certain embodiments, the composition comprises about 1%, about 2%, about 3%, about 4%, about 1% to about 4%, etc. pilocarpine on a weight basis. In certain aspects, the devices and methods are used to treat or alleviate one or more symptoms of presbyopia, particularly presbyopia in adults aged 40 or older.

In certain aspects, a therapeutically effective small volume microdose of the composition may be delivered to the eye, for example, in a volume of 3/4, 1/2, 1/4, 1/6, 1/8, (e.g., about 0.02-0.75), and the like, of a standard eye dropper volume. For example, in certain embodiments, microdoses of the composition of 0.5 μ l to 15 μ l, 3 μ l to 8 μ l, 7 μ l to 8 μ l, less than 15 μ l, less than 13 μ l, less than 10 μ l, less than 8 μ l, less than 5 μ l, etc., can be delivered to the eye of a subject while achieving equivalent or improved therapeutic effect as compared to about 25 μ l to about 70 μ l by a standard eye dropper.

The administration strategy may also include various methods of starting treatment, stopping treatment, switching treatment, and responding to different subject states. Examples of modes or strategies of administration include once daily, twice daily, three times daily, continuous, bolus, weekly, monthly, tapered (taper), on demand, and feedback administration by a physician, supplier, subject, or family member. In addition, the dosing regimen may include dosing per eye, as desired. Clinical situations in which these modes or strategies of administration may be employed include chronic diseases, disease exacerbations, the need for inhibition therapy, the need for relapse therapy, or treatment states such as drug tolerance.

One embodiment discloses a method of delivering a therapeutically effective small volume microdose composition to the eye of a subject in need thereof, e.g., for treating or alleviating one or more symptoms of presbyopia (particularly presbyopia in an adult aged 40 years or older), as compared to the dose volume of a standard eyedropper, the method comprising: (a) generating a directed stream of droplets of a small 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 a small volume microdose composition to the eye of the subject, wherein the droplets deliver a desired percentage of the droplet ejection volume to the eye.

Also, in certain aspects, the small volume microdose of the composition comprises pilocarpine at the following concentrations: at least about 0.5 wt%, at least about 1 wt%, at least about 2 wt%, at least about 3 wt%, at least about 4 wt%, about 1 wt%, about 2 wt%, about 3 wt%, about 4 wt%, about 0.5 to about 1 wt%, about 0.5 to about 2 wt%, about 0.5 to about 3 wt%, about 0.5 to about 4 wt%, about 1 to about 2 wt%, about 1 to about 3 wt%, about 1 to about 4 wt%, and the like.

In certain embodiments, the methods and devices may utilize compositions comprising a relatively high concentration of pilocarpine as the single active agent. In certain embodiments, the pilocarpine-containing composition is free of analgesic drugs, including non-steroidal anti-inflammatory drugs (NSAIDs, such as nepafenac or diclofenac), antihistamines (such as pheniramine or decongestants (such as oxymetazoline, phenylephrine, or naphazoline), or other active agents.

In certain embodiments, the methods provide for the treatment and/or alleviation of one or more symptoms of presbyopia in a subject in need thereof. In certain embodiments, treating and/or alleviating one or more symptoms of presbyopia comprises increasing vision accommodation within less than about 30 minutes, less than about 1 hour, less than about 2 hours, less than about 3 hours, less than about 4 hours, less than about 5 hours, less than about 6 hours, etc., from initial application of the droplet stream. In certain embodiments, the vision adjustment has a sustained effect of at least 2 hours, at least 4 hours, at least 6 hours, and the like. In certain embodiments, a 10% increase, a 20% increase, a 25% increase, a 30% increase, a 40% increase, a 50% increase, etc., in regulatory capacity is obtained. In certain embodiments, a% 2 line improvement in visual accommodation over naked eye vision (UCVA) is achieved.

Described herein are devices capable of providing and delivering therapeutically effective small volume microdose compositions to the eye. For example, the 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 its thickness. The piezoelectric actuator may be operable to oscillate the generator plate, directly or indirectly, with a frequency that produces a directed stream of droplets of a small volume microdose composition.

Without being limited thereto, the droplet delivery device may be as described in US 8,684,980 or WO 2018/227190, herein incorporated by reference in their entirety.

In one embodiment, the device further comprises a fluid enclosure (enclosure) system to facilitate the ejection of a stream of droplets. In this embodiment, the fluid to be delivered to the eye is contained in an enclosure that holds the fluid to be dispensed in a chamber defined by the enclosure. The enclosure keeps the fluid dose near the opening of the generator plate of the ejector mechanism, whereby the fluid can be ejected in a short time and little residual volume is left behind.

The enclosure has a lip (lip) positioned adjacent to the generator plate. The lip may be unconnected to the generator plate but still in contact with the generator plate or may be spaced a small distance apart whereby surface tension holds the fluid in the chamber. The generator plate may have a relatively small maximum amplitude of vibration when vibrating, 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 enclosure may also be shaped to cooperate with the generator plate to avoid capillary feed near the generator plate opening. To this end, the enclosure may be spaced from the generator plate such that at least 75%, at least 95%, or all of the openings are spaced from the nearest portion of the enclosure by at least 0.014. The enclosure may also be formed so that all of the fluid reaches the generator plate openings in a short time. The enclosure may be configured with an inner surface shape that is in contact with the fluid, whereby at least 75%, at least 95%, or even all of the inner 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 enclosure has an inner surface shaped such that at least 75%, at least 95%, or all of the inner surface of the cells formed has a direct line of sight to the at least one opening of the generator plate. The inner surface of the enclosure may be hydrophobic over at least 70% of the inner surface in contact with the fluid.

The lip may be biased against the generator plate with moderate force to prevent fluid from escaping without over-dampening the vibration. The lip may exert a force on the vibratory element of no more than 3 grams-f, measured in the direction of the central axis of the vibratory element. The lip may also apply a spring load to the generator plate, thereby accommodating small displacements due to temperature, pressure, or shock from an impact (drop). The spring load may also help to account for manufacturing tolerances that affect the load that the lip exerts on the generator plate. For displacements up to 0.050mm, the lip may exert a spring load on the generator plate with an average spring constant of no more than 60 grams-f/mm. The enclosure itself may be resilient, with the walls of the enclosure having a tapered portion with a relatively thin wall to provide flexibility. The ratio of radial displacement to longitudinal displacement of the tapered portion of the wall is at least 1:3, at least 1:2, and may be at least 1: 1. In other words, the tapered portion also extends radially relative to the open end of the enclosure by at least half of the effective radius of the open end of the enclosure. The lip and/or the vibrating element may have PTFE coatings abutting each other to reduce friction therebetween. The coating may extend at least 270 degrees around when viewed along the central axis.

The enclosure may allow air to enter to replace the spray fluid through the opening of the generator plate and/or between the lip and the generator plate, and may not include a dedicated air vent. The maximum amplitude may be slightly less, which allows air to enter the chamber while still preventing fluid from escaping from the chamber. The enclosure-to-generator plate interface defines an enclosure boundary (which may be defined by a generator plate or enclosure) that is slightly larger than the extent of the opening, with additional regions that extend radially outward at least 0.3 times the effective radius of the enclosed liquid feed region.

The enclosure may include a wall opening through the wall that exposes the chamber through the wall. The wall is open. The wall opening extends through the wall to expose the chamber through the wall without allowing fluid to escape, while allowing air to enter when the 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 enclosure also has an inner wall with a side facing the opening of 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 enclosure facing the opening. The radial dimension of the wall opening may be no more than 10% or no more than 5% of the lip periphery.

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 taper is oriented in the direction of the fluid inlet to the enclosure 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 delivered rapidly and at relatively high velocity and pressure to encourage all of the fluid to be concentrated in the chamber. The total downstream volume of the fluid path from the pump or valve that isolates the cells may be slightly larger than the volume that allows the fluid to move slightly within the enclosure 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 enclosure may also divide the flow of liquid to at least two (and possibly three, four or more) inlets of the cell. Each inlet directs fluid at the side wall before it is directed at the plurality of openings of the generator plate. The enclosure has a main inlet that directs fluid flow in a direction within 30 degrees of the central axis, while the inlet to the chamber is oriented at 60-90 degrees of the central axis and directed at the side wall. The enclosure 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. Between the two parts a cavity is formed, in which the fluid is sucked and subsequently discharged into the chamber. The air supply 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 split into a myriad of different combinations of reusable and disposable portions. For example, the enclosure may form part of a reusable device with the ejector mechanism, or may be disposable with the reservoir, without departing from the scope of the invention.

In certain aspects, the droplet streams can be generated by the devices described herein in controllable size distributions, 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 velocity, which helps the fluid "adhere" to the target tissue (in this case, corneal tissue), achieving direct coverage of the corneal surface by the fluid. In another aspect, the eye dropper does not have the ability to target a particular area of the eye and deliver fluid at high speed. The eye drops are large enough to migrate and penetrate into undesired areas after delivery. In this regard, the droplets can have an average initial ejection velocity of about 0.5m/s to about 20m/s, such as about 0.5m/s to about 15m/s, about 0.5m/s to about 10m/s, about 1m/s to about 10m/s, about 4m/s to about 12m/s, about 1m/s to about 5m/s, 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 at the target will cause a partial amount of the droplets, including their composition, to be deposited at the desired location.

In certain aspects of the present disclosure, the ejector device will eject droplets without substantially evaporating, entraining air, or deflecting away from a target surface (e.g., eye surface), which facilitates consistent drug delivery. The average ejected drop size and average initial ejection velocity depend on factors including fluid viscosity, surface tension, ejector plate characteristics, geometry and dimensions, and the operating parameters of the piezoelectric actuator, including its drive frequency. In some embodiments, from about 60% to about 100%, from about 65% to about 100%, from about 75% to about 100%, from about 80% to about 100%, from about 85% to about 100%, from about 90% to about 100%, from about 95% to about 100%, etc., of the ejected droplet volume deposits on the surface of the eye, such deposits being repeatable, regardless of operating conditions and use conditions.

The direction of flow of the stream of droplets may be horizontal or any direction that a user selects to aim the actuation mechanism during use. In certain aspects, the device can be substantially horizontal, e.g., within 5 ° of horizontal, within 10 ° of horizontal, within 15 ° of horizontal, within 20 ° of horizontal, within 25 ° of horizontal, etc., and can assist a user in aiming the device. For example, lights, mirrors or other visual alignment features as known in the art may be used. Horizontal delivery with alignment assistance may also improve ease of use and repeatability as 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 higher pharmacodynamic effects are achieved using the same amount of drug horizontally targeted for corneal delivery and coverage as compared to administering the same amount of drug with an eye dropper.

Droplet properties are generally related to particle diameter. Without intending to be limited, 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 drop reaches a terminal velocity, at which point the resistance force equals gravity. The ejected droplets may carry air with them, creating an entrained airflow, which helps to subsequently carry the ejected droplets beyond the calculated stopping distance. However, an increase in the level of entrained air can result in the ejected droplets flowing past the impingement surface (e.g., the eye surface) because the entrained air flow must turn 90 degrees at the surface. Small 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 an equivalent amount of smaller droplets, and have sufficient momentum to impact a surface. The jetted drop stopping distance is a measure of this effect.

Various factors, including those described herein, can affect the desired dosage. Once the desired dose, and likewise the desired frequency, is determined, if desired, the 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 can be detected by, for example, chemical markers, antigen levels, or time to a measurable event (e.g., morbidity or mortality). The exact effective amount for a subject will depend on the weight, size and health of the subject; the nature and extent of the condition; and selecting the treatment or combination of treatments to be administered. An effective amount for a given situation can be determined by routine experimentation, within the skill and judgment of the clinician. Any of the drugs can be provided in an effective amount.

In one aspect, the concentration of the active ingredient in the medicament is determined as the 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 range of the active ingredient is determined as a weight percent of the solution starting 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%. In certain embodiments, the concentration of active ingredient ranges from about 0.5% by weight, at least 0.8% by weight, 1% by weight or more, 2% by weight or more, 3% by weight or more, 4% by weight or more, 0.5-1.2% by weight, 0.5-2% by weight, 0.5-3% by weight, 0.5-4% by weight. However, in view of the lower dosage provided by the methods of the present disclosure, higher concentrations may be used depending on the intended use.

Examples

Described herein is a multi-center, double-blind, placebo-controlled study that evaluates the safety and efficacy of administering a relatively high concentration (1% -4%) of pilocarpine solution in a small volume microdose to temporarily improve near vision in subjects with presbyopia.

Purpose of study

The primary objective of this study was to evaluate the safety and efficacy of administration of pilocarpine solution (1% -4%) via the piezoelectric droplet delivery device described herein for the temporary improvement of functional near vision for presbyopia as compared to placebo.

Research products

Product, dosage and mode of administration:

1% (about 8 μ l) ophthalmic solution of pilocarpine self-administered bilaterally in microdose using a piezoelectric droplet delivery device

2% (about 8 μ l) ophthalmic solution of pilocarpine self-administered bilaterally in microdose using a piezoelectric droplet delivery device

4% (about 8 μ l) ophthalmic solution of pilocarpine self-administered bilaterally in microdose using a piezoelectric droplet delivery device

Placebo, dose and administration mode: a carrier of pilocarpine solution for self-administration by a liquid droplet device.

Research population

Up to 120 volunteer participants will be enrolled at 4-6 study sites and a minimum of 96 subjects will be randomized to study drug self-administration at treatment visit 1 to complete the follow-up visit to 84 or more subjects.

Design of research

This trial was a double-blind, actively controlled cross-dominance study that evaluated 4 study drugs administered by piezoelectric droplet delivery devices. The drugs evaluated were:

a 1% pilocarpine ophthalmic solution,

a 2% ophthalmic solution of pilocarpine,

a pilocarpine 4% ophthalmic solution, and

vehicle solution (placebo)

Volunteer participants will be screened for study eligibility during the screening visit and enrolled after signing the study specific Informed Consent Form (ICF). Subjects meeting all inclusion/exclusion criteria will be scheduled 4 treatment visits that must be performed at least 3 days apart but not more than 10 days apart. At each treatment visit, baseline measurements will be taken, followed by self-administration of 1 spray of dispensed study drug to both eyes (OU). Then, the efficacy and safety evaluation will be performed at specific time intervals. Study drug administration for each subject will likewise be randomized to one of 12 possible ranks of study drugs, and each subject will have received all four study drugs at the completion of the 4 th treatment visit. At several time points within 4 hours after drug administration, major study evaluations (DCNVA, DCIVA and pupil size) will be performed; the primary efficacy endpoint will be evaluated at 3 hours.

The crossover design will randomly assign subjects to one of 12 possible treatment orderings based on an orthogonal latin square design with 3 4x4 matrices. Jones, b, and m.g. kenward, 2015. Design and analysis of cross-over experiments (Design and analysis of cross-over trials.) CRC press, page 140. This design balances the lag effect in that each treatment is performed twice after each other treatment.

The study will be double blind. There will be no difference in the presentation of the administered study drug and study drug distribution will be hidden to all investigators performing ophthalmic assessments. A person observing study drug administration to a subject on a given day would not be allowed post-dose ophthalmic evaluation on that day. Subjects who missed an assessment or were otherwise unevaluable at any of the scheduled study time points will not be replaced.

The use of any systemic medication that may affect mydriasis or constriction will be recorded with the intention that no changes in frequency, dose or route of administration will occur during the course of the study unless medically indicated.

Inclusion criteria

The subjects eligible to participate in the study must meet the following criteria. Both eyes must meet eye criteria.

Male or female, age 40-60 years at screening visit

Complaints about poor near vision, effects activities related to daily life and the need to use reading glasses or bifocal glasses frequently

Near add power from +1.0D to +2.0D based on near visual acuity refraction requirements at screening visits

Monocular DCNVA was between 20/60-20/100 (inclusive) at both screening visit and baseline visit

Female subjects must have negative serum pregnancy test results at visit 1, after menopause, surgical sterilization or if fertility is possible, and agree to adopt an acceptable contraceptive modality throughout the study.

Acceptable methods include the use of at least one of:

intrauterine (intrauterine device), hormonal (oral, injection, patch, implant, ring), barrier with spermicide (condom, diaphragm) or abstinence.

Myopia ametropia (MRSE) is not less than-0.50D and not more than + 1.00D.

Best Corrected Distance Vision (BCDVA) of 20/20 or better for each eye

Understanding the protocol requirements and being able to provide signed informed consent prior to participation in any study-related operations

Ability to respond to all study treatment visits.

Exclusion criteria

Subjects with any of the following diseases, surgeries, or conditions are ineligible for study participation. Subjects were not enrolled if any of the eyes met any of the eye exclusion criteria.

Irregular or scattered light ≥ 1.00D

Diagnosis of any type of glaucoma or ocular hypertension

Previous narrow anterior angle, angle closure glaucoma or previous iridotomy, known pilocarpine hypersensitivity or pilocarpine contraindication

Benzalkonium chloride allergy

Clinically significant corneal, lens, central retina, ciliary body, or iris abnormalities including any of the following:

irregularly shaped pupils secondary to ocular trauma or congenital defects

Mydriatic fundus examination abnormalities recorded within 3 months of screening visit, or known history of retinal detachment or clinically apparent retinal disease history

History of traumatic iritis or hyphema

History of traumatic mydriasis or atrial recession

History of neurogenic pupil disorders (e.g., Hohner's syndrome, third cranial nerve palsy, Idle's pupil, Allo's pupil syndrome, etc.)

History of iris atrophy

History of chronic or acute uveitis

History of heterochromia iridis

Iris-corneal synechia (aposition)/history of contact

External ocular inflammation within 30 days of the screening visit

Screening visits preceded by any type of eye surgery or laser treatment, including any type of iris surgery (e.g., iridotomy, iridectomy, pupillometry)

The history of the occurance or past of dominant strabismus, amblyopia or ocular shock

Preexisting neurological diagnosis (e.g., cerebral palsy) or hereditary syndrome (e.g., Down's syndrome)

Temporary or permanent punctal plugs or history of pinhole cautery for monocular or binocular use

Gestation or lactation, or conception within 3 months after the screening visit

Mesopic pupillometry measurement <4.0mm

Any interventional study participating in testing drugs or devices within 30 days prior to screening visit or at any time during the study

Eyelid depressors (e.g., blepharospasm)

There was a history of RGP lens use within 4 weeks of screening and reluctance or inability to discontinue RGP lens use throughout the study period

Unwilling or unable to stop using soft contact lenses at all treatment visits

There was a history of drug or alcohol abuse within 1 year prior to the screening visit

Congenital heart abnormalities, valvular or other heart diseases with a history of present or past

A history of active ocular disease requiring topical or systemic ophthalmic drug, except for dry eye treated with Artificial Tears (AT). AT must be deactivated on the day of each treatment visit.

The presence of severe/severe ocular conditions or any other unstable physical condition that may appear to the investigator to interfere with study treatment and/or follow-up

Disabling arthritis or limited coordination of movement that would limit self-operation of the droplet device, at the discretion of the researcher

The immediate relatives of the investigators assigned to the study assessment or procedure.

End of therapeutic effect

Mesopic vision (2-3 cd/m) will be evaluated at baseline, 30 minutes, 90 minutes, 3 hours and 4 hours²) High contrast binocular DCNVA (near vision in distance vision correction). The primary efficacy endpoint will be assessed at 3 hours.

Mainly comprising

A proportion of subjects who benefited 15 letters or more on mesopic high contrast binocular DCNVA (near vision in distance vision correction) 3 hours after treatment compared to baseline.

Exploratory results: near Vision (DCNVA) (40cm) under far vision correction

High contrast DCNVA in mesopic vision 3 hours post treatment compared to baseline DCNVA

Proportion of subjects who benefited from 3 lines (15 letters) or more (primary endpoint was binocular DCNVA) (monocular)

Proportion of subjects who benefited 3 lines (15 letters) or more (primary endpoint of binocular DCNVA) on mesopic high contrast DCNVA (monocular and binocular) at other time points

Proportion of subjects who benefited 2 lines (10 letters) or more on mesopic high contrast DCNVA (monocular and binocular) at each time point

Mean change in DCNVA (monocular and binocular) from baseline at each time point

DCNVA distribution at each time point

Time from baseline to maximum average DCNVA

Exploratory results: intermediate (intermediate) vision (DCIVA) with distance vision correction (40cm)

High contrast DCIVA in mesopic vision 3 hours after treatment compared to baseline DCIVA

Proportion of subjects who benefited on (eyes) 3 lines (15 letters) or more

Proportion of subjects who benefited 3 lines (15 letters) or more on mesopic high contrast DCIVA (eyes) at other time points

Proportion of subjects who benefited from 3 lines (15 letters) or more on mesopic high contrast DCIVA (monocular) at each time point

Proportion of subjects who benefited 2 lines (10 letters) or more on mesopic high contrast DCIVA (monocular and binocular) at each time point

Mean change in DCIVA (monocular and binocular) from baseline at each time point

DCIVA distribution at each time point

Time from baseline to maximum mean DCIVA

Exploratory (others)

Pupil diameter and appearance/roundness changes under mesopic conditions compared to baseline (evaluation at 30 min, 90 min, 3 h and 4 h)

Patient preference and availability feedback

Change in defocus curve evaluated at 3 hours compared to baseline

Analysis of efficacy

Mainly comprising

The primary analysis will be stratified by the baseline DCNVA (above and below 20/80) for this presbyopic study population.

The proportion of subjects who benefited from 15 letters or more of the binocular DCNVA 3 hours post-dose will be summarized by treatment group, baseline DCNVA layer, and visit with descriptive statistics (including across all visits).

For each baseline layer, a conditional logistic regression will be fitted to the binary response data. The following covariates will be included in the logical (logistic) model: treatment, period, first-order lag, iris color (dark or light), baseline DCNVA, age (continuous), add-on, and use of systemic medications (yes or no) that can cause mydriasis/contraction at screening. To condition for subject effects, subjects were assigned to the hierarchy (with SAS). The Firth method will be used to allow continued evaluation even if there are no responders in the placebo group. Since the design balances lag, there is no need to introduce random subject effects unless there is a large number of visits. Jones and Kenward, 2015, section 6.2.2.4.

A1% (about 8. mu.l) ophthalmic solution of Pilocarpine (PC) was performed based on the fitted model_1％) 2% (about 8. mu.l) pilocarpine ophthalmic solution (PC)_2％) And pilocarpine 4% (about 8. mu.l) ophthalmic solution (PC)_4％) Pairwise comparison with Placebo (PLC).

The following three hypotheses will be tested within each baseline layer:

H₀：PC_xlogarithm of ratio to PLC<＝0

H_A：PC_xLogarithm of ratio to PLC>0

Where x is one of { 1%, 2%, 4% }

The study success criteria is that at least one of the three null hypotheses for the primary outcome will be rejected by at least one baseline layer. To maintain the class I trial error probability at 0.025 (single sided):

apply Bonferroni correction to the baseline layer, and then

Within each level, the significance level of pilocarpine compared to placebo for each of the three comparisons will be selected based on the Dunnett's (1955) program.

For each pairwise comparison within each level, the expected marginal mean (least squares mean) will be calculated based on logistic regression model comparison value ratio log (i.e., three comparisons between each pilocarpine group and placebo group). When constructing these comparisons, all other covariates in the model are set to their average observations. Confidence intervals will be constructed for each pair of comparisons using the likelihood profile method from Firth logistic regression.

The level of confidence interval will be set to control the one-sided class I trial error probability to 0.025, as described above. For each comparison, if the lower confidence interval limit for the log of the odds ratio is greater than 0.0, then the null hypothesis for that comparison will be rejected.

The primary analysis is repeated for the contralateral eye if the study success criteria are met.

As a sensitivity analysis, a global model containing two baseline layers, which culled covariates that were not significant at the p-0.10 level, would be fitted.

Exploratory results: near Vision (DCNVA) at far vision correction, intermediate vision (DCIVA) at far vision correction and diameter of pupil

The following will be analyzed in the same way as the main results:

proportion of subjects who benefited 3 rows (15 letters) on mesopic high contrast DCNVA (monocular) 3 hours post-treatment compared to baseline DCNVA

Proportion of subjects who benefited 3 lines (15 letters) on mesopic high contrast DCNVA (monocular and binocular) at other time points

Proportion of subjects who benefited 2 lines (10 letters) on mesopic high contrast DCNVA (monocular and binocular) at each time point

Proportion of subjects who benefited 3 lines (15 letters) on high contrast DCIVA (binocular) of mesopic vision 3 hours after treatment compared to baseline DCIVA

Proportion of subjects who benefited 3 lines (15 letters) on high contrast DCIVA (binoculi) of mesopic vision at other time points

Proportion of subjects who benefited 3 lines (15 letters) on mesopic high-contrast DCIVA (monocular) at each time point

Proportion of subjects who benefited 2 lines (10 letters) on mesopic high contrast DCIVA (monocular and binocular) at each time point

Generalized Additive Model (GAM) with (4df) smoothing term for assay time (independent estimates for each tier and treatment group) will be used, and fixed effect analysis for treatment, period, lag, iris color, baseline DCNVA/dciva (logmar), age, and addition luminosity are below. The subjects were included in the model as random effects, taking into account the correlation between assay times.

Mean change from baseline in logMAR DCNVA and DCIVA (monocular and binocular) by treatment at each time point

Time from baseline to maximum mean logMAR DCNVA and DCIVA by treatment

The fitted time smoothing function will be used to predict the mean change from baseline logMAR DCNVA and DCIVA, to determine the maximum mean change in logMAR DCNVA and DCIVA over the treatment, and to estimate the maximum time for each treatment.

Nonparametric quantile smoothing will be used to analyze the following:

logMAR DCNVA and DCIVA profiles at various time points

Pupil diameter distribution at each time point

Distribution of change from baseline pupil diameter at each time point

The logMAR DCNVA, DCIVA and pupil diameter distributions at each time point will be characterized by 5df quantile smoothing splines applied across time. Splines will be fitted to the following quantiles: 0.025, 0.10, 0.25, 0.50, 0.75, 0.90, 0.975. Note that at each time point the 5df spline will be inserted smoothly into the observation quantile.

A smooth spline fitted to the median will be used to characterize the change in logMAR over time:

median improvement of both ocular DCNVA and DCIVA by level and treatment group to 15 letters (0.3 logMAR units) start time, end time and total time.

Total area under logMAR improvement curve from 0 hours to 3 hours, by level and treatment group.

For each of these measurements, a confidence interval (with single subject as cluster) will be constructed using a clustering bootstrap.

Safety results

Slit-lamp examination and fundus visualization

Mean change in IOP at hour 4?

Rate of ocular and non-ocular Adverse Events (AE)

Mean change from baseline in best corrected distance vision (monocular and binocular) measured at hours 3 and 4

Mean change from baseline in distance vision (monocular and binocular) with naked eye measured at hours 3 and 4

Evaluation of eye comfort after instillation of study medication and 30 minutes after instillation (visual analog scale)

Sample size

The study was designed as a graph-balanced latin square with 4 treatments, 4 epochs, 3 blocks and 12 orderings. Jones and Kenward, 2015, section 4.2.1. This design balances all first-order lag effects and allows estimation using a fixed-effect ANOVA model. To maintain the balance of each of the two DCNVA baseline layers, the total sample size would need to be a multiple of 24 (per level 12, see table 1).

Table 1: graph-balanced latin square with 4 treatments, 4 epochs, 3 blocks, and 12 sorts.

The sample size is calculated using simulations of the selected invalid and alternate contexts. Note that since the expected response rate of the placebo group is very small (p ═ 0.02), normality is not reasonable, so Dunnett's adjustment is also calculated by simulation.

Table 2 below shows the calculated sample size (evaluable study eye) which provides:

efficacy was tested for > 96% of a range of ratios in the placebo (p0) and treatment groups (p1, p2 and p3) (to reject at least one of the three group comparisons of at least one of the two levels). The test efficacy calculation assumes two levels, each level is assigned an α of 0.0125, and Dunnet's adjustment is applied within the level to compare the three active treatment groups with placebo control. Within each level, the test efficacy was set to 80% resulting in a total test efficacy of about 96%.

Note that:

if covariates in the logical model predict the result, then this calculation based on a simple comparison of the proportions should be conservative,

given that the sample size was rounded to the closest multiple of 24, and also allowed 5% missed visits, the actual test efficacy may be higher,

the calculation assumes that the results within 4 subjects were independent between treatments. If there is a positive correlation, the test efficacy will increase because the variance of the differences within the subjects will be smaller.

The required total number of randomly grouped subjects was then calculated prior to the primary efficacy analysis to allow approximately 5% missed visits and then rounded to the nearest 12 per level. Based on the 2% proportion of expected responders in the placebo group and the 20%, 25% and 30% proportion of expected responders in the pilocarpine group, at least 96 subjects (48 per level) were required to be randomly grouped to achieve the required test efficacy after adjusting multiple comparisons against a single control. This will result in at least 84 evaluated study eyes (42 per level) at the end of the study.

Considering the failure of the screening, the study will screen up to 120 subjects, and continue until 48 subjects are randomly assigned to each level.

Note that because both eyes of each subject were treated during the study, safety information was available for approximately 192 eyes from 96 subjects who were randomized and started treatment with a microdose of pilocarpine (1%, 2% or 4%) administered using a piezoelectric droplet delivery device.

TABLE 2 for PC_1％vs PLC、PC_2％vs PLC or PC_4％The significance of the vs PLC is>95% test efficacy for each level and overall required sample size. P0, P1, P2 and P3 are for PLC and PC_1％、PC_2％And PC_4％Hypothetical responder ratio. The study was a 4-treatment 4-epoch crossover with 2 baseline layers, assuming no hysteresis effect. Evaluable N is the number of evaluable subjects required to provide the prescribed test efficacy. Randomized N assumes 5% miss and balance within the hierarchy (thus rounded to the closest multiple of 24).

While the invention has been described with reference to certain embodiments, various modifications can be made without departing from the features and aspects of the invention.