Piezoelectric Fluid Dispenser

Abstract

Fluid delivery devices and methods are provided, where the device may include a piezoelectric actuator operably coupled to an ampoule containing a fluid under a preload force. The ampoule may include a thin-walled thermoplastic package including one or more holes positioned in the wall of the ampoule. The piezoelectric actuator may be configured to at least partially clamp the periphery of the ampoule and apply vibrations to the wall. The vibrations, typically at ultrasonic frequencies, impart acoustic pressure cycles to the fluid, causing droplets or streams of fluid to be ejected through the holes.

Description

[Technical Field]

[0001] The present invention relates to a device for projecting a fluid stream, particularly, but not exclusively, for topical ocular application. [Background technology]

[0002] A typical medical eye dropper dispenses a single drop of approximately 40–50 μL. However, because the human eye can typically retain only 7 μL of fluid on the corneal surface, a larger drop can result in overflow of most of the medication from the ocular surface, resulting in losses. Furthermore, a single drop of a larger volume, such as 30 or 50 μL, can trigger a blink reflex, removing most of the fluid from the ocular surface, causing discomfort and reflex tearing. These factors can make self-administration of eye drops uncomfortable, potentially leading to poor compliance.

[0003] By way of example, droplet generators for ocular drug delivery are described in more detail in U.S. Pat. Nos. 5,630,793 and 8,684,980, each of which is incorporated herein by reference in its entirety. These devices generally include a piezoelectrically actuated droplet generator for delivering small droplets to the eye and further incorporate a piezoelectric fluid ejector for dispensing the droplets onto the surface of the eye. Such ejection mechanisms are integrally coupled to a fluid reservoir that can be periodically refilled by the user. However, refilling carries the risk of bacterial contamination, which can result in eye infection. Generally, drug filling or refilling of fluid reservoirs, particularly ophthalmic ones, must be handled in a strictly controlled, sterile environment that is not normally accessible to the typical user. Summary of the Invention

[0004] Another problem associated with aerosol or jet delivery as described in the prior art is the user's ability to accurately direct the aerosol stream onto the surface of the eye. Misalignment between the dispensing device and the eye can result in inaccurate dosing.

[0005] The devices and methods described herein for injecting therapeutic fluid into the cornea or conjunctival tissue of the eye advantageously utilize a disposable sterile drug ampoule, which may include a dispensing nozzle, that is easily attachable to and detachable from the piezoelectric transducer, thereby eliminating the need for refills, thereby reducing the possibility of bacterial contamination and providing a cost-effective approach by reusing the piezoelectric actuator for subsequent operations.

[0006] The described devices and methods further provide a mechanism for delivering a liquid stream and aligning the stream with the eye before actuation, ensuring convenient and accurate dosing. In one variation, it was surprisingly discovered that delivering a single stream is less irritating to the eye and therefore more convenient than delivering a mist or a random distribution of small droplets with the same total volume. Unlike a mist or spray, a stream can be precisely oriented to target specific locations on the cornea or conjunctival tissue of the eye. This characteristic is primarily due to the aerodynamic behavior of the stream. In particular, delivery of a mist involves turbulence, which causes droplets to deviate from the target, whereas a stream propagates through the air and reaches the target area more precisely.

[0007] A fluid ejection device is described for ejecting a fluid into a patient's body site, e.g., for treating eye diseases by topical administration, wherein a disposable medication or fluid package, such as an ampoule, may be separate or separable from a piezoelectric actuator. The piezoelectric actuator is configured to vibrate the ampoule, thereby generating acoustic pressure in the fluid therein, which in turn causes cycling of the acoustic pressure within the fluid and ejection of droplets or a flow of fluid from one or more holes defined along the ampoule. The ampoule medication package is easily attachable to and detachable from the piezoelectric actuator assembly, and the empty medication or fluid package is disposable, thereby eliminating the need for user loading and the risk of bacterial contamination. In one embodiment, only the ampoule is disposable, while in another embodiment, the entire assembly including the piezoelectric actuator and ampoule is disposable.

[0008] The embodiments and features described herein may be utilized in any number of combinations with various features described in more detail in U.S. Patent Application No. 14 / 992,975, filed January 11, 2016 (U.S. Patent Application Publication No. 2016 / 0199225), U.S. Patent Application No. 15 / 094,849, filed April 8, 2016 (U.S. Patent Application Publication No. 2016 / 0296367), each of which is incorporated herein by reference in its entirety for all purposes.

[0009] The piezoelectric fluid ejection device is configured to directly dispense the contents of a fluid-filled ampoule, eliminating the need to transfer the contents of the ampoule to a secondary dispensing device and the need to sterilize the dispensing device before fluid filling. This is particularly useful for delivering eye drops to the surface of the eye. The device generally includes a piezoelectric clamp actuator and, in one variation, a separable, disposable, fluid-filled ampoule comprising a thin-walled thermoplastic package including a first or proximal portion (e.g., a conduit portion) and a second or distal portion (e.g., a bulbous portion). One or more holes may be located in the wall of the first portion of the ampoule.

[0010] A piezoelectric clamping actuator may be configured to clamp around the first portion, while leaving one or more holes uncovered to allow fluid release. In one embodiment, the clamping actuator may be configured to at least partially clamp around the first portion adjacent one or more holes, while simultaneously applying cycles of vibration in the clamping direction. The vibrations, usually at ultrasonic frequencies, generate cycles of acoustic pressure in the fluid contained within the ampoule, forcing the ejection of fluid droplets or a fluid stream from one or more holes. The fluid-filled ampoule may be held in a first orientation, e.g., vertically relative to the ground, while the fluid droplets or stream are ejected in a second orientation, e.g., horizontally. In this manner, fluid may be continuously supplied from the second reservoir portion to the first conduit portion of the ampoule, while the fluid droplets or stream may be ejected horizontally from one or more holes. This orientation is particularly useful for delivery to the surface of the eye. Advantageously, the fluid may be injected directly from the ampoule without the need to transfer the fluid contents to a container, a step that would normally require sterilization of the container.

[0011] The ampule can be easily coupled to or detached from the piezoelectric clamp actuator, so that the empty drug or fluid package can be easily removed, eliminating the need for drug filling by the user and the risk of bacterial contamination. The fluid package may be coupled to the clamp by, for example, friction or an interference fit, and may generally require an insertion force of less than, for example, 5 Newtons, or less than, for example, 10 Newtons. The amount of insertion force may be adjusted accordingly.

[0012] The drug or fluid package is configured to dispense microdroplets via one or more vibrations applied to the exterior surface or conduit portion of the ampoule drug package by a piezoelectric actuator clamp. The ampoule can be detached from the piezoelectric actuator, allowing for disposal of the used package, and the piezoelectric clamp transducer may then be reused with another ampoule, providing a cost-effective approach for topical drug delivery, for example, to the eye. The ampoule (or at least a portion of the ampoule) may be manufactured, for example, by a blow-fill-seal process, in which the ampoule may be filled and sealed while held in a mold cavity. Such processes are described, for example, in U.S. Patent Publication No. 2013 / 0345672 A1, U.S. Patent Publication No. 2012 / 0017898, and U.S. Patent No. 5,624,057, each of which is incorporated herein by reference in its entirety for purposes of illustration. The ampoule itself may be manufactured from a thermoplastic polymer, such as, for example, terephthalate, polyethylene, or polypropylene, either high or low density.

[0013] The piezoelectric clamping actuator may be configured as a relatively small module for use in a handheld device or as an accessory to eyewear items such as eyeglasses or sunglasses, for example.

[0014] In one embodiment, the fluid ejection device may include a piezoelectric clamp configured to vibrate at ultrasonic frequencies and further includes an ampoule containing the fluid to be dispensed. The ultrasonic vibrations generated by the clamp actuator may be transmitted to a conduit portion of the ampoule, causing the fluid to generate acoustic pressure cycles, thereby ejecting droplets from one or more holes in the ampoule.

[0015] In one embodiment, the piezoelectric transducer includes a clamp with two jaws structurally connected to a bending actuator, which may generally consist of a laminate having two active piezoelectric ceramic plates oriented with opposite polarities, commonly known as a bimorph actuator, that vibrates in a bending mode causing the clamp to periodically open and close relative to the ampoule conduit.

[0016] In another embodiment, the bending actuator may comprise a stack of two active piezoelectric ceramic plates and one passive plate positioned between the two active piezoelectric ceramic plates. The passive layer may comprise, for example, a printed circuit board (PCB) made from FR-4 material. The PCB may include a controller having electronic circuitry for driving and controlling the piezoelectric ceramic clamps. The piezoelectric ceramic plates may be attached to the PCB by a solder reflow process, and electrical connections to the piezoelectric ceramic plates may be made, for example, via one or more copper pads on the PCB.

[0017] A controller having electronic circuitry may be in electrical communication with the bending actuator and may generally include circuitry configured to generate and transmit one or more electrical pulses or waveforms to the piezoelectric actuator. In one embodiment, the circuit may comprise a half-bridge driver, which may include a half-bridge driver chip and two MOSFET transistors. The half-bridge driver receives an input signal and transmits a switching output that sequentially drives a pair of MOSFET transistors "on" and "off." In this manner, the driver converts the low-voltage input signal into high-power electrical pulses capable of driving the piezoelectric actuator. The circuit may further include an inductor that boosts the input voltage to the piezoelectric actuator. The inductance of the inductor and the capacitance of the piezoelectric actuator may be adjusted to operate at a selected frequency at electrical resonance. The input signal transmitted to the half-bridge driver chip may be generated by a microprocessor or a signal generator IC (integrated circuit).

[0018] In one embodiment of the driver, the transistors and microprocessor may be fabricated on a single integrated circuit. Such an IC may be directly attached to and encapsulated on a PCB using a chip-on-board (COB) packaging process. In the field of microelectronics, COB is used to reduce the size of a circuit. The input voltage of the circuit is preferably, for example, less than 5 volts, more preferably less than 3 volts, and even more preferably less than 1.5 volts. The energy source may be provided by a power supply such as a capacitor or a battery, which may optionally be rechargeable. As described above, sequentially turning the circuit "on" and "off" causes the fluid stream to be emitted from one or more holes as individual droplets. However, when an inductor is added and tuned to operate at the circuit's electrical resonance, the electrical output becomes sinusoidal, and the fluid is emitted as a collimated continuous stream without individual droplets, or as a collimated discontinuous stream of individual droplets.

[0019] The volume of droplets released from the device may generally be, for example, 100-1000 pL in one variation, and the orifice size may typically be, for example, 10-100 microns for a discrete stream of droplets. For a continuous stream of fluid, the stream diameter may be in a range similar to the orifice diameter range, for example, 0.070-0.130 mm, with the total volume determined by the duration. Furthermore, various fluids, compositions, and / or therapeutic agents may be used with the devices and methods described herein for inclusion in the ampoule and release through one or more orifices. For example, U.S. Patent Publication No. 2012 / 0070467 (incorporated herein by reference in its entirety for all purposes) describes examples of various ophthalmic compositions and therapeutic agents that may be used with the devices and methods described herein.

[0020] In other embodiments, the dispensing device may include an optical mechanism for aligning or directing the dispensing hole to the ocular surface or conjunctival region prior to activation. Such alignment ensures that the entire dose reaches the ocular surface. The device may include a tubular member having proximal and distal openings, with the distal opening positioned near a visible light source, such as a red LED, and the proximal opening of the tube being brought close to the user's eye. The tubular member may be parallel to the droplet ejection direction or positioned at a predetermined offset. Prior to activation of the dispensing device, the user may align the eye to be treated with the proximal opening of the tube and then manipulate the device's orientation until the light at the distal end of the tube is visible. In this manner, the device is aligned with the optical axis or center of the pupil of the eye to be treated. The dispensing nozzle may be positioned at a predetermined small offset relative to the optical axis of the tube. When the device is activated, a fluid stream reaches the target surface of the corneal or conjunctival tissue, depositing the fluid at the aforementioned offset from the optical axis of the eye.

[0021] It should be noted that the alignment or targeting methods described herein may be used to align the nozzle with the eye in any topical delivery system or eye dropper, including a squeeze bottle.

[0022] The length of the optical tube is, for example, 20 mm, 30 mm, or 40 mm, while its inner diameter is, for example, 1 to 5 mm. Optionally, the inner surface of the tube may be coated with an optically black, anti-reflective coating.

[0023] For example, a typical volume of 1-10 μL may be delivered to the eye within the time it takes to fixate the eye on the target, typically less than 1 second, preferably within 250 milliseconds in one variation, or within 400-600 milliseconds in another variation. In one embodiment, the dispensing device includes one or more, but typically fewer than, for example, 20, holes, preferably fewer than, for example, 10, holes, and most preferably a single hole. The holes are positioned at a predetermined offset relative to the optical axis of the alignment tube. This offset determines where the fluid stream is deposited relative to the optical axis of the eye or the center of the pupil or iris. Typically, the offset may be, for example, 2-20 mm from the center of the pupil, either vertically or horizontally, or both vertically and horizontally.

[0024] In other variations in which multiple holes are utilized for dispensing, each hole may be configured to preserve the uniqueness of each individual stream rather than forming a mist. Therefore, factors such as hole size and hole spacing may be adjusted to maintain the morphology of each individual fluid stream and minimize or prevent mixing or merging of the individual fluid streams. For example, holes with relatively large dimensions, e.g., 80-100 microns, may allow for relatively short pulse durations to deliver equal volumes of fluid. Furthermore, holes with such dimensions may also allow for the use of relatively viscous fluids, such as artificial tears, typically composed of methylcellulose or carboxymethylcellulose, hyaluronic acid derivatives, or other hydrogels, that would otherwise block or clog smaller holes, e.g., 10-12 microns.

[0025] The fluid(s) that may be used in the dispensing device may vary to include any number of medications depending, for example, on the treatment, the area of ​​the body to which the fluid is applied, etc. Examples of various fluids or agents that may be used may include, but are not limited to, for example, anti-infectives (including, but not limited to, antibiotics, antivirals, etc.), anti-inflammatory agents (including, but not limited to, steroids and nonsteroidal anti-inflammatory drugs (NSAIDs)), anti-allergies (including, but not limited to, antihistamines and mast cell stabilizers), antifungals, vasoconstrictors, mydriatics (pupil dilation), miotics (pupil constriction), biologics (e.g., proteins, modified proteins, etc.), small molecules, anesthetics, analgesics, intraocular pressure reducing agents (including, but not limited to, prostaglandin analogs, ROK inhibitors, beta-blockers, carbonic anhydrase inhibitors, alpha agonists, etc.), lubricants (including, but not limited to, saline, polymer solutions, proteoglycans, glycosaminoglycans, carbohydrates, etc.), iodine derivatives, etc., and / or various combinations thereof. Additional drugs and agents that may be utilized with the described devices may include any number of agents disclosed in further detail in U.S. Patent Application Publication No. 2017 / 0344714 and U.S. Patent No. 9,087,145, each of which is incorporated herein by reference for that purpose.

[0026] In one variation of the dispensing device, the device may generally include an ampoule containing a liquid to be dispensed and having a first portion and a second portion, the first portion defining one or more holes, and a piezoelectric assembly configured to secure the first portion and to provide a primary vibration in the first portion along a first direction, thereby inducing a secondary vibration in the first portion along a second direction perpendicular to the first direction. The primary and secondary vibrations may be coplanar with one another, and the one or more holes may be aligned along the second direction such that the secondary vibration dispenses a flow of liquid through the one or more holes.

[0027] In another variation, a fluid dispensing device may generally include a fluid reservoir having a proximal portion and a distal portion, a side of the proximal portion defining one or more holes. The device may also include a clamping member defining a receiving channel dimensioned to hold the proximal portion of the fluid reservoir, and a piezoelectric actuator in vibrational communication with the clamping member, wherein actuation of the piezoelectric actuator deforms the clamping member to produce a primary vibration in the proximal portion along a first direction, thereby causing a secondary vibration in the proximal portion along a second direction perpendicular to the first direction. The primary and secondary vibrations may be coplanar with each other, and the one or more holes may be aligned along the second direction such that the secondary vibration caused in the proximal portion is sufficient to eject fluid through the one or more holes.

[0028] In another variation for dispensing a fluid, the method may generally include providing a piezoelectric assembly configured for removable engagement with a fluid reservoir; causing a primary vibration in a proximal portion of the fluid reservoir along a first direction, whereby a secondary vibration is induced in the proximal portion along a second direction that is perpendicular to the first direction, the primary and secondary vibrations being coplanar with each other; and ejecting the fluid from one or more holes defined along a side of the proximal portion, the one or more holes being aligned along the second direction.

[0029] In another embodiment, a fluid ejection device may generally include at least one piezoelectric actuator configured to vibrate at a selected frequency, an ampoule configured to dispense fluid through an aperture, and a vibration transmission component defining a longitudinal axis and having an elongated portion and a mounting portion. The elongated portion, transitioning from the mounting portion, may define a lumen, and the at least one piezoelectric actuator may be mounted to the mounting portion, and the ampoule is removably mountable to the elongated portion such that the aperture is aligned with the longitudinal axis upon assembly.

[0030] In one method of use for ejecting a fluid, the method may generally include securing an ampoule to a vibration transmission component defining a longitudinal axis and having an elongated portion and a mounting portion such that an aperture defined by the ampoule is aligned with the longitudinal axis; actuating at least one piezoelectric actuator secured to the mounting portion such that vibrations are transmitted from the mounting portion through the elongated portion to the ampoule; and ejecting fluid from the ampoule through the aperture.

[0031] In another embodiment of the ampoule, the ampoule may generally comprise an ampoule body having a cylindrical portion and a tapered portion narrowing to an opening defining a bore in fluid communication with a volume defined by the ampoule body, and an insert having an outer surface that continues to the inner surface of the ampoule body in a corresponding manner such that an annular capillary passage in fluid communication with the bore is formed between the outer surface and the inner surface.

[0032] Having summarized the general nature of the present invention and some of its features and advantages, certain preferred embodiments and modifications thereof will become apparent to those skilled in the art from the detailed description herein, taken in conjunction with the following drawings. [Brief explanation of the drawings]

[0033] [Figure 1] 1A shows a perspective exploded view of a piezoelectric clamp actuator and an ampoule. FIG. 1B shows a perspective view of a piezoelectric clamp actuator and an ampoule secured by the actuator. [Figure 2] FIG. 1 shows a cross-sectional end view of a piezoelectric clamping actuator. [Figure 3] A shows a cross-sectional end view of a piezoelectric actuator in bending mode with the clamping jaws widened as a result of harmonic analysis. B shows a cross-sectional end view of a piezoelectric actuator in bending mode with the clamping jaws narrowed as a result of harmonic analysis. [Figure 4-1]A shows a perspective view of an ampoule formed via a form-fill-mold process; B shows a front view of an ampoule formed by a form-fill-mold process; C and D show a cross-sectional view and a side view, respectively, of an ampoule showing the insert contained in the mold. [Figure 4-2] 1E shows a detailed front view of another variation of an ampoule aperture formed partially from a separate tubular member. [Figure 5-1] A shows a perspective view of an ampoule secured in a piezoelectric clamp actuator that also includes a controller assembly with drive circuitry. B and C show front and side views of the assembly with the ampoule and piezoelectric clamp actuator. D shows a detailed side view of the interface between the piezoelectric clamp actuator and the printed circuit board. [Figure 5-2] E shows a side view of the dispensing device aligned with the eye for treatment. [Figure 6] 1A and 1B show perspective views of an alternative embodiment of an actuator having a partial tubular component. [Figure 7] 1A and 1B show detailed perspective views of the actuator with the elongated portion and mounting portion reversed. [Figure 8] 1A and 1B show a side assembly view and a perspective assembly view of the actuator. [Figure 9] 1A and 1B show alternative perspective views of an embodiment of a dispensing device utilizing a piezoelectric actuator assembly. [Figure 10-1] 10A and 10B show perspective assembly and exploded views of an alternative embodiment of a bimorph piezoelectric actuator and ampoule holder components. [Figure 10-2] 1C and 1D show exploded and perspective views of a piezoelectric actuator having a single piezoelectric ceramic plate. [Figure 11] 1A and 1B show perspective views of a piezoelectric actuator, an ampoule, and a cup and alternative ampoule holder components. [Figure 12] A and B show an exploded view and a cross-sectional view of the ampoule. [Figure 13] FIG. 1 shows an exploded view of the dispensing assembly and housing. [Figure 14] FIG. 1 shows a perspective view of the dispensing assembly and housing. [Figure 15] 1 shows an exploded view of the housing, dispensing assembly, and ampoule. [Figure 16] FIG. 1 shows a perspective view of the housing, dispensing assembly, and ampoule. [Figure 17] FIG. 1 shows a side view of a dispensing device aligned with an eye for treatment. [Figure 18] 1 shows a perspective view of the dispensing device in use by a patient. DETAILED DESCRIPTION OF THE INVENTION

[0034] Various embodiments of the invention described herein relate to devices for delivering drugs to the ocular surface to treat ocular diseases. In the systems and methods described herein, droplets are dispensed at high frequencies, either in single droplet form or in a continuous stream, depending on the electrical signal input, as described above. When droplets are generated, they generally have extremely small volumes, ranging from about several hundred picoliters to about one nanoliter. Generally, droplets of such volumes, or a single stream of continuously (or discontinuously) collimated droplets, do not elicit a blink reflex.

[0035] The dispensing devices and clamp actuators described herein may be utilized with any of the embodiments, and any combinations, described in more detail in U.S. Patent Application No. 14 / 992,975, filed January 11, 2016 (U.S. Patent Application Publication No. 2016 / 0199225), and U.S. Patent Application No. 15 / 094,849, filed April 8, 2016 (U.S. Patent Application Publication No. 2016 / 0296367), each of which is incorporated herein by reference in its entirety for all purposes. Additionally and / or alternatively, although devices and methods are described for ejecting droplets or streams of fluid onto or onto the surface of the eye for ophthalmic treatment, the devices and methods may likewise be utilized in any number of non-ophthalmic applications, such as otolaryngology (e.g., eardrum), endoscopy (e.g., gastrointestinal tract), gynecology (e.g., cervix, uterus, reproductive treatment (fallopian tubes)), laparoscopy (e.g., body cavities, abdomen), laryngoscopy (e.g., throat, vocal cords), bronchoscopy (e.g., bronchial or other lung tissue), urology (e.g., bladder, prostate), oral cavity (e.g., tonsils, teeth, pharynx), neurosurgery (e.g., through a hole drilled in the skull), and dermatology (e.g., localized topical chemotherapy or chemical cauterization).

[0036] For devices placed in a body cavity (such as endoscopic, laparoscopic, or laryngoscope devices), the assembly may reside along a rigid or flexible / articulating shaft, with the piezoelectric actuator and ampoule positioned distally to enter the body cavity and the power source positioned proximally to remain outside the body cavity, while current flows through the rigid or flexible shaft or flexible arm of the instrument to activate the piezoelectric actuator. In one embodiment, the ampoule resides next to the distal face of the light source and camera lens (e.g., adjacent to where the light originates from the shaft and where the camera lens is located). Alternatively, the assembly does not have a light source or camera, and these elements are provided on a separate instrument. In another embodiment, the ampoule and piezoelectric actuator may remain on the proximal dimension of the shaft, such that fluid dispensed from the hole flows longitudinally through the shaft and exits at the distal or tip end of the shaft. The length of the rigid or flexible / articulating arm will vary in length and inner diameter / diameter depending on the application (e.g., relatively long for laparoscopic, endoscopic, and gastrointestinal applications, relatively short for ENT applications, and others in between).

[0037] The dispensing device may advantageously utilize a disposable, removable, or separable drug or fluid package, while desirably retaining the piezoelectric actuator or transducer for subsequent further use, thereby allowing for economical reuse of the piezoelectric actuator or transducer for further operations. This provides a cost-effective and cost-effective approach. Thus, in any of the described embodiments, the assembly may utilize a reusable actuator and / or housing, with the ampoule being separate or separable and implemented as a disposable or reusable ampoule. Alternatively, in any of the embodiments, the actuator and / or housing may be integrated with the ampoule, in which case the entire assembly may be completely disposable or reusable. Various components of the assembly may optionally be reusable or disposable, and the implementation of such components is not intended to be limiting.

[0038] 1A and 1B show exploded and assembled perspective views of one variation of a dispensing device assembly (1000). The device assembly (1000) may generally include a piezoelectric clamp actuator (1010) and a separable, disposable, fluid-filled ampoule (1020). The ampoule (1020) may comprise a thin-walled thermoplastic package including a second portion (1022), generally including a bulb or reservoir portion, and a first portion (1021), generally including a neck or elongated portion extending from the second portion (1022). The first portion (1021) may have a cylindrical shape with a circular or oval cross-sectional shape. Other cross-sectional shapes, such as triangular, square, pentagonal, hexagonal, and octagonal, are also possible. One or more holes (1023) are located in the wall of the first portion (1021).

[0039] The piezoelectric actuator assembly 1010 may generally include a piezoelectric clamp actuator 1014 configured to at least partially secure or engage the periphery of the first portion 1021 and adjacent one or more apertures 1023. Thus, the clamp actuator may have at least two opposing jaw members 1016A and 1016B designed to support and engage the first portion 1021 in a receiving channel 1011 defined between the jaw members 1016A and 1016B via a tight engagement, such as an interference fit, as shown in FIG. 1B. When the first portion 1021 of the ampoule is engaged between the jaw members 1016A and 1016B of the actuator assembly 1010, the assembly 1010 may impart a cycle of vibration in a clamping direction against the wall of the ampoule, as indicated by arrows 1014A and 1014B. Vibration of the ampoule first portion (1021) may periodically deform the cross section of the first portion (1021), so that the portion oscillates, for example, between a circular and an elliptical shape, resulting in cycling of acoustic pressure in the fluid held within the first portion (1021).

[0040] As shown, a primary vibration may be imparted by the jaw members 1016A, 1016B along a first direction 1030 relative to the first portion 1021, which induces a secondary vibration in the first portion 1021 along a second direction 1032 that is perpendicular to the first direction 1030. The primary and secondary vibrations may then eject fluid 1024 held within the first portion 1021 from one or more holes 1023, whereby the ejected fluid 1024 may be ejected in a stream of individual droplets or as a continuous stream of fluid, depending, for example, on the frequency of the vibration. The emitted fluid (1024) may be ejected from one or more holes (1023) in a direction perpendicular to the longitudinal axis of the assembly (1000) such that the initial angles of the fluids (1024) relative to the first portion (1021) are perpendicular to each other. Alternatively, the fluid (1024) may be ejected at a predetermined angle relative to the first portion (1021). In yet another alternative, multiple fluid streams may be ejected simultaneously or sequentially from different holes, each of which may be at a uniform angle or at different angles relative to each other, for example, to eject fluid streams at different regions of a patient's eye when the assembly (1000) is maintained in a restrained position relative to the eye.

[0041] Generally, the vibration amplitude of the jaw members (1016A), (1016B) may be less than 2 microns, for example. As fluid is released from the first portion (1021), the fluid held within the second portion (1022) may provide a continuous flow of fluid to the first portion (1021) during use, and the fluid may then be released from the first portion (1021) in a continuous or discontinuous fluid stream. The first portion (1021) of the ampoule (1020) may be inserted into the piezoelectric receiving channel (1011) with a relatively light force, typically less than 10 Newtons in some variations and less than 5 Newtons in other variations.

[0042] Referring now to FIG. 2, a cross-sectional end view of the piezoelectric actuator assembly 1010 and the first portion 1021 held between jaw members 1016A and 1016B within the receiving channel 1011 is shown. The actuator assembly 1010 may have a base plate 1015 from which the jaw members 1016A and 1016B extend coplanar relative to one another. In this variation, the first piezoelectric ceramic plate 1012 may be bonded to the second piezoelectric ceramic plate 1013, which may be bonded to the base plate 1015. A passive layer 1017 may optionally be positioned between the two piezoelectric ceramic plates 1012 and 1013. Furthermore, these two plates (1012, 1013) may be glued together face-to-face, with each plate facing in an opposite poling direction. The dimensions and configuration of the plates (1012, 1013) may match each other and the dimensions and configuration of the base plate (1015). Such a piezoelectric stack is also known as a bimorph bender, in which each piezoelectric ceramic plate (1012, 1013) expands and contracts in opposite directions relative to each other. The variation shown illustrates how the first plate (1012) is configured to expand in a plane, as indicated by the arrow (1012P), while the second plate (1013) is configured to contract in a plane, as indicated by the arrow (1013P), thereby vibrating the piezoelectric ceramic stack in a resulting bending mode. The base plate (1015) may be attached to the piezoelectric ceramic stack with a structural adhesive, such as a high-strength epoxy. In this manner, the bending of the piezoelectric stack causes the clamping member (1014) to bend, which in turn causes the clamping jaws (1016A), (1016B) to apply a cyclic clamping force onto the first portion (1021) of the ampoule, after which the fluid held therein is ejected from the hole by the resulting secondary vibrations (1032).

[0043] Figures 3A and 3B show harmonic analysis results generated by finite element analysis, illustrating the frequency response of the clamping jaws (1016A) and (1016B) and the first portion of the ampoule (1021). The figures show that, at a vibration frequency of at least 22,000 Hz, the clamping jaws (1016A) and (1016B) are actuated by the piezoelectric ceramic plates (1012) and (1013) to vibrate in the indicated direction (1030), alternately compressing the first portion of the ampoule (1021) and alternating its circular cross section into an oval or elliptical shape. Generally, when the piezoelectric assembly is actuated, the operating frequency of the clamping jaws can be near or at its resonant frequency. For illustrative purposes, the deflection of the ampoule has been magnified by a factor of 4000. Actual analytical measurements indicate that the amplitude of the first portion of the ampoule (1021) near the one or more holes (1023) is, for example, only about 1 micron. The actual measurements were carried out with a laser vibrometer (Model Polytec Gmbh, Polytec Platz D-76337 Waldbronn).

[0044] During manufacture of the ampoule 1020, the first and second portions 1021 and 1022 may be constructed as separate components attached to one another, or they may be constructed as a single, integral structure. They may be made of the same material or two different materials with different material properties. For example, the first portion 1021 may be made of a relatively more rigid material, while the second portion is made of a relatively more flexible material. The first and second portions 1021 and 1022 may engage with one another in various ways. For example, a luer lock mechanism may be used to connect the first and second portions 1021 and 1022. In other embodiments, a piercing mechanism or a threading mechanism may be used. Some mechanisms may allow fluid from the second portion 1022 to be released into the first portion 1021. One example for manufacturing an ampoule (1020) is shown in the perspective view of FIG. 4A, which shows an ampoule (1020) that may be manufactured via a mold-fill-in process that includes a nozzle member inserted into the mold. Because the blow molding process has limited precision, small features such as dispensing holes can be difficult to manufacture by blow molding. Therefore, an insert member (1041) containing the hole may be manufactured separately using injection molding or laser drilling techniques. The insert member (1041) may then be placed into the blow mold cavity and captured by the blown part during the blow molding process.

[0045] 4A and 4B show a perspective view and a front view of the final shape of the ampoule (1040) after the blow molding process. FIG. 4D shows a side view of the final shape of the blown-molded ampoule (1040). FIG. 4C shows a cross-sectional side view of the resulting blown ampoule and the ampoule showing the insert member (1041) placed in the mold and captured by the blown-molded ampoule. The insert member (1041) may include other features, such as a valve or a vent. Blow-molded ampoules may generally be made from, for example, low-density polyethylene (LDPE), high-density polyethylene (HDPE), etc., while the insert member (1041) may be made from, for example, Delrin® (EI du Pont de Nemours and Company) acetal homopolymer resin, polypropylene, etc.

[0046] With regard to machining one or more holes (1023), forming such small diameter holes (e.g., on the order of 100 microns) can be relatively difficult due to the nature of thermoplastic materials during processes such as laser machining. One alternative may include forming a structure with holes separate from the ampoule fabrication, allowing the holes to be formed with greater accuracy and precision. Such a structure may include the use of a polyimide thin film that is stable over a wide range of temperatures, such as Kapton® (EI du Pont de Nemours and Company). Other suitable polyimide materials may include, for example, a composition of Kapton® and PTFE, synthetic polymers such as Nylon (EI du Pont de Nemours and Company), and the like.

[0047] 4E, in some variations, the first portion 1021 may include a thin-walled tubular member 1042 made from a polyimide such as Kapton® with one or more holes 1023 formed therein, the tubular member 1042 being fabricated separately from the ampoule and then secured, e.g., press-fit, onto the outer diameter of the first portion 1021 to define a relatively large opening. This opening may be covered by the tubular member 1042 to allow fluid contact with the inner surface of the tubular member 1042 for fluid injection through the holes 1023. Due to the thermally stable properties of the tubular member 1042, the one or more holes may be laser micromachined and / or drilled. The tubular member (1042) may have an inner diameter of, for example, 6 mm, a tube thickness of, for example, 0.1 mm, and one or more holes (1023) with an exit opening of, for example, 0.070-0.130 mm. The one or more holes (1023) may optionally be tapered to provide efficient fluid ejection.

[0048] In other variations in which multiple holes are utilized for dispensing, each hole may be configured to preserve the uniqueness of each individual stream rather than forming a mist. Therefore, factors such as hole size and hole spacing may be adjusted to maintain the morphology of each individual fluid stream and minimize or prevent mixing or merging of the individual fluid streams. For example, holes each having relatively large dimensions, e.g., 80-100 microns, may allow for relatively short pulse durations to deliver equal volumes of fluid. Furthermore, holes with such dimensions may also allow for the use of relatively viscous fluids, such as artificial tears, typically composed of methylcellulose or carboxymethylcellulose, hyaluronic acid derivatives, or other hydrogels, that would otherwise block or clog smaller sized holes, e.g., 10-12 microns.

[0049] The fluid(s) that may be used in the dispensing device may vary to include any number of medications depending, for example, on the treatment, the area of ​​the body to which the fluid is applied, etc. Examples of various fluids or agents that may be used may include, but are not limited to, for example, anti-infectives (including, but not limited to, antibiotics, antivirals, etc.), anti-inflammatory agents (including, but not limited to, steroids and nonsteroidal anti-inflammatory drugs (NSAIDs)), anti-allergies (including, but not limited to, antihistamines and mast cell stabilizers), antifungals, vasoconstrictors, mydriatics (pupil dilation), miotics (pupil constriction), biologics (e.g., proteins, modified proteins, etc.), small molecules, anesthetics, analgesics, intraocular pressure reducing agents (including, but not limited to, prostaglandin analogs, ROK inhibitors, beta-blockers, carbonic anhydrase inhibitors, alpha agonists, etc.), lubricants (including, but not limited to, saline, polymer solutions, proteoglycans, glycosaminoglycans, carbohydrates, etc.), iodine derivatives, etc., and / or various combinations thereof. Additional drugs and agents that may be utilized with the described devices may include any number of agents disclosed in further detail in U.S. Patent Application Publication No. 2017 / 0344714 and U.S. Patent No. 9,087,145, each of which is incorporated herein by reference for that purpose.

[0050] The dispensing device assembly (1000), including the ampoule (1020) and the actuator assembly (1010), may be controlled via a controller, which may include a platform or substrate on which the actuator assembly (1010) may be positioned. Figure 5A shows a perspective assembly view of an alternative form of clamping the transducer assembly (1200), in which the actuator assembly (1010) may be mounted directly on a printed circuit board (PCB) (1005) that includes a circuit portion (1005C) at a first end and a piezoelectric mounting portion (1005P) at a second end to which the actuator assembly (1010) may be mounted. Thus, when the first portion (1021) of the ampoule (1020) is secured within the clamp assembly (1014), the components may form an assembly supported on the PCB (1005). The piezoelectric driver circuit (1051) mounted on the PCB (1005) of the circuit section (1005C) may include, for example, a programmable processor, which is in electrical communication with the actuator assembly (1010) and controls the actuation and ejection of the fluid contained within the ampoule (1020).

[0051] As previously described, the piezoelectric clamp 1014 may include a first piezoelectric ceramic plate 1012 bonded to a second piezoelectric ceramic plate 1013, which may be attached to the PCB 1005 along a piezoelectric mount 1005P, and the clamp 1014 may be structurally bonded to a surface of the second piezoelectric plate 1013. Both piezoelectric ceramic plates 1012 and 1013 may be aligned with one another, and the combination of the piezoelectric ceramic plates 1012 and 1013 and the PCB 1005 may form a laminate known as a bimorph bender that vibrates in a bending mode, thereby causing an oscillatory clamping action on the clamp 1014, which is electrically configured to vibrate in a bending mode, as described herein, resulting in a droplet or stream of fluid 1024 being ejected from one or more holes 1023.

[0052] In another variation, the first piezoelectric ceramic plate (1012) may be mounted on a first or back side of the PCB (1005), and the second piezoelectric ceramic plate (1013) may be mounted on a second or front side of the PCB (1005), such that the PCB (1005) is sandwiched between the respective plates (1012), (1013). As previously mentioned, the clamp (1014) may be mounted on the second piezoelectric ceramic plate (1013), and the plates (1012), (1013) may remain aligned relative to each other. In one variation, the piezoelectric ceramic plates (1012), (1013) may be soldered to the PCB (1005) during a solder reflow process in which all electronic components (1051) are assembled. In this variation, PCB (1005) functions as a passive layer, collectively forming the bimorph bender, as shown in the side view and detailed side view of Figures 5C and 5D. Either a mounting configuration in which plates (1012), (1013) are directly attached to each other and then attached to PCB (1005), or a mounting configuration in which PCB (1005) is sandwiched between plates (1012), (1013), can be utilized with any of the ampoule (1020), PCB (1005), controller, and / or housing variations described herein.

[0053] The piezoelectric mounting portion (1005P) of the PCB (1005) may be at least partially separated from the circuit portion (1005C) by one or more cutouts. Referring now to the front view of FIG. 5B, cutouts (1052), (1054), (1053), and (1055) may extend laterally inward from the outer edge of the PCB (1005) and define, for example, proximally and distally positioned channels or notches in the piezoelectric mounting portion (1005P). The cutouts (1052), (1054), (1053), and (1055) can at least partially separate, prevent, or limit the transmission of vibrations from the piezoelectric mounting portion (1005P) to the remainder of the PCB (1005) and the circuit portion (1005C). In other variations, instead of cutouts, other vibration absorbing mechanisms may be used to vibrationally isolate the piezoelectric mount (1005P). The electronics may be sealed and / or isolated from the mechanical portions of the device to not only isolate vibrations from the electronics, but also to protect the electronics from fluids, debris, etc.

[0054] As described herein, the fluid ejection device may include an optical alignment mechanism that assists in aligning or aiming one or more holes to the ocular surface or the inferior conjunctival region prior to actuation to ensure the entire dose reaches the ocular surface. For example, FIG. 5E shows a side view of an actuator assembly with an exemplary alignment mechanism (1064) positioned relative to a patient's eye (1060). The alignment mechanism (1064) may include any of the variations described herein or any number of other optical alignment devices that may be used with the actuator assembly. The housing is not shown solely for clarity.

[0055] Prior to fluid ejection, a user may align the eye (1060) to be treated with the alignment mechanism (1064) so ​​that the device is aligned with the optical axis (1062) or the center of the pupil of the eye (1060) to be treated. Proper alignment with the optical axis (1062) may involve placing one or more holes (1023) at a predetermined small offset (D), e.g., 4-12 mm, relative to the indicated optical axis (1062), depending on the preset offset (D). When the device is activated, a stream of fluid (e.g., a continuous or discontinuous stream of droplets) reaches the target surface or conjunctival tissue of the eye (1060) and deposits the fluid at the offset (D) from the pupil as described above.

[0056] In yet another alternative embodiment of the actuator (2000), a transducer assembly configured to vibrate a disposable medication ampoule (2015) to dispense fluid from the ampoule is shown in an exploded perspective view in FIG. 6A. The assembly may be used, for example, to dispense fluid to the corneal surface of an eye or other site on a patient's body. This embodiment may include a vibration transmission component having, for example, an elongated portion (2001) formed as a partially tubular component, extending distally from a transducer mounting portion (2002) generally configured with a rectangular cross-section. The two portions (2001) and (2002) may be fused to one another via a junction (2003), which may form a tapered or stepped transition between the two.

[0057] The joint portion (2003) may project radially from the attachment portion (2002) to a transition portion, as described above, and may form an elongated portion (2001) that further extends longitudinally and symmetrically about the longitudinal axis (2005) and terminates in a flat interface surface (2012) formed perpendicular to the axis (2005). The entire assembly (2001), (2002), (2003) may be formed from a thermoplastic material, preferably having a modulus of elasticity greater than 3 GPa, such as acrylic, acrylonitrile butadiene styrene (ABS), polyaryletherketone (Peek), etc. The assembly may also optionally be formed from metal (e.g., machined, cast, etc.).

[0058] The transducer mounting portion 2002 may be formed with symmetrically aligned, flat mounting surfaces 2004A and 2004B that are parallel to each other and to the longitudinal axis 2005 of the transducer assembly 2000. The piezoelectric plates 2006A and 2006B may be similarly or identically sized and mounted opposite each other. The mounting portion 2002 may further include one or more mounting protrusions 2007 extending from one or both sides of the mounting portion 2002 to facilitate securing the assembly 2000 in use.

[0059] The mounting arrangement of piezoelectric plates 2006A and 2006B is advantageous because transducer assembly 2000 can be made from a thermoplastic material, which can optionally provide a disposable product at a relatively low cost. Conventional longitudinal transducers, such as those described in U.S. Pat. No. 4,655,393, U.S. Pat. No. 4,352,459, and U.S. Patent Application Publication No. 2010 / 44460, are typically made from metals such as aluminum or stainless steel. Each of these references is incorporated herein by reference in its entirety and for all purposes. These transducers often have a clamping feature that fastens the piezoelectric plate to the end face of the transducer shaft. That is, the flat surface of the piezoelectric plate is perpendicular to the transducer shaft, and this arrangement allows the transducer to incorporate a clamping screw to secure the piezoelectric plate. However, it has been found that thermoplastic materials under clamping stress tend to creep over time, resulting in relaxation of the preload force and degradation of the transducer's functionality over time. Thus, piezoelectric plates 2006A and 2006B may be simply bonded to their respective mounting surfaces 2004A and 2004B via adhesive rather than using clamping forces, provided that any discontinuities at the interface between plates 2006A and 2006B and surfaces 2004A and 2004B are minimized. An advantage of using a plastic transducer assembly is a significant reduction in manufacturing costs, since plastic can be molded into any desired shape very inexpensively, completely eliminating the need for fastening plates 2006A and 2006B.

[0060] As shown, the elongated portion 2001 may be formed by stretching a tubular member defining a uniform thickness. The elongated portion 2001 may be partially hollow and may define a lumen 2014 as it transitions from the attachment portion 2002 and the joint portion 2003. While the elongated portion 2001 shown may be formed as a tubular portion, other cross-sectional shapes, such as oval, octagonal, hexagonal, pentagonal, rectangular, etc., may also be used, and the length of the elongated portion 2001 may be anywhere from 1 to 10 cm, for example. However, when the elongated portion 2001 is formed as a tubular member, this cross-sectional shape may be optimal for transmitting vibrations from the piezoelectric plates 2006A and 2006B through the length of the elongated portion 2001.

[0061] The ampoule attachment element (2008) may be configured to attach to the distal end of the elongated portion (2001), such that a first proximal side (2011) of the element (2008) contacts and / or contacts the interface (2012) and a second distal side (2010) of the element (2008) is presented for interfacing with the ampoule (2015). The element (2008) may further define an ampoule engagement mechanism (2009) for coupling with the ampoule (2015). In one particular embodiment, the element (2008) may be formed into a cup-shaped member connected to the end of the elongated portion (2001) via the proximal side (2011). The inner diameter of the cup-shaped configuration may securely engage over the distal end of the elongated portion (2001), for example, via an interference fit or any other securing mechanism. Ampoule engagement feature (2009), in this embodiment, may be formed as a threaded opening that is aligned with longitudinal axis (2005).

[0062] Referring now to the ampoule 2015, the proximal end of the ampoule 2015 may be formed as an engagement rod 2017 extending proximally from the body 2016 of the ampoule 2015. The rod 2017 may be threaded to allow for optional threaded engagement with the ampoule engagement mechanism 2009 of the ampoule attachment element 2008. This may allow for secure threaded engagement of the ampoule 2015 to the attachment element 2008 and for quick removal and replacement of the ampoule 2015 from the assembly 2000, for example, for replacement when the ampoule 2015 is emptied after use. Other embodiments of the ampoule may utilize other attachment mechanisms rather than the rod 2017, such as a friction fit, a magnetic coupling, or the like.

[0063] The ampoule (2015) may further include a distal tapered portion (2018) that narrows from the body (2016) to a distal end that defines an opening (2019) through which a fluid or medication contained within the ampoule (2015) can be dispensed during use of the assembly (2000). The reservoir volume of the ampoule (2015) may vary, for example, from anywhere from 0.2 to 5 ml, or more preferably from 0.5 to 1.5 ml, although other volumes may be sized accordingly.

[0064] 6B shows a perspective view of the partially assembled assembly 2000. The attachment element 2008 is shown attached to the distal end of the elongated portion 2001, ready to receive the engagement rod 2017. In this embodiment, the ampoule 2015 is shown having a flattened distal portion 2020 in which a dispensing hole 2019 is defined.

[0065] 7A and 7B show detailed perspective views of the elongated portion (2001) and the mounting portion (2002) inverted. Figure 7A shows a see-through view of the assembly for clarity. As shown, the elongated portion (2001) may have a lumen (2014) defined at least partially through the interior of the elongated portion (2001), thereby defining an inner wall (2030) therein, which narrows or tapers along a conical region (2031) through a proximal portion of the elongated portion (2001) to a second lumen (2032) having a smaller diameter than the lumen (2014). This second lumen (2032) may extend through the mounting portion (2002) and terminate at an opening (2033) defined at the proximal end of the mounting portion (2002). This lumen may provide a channel into lumen (2014) to provide drainage of any fluid that may leak and also prevent pressure differences from building up within lumen (2014) when the assembly is vibrating.

[0066] Referring to FIG. 8A , which shows a side view of the assembly, in use, the two piezoelectric plates (2006A) and (2006B) may be seen to be symmetrically aligned and parallel to one another. Because the plates (2006A) and (2006B) are configured to have the same polar orientation and electrical connections, the two plates (2006A) and (2006B) expand and contract simultaneously in the same direction, with no phase shift between the plates (2006A) and (2006B), as indicated by the vibration direction (2040). Thus, when the plates (2006A) and (2006B) are actuated to vibrate via a pulse generator (described herein) at a frequency equal to the longitudinal natural frequency of the elongated portion (2001), stress is induced in the mounting portion (2002) below the plates (2006A) and (2006B). This vibration is transmitted through the attachment portion 2002, the joint portion 2003, and into the elongated portion 2001. As a result, stresses propagate back and forth through the cylindrical wall of the elongated portion 2001, in accordance with the principles of acoustic wave propagation, causing the elongated portion 2001 to vibrate at a relatively high amplitude, expanding and contracting along its longitudinal axis 2005, as indicated by the vibration direction 2041. Because the elongated portion 2001, attachment portion 2002, and joint portion 2003 may be fabricated from a single material to form an integral part, the vibrations can propagate relatively unimpeded through the device.

[0067] Because ampoule attachment element 2008 is securely attached to the distal end of elongated portion 2001, the surface of element 2008 may be forced to resonate at approximately the same resonant frequency as elongated portion 2001. At that natural frequency, the surface of element 2008 may vibrate in a bending mode whereby the amplitude near the periphery of its annular opening 2009, as shown by vibration direction 2042 and phantom lines 2044, which indicate the displacement motion of element 2008 relative to elongated portion 2001, is highest across element 2008.

[0068] Advantageously, the ampoule may be attached to the aperture (2009) via a rod (2017), such that its highest amplitude vibrations (2042) are transmitted to the ampoule body (2016), resulting in corresponding vibrations (2043) of the ampoule body (2016). Consequently, fluid contained within the ampoule (2015) may be ejected from the ampoule body (2016) through the aperture (2019) into a stream of fluid (2045) for treating a patient's eye or other part of the patient's body, as shown in the perspective view of FIG. 8B. Depending on the frequency generated by the pulse generator, the stream (2045) may be ejected as a stream of individual droplets that are collinear when dispensed. If the pulse generator generates a frequency above a threshold frequency, the stream (2045) may be configured such that the individual droplets coalesce into a single continuous stream of fluid.

[0069] 9A and 9B show alternative perspective views of an embodiment of a dispensing device (2050) utilizing a piezoelectric actuator assembly (2000). The assembly may be contained within a device housing having an annular opening (2009) exposed at the distal end of the device (2050). As described above, an ampoule rod (2017) may be inserted into or otherwise attached to the device (2050) through the annular opening (2009). When the ampoule is properly attached and seated, the ampoule dispensing hole (2019) is aligned with the perforation (2053) of the light source (2052) by an offset distance. As described herein, the perforation (2053) of the light source (2052) is aligned with the optical axis of the eye or the center of the pupil, while the dispensing hole (2019) is offset a predetermined distance below the optical axis of the eye, e.g., 2-20 mm. Thus, when the device (2050) is activated, for example, by manipulating one or more controls (2051), a dispensed flow of fluid may be ejected to reach an area of ​​the eye under the optical axis for treatment.

[0070] 10A and 10B show perspective and exploded perspective views of a piezoelectric transducer 3000 that functions similarly to the previously described embodiments. The transducer 3000 comprises a bimorph actuator 3010 that includes an ampoule holder 3020 that may hold and accommodate an ampoule 3030 containing a fluid to be dispensed. Ultrasonic vibrations generated by the bimorph actuator 3010 may propagate to the ampoule holder 3020, as described herein, and then to the ampoule therein, resulting in the cycling of acoustic pressure in the fluid and the ejection of a droplet 3032 from a hole 3033 in the tip of the ampoule.

[0071] The bimorph actuator 3010 may comprise a stack of one passive plate 3011 and two active piezoelectric ceramic plates 3012 and 3013, with the passive plate 3011 positioned between the two piezoelectric ceramic plates 3012 and 3013, one on each side of the passive plate. Surfaces 3011A and 3011B of the passive plates may be attached or bonded to the surfaces of one piezoelectric ceramic plate 3012 and one piezoelectric ceramic plate 3013, respectively, while the passive plates themselves extend as cantilevers from the ampoule holder 3020 via joint interfaces 3025. The vibrations of the piezoelectric ceramic plates (3012), (3013) are transmitted to the passive plate (3011) and to the ampoule holder via the connections therebetween, as will be further explained below.

[0072] In one embodiment, both piezoelectric ceramic plates (3012), (3013) may have the same piezoelectric poling direction, indicated by arrows (3012P), (3013P), and the same electrical connection for piezoelectric poling relative to their attachment to the passive plate, such that when the two piezoelectric ceramic plates receive an AC voltage signal, the bimorph actuator (3010) expands and contracts along its lateral dimension in response, generating a vibration amplitude in the lateral direction, indicated by arrow (3011L). The lateral vibration is transferred to the ampoule holder (3020) via the attachment between the structural plates and the ampoule holder (3020).

[0073] This embodiment, similar to the piezoelectric ceramic plate configuration described above, illustrates the use of two symmetrically mounted plates. However, in other embodiments, fewer or more than two plates may be utilized. Furthermore, it is within the scope of this description that other variations of plates may be used, having different configurations, as desired.

[0074] The frequency of the AC electrical signal is approximately equal to the resonant frequency of the dispensing device in its transverse or longitudinal mode. In one embodiment, the length of the bimorph actuator (3010) may be, for example, 15 mm, and its width may be, for example, 10 mm. The passive plate may be an integral part of the ampoule holder, and the overall length of the piezoelectric actuator (3010) may be, for example, 35 mm, and the diameter of the ampoule holder may be, for example, 8-12 mm. The resonant frequency of the piezoelectric actuator may be, for example, 22.5 kHz. The passive plate (3011) may extend perpendicular to the ampoule holder as a cantilever plate, or optionally, the passive plate may extend at an angle to the longitudinal axis (3026) of the ampoule holder.

[0075] As described further below, the ampoule (3030) is easily attachable to and detachable from the ampoule holder (3020). Referring to FIG. 10B, it can be seen that the ampoule (3030) may have a cylindrical shape (3031) that transitions to a conical shape (3032) so as to taper from the body of the ampoule (3030) to a relatively small opening (3033) that defines the outlet opening of the dispensing hole. The ampoule (3030) may further include a flange (3034) at the end of the cylindrical body that is used to engage with the ampoule holder (3020) to receive ultrasonic vibrations from the ampoule holder (3020) when the flange (3034) is held against the surface (3021) of the ampoule holder (3020). This flange (3034) may be integral with the body of the ampoule (3030) to ensure that no interface is formed between the two, although in other variations, the flange (3034) may be formed as a separate component and securely attached to the body of the ampoule (3030).

[0076] The ampoule (3030) may further include annular projections or ridges (3035) disposed around the periphery of the ampoule (3030) proximal to the surface of the flange (3034), typically 1-4 mm from the surface. The projections (3035) may be used as anchoring points to securely hold the ampoule (3030) within the ampoule holder (3020). These projections or ridges may be shaped in any number of different configurations and may be arranged in any number of patterns, so long as the projections (3035) securely hold the ampoule (3030) within the ampoule holder (3020).

[0077] The ampoule holder (3020) includes an end face (3021) and an internal bore (3022) having a diameter slightly larger than the diameter of the ampoule. The internal bore may have a hump or restricting feature (3023) around its inner diameter, which may be shaped, for example, like a rounded circumferential ridge. When the ampoule (3030) is inserted into the ampoule holder (3020), the flange (3034) may engage the end face (3021) when the protrusion (3035) partially intersects with the hump (3023). In this way, the ampoule (3030) can be securely fastened to the end face of the ampoule holder, and ultrasonic vibrations can therefore be effectively transmitted. FIG. 10A shows an illustration of the ampoule (3030) when it is held within the ampoule holder (3020). Typically, the insertion force of the ampoule (3030) into the ampoule holder is, for example, less than 5N.

[0078] 10C and 10D show an alternative piezoelectric transducer using an actuator with a single piezoelectric plate and two passive plates. As shown, the actuator (3010) may comprise a stack of a single piezoelectric ceramic plate (3010) and two passive plates (3011, 3012), configured such that the piezoelectric ceramic plate (3010) is between the two passive plates (3011, 3012), one passive plate on each side of the piezoelectric ceramic plate. The surfaces of the passive plates (3011, 3012) that contact both sides of the piezoelectric ceramic plate (3010) may be attached or bonded to the surface of the piezoelectric ceramic plate (3010), while the two passive plates (3011, 3012) are structurally connected to the ampoule holder (3020). The vibration of the piezoelectric ceramic plate (3010) is transmitted to the passive plates (3011) and (3012) and to the ampoule holder (3020) via the connections therebetween. In one embodiment, the frequency of the AC electrical signal is approximately equal to the resonant frequency of the dispensing device in its transverse or longitudinal mode. Furthermore, in this variation, the piezoelectric ceramic plate (3010) may be mounted along the longitudinal axis of the ampoule holder (3020), so that the two passive plates (3011) and (3012) are aligned symmetrically with respect to the longitudinal axis.

[0079] As shown, the actuator (3010) may include one or two piezoelectric ceramic plates and one or two passive plates. In this embodiment, the passive plates may be made from a thermoplastic elastomer, such as acrylic or PEEK. The elastomer has a relatively small elastic modulus, approximately 3 GPa, compared to the elasticity of the piezoelectric ceramic material, which has an elastic modulus of approximately 60 GPa. This subsequently enables the use of relatively thin piezoelectric plates to generate cycles of structural deformation. Thinner piezoelectric ceramic plates require proportionally smaller input voltages, substantially eliminating the need to include boost circuitry such as a DC-DC converter. Thus, fabricating the transverse-longitudinal transducer from the described thermoplastic materials reduces the cost of the electronic circuitry and the resulting product itself. The lateral or longitudinal transducer and the ampoule holder may be made from a thermoplastic material, for example by an injection molding process, the thermoplastic material having an elastic modulus of, for example, less than 4 GPa, more preferably, for example, 3-4 GPa, while the thickness of the piezoelectric ceramic plate may be, for example, less than 1 mm, preferably, for example, less than 0.5 mm.

[0080] Referring now to FIG. 11A , it can be seen that the ampoule (3030) may include a cup or cap (3040) that seals the opening of the hole (3033) during storage and when not in use. The cup or cap (3040) may be configured to engage with the external threads (3036) or other feature, or may be retained via the ampoule holder (3020). The ampoule (3030) may dispense fluid in any orientation, thereby allowing the user (P) to conveniently position their head, for example, tilted downward toward the ground, while the dispensing device (3050) is tilted at an angle, such as tilted upward at an angle (θ) relative to the horizontal, as shown in FIG. 18 . In this position, liquid stored in the ampoule may migrate away from the hole due to gravity. However, in this embodiment, ampoule (3020) may include capillary features that draw fluid directly into the pores regardless of the orientation of ampoule (3020) and the fluid level therein.

[0081] 11B shows a perspective view of another variation of ampoule holder 3020, which may define grooves or channels along the sides of holder 3020 to accommodate expansion of holder 3020, as indicated by the arrows. When ampoule 3030 is inserted or removed from holder 3020, both sides of holder 3020 may expand radially due to the presence of the corresponding grooves or channels for securing or releasing ampoule 3030.

[0082] 12A and 12B show an exploded view and a cross-sectional side view of ampoule assembly 4000. Ampoule assembly 4000 can be seen to comprise a hollow cylindrical body 3030 that transitions from a cylindrical body to a conical shape 3032 that tapers to a narrow opening 3033 that defines the outlet for dispensing hole 3037. Ampoule 3030 further includes an insert 3030i that may be placed inside ampoule 3030, forming a gap between the outer surface 3031i of insert 3030i and the inner surface 3038 of ampoule 3030. Insert 3030i corresponds to the shape or volume of the interior defined by ampoule 3030, but may be slightly smaller, tapering to a conical configuration, such that the body of insert 3030i may also be cylindrical. 12B shows a cross-sectional view of ampoule 3030 when insert 3030i is placed inside ampoule 3030. It can be seen that a gap 3033i, typically 0.3 to 1 mm, is formed between the two surfaces, such that the outer surface of insert 3030i conforms correspondingly to the inner surface of ampoule 3030. In this manner, a stable or uniform gap may be formed between the outer surface of insert 3030i and the inner surface of ampoule 3030, as well as between the conical portions of both, as shown.

[0083] This gap 3033i creates an annular capillary passage that draws fluid from ampoule 3030 to bore 3037. Insert 3030i may include one or more openings 3034i around its periphery, which allow fluid to flow from the center of ampoule 3030, through openings 3034i, to annular capillary gap 3033i and bore 3037. The inner surface of annular capillary gap 3033i may be treated with a hydrophilic coating, such as HYDROPHILIC COATING FORMULA B (Coating 2Go, Carlisle, MA).

[0084] Thus, no pumping mechanism is required, as fluid is drawn directly into the hole 3037 by capillary action through the gap 3033i. Rather, capillary action ensures that fluid movement into the hole is independent of the orientation in which the ampoule 3030 is held by the user, and further independent of the fluid level contained within the ampoule 3030, i.e., dispensing of fluid from the ampoule 3030 is not dependent on gravity. Conventional fluid reservoirs typically require some active pumping mechanism to draw fluid in for dispensing, especially when the fluid level is low relative to the hole, for example, when the user is holding the fluid reservoir at an extreme angle, or when fluid is running low.

[0085] Regardless of the orientation of the ampoule (3030) or the amount of fluid remaining in the ampoule (3030), for example, when fluid is running low, the capillary action created between the ampoule (3030) and the insert (3033i) ensures that fluid is drawn into the hole (3037).

[0086] The ampoule 3030 and insert 3030i can be made from a thermoplastic polymer, such as polypropylene or polyethylene, and preferably a hydrophilic polymer or a polymer with a surface modified to have hydrophilic properties. The insert 3030i can be made from hydrophilic porous polypropylene (Porex Corporation, Fairburn, Ga.). The ampoule may further include a vent hole 3038 to allow for pressure equalization when fluid is dispensed from the ampoule. As shown, the ampoule 3030 may include a cup or cap 3040 that closes the opening of the bore 3033 when the device is not in use. The cup or cap 3040 may be attached to the ampoule body, for example, by threads 3036, 3041, or other engagement mechanism, sealing the tapered end 3032 of the ampoule against the tapered bore 3042 of the cup or cap 3040.

[0087] When the cup or cap (3040) fully engages with the ampoule (3030), both the hole (3033) and the vent hole (3038) are sealed. The diameter of the vent hole (3038) may be, for example, 0.1 to 0.6 mm, which is small enough to prevent fluid from leaking or escaping from the ampoule. The angular dimension (Ang) of the conical portion (3036) may be, for example, 30 to 60 degrees, while the tube thickness (Thk) of the ampoule may be, for example, 0.3 to 1 mm. The diameter (D) of the ampoule is typically, for example, 4 to 10 mm, while its length (L) may vary based on the desired liquid volume to be stored in the ampoule, which is typically, for example, 0.5 to 3 mL. The ampoule assembly (3000) may further include an end cup (3030c) that seals the ampoule after aseptic drug filling.

[0088] Reference is now made to FIG. 13, which illustrates an exploded view of a fluid ejection device 5000 including an ultrasonic transducer 3020 and a housing 3050. The housing 3050 provides an enclosure for the ultrasonic transducer and its electronics, a battery, and an optical aiming device 3052. The ultrasonic transducer 3020 may be provided with an extension or protrusion 3027 that captures the ultrasonic dispenser within the housing 3050. The housing 3050 may be configured in any number of shapes or dimensions suitable for holding, manipulating, or carrying by a patient. For example, the housing 3050 may be configured to generally resemble the form factor of a conventional squeeze bottle eye dropper to create a device that is highly intuitive for use by a patient. The housing 3050 may further include an activation switch 3051 and an aiming mechanism 3052.

[0089] Figure 14 shows assembly (6000) with housing (3050) assembled with ampoule holder (3020) inserted therein, and Figure 15 further shows ampoule holder (3020) in an exploded view showing the addition of a separate cup or cap (3040) as well as housing (3050) with ampoule (3030). Figure 16 shows a perspective view of the fluid ejection device showing housing (3050) when ampoule (3030) is fully inserted into ampoule holder (3020).

[0090] In some embodiments, the fluid ejection device may include an optical device that aligns or aims the dispensing hole with the ocular surface or the inferior conjunctival region prior to actuation, as described further herein. Such alignment ensures that the entire dose reaches the ocular surface. Referring now to FIG. 17 , a dispensing device is shown in partial cross section with an alignment fixture. In one variation, the alignment feature can be seen to comprise a tubular member (3080) and a light source (3081). The tube (3080) has a proximal opening (3080A) and a distal opening (3080B), with the distal opening positioned near the light source (3080), such as an LED (3081), e.g., a red LED, such that the proximal opening (3080A) of the tube is brought close to the user's eye (3089). The tubular member (3080) may be positioned parallel to the droplet ejection direction of the droplet (3032) but at a predetermined offset position (D). Prior to actuation of the dispensing device, the user may align the eye to be treated with the proximal opening of the tube (3080A) and then orient the device until the LED light (3081) at the distal end of the tube is visible, thus aligning the device with the optical axis or pupil center of the eye to be treated.

[0091] The dispensing nozzle (3033) may be positioned at a predetermined small offset position (D), e.g., 4-12 mm, relative to the optical axis (3084) of the tube, depending on the preset offset position (D). When the device is activated, a stream of fluid (e.g., a continuous or discontinuous stream of droplets) reaches the target surface of the eye or conjunctival tissue, depositing the fluid at the offset position from the pupil as described above.

[0092] The length of the optical tube (3080) is, for example, 20 mm, 30 mm, or 40 mm, while its inner diameter is, for example, 1 to 5 mm. The inner surface of the tube may optionally be coated with an optically black, anti-reflective coating.

[0093] The applications of the invention as described and disclosed above are not limited to the described embodiments, but may include any number of other applications and uses. Modifications of the above-described methods and apparatus for carrying out the invention, and variations of aspects of the invention that are obvious to those skilled in the art, are intended to be within the scope of this disclosure. Moreover, various combinations of aspects between the embodiments are also anticipated and are considered to be within the scope of this disclosure.

[0094] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 448,791, filed January 20, 2017, U.S. Provisional Patent Application No. 62 / 492,624, filed May 1, 2017, U.S. Provisional Patent Application No. 62 / 520,270, filed June 15, 2017, U.S. Provisional Patent Application No. 62 / 523,071, filed June 21, 2017, and U.S. Provisional Patent Application No. 62 / 534,083, filed July 18, 2017, each of which is incorporated herein by reference in its entirety.

Claims

1. an ampoule containing a liquid to be dispensed, the ampoule having a first portion and a second portion, the first portion defining one or more holes through a sidewall of the first portion; an actuator configured to produce vibrations to cause a flow of the liquid through the one or more holes; Equipped with the actuator continuously surrounds a circumferential region of the sidewall of the first portion, including the one or more holes, and engages with a portion of the region, but not the entire circumferential region, in surface contact along the circumferential and longitudinal directions, fixing the first portion without covering the one or more holes, and causing vibrations in the sidewall of the first portion; the actuator comprises a piezoelectric assembly; the vibrations induced on the sidewall of the first portion include a primary vibration to a location on the first portion along a first direction, the primary vibration inducing a secondary vibration on the sidewall of the first portion along a second direction perpendicular to the first direction to expel fluid from the one or more holes; Dispensing equipment.

2. the one or more holes are a plurality of holes; the primary vibration and the secondary vibration are coplanar with each other, the plurality of holes are aligned along the second direction such that the secondary vibration dispenses the fluid through the plurality of holes.

10. The dispensing device of claim 1.

3. the piezoelectric assembly includes a vibrating structure configured to clamp the first portion; The dispensing device according to any one of claims 1 to 2.

4. the first portion is secured to the clamp by an interference fit; 4. The dispensing device of claim 3.

5. the operating frequency of the piezoelectric assembly is close to or is the resonant frequency of the clamp; A dispensing device according to claim 3 or 4.

6. further comprising an electronic circuit programmed to drive the actuator; A dispensing device according to any one of claims 1 to 5.

7. the liquid comprises an ophthalmic medication; A dispensing device according to any one of claims 1 to 6.

8. and an optical alignment system that allows the patient to align the one or more holes with a target site on the surface of the patient's eye.

8. A dispensing device according to claim 7.

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