Patent Application
20200197220
The present invention relates to devices for ejecting fluid stream specifically but not exclusively for topical administration of ophthalmic therapeutics.
A typical medical eye dropper dispenses single drops which have large volumes, typically about 50 μL. However, since the human eye can typically retain only 7 μL of fluid on the corneal surface at a time, larger volume results in overflow and loss of part of the medication from the eye surface. In addition, a large volume of a single drop, such as 30 or 50 μL, causes a blinking reflex which removes majority of the fluid from the cornea, and inconvenience which leads to poor compliance. U.S. Pat. Pub. 2012/0070467 A1 (incorporated herein by reference in its entirety) describes a droplet generating device for drug delivery to the eye which comprises a piezoelectric actuated droplets generator for delivering small droplets to the eye. This device operates on the principle of nebulizers which use a vibrating plate with multiple apertures to generate aerosol. Such ejector mechanisms are integrally coupled to a fluid reservoir which is periodically refilled by the user. Refilling, however, carries the risk of bacterial contamination and the risk of ocular infection. Generally, drug filling, particularly for ophthalmic use, must be processed in tightly controlled aseptic environment which is not available to the user. Another problem associated with the aerosol delivery as described in the prior art is the user ability to direct the aerosol stream to the surface of the eye. Any misalignment of the dispensing device with the eye will result is inaccurate dosing.
The present invention provides a devices for ejecting therapeutic fluid to surface of the eye or to the conjunctival tissue. The device advantageously utilizes a disposable sterile drug ampoule which can be attached to and detached from a piezoelectric actuator, thereby eliminating the need of refilling and mitigating the possibility of bacterial contamination and providing a cost effective approach reusing the piezoelectric actuator for further operation. The invention further provides a delivery of a single stream and a mechanism to align the stream to the eye prior to actuation to assure convenient and precise dosing. Surprisingly, it has been found that delivery of a single stream imparts lesser impact on the eye and is therefore is more convenient to use when compared to delivery of a mist or a distribution of small droplets which has the same accumulated volume. Unlike a mist or spray, a single stream can be precisely oriented to target a specific location on the surface of the eye or the conjunctival tissue. This characteristic is largely attributed to the aerodynamic behavior of the stream. Specifically, delivery of a mist generally produces a turbulence which causes divergence of the droplet from the target while a stream pierces through the air and reach the target area more precisely.
The invention provides a miniature fluid ejection device for treatment of ophthalmic diseases by topical administration. The device comprises a piezoelectric actuator and separable disposable drug or fluid package. The piezoelectric actuator is configured to transmit energy to the drug or fluid package such as acoustic energy or oscillation. The device is characterized in its drug packaging which can be easily attached to or detached from the piezoelectric actuator. Empty drug or fluid packages are disposed, thereby eliminating the need for filling the drug by the user and the risk of bacterial contamination.
The drug or fluid package is configured to dispense micro-droplets by one or more acoustic pulses exerted by the piezoelectric actuator onto the external surface of the disposable drug package. The drug package can be decoupled from the piezoelectric actuator allowing disposal of used packages while the piezoelectric actuator is subsequently reused with another drug or fluid package. The invention provides a cost effective approach for topical drug delivery to the eye.
The piezoelectric actuator is a small module which can be used as a handheld device or as an attachment to an eyewear article such as optical or sunglasses. In one embodiment the drug or fluid package is comprised of a blow-fill-seal package or an ampoule containing an ophthalmic formulation.
U.S. Pat. Pub. 2012/0070467 (the entirety of which is hereby incorporated by reference herein and for any purpose) describes examples of various ophthalmic compositions and therapeutics which may be used with the devices and methods described herein.
The drug or fluid package is made of a thermoplastic polymer such as polyethylene, terephthalate, polyethylene or polypropylene. The drug or fluid package includes a drug reservoir and an aperture plate containing one or more apertures. The drug or fluid package further includes fluid channel which connects between the drug reservoir and the aperture plate. Drug or fluid package contains ophthalmic formulations which fills the volume of the drug reservoir and the channel. Drug or fluid package optionally includes a valve that is configured to seal the opening of the aperture plate to prevent or minimized bacterial contamination. The valve may be open by mechanical mechanisms simultaneously when the device is electrically actuated.
Droplet volumes are generally between, e.g., 100 to 1000 pL, and the size of the aperture is typically between, e.g., 10 to 100 micron
In some embodiments the dispensing device includes an optical mechanism to align or target the dispensing aperture to the ocular surface or to the area of the lower conjunctiva prior to actuation. Such alignment assures that the entire dose reaches the surface of the eye. The alignment mechanism may include a collimated beam of light with visible wavelength generated by, e.g., LED, laser or a lamp. For example, it may include a tubular member with proximal and distal openings; the distal opening may be positioned near a light source while the proximal opening of the tube is brought into proximity near the eye of the user. Prior to actuation of the dispensing device, the user may align the eye to be treated with the proximal opening of the tube and then manipulate the orientation of the device until the light at the distal end of the tube becomes visible. In this way the device is brought to an alignment with the optical axis of the eye to be treated or the center of the pupil. The dispensing nozzle is positioned at a predetermined small offset relative to the optical axis of the tube. When the device is actuated, a stream of fluid will reach the targeted surface of the eye or the conjunctival tissue and will deposit fluid at the above mentioned offset from the pupil.
The optical tube may have a length of, e.g., 20, 30, or 40 mm while its internal diameter ranges between, e.g., 1 to 5 mm. Preferably, the internal surfaces of the tube are coated with optically-black non-reflective coating.
A typical volume of, e.g., 4 to 10 μL, may be delivered during the eye fixation time, typically under 1 second, and preferably within 250 ms. In one embodiment the dispensing device includes one or more apertures but typically less than, e.g., 20 apertures, and preferably less than, e.g., 10 apertures and most preferably a single aperture. The apertures are positioned in a predetermined offset relative to the optical axis of the alignment tube. This offset determines where the fluid stream is deposited relative to optical axis of the eye or relative to the center of the pupil or the center of the iris. Typically, the offset may be, e.g., 2-20 mm, from the center of the pupil in the vertical or horizontal directions, or in both vertical and horizontal directions.
The drug or fluid package can be removed and replaced, while the piezoelectric actuator can be reused with another drug package. In one embodiment the drug or fluid package is manufactured by an aseptic blow-fill-seal process commonly used in packaging of pharmaceutical liquids. Such processes are described for example in U.S. Pat. Pub. 2013/0345672 A1; 2012/0017898; and U.S. Pat. No. 5,624,057, each of which is incorporated herein by reference in its entirety and for any purpose.
The device further includes an electronic circuit that is configured to generate and transmit an electric pulse or wave form to the piezoelectric actuator. The circuit may be comprised of a half-bridge driver which generally includes a half-bridge driver chip and two MOSFET transistors. The half-bridge driver receives an input signal and transmits a switching output which drives a pair of MOSFET transistors sequentially “on” and “off”. In this way it translates the low voltage input signal to a high power electrical pulse that is capable of driving the piezoelectric actuator. The circuit may further include an inductor that increases the output to higher voltage level. Preferably the inductance of the inductor and the capacitance of the piezoelectric actuator may be tuned to operate in resonance at the selected output frequency. The input signal which transmitted to the half bridge driver chip may be generated by a microprocessor or by a signal generator IC (integrated circuit). In one embodiment the driver, the transistors and the microprocessor are fabricated on a single integrated circuit. Preferably such IC is attached and encapsulated directly to a printed circuit board (PCB) utilizing a chip-on-board (COB) packaging process. In the field of microelectronics COB is used to reduce the size of the circuit. The input voltage of the circuit is preferably below, e.g., 5 volts, and more preferably below, e.g., 3 volts, and even more preferably below, e.g., 1.5 volts. The source of energy may be provided by a power supply such as capacitors, batteries, etc. which may be optionally rechargeable. When the circuit is driven sequentially “on” and “off” as described earlier the fluid stream emits from the aperture as individual droplets. However, when an inductor is added and is tuned to operate at the electrical resonance of the circuit then the electrical output becomes sinusoidal and the fluid emits as a collimated and continuous stream without individual droplets.
Having thus summarized the general nature of the 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 having reference to the figures that follow, of which:
The preferred embodiments of the invention described herein relates to a device for drug delivery to the ocular surface for treatment of ophthalmic diseases. In the systems and methods described herein droplets are dispensed in high frequency but in a single drop format or in a continuous stream depending on the electric signal input as described earlier. When droplets are produced they generally have ultra-small volumes ranging from about a few hundred pico-liters to about one nano-liters. Generally, droplets of such volume or continuous collimated single stream do not cause blinking reflex.
In the first aspect embodiments the dispensing devices advantageously utilize a disposable, removable or separable drug or fluid package while desirably retaining the piezoelectric actuator or transducer for subsequent further uses, thereby providing an economical and cost effective approach with reuse of the piezoelectric actuator or transducer for further operation.
As illustrated in
Acoustic cavity (123) comprising a cylindrical chamber sealed by a thin-wall membrane (123-A). Drug or fluid package (120) is configured to dispense a micro-droplet each time a pulse displacement is exerted by the actuator (110) onto the surface of the thin-wall membrane (123-A). Such pulse displacement generates an acoustic pressure within the acoustic cavity (123) which then propagates through the fluid in conduit (126) toward the aperture (124) whereas droplets are dispensed in a single drop format to the surface of the eye.
Piezoelectric actuator (110) comprising a piezoelectric clamp and an electronic circuit. The piezoelectric clamp is configured to apply pulse displacements to the acoustic cavity while it is being clamped under spring pressure.
Piezoelectric actuator (110) includes a printed circuit board (PCB) (115) capable of generating electrical pulses at a selected frequency. Referring to
Drug or fluid package (120) may be inserted into, or removed from actuator (110) in the directions indicated by arrows (127-IN) and (127-OUT).
Piezoelectric chip (114) comprises of a monolithic co-fired piezoceramic stack model PA3CE sold by Thorlabs Inc., Newton, N.J., USA. The chip expands and contracts under the input of an alternating voltage. Co-fired piezoceramic stack produces large displacement, generally in the range of 1-5 micron. In comparison a single crystal piezoceramic element, produces a displacement in the range of a 0.1-0.5 micron, therefore normally requires structural attachment to the oscillating structure. Thus, the co-fired piezoceramic stack enables the separation of the drug or fluid package and an economical, cost effective and practical solution.
In one embodiment the device may have one or more apertures. Typically the diameter of each aperture is in the range of 10-120 micron.
In some embodiment the cross section area of channel (501) is between 0.25-1 mm while cross section of the restricted section (501-N) is about 50-90% smaller. The cross sectional area of the restriction (501-N) is the effective area through which the acoustic wave propagates as indicated by the arrow symbol R-R and C-C. The cross sectional shape may be but is not limited to circulator or rectangular shape.
The end section of channel (501) is used as a venting port to the drug reservoir (122). The end section of the channel (501-V) extends from the drug reservoir to tab section (503). Before use the tab is broken and the opening of channel (501-V) is exposed to the atmosphere. Venting is necessary to prevent vacuum build up in the drug reservoir during use. The vent is made from porous polyethylene plug which filters out particles larger than, e.g., 0.2 micron such as airborne microorganisms and the like.
In some embodiment the diameter of the drug reservoir (122) is between, e.g., 8 mm to 14 mm, and its volume is in the range between, e.g., 0.5 mL to 3.0 mL (3000 μL). In some embodiment the diameter the acoustic cavity is between 5-8 mm and its volume is 30-100 μL
The length of the channel (501) between the acoustic cavity (123) and the aperture (114) is designated by the letter L in
f=iC/(2L) (1)
When substituting C, L and i=1 it can be found that the natural frequency of the fluid in the channel (501) is 19,500 Hz, therefore the operating frequency of the electronic circuit should also be 19,500 Hz. The volume of liquid dispense is determined by the number of cycles that the piezoelectric actuator operates in this frequency.
All the internal fluid passage shown in cross sectional view of
L=1/(2πfC) (2)
where, L=2.22 mH.
An inductor that has a value of 2.22 mH connected in series to the piezo chip will cause the circuit to resonate and as a result the voltage level of the battery will increase typically by, e.g., 5, 10, 20 times. In the present invention the size of the droplets is in the range of 500 pL (pico-Liter). In comparison, the lachrymal tear flow is about 1 μL/min, thus such volume can be created by generating, e.g., 2000 pulses at a frequency of 19,500 Hz during a period of about 0.1 sec.
Embodiments of the dispensing devices advantageously utilize a disposable, removable or separable ampoule or vial while desirably retaining the piezoelectric actuator or transducer for subsequent further uses, thereby eliminates the need for the user to refill drug, mitigating the possibility of bacterial contamination and providing an economical and cost effective approach with reuse of the piezoelectric actuator or transducer for further operation such as with a variety of ophthalmic therapeutics.
The preloading C-clamp (601) and the ampoule (602) are engaged in slight pressure interference fit which allows them to be engage or disengaged by applying an axial pulling or pushing force illustrated by the arrow (612). Conveniently the pulling or pushing force is smaller than, e.g., 10 Newton.
In operation, a burst of voltage pulses actuates the piezoelectric chip (608) so that it expands and contracts toward the anvil (604) while radial force (611) is exerted or applied on the wall of the tube (602T). This radial force (611) causes a small deformation and radial displacement of the wall of the tube. Further, acoustic stress wave propagates or is transmitted axially or longitudinally from the clamp region of the tube, through the wall of the tube (602T) and toward the tube tip (603) which undergoes axial or longitudinal motion, displacement or movement in the axial direction (612). Thus, a stress or pressure wave passes longitudinally or axially through the tube wall and provides for transmission or conversion of tube radial motion (611) to axial or longitudinal motion (612) at the tip of the tube (603).
On completion of one cycle, the tube (602T) reverts back to its deactivated state with radially outward tube motion (611) and retracting tube tip axial motion (612). When multiple pulses of an alternating voltage cause expansion and contraction of the piezoelectric chip (608) the tube tip (603) undergoes multiple axial or longitudinal oscillations. The axial oscillation oscillates the aperture plate (605) which causes fluid droplets (607) to be ejected from the aperture plate (605).
While the fluid which is ejected from the aperture plate in this and other embodiments may be described as droplets, the ejected fluid may be emitted as individual droplets separated from one another or the ejected fluid may be emitted as a continuous stream of fluid with no separation until the transducer is no longer actuated (or until the fluid runs out). The emission of the continuous stream of fluid may be implemented in this embodiment or any of the other embodiments described herein.
Typically the external diameter of the tube is about, e.g., 1-4 mm, and the inside diameter is between, e.g., 0.5 to 2.5 mm.
In some embodiment the length of optical tube (905) is, e.g., 20, 30, or 40 mm, while its internal diameter ranges from, e.g., 1 to 5 mm. Preferably, the internal surfaces of the tube are coated with optically-black non-reflective coating.
In other alternative embodiments, the light source may instead be used as a fixation device to ensure delivery of the stream of fluid (607) to the proper portion of the eye. Rather than the patient aligning the optical axis of the tube with the optical axis of their eye, the light can instead be directed onto the eye by someone other than the patient, e.g., physician, nurse, family member, etc., such that the light source functions as an aiming or guiding device for directing the stream of fluid (607) onto the eye surface.
The dispensing assembly is seated or assembled on a printed circuit board (902) which includes a battery (903) and a pulse generator circuit.
Following the alignment of dispensing device (900) with the optical axis of eye electrical switch (909) is then activated by pressing on electrical switch (909). Arrow (910) illustrates the actuating vector. Electrical switch (909) further includes a linkage (908) which presses on a pedestal (802) to open the valve of the ampoule (602) as described in relation to
The natural or resonance longitudinal frequency of transducer plate may be calculated by the following formula below:
It can be seen that the first natural frequency of the aluminum plate (i=1) is 31,430 Hz; the second natural frequency (i=2) is 62,850 Hz; the third natural frequency (i=3) is 94,280 Hz, etc.
Preferably the operating frequency will be the first or second natural frequency 31,430 Hz, although other natural frequencies may be selected. Advantageously, lower frequencies reduce the impact force of the droplets on the ocular surface of the eye.
where i=1, 2, 3, . . . .
It can be seen that the longitudinal displacement has a cosines profile wherein the maximum value is at the proximal and distal edges of the plate while the minimal value amplitude at the center of the plate x=Y/2=37.5 mm. This indicates that at the first longitudinal natural frequency the middle of the plate (x=37.5 mm) does not vibrate, or practically has very small vibration amplitude. Preferably the aluminum plate will be supported at or near the center such that the support minimally interferes with the vibration. In the preferred embodiment the support is made of soft elastomeric material such as silicon rubber, EPDM or the like preferably with modulus of elasticity of about, e.g., 0.3, 0.4, 0.5 GPa.
Transducer (1100) may be used to oscillate an ampoule as will explain further below. Preferably the attachment of the ampoule will be near the proximal end of the plate whereat the amplitude has a maximum value. The natural frequency of the plate is a function of its length and material properties of the plate but is nearly independent of the load, namely the weight of the ampoule, thus various sizes and types of ampoules may be used with the same transducer. Transducers with shorter or longer plates may also be selected however generally the length of the plate (L-plate) is between, e.g., 10 mm and 200 mm, and the resonance frequency is generally lower than, e.g., 500 KHz.
In one embodiment the length of piezoceramic plates (1103) and (1102) (L-Piezo) is, e.g., 10 mm. In one embodiment the length piezoceramic plate (1103) is greater than the length of piezoceramic plate (1102). In one embodiment length (L-Piezo) of piezoelectric plate (1102) may be, e.g., 20, 30, 50, or 80%, longer than piezoelectric plate (1103). In such case substrate plate (1101) will have a vibration mode which comprises of a superposition of bending mode and longitudinal mode.
In one embodiment the piezoceramic plates (1103) and (1102) are made of soft piezoceramic material such as APC 850 or APC 855 manufactured by American Piezo Corporation (APC) Mill Hall, Pa. USA.
In one embodiment the longitudinal transducer plate includes a third piezoceramic plate (1102) which is configured to produces a bending mode at the proximal end of the plate. Such a bending mode disperses the drops (1210) and reduces the droplets impact for on the eye. In one embodiment the length piezoceramic plates (1103) is, e.g., 20 mm, and the length of piezoceramic plate (1102) is, e.g., 10 mm, which in turn produces a superposition of bending and longitudinal modes which in turn causes a dispersion of droplets (1210).
In one embodiment piezoceramic stack (1306) manufactured by NEC part No. AE203D04F is sold by THORLABS INC. Newton, N.J. USA. In one embodiment the angle (1309) of the flexible linkage (1304) is, e.g., 150 deg. In some embodiment mechanical oscillator (1301) is made of extruded material such as aluminum type 2024 or thermoplastics such as Delrin™.
Dispensing device (1300) further includes a disposable ampoule (602) and two dowel pin similar to the one discussed earlier in relation to
Advantageously, operation of device (1300) is not dependent of the natural frequency of the oscillator (1301). Device (1300) will operate at subsonic frequencies which further reduces the impact force of the drop on the eye. Preferably the electrical input signal to the piezoceramic stack (1306) is a square wave with a rapid rise and fall. Preferably operating frequency is below, e.g., 10 kHz, and more preferably at about, e.g., 4 kHz. Lower frequencies further reduce the impact force of the droplets against the surface of the eye.
Referring now to
With respect to the amount of magnetic force, the embodiment shown may generally utilize at least, e.g., 0.5 N, of magnetic force between the magnets and in other embodiments, at least, e.g., 25 N, of magnetic force to securely maintain the ampoule position relative to the transducer and housing during transducer vibration.
Dispensing assembly (1700) further includes a handle (1705) and an activation switch (1703). Dispensing assembly (1700) further includes an optical mechanism to align the dispensing device to the inferior conjunctiva of the eye prior to actuation. The alignment mechanism includes a small diameter bore (1702) having a predetermined diameter and depth. A light source (not shown) may be positioned inside the distal end of the bore (1702) while the proximal opening of the bore is generally oriented toward the eye.
Referring now to
It can be seen that transducer plate (1906) is relatively wider near the piezoceramic elements and is gradually tapering along the length (L-Plate) of the substrate plate (1906). In this way the stress distribution is gradually increased toward the distal end. As illustrated oscillation amplitude (1908) at the distal end of the transducer are relatively higher than the oscillation amplitude (1909) near the proximal end where the piezoceramic elements are located. It can be seen that substrate plate (1906) further includes an extension (1904) that extends in a perpendicular direction relative to the length of the substrate plate (1906). Extension (1904) function as a cantilever beam that is attached to the substrate (1906) at its distal end (1910) and is free to oscillate at the second end (1911) of the extension (1904). The free end (1911) oscillates at a relatively higher amplitude (1907) when compared to the oscillation of the transducer (1902) and (1903). Extension (1904) may further includes a groove or notch, e.g., V-groove (1905), defined along a proximal edge of the extension (1904) that may be used to secure the ampoule to the transducer. Preferably the natural frequency of the cantilever beam (1904) is equal to the natural frequency of the transducer (1900).
The applications of the disclosed invention discussed above are not limited to the embodiments described, but may include any number of other applications and uses. Modification of the above-described methods and devices for carrying out the invention, and variations of aspects of the invention that are obvious to those of skill in the arts are intended to be within the scope of this disclosure. Moreover, various combinations of aspects between examples are also contemplated and are considered to be within the scope of this disclosure as well.
This application is a continuation of U.S. Ser. No. 15/094,849, filed on Apr. 8, 2016 and incorporated herein by reference in its entirety. U.S. Ser. No. 15/094,849 claims the benefit of priority to U.S. Prov. App. 62/178,464 filed Apr. 10, 2015, which is incorporated herein by reference in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 62178464 | Apr 2015 | US |
| Number | Date | Country | |
|---|---|---|---|
| Parent | 15094849 | Apr 2016 | US |
| Child | 16805188 | US |
