Patent Application
20150018781
The subject matter described herein relates generally to systems, devices, and methods for the topical delivery of drugs and other substances to the eye.
A number of prescription drugs are available for topical application to the eye to treat a variety of diseases. The application of these drugs in a reliable, controllable, and measurable fashion, however, presents many challenges. The drugs are commonly applied by way of an eye dropper, where the force of gravity carries the drug into the eye. Patients using an eye dropper frequently apply the dosage away from the center of the eye or miss the eye altogether, resulting in less than the full dosage being delivered. This problem is exacerbated if the patient is elderly or in poor health and lacks the requisite coordination or steadiness. The patient may also hold his or her eye open for an extended period of time while lining up the dropper for application, thereby drying the eye out and resulting in excessive blinking and/or tears that dilute and transfer the dosage out of the eye.
These challenges can lead to uncertainty as to whether the prescribed dosage was actually delivered at the prescribed intervals, which can significantly hinder an assessment of the effectiveness of the drug and can even lead to detrimental changes in a patient's treatment program. If a significant volume of the drug is not actually absorbed into the body, not only does this hinder the patient's treatment but it also results in significant over-expenditure, as many of the drugs are often expensive.
A number of devices have been proposed to address the challenges presented by use of the standard eye dropper, such as that described in US Patent Application Publication 2012/0143152 to Hunter et al. These devices, however, tend to be cumbersome, ineffective, excessively complex, difficult to align, and/or overly expensive. Some of these proposals come in the form the handheld devices that, even with automated alignment techniques, can be difficult to first align and then keep aligned to the eye, especially given that the patient's that have the most difficulty in topical drug application are the elderly and the sick. These and other proposals transfer the drug to the eye in the form of a sprays, mists, or fogs that, by their nature, tend to lack precision and have small particulate sizes. A significant amount of the drug can fail to be absorbed by the body, either by landing away from the center of the eye (or even off of the eye) as a result of imprecise delivery or by being carried off (e.g., floating away) as a result of the susceptibility of the substantial number of small particulates to minor air currents. Still other proposals fail to provide adequate safeguards against the drying out of the eye before drug application and/or against excessive blinking of the eye just after application.
As a result, needs exists for improved systems, devices, and/or methods for the topical delivery of drugs and other therapeutic substances to the eye.
Many example embodiments of systems, devices, and methods for the topical delivery of drugs and other substances to the eye are disclosed herein. Some of these embodiments utilize a drug delivery apparatus that includes a wearable frame, an ejection device, a sensor, and control circuitry. The wearable frame can resemble an eyeglass-frame and can provide a simple “hands-free” manner of alignment of the ejection device to the subject's eye.
These and other embodiments can utilize the emission and detection of infrared light, in some cases pulsed infrared light, to detect whether the subject's eye is open or closed. The drug delivery apparatus can actuate the ejection of the drug toward the eye upon detection of a blink by the patient, which increases the likelihood that the eye will be open when the drug makes contact with the subject, and also guards against drying-out of the eye before application.
Certain embodiments of the drug delivery apparatus include a single aperture in the ejection device and are configured to apply the entire dosage in one single drop, or a small number of single drops, propagated from the ejection device. The drop size can be adjusted to meet the prescribed dosage. This larger drop approach overcomes many of the disadvantages associated with sprays, mists, and fogs.
Still other systems, devices, methods, features and advantages of the subject matter described herein will be or will become apparent to one with skill in the art upon examination of the following figures and detailed description. It is intended that all such additional systems, devices, methods, features and advantages be included within this description, be within the scope of the subject matter described herein, and be protected by the accompanying claims. In no way should the features of the example embodiments in this or any section hereof be construed as limiting the appended claims, absent express recitation of those features therein.
The details of the subject matter set forth herein, both as to its structure and operation, may be apparent by study of the accompanying figures, in which like reference numerals refer to like parts. The components in the figures are not necessarily to scale, emphasis instead being placed upon illustrating the principles of the subject matter. Moreover, all illustrations are intended to convey concepts, where relative sizes, shapes and other detailed attributes may be illustrated schematically rather than literally or precisely.
The present subject matter is not limited to the particular embodiments described, as those are only examples and may, of course, vary. Likewise, the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present disclosure will be limited only by the appended claims.
Delivery apparatus 101 can be used to treat a host of tissue conditions, including but not limited to glaucoma, infection, dry eye disease, corneal abrasions, intraocular inflammation (uveitis), postoperative prophylaxis against infection and inflammation, and others. Apparatus 101 can be used by the subject directly in any environment (e.g., home, business, etc.) and can also be used by a medical professional (e.g., practitioner or technician) in a clinical setting, such as for the administration of therapeutic substances for the dilation of the pupil or for anesthesia of the ocular surface to aid in examination of or procedures on the subject patient.
Ejection device 104, sensor unit 106, and adapter unit 108 are shown in a location corresponding to the subjects left eye, but these components can also be positioned on the opposite side of frame 102 for treatment of the subject's right eye, as an alternative to or in addition to the components shown. In some embodiments, a single adapter unit 108 can be used for eyepieces 104 located on both the left and right sides.
Wearable frame 102 can take many forms. In
In other embodiments, apparatus 101 can be configured to extend over only one eye, for example, such as by one of the side struts 114 or 118 and the adjacent base portion 113, but leaving nose rest 112 and the base portion 113, and side strut on the side of the head with the eye to be treated. Also, other manners of attachment of apparatus 101 can be used instead of side struts 114 and 118, including one or more straps, bands, clamps, and so forth. The embodiments described herein can also be used in other devices that do not include a wearable frame.
Frame 102 can be fabricated from similar materials and in a similar manner to prescription or sunglass frames. In certain embodiments, these frames are custom tailored to the subject's face ensuring that both sensor unit 106 and ejection device 108 are properly aligned. For example, frame 102 can be 3D printed based on the facial geometry of the subject. In certain embodiments, after placing frame 102 on the subject's face, either or both of sensor unit 106 and ejection device 108 can be adjustably aligned to the subject's eye and then locked in place.
Ejection device 104 includes a pump 124 that receives the therapeutic substance over a fluidic channel or pathway from adapter unit 108 and causes it to be ejected through nozzle 122 to the eye.
Pump 124 includes a piezo-electrically actuatable device 134 (e.g., a crystal, ceramic, polymer, and the like) in a planar (or sheet-like) configuration with a circular profile. Other configurations and shapes can also be used depending on the needs of the application. A control (or actuation) signal is provided to device 134 by way of electrodes 133 and 135 in position on opposite sides of device 134. Here, electrodes 133 and 135 have similar profiles to device 134 and can flex or displace with device 134. Biasing of electrodes 133 and 135 with the control signal induces movement of device 134, which in turn causes corresponding movement in flexible wall 132, which is located at the rear of pump chamber 130.
Flexible wall 132 can be fabricated from the same material as the walls of chamber 130, or from a different material. Flexible wall 132 can be integral to chamber 130, such that chamber 130 and wall 132 are of monolithic construction, or wall 132 can be a separate piece securely coupled with chamber 130, such as with adhesive, coupling elements (screws, rivets, clamps, etc.) and the like. Flexible wall 132 can be in the form of a membrane, sheet, plate, or the like.
A rigid displaceable wall can also be used, for instance, by acting as a piston or other rigid driving mechanism that travels back and forth to adjust the volume of chamber 130. An example embodiment of such a configuration is depicted in the cross-sectional views of
Pump chamber 130 can of rigid or semi-rigid construction, as is readily understood by those of ordinary skill in the art. Chamber 130 can have be compressed and expanded by the movement of rear wall 132 or 212, or by the movement of one or more of the front, top, bottom, rear, and/or side walls, and any combination thereof. In certain embodiments, chamber is of rounded construction (such as a flexible tube or ball-like cavity).
Also shown in
Movement of device 134 (and wall 132) away from nozzle 122 increases the volume of chamber 130 and causes therapeutic substance 200 to flow into chamber 130 through valve 126. The other one-way valve 128 prevents therapeutic substance 200 (or any priming fluid) from moving from nozzle 122 back into chamber 130. Movement of device 134 (and wall 132) towards nozzle 122 decreases the volume of chamber 130 and causes therapeutic substance 200 to flow from chamber 130 through outlet 123 and out of nozzle 122. This is shown in
Nozzle 122 is in a position on ejection device 104 that corresponds to the center of the subject's eye when frame 102 is being worn. As noted herein, other parts of the eye (or around the eye) can be targeted as well. Nozzle 122 is oriented to eject the therapeutic substance at an angle perpendicular to the surface of
Nozzle 122 can be integrated with ejection device 104 (in a monolithic or pseudo-monolithic fashion) or can be a discrete component that is interchangeable with other nozzles 122 of varying dimension or type, which can allow apparatus 101 to convert from single drop ejection to spray ejection and so forth.
Nozzle 122 may be fabricated from any of the following biocompatible polymers: polysulfone, silicone, ultra-high-density polyethylene (UHDPE), polytetrafluoroethylene (PTFE), polycarbonate, polyether ether ketone (PEEK), cyclic olefin copolymer (COC), and the like. The nozzle's one or more apertures may be fabricated from the same material as nozzle 122 or a different material, such as a metal like stainless steel or 6Al4V titanium, or with precious stones such as ruby, diamond, or sapphire. Although not limited to such, the one or more nozzle apertures can each have a diameter in the range of 1-500 microns (μm). In certain embodiments the nozzle has a single aperture with a diameter in the range of 50-400 μm, 101-400 μm, 150-350 μm, or 200-300 μm, to name a few. Outlet 123 can have a taper with a decreasing diameter as progressing towards nozzle 122, can taper with an increasing diameter as progressing towards nozzle 122, or can have a constant cross-sectional diameter as depicted in
The peripheral profile of the nozzle aperture(s) can be rounded, such as circular or elliptical and the like. In a preferred embodiment, nozzle 122 has an aperture with a single circular profile (from the perspective of
Apparatus 101 can include one or more one-way valves 126 or 128 that assist in the movement of the therapeutic substance through the internal fluidic channels of the device. These one-way valves 126 and 128 may be of any desired type, including but not limited to umbrella, duck-bill, ball valve, multi-leaflet, flap valves, or Belleville valves. One-way valves 126 and 128 are oriented to ensure the fluid is continually moving out of apparatus 101.
For example, when flexible wall 132 is actuated the pressure generated in the adjacent fluidic chamber 130 causes one-way valve 126 on the inlet to close and one-way valve 128 on the outlet to open resulting in a surge of fluid towards nozzle 122. When the membrane is actuated in the reverse direction, one-way valve 128 on the outlet closes and one-way valve 126 on the inlet opens allowing new fluid to be drawn into the fluidic chamber. In a similar embodiment multiple one-way valves 126 and 128 are located on both the inlet and outlet sides of pump 124. Although not shown, ejection device 104 can have one or more on/off valves allowing the isolation of the therapeutic substance therein. The on/off valve can include a closure such as an interference fitting or screw on cap. The on-off valves can be used in conjunction with one or more one-way valves 126 and 128.
Ejection device 104 can also operate in a pump-less manner.
Referring back to
Sensor unit 106 can include a sensor for sensing photonic energy that can be used to determine the state of the eye. This photonic energy can include ultraviolet light, optical light, infrared (IR) light, or photons at any other frequency. Sensor unit 106 can also detect other forms of non-photonic energy as desired. The energy can be sourced from the environment, e.g., sunlight or indoor lighting, or can be sourced from an energy emitter that is included as part of sensor unit 106. Although not limited to such, in certain embodiments the wavelength of energy emitted is 300 nanometers to 2 microns.
Sensor unit 106 is shown in
IR sensor 303 can be any device capable of sensing IR energy, such as one or more photodiodes (avalanche or otherwise), phototransistors, photodarlingtons, charge coupled devices (CCD), CMOS imagers, or any combination thereof. If multiple devices are used they can be placed in an arrayed fashion. If desired, the peak spectral wavelengths of the emitter can match that of the sensor.
As can be seen in
One such alternate arrangement is depicted in
Referring back to
The conditions used by comparator 308 can be adjustable to accommodate variations between subjects, such as variations in skin color and so forth. In some embodiments, a routine is run by apparatus 101 that automatically calibrates comparator 308 to the reflectivity of the subject's skin. Any desired condition can be used to initiate ejection. For example, the conditions can include, but are not limited to: the sensed energy increasing by a threshold percentage or amount; the sensed energy decreasing by a threshold percentage or amount; the sensed energy increasing to a qualifying maximum and then decreasing; the sensed energy increasing to a qualifying maximum and then decreasing to a threshold percentage of the maximum (e.g., 90%, 85%, or 80% and so forth) or by a threshold amount from the maximum; a threshold rate of change in the sensed energy; a threshold rate of rate of change in the sensed energy; and any combination thereof. Each of the aforementioned conditions can also have temporal limitations, for example, a requirement that the sensed energy increase to a qualifying maximum and then decrease to a threshold percentage of the maximum or by a threshold amount from the maximum within a predetermined amount of time.
If the signal passed to comparator 308 satisfies the threshold or condition, then comparator 308 outputs an indication of such to timing circuit 306. Timing circuit 306, like comparator 308, can be implemented with discrete or dedicated circuitry or by software executed by one or more processors. In addition to providing the control signal that strobes IR emitter 302 as discussed above, timing circuit 306 can include a clock that is used to time various actions taken by the electrical circuitry 310. Upon receiving the positive state indication (e.g., occurrence of a blink) from comparator 308, timing circuit 306 generates an outputs a signal to actuator driver 309, which is responsible for activating pump 124 and thereby causing the ejection of the therapeutic substance (shown here as a single drop 201) to the subject's eye. Actuator driver 309 can be configured for operation with the various types of pumps described herein. For example, in the case of a piezoelectric pump 124, actuator driver 309 can be a piezoamplifier. In some embodiments, the signal received at pump 124 is of a magnitude and duration that corresponds to the desired dosage (described in more detail below).
In certain embodiments, ejection of the therapeutic substance is desired to occur immediately after the detection of a blink. Thus, timing circuit 306 can be configured to output on the very next clock cycle after receipt of the positive state indication. In some cases, a small amount of delay is desirable to ensure that the blank has completed prior to ejection. There will be delays inherent in the operation of apparatus 101 itself which may be sufficient to generate the desired delay, but if additional delay is required then timing circuit 306 can be configured to output the actuator signal after a number of clock cycles have passed. This delay can be adjustable by a user to account for individuals that might have abnormally short or long blink times. Although not limited to such, this user adjustable delay can be up to 500 milliseconds.
Also depicted in
Communication circuitry 316 includes the circuitry for communicating with external devices across either wired or wireless links. Communication circuitry 316 can include one or more ports for wired connection to a power source or an external computer (e.g., a USB or ethernet connection). Communication circuitry 316 can also provide wireless communication functionality according to any desired protocols, such as Bluetooth, Bluetooth Low Energy (BTLE), near field communication (NFC), Wi-Fi, and others. In certain embodiments, apparatus 101 is configured to interface with software running on a website, personal computer, PDA, or mobile communication device (e.g., a smartphone or wearable device like GOOGLE GLASS) and communication circuitry 316 provides this capability.
Processing hardware 324 can include one or more processors, microprocessors, controllers, microcontrollers, field programmable arrays (FPGAs), and the like, each of which can be a discrete chip or distributed amongst (and a portion of) a number of different chips. As noted above, comparator 308 and timing circuit 306, although shown separately, can be functionally implemented by processing hardware 324 and other components such as analog-to-digital and digital-to-analog converters (ADCs, DACs) and clocking circuitry (crystal oscillator, VCO, PLL, etc.).
Memory 322 can be shared by one or more of the various functional units present within apparatus 101, or can be distributed amongst two or more of them (e.g., as separate memories present within different chips). Memory 322 can also be a separate chip of its own. Memory 322 is non-transitory, and can be volatile (e.g., RAM, etc.) and/or non-volatile memory (e.g., ROM, flash memory, F-RAM, etc.).
Now referring back to
In still other embodiments adapter unit 108 can be omitted and therapeutic substances can be manually or mechanically supplied to one or more internal reservoirs 320, such as with a syringe. Numerous therapeutic substances can be supplied to apparatus 101 and mixed therein (such as within internal reservoir 320 of
Once the source of the therapeutic substance has been connected, apparatus 101 can be primed or filled with the fluid. Priming can be achieved by setting apparatus 101 in a priming mode where ejection device 104 draws the fluid into internal reservoir 320. Internal reservoir 320 can be a chamber connected with pump 124 or can be realized by the volume of fluid held within the internal fluidic channels of apparatus 101. The subject may squeeze the external container creating the pressure needed to fill apparatus 101 with fluid. In other embodiments, a prefilled priming reservoir may be used.
As mentioned, apparatus 101 may be used as part of a larger system 100 that includes other devices such as a smartphone or personal computer. A software application can be downloaded or installed, or a website can be utilized, that provides assistance to the user in performing dosage administration at the proper times and with the proper amounts. For example, a notification routine can be initiated that provides notification to the subject to take certain actions, such as to place apparatus 101 on the subject's face and begin a dosage administration procedure. The notification can be sent to the subject's phone in the form of a text message or email, or can be generated in visual, audible, and/or tactile (e.g., vibration) format on the subject's phone, tablet, or computer (typically not tactile).
Apparatus 101 can then be placed on the subject's face and, when the subject is ready for administration of the dosage, transitioned from the priming mode to a delivery mode. Placement on the face automatically orients sensor unit 106 so that emitter 302 and sensor 303 are focused on the eye of the subject enabling the opening and closure of the eye to be detected. Ejection device 104 is also automatically oriented such that nozzle 122 is aimed at the desired portion of the subject's eye, which may be either corner of the eye, the center of the eye, a center region of the eye, or a tear duct. If a correction of the alignment of sensor unit 106 or ejection device 104 is needed, the subject can manually adjust either unit 106 or device 104 as needed and then lock into place.
Apparatus 101 monitors for the occurrence of a blink. Once detected, after a small delay ejection device 104 is triggered causing the therapeutic substance to be propelled towards the eye. The therapeutic substance is propelled with sufficient velocity to overcome the force of gravity if the subject is in a sitting or standing position or looking downwards. Upon transitioning apparatus 101 to the delivery mode, a minor delay of a few seconds may be built into apparatus 101 to give the subject time to ready him or herself for administration of the dosage, which can include blinking the eye one or more times to adequately moisten it. An audible or other notification may be output by apparatus 101 once apparatus begins monitoring.
To facilitate detection of the blink, in some embodiments it can be desirable to include an optical light (e.g., an LED) or camera flash that, when set off, induces a blink at a point in time when apparatus 101 can expect it and then more easily sense it. The optical light can be part of apparatus 101 or, when used in conjunction with a smartphone, the smartphone's camera flash can be triggered by user or system 100 itself.
Details of the delivery such as dosage, dose frequency, response, and times may be logged and stored on apparatus 101 or broadcast wirelessly to one of the aforementioned external devices, at which point those details can be uploaded to a server and communicated to a medical professional. Responses to the delivery may be logged in a form of photograph through an optical imager attached to frame 102.
Molecular tags such as fluorophores may be utilized in the therapeutic substance linked to physiological markers to provide information regarding the dose, pharmacokinetics, or pharmacodynamics. Any of multiple wavelengths may be used for detection and excitation of different biomarkers. Dosage can then be adjusted, e.g., in real time, to match a particular pharmacodynamic or physiological response. This data may be used to indicate when to administer the medicament. In certain embodiments, apparatus 101 can include an opthalmoscope.
As mentioned above, apparatus 101 can deliver the entire desired dosage with a single drop (or continuous fluid body). The use of a single drop having a known volume provides greater confidence that the entire volume with be transferred to the subject's eye, as compared to mists, fogs, and even focused, jet-like sprays that break the dosage down into many small particulates to transfer to the eye.
The embodiment pictured here has a pump wall 132 configured as a membrane (not shown).
As seen in
Certain subject matter described herein was arrived at through a joint research agreement between the Regents of the University of California (San Francisco Campus) and the California Institute of Technology.
All features, elements, components, functions, and steps described with respect to any embodiment provided herein are intended to be freely combinable and substitutable with those from any other embodiment. If a certain feature, element, component, function, or step is described with respect to only one embodiment, then it should be understood that that feature, element, component, function, or step can be used with every other embodiment described herein unless explicitly stated otherwise. This paragraph therefore serves as antecedent basis and written support for the introduction of claims, at any time, that combine features, elements, components, functions, and steps from different embodiments, or that substitute features, elements, components, functions, and steps from one embodiment with those of another, even if the following description does not explicitly state, in a particular instance, that such combinations or substitutions are possible. Express recitation of every possible combination and substitution is overly burdensome, especially given that the permissibility of each and every such combination and substitution will be readily recognized by those of ordinary skill in the art upon reading this description.
Where a range of values is provided, it is noted that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure and can be claimed as an sole value or as a smaller range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.
Where a discrete value or range of values is provided, it is noted that that value or range of values may be claimed more broadly than as a discrete number or range of numbers, unless indicated otherwise. For example, each value or range of values provided herein may be claimed as an approximation and this paragraph serves as antecedent basis and written support for the introduction of claims, at any time, that recite each such value or range of values as “approximately” that value, “approximately” that range of values, “about” that value, and/or “about” that range of values. Conversely, if a value or range of values is stated as an approximation or generalization, e.g., approximately X or about X, then that value or range of values can be claimed discretely without using such a broadening term.
However, in no way should a claim be limited to a particular value or range of values absent explicit recitation of that value or range of values in the claims. Values and ranges of values are provided herein merely as examples.
In some instances entities are described herein as being coupled to other entities. It should be understood that the terms “coupled” and “connected” (or any of their forms) are used interchangeably herein and, in both cases, are generic to the direct coupling of two entities (without any non-negligible (e.g., parasitic) intervening entities) and the indirect coupling of two entities (with one or more non-negligible intervening entities). Where entities are shown as being directly coupled together, or described as coupled together without description of any intervening entity, it should be understood that those entities can be indirectly coupled together as well unless the context clearly dictates otherwise.
As used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise.
The scope of the claims originally filed herewith is not intended to define the limits of the subject matter that may be claimed on the basis of this description. Broader and/or altogether different subject matter may, in fact, be claimed in the future without departing from the scope of the present description.
While the embodiments are susceptible to various modifications and alternative forms, specific examples thereof have been shown in the drawings and are herein described in detail. It should be understood, however, that these embodiments are not to be limited to the particular form disclosed, but to the contrary, these embodiments are to cover all modifications, equivalents, and alternatives falling within the spirit of the disclosure. Furthermore, any features, functions, steps, or elements of the embodiments may be recited in or added to the claims, as well as negative limitations that define the inventive scope of the claims by features, functions, steps, or elements that are not within that scope.
This application claims the benefit of and priority to U.S. Provisional Patent Application Ser. No. 61/810,614, filed on Apr. 10, 2013, which is incorporated by reference herein in its entirety for all purposes.
| Number | Date | Country | |
|---|---|---|---|
| 61810614 | Apr 2013 | US |
