Systems and methods for ultrasound-enhanced delivery of drugs

Abstract

A drug applicator (202) for ultrasound-enhanced delivery of at least one drug to a target site in an intraocular space (100), the system comprising a signal generating unit (300) operatively connected to an ultrasound transducer (202), wherein the drug applicator includes at least one space (800) for holding the drug, made of a low-ultrasound-attenuation material, configured to provide low-ultrasound-loss coupling between the system and the sclera, and configured to be mechanically coupled to the system and further configured to be coupled to the ultrasound transducer with low-ultrasound-loss. The signal generating unit and / or the ultrasound transducer are configured to emit an ultrasound pattern in at least one application cycle, the application cycle comprising at least one ultrasound emission event having a duration TA and a waiting period having a duration TW.

Description

[0001] This application is a divisional application of Chinese patent application No. 201780058837.3, entitled "System and method for ultrasound-enhanced delivery of drugs" (the corresponding PCT application was filed on May 18, 2017, with application number PCT / EP2017 / 061983).

[0002] Cross-references

[0003] This application claims the benefit of European application serial number 16 17 0141.2, filed on 18 May 2016, which is incorporated herein by reference in its entirety and for which this application claims priority. Background of the Invention

[0004] Transscleral drug delivery is an important aspect of ophthalmic care. For the treatment of many diseases and / or conditions, delivery of at least one medication into the intrascleral space is necessary, including conditions such as central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), central serous retinopathy, cytomegalovirus retinitis (CMV retinitis), retinoblastoma, intraocular lymphoma, ocular melanoma, giant cell arteritis (GCA), histoplasmosis, ischemic optic neuropathy (ION), macular folds, macular telangiectasia, uveitis, choroidal neovascularization, age-related macular degeneration, diabetic retinopathy, glaucoma, retinitis pigmentosa, macular edema, macular degeneration, multiple recurrent pterygium, ocular toxoplasmosis, proliferative vitreoretinopathy (PVR), Stevens-Johnson syndrome (SJS), ocular cicatricial pemphigoid (OIP), ocular degenerative conditions, and postoperative conditions.

[0005] However, the eye is a well-protected organ with several natural barriers to prevent foreign substances from entering the anterior and / or posterior segments of the eye. Furthermore, many therapeutic agents used to treat posterior segment eye diseases have high molecular weights, making it difficult for them to diffuse across the ocular tissues when applied to the scleral surface. In other words, external application is ineffective.

[0006] Intravitreal injection is the most common method used to deliver medication into the space within the sclera. While most ophthalmologists consider it a treatment, it is a surgical procedure. Intravitreal injection carries risks and problems, such as low patient compliance and high time consumption. Furthermore, it can only be performed by a surgeon and results in an open wound in the eye, making it susceptible to infection and potentially causing side effects.

[0007] US 2008 0177220 A1 relates to a process, system, and apparatus for delivering a pharmaceutical preparation through the sclera to the eye using ultrasound. In one embodiment, a transducer is positioned to contact a coupling medium contained in a coupling aperture that contacts the sclera. When the transducer is positioned at a desired standoff distance, ultrasound waves are emitted to increase tissue porosity and transport the therapeutic agent through the scleral tissue and into the eye. In another embodiment, a functional generator is coupled to an amplifier, a matching network, and a transducer configured to maximize the cavitation effect of the ultrasound waves for drug delivery through the sclera.

[0008] US 20100226971 A1 relates to a system and method for delivering a therapeutic agent comprising macromolecules transscleral to a target site within the intrascleral space using ultrasound. This system enhances the transscleral diffusion of the macromolecular therapeutic agent and causes minimal damage to ocular tissues and structures.

[0009] The corresponding equipment for ultrasound-based drug delivery is complex and expensive, and the methods of use are inconvenient for both patients and physicians. For example, the ultrasound emission from current technologies is intense and produces cavitation effects and / or heating of ocular tissues. The latter two are dangerous and uncomfortable for patients. Summary of the Invention

[0010] There is a need for improved non-invasive methods to deliver drugs to the posterior segment of the eye.

[0011] Other advantages, objects, and features of the invention will be set forth in part in the description which follows, and will become apparent in part to those skilled in the art upon review of the following, or may be learned by practice. These objects and other advantages can be realized and achieved by means of the structures particularly pointed out in the written description, its claims, and the accompanying drawings. The subject matter of the independent claims addresses the foregoing problems. The dependent claims relate to other aspects of the invention.

[0012] One aspect of the invention relates to a drug applicator for a system for ultrasound-enhanced delivery of at least one drug to a target site in the intraocular space, the system including a signal generating unit operatively connected to an ultrasound transducer. The drug applicator includes at least one space for holding the drug. The drug applicator is made of a low-ultrasound-attenuation material. Furthermore, the drug applicator is configured to provide low-ultrasound-loss coupling between the system and the sclera, and the drug applicator is configured to be mechanically coupled to the system and further configured to be coupled to the ultrasound transducer with low-ultrasound-loss. The signal generating unit and / or the ultrasound transducer is configured to emit an ultrasound pattern in at least one application cycle, the application cycle including at least one ultrasound emission event having a duration TA and a waiting period having a duration TW.

[0013] One aspect of the invention relates to a system for ultrasound-enhanced transscleral delivery of at least one drug (molecule) to a target site in the intraocular space. The system includes a signal generating unit operatively connected to an ultrasound transducer and a drug applicator. The drug applicator includes at least one space for holding the drug. The drug applicator is made of a low-ultrasound-attenuation material. Furthermore, the drug applicator is configured to provide low-ultrasound-loss coupling between the system and the sclera, and the drug applicator is configured to be mechanically coupled to the system and further configured to be coupled to the ultrasound transducer with low-ultrasound-loss. The signal generating unit and / or the ultrasound transducer is configured to emit an ultrasound pattern in at least one application cycle, the application cycle including at least one ultrasound emission event with a duration TA and a waiting period with a duration TW.

[0014] The term "low ultrasonic attenuation material" refers to any material with ultrasonic attenuation of less than 10 dB / (MHz cm), preferably less than 6 dB / (MHz cm), and more preferably less than 5 dB / (MHz cm). The term "low ultrasonic coupling loss" refers to coupling between two elements with a loss of less than 20%, preferably less than 10%, at the coupling interface. However, those skilled in the art will understand that the above figures reflect values ​​generally considered low for the corresponding properties.

[0015] In embodiments of the invention, the drug is provided in a liquid state. In alternative embodiments, the drug may be encapsulated in a hydrophilic material such as a gel or another similar material. In alternative embodiments, the drug may be encapsulated in an amphiphilic material such as amphiphilic nanoparticles or a gel matrix. In alternative embodiments, the drug may be encapsulated in a hydrophobic material. In alternative embodiments, the drug may be in solid form. According to the embodiments, it may be advantageous to provide additional substances to modify at least one physical, chemical, and / or pharmaceutical property of the drug.

[0016] In embodiments of the present invention, the drug is selected from the following list: antibodies, biological agent conjugates, protein drug conjugates, corticosteroid drug conjugates, nanoparticles encapsulating drugs, nanoparticles conjugated with drugs, protein drugs, biological agents, corticosteroid drugs, nonsteroidal anti-inflammatory drugs, charged molecules, uncharged molecules, nucleotides, DNA / RNA aptamers, and DNA / RNA conjugated with proteins / antibodies.

[0017] In an embodiment of the invention, the ultrasound application cycle actually comprises a single application cycle consisting of an ultrasound emission event with a duration TA and a waiting period with a duration TW.

[0018] In embodiments of the invention, the application cycle is repeated multiple times, each application cycle comprising an ultrasonic emission event with a duration TA and a waiting period with a duration TW. Preferably, the application cycle is repeated 2 to 10 times, more preferably 4 times.

[0019] In embodiments of the present invention, different application cycles have different ultrasonic emission durations and different waiting period durations.

[0020] The drug applicator can be configured to be replaceable and / or designed for single-use applications.

[0021] In embodiments of the invention, at least one surface of the drug applicator and at least one surface of the ultrasonic transducer and / or the application head including the ultrasonic transducer are formed to receive each other and facilitate coupling. Preferably, the coupling is a positive mating and / or friction-locking connection; however, other coupling methods are available. Replaceable drug applicators are designed for multiple coupling and decoupling from the system, and single-use drug applicators are designed for at least one coupling and decoupling from the system.

[0022] In an embodiment of the invention, the ultrasonic transducer and / or at least one surface of the application head including the ultrasonic transducer is formed for receiving a differentially formed drug applicator.

[0023] In embodiments of the invention, the appearance of the drug applicator indicates the drug contained therein. In this embodiment, the appearance relates to the shape of at least one surface, preferably the shape of a coupled surface, and / or at least one human-readable or machine-readable label. Additionally or alternatively, color coding is used to indicate the drug contained therein.

[0024] In an embodiment of the invention, the drug receiving space is substantially sealed at a surface designated for coupling with the sclera, and the seal is configured to allow drug penetration.

[0025] In one embodiment of the invention, the drug applicator includes a drug receiving space adjacent to the external space, thereby sealing the drug to prevent any undesirable contact with external gases or substances. In this embodiment, at least one sealing surface is preferably configured to allow drug permeation, which is preferably during the ultrasonic application or waiting period of the application cycle.

[0026] In another embodiment of the invention, the drug receiving space is substantially open at a surface designated for coupling with the sclera.

[0027] In one embodiment of the invention, the drug receiving space is substantially sealed before use, i.e., during manufacturing, storage, and / or transportation. At least one surface is preferably configured such that the seal can be completely or partially removed before use, thereby forming an opening at a surface designated for coupling with the sclera.

[0028] In embodiments of the invention, the drug applicator is configured to be filled and / or refilled, and wherein the drug applicator receives 10 μL to 1 mL of the drug and optionally at least one other substance.

[0029] In one embodiment of the invention, the drug receiving space is an empty space. The empty space is configured to be filled with the drug. The filling is performed using, for example, an injection needle, and the drug applicator substantially self-seales the needle orifice after the drug has been injected into the drug receiving space and the needle has been removed. Alternatively, the filling can be performed using a port structure formed at the drug applicator. The port structure is configured to receive a needle and / or a drug container and has a channel allowing the drug to be filled into the drug receiving space. Furthermore, the port structure is preferably configured to seal the drug receiving space after the drug has been inserted.

[0030] In one embodiment of the invention, the drug receiving space is substantially open at a surface designated for coupling with the sclera. In this embodiment and any similar embodiments, the drug receiving space is preferably filled directly using an opening at the surface designated for coupling with the sclera.

[0031] In one embodiment of the invention, at least one additional substance, such as an ultrasound coupling agent, is filled into the drug receiving space.

[0032] In any embodiment of the system, the drug applicator may be made of an elastic material with a Young's modulus of less than 10 GPa.

[0033] According to the invention, the design of the drug applicator is not governed by the characteristics of ultrasonic transmission. In particular, it is not necessary to maintain a defined gap between the ultrasonic transducer and the sclera. Instead, the design is variable and preferably optimized to achieve low-loss coupling and a pleasant user experience.

[0034] In one embodiment of the invention, the drug applicator is relatively flexible and adaptable to different application angles and different eye shapes. Therefore, usability is optimized.

[0035] The drug applicator may be prepared from at least one of the following materials: epoxy resin, polyurethane rubber, polycarbonate, nylon 6-6, polyvinyl chloride, polyester, ultra-high molecular weight polyethylene, polypropylene, Teflon, polystyrene, chloroprene rubber, polyvinyl alcohol, polydimethylsiloxane, silicone rubber, silicone hydrogel, and silicone rubber. In the same aspect of the invention, the drug applicator is additionally or alternatively prepared from silicone rubber doped with at least one of the following materials: nickel, silver, palladium, tungsten, gold, platinum, silicon dioxide, titanium dioxide, aluminum oxide, barium sulfate, iron oxide, zirconium dioxide, cerium oxide, bismuth oxide, ytterbium oxide, lutetium oxide, and hafnium oxide.

[0036] The system further includes a controller configured to control at least one of a plurality of parameters of the application cycle, the plurality of parameters of the application cycle being selected from: the duration TA of the ultrasonic emission event, the duration TW of the waiting period after the ultrasonic emission event, the number of application cycles, the intensity of the ultrasonic emission event, the center frequency of the ultrasonic emission event, the mechanical index of the ultrasonic emission system, and in the case of pulsed ultrasonic emission events: the repetition rate of the ultrasonic emission event and the duty cycle of the ultrasonic emission event.

[0037] In embodiments of the invention, the controller is operatively connected to at least one of the following: the application head, the signal generating unit, the ultrasonic transducer, and the drug applicator. The connection is preferably wireless or via cable.

[0038] In an embodiment of the invention, the ultrasonic signal has a sinusoidal waveform with a center frequency of 20 kHz to 100 kHz, preferably 40 kHz. In one embodiment of the invention, the ultrasonic signal has a spatially and temporally averaged intensity of no more than 4 W / cm², preferably 0.005 W / cm² to 1 W / cm². In one embodiment of the invention, the ultrasonic transmitting device and / or the controller are configured to generate a continuous or pulsed wave, and the ultrasound is applied as a pulsed wave with a duty cycle preferably 30% to 0% and a pulse repetition rate preferably 1 Hz to 100 Hz.

[0039] In embodiments of the invention, the mechanical index of the ultrasound application cycle does not exceed 0.20 to avoid severe effects and tissue damage caused by ultrasound. The mechanical index predicts cavitation activity during periods when ultrasound is applied with a specific combination of frequency and intensity. Therefore, the mechanical index is preferably controlled by the frequency and intensity of the ultrasound emission.

[0040] In embodiments of the invention, the system may further include an information receiving and / or transmitting unit. The information receiving and / or transmitting unit may be configured to receive and / or transmit information related to the drug. The information receiving and / or transmitting unit may optionally be connected to the signal generating unit and / or the controller. Alternatively, the information receiving and / or transmitting unit may be operatively connected to the signal generating unit and / or the controller, and the controller may be configured to control at least one of a plurality of parameters of the application cycle based on the information related to the drug. Preferably, the information related to the drug is stored on the drug applicator.

[0041] For efficient delivery, different types of drugs may require different parameters for the application cycle. In an embodiment of the invention, the system is able to receive information from and identify the drug applicator, thereby identifying the drug type and controlling the different parameters of the application cycle accordingly.

[0042] Different methods can be used to store information related to the drug and / or the drug applicator in, at, and / or on the drug applicator, and different methods are required for retrieving information from the drug applicator for the information receiving and / or transmitting unit.

[0043] In embodiments of the invention, a key and lock method is used to identify the drug applicator. At least one surface of the drug applicator has a matching shape with at least one corresponding surface of the application head to allow positive locking connection. Due to this positive locking, the drug applicator is identified and different parameters of the application cycle are controlled accordingly. Positive locking of more than one different drug applicator is possible, preferably using different locking surfaces on the application head. The different drug applicators are locked at different end positions, and information about the drug applicators is encoded at these different end positions and retrieved via the information receiving and / or transmitting unit.

[0044] In embodiments of the invention, human-readable and / or machine-readable tags are used to store information about the drug applicator. Therefore, the information receiving and / or transmitting unit will include appropriate means for reading the human-readable and / or machine-readable tags. Alternatively or additionally, it is preferable to use an RFID chip embedded in or on the drug applicator to store information about the drug applicator. Accordingly, the information receiving and / or transmitting unit will include an RFID reader.

[0045] Information about the drug applicator preferably includes at least one of the following: information about the drug in the drug applicator, information about the shelf life of the drug, and information about the application cycle.

[0046] The above list is not intended to limit the scope of the subject matter protection sought. Technicians encountering problems with storing information on drug applicators will consider various improvements and / or variations of the solutions described above.

[0047] In one embodiment, the drug applicator is filled with drug from a container holding a plurality of doses of the drug. In this embodiment, the information receiving and / or transmitting unit is configured to receive information about the drug from the container.

[0048] In embodiments of the invention, when the drug comprises molecules of 70 kDa or smaller, the controller is configured to control the duration TA to between 30 s and 300 s, and the drug applicator is configured to deliver the drug through the sclera during the duration TA. Alternatively or additionally, when the drug comprises molecules larger than 70 kDa, the controller is configured to control the duration TW to between 60 s and 600 s, and the drug applicator is configured to deliver the molecular drug through the sclera within the duration TW.

[0049] In embodiments of the invention, delivery effectiveness depends on molecular size. For relatively small molecules, preferably less than 70 kDa, penetration rate and / or depth are effectively controlled by controlling the duration of the ultrasonic emission event of the at least one application cycle. For relatively large molecules, preferably greater than 70 kDa, penetration rate and / or depth are effectively controlled by controlling the duration of the waiting period following the ultrasonic emission event of the at least one application cycle. Thus, for each drug, an optimal set of parameters for the application cycle can be found.

[0050] In embodiments of the invention, the optimal set of parameters for the application cycles of different drugs is stored in the system. Additionally or alternatively, the optimal set can be added, modified, or deleted by a user and / or via remote access using a connection. The system is preferably further connected to a central database configured to manage and allocate the optimal set.

[0051] In an embodiment of the invention, the optimal set of parameters for the application cycle of the corresponding drug contained in the drug applicator is stored in, within and / or on the drug applicator itself and can be retrieved by the information receiving / transmitting unit.

[0052] In embodiments of the invention, the system further includes a display and / or a manual input unit configured to display and / or manually set at least one of the plurality of parameters of the application cycle.

[0053] In some cases, such as specific individual eye conditions requiring treatment, it is necessary to manually change at least one of the parameters of the application cycle. In one embodiment of the invention, the system includes a display unit configured to display the parameters of the application cycle and preferably other information to assist the user. In one embodiment of the invention, additionally or alternatively to the display unit, the system includes a manual input unit for setting at least one of the parameters of the application cycle.

[0054] The display unit and the manual input unit are preferably combined in a single unit, such as in a touchscreen device. The display unit and / or the manual input unit are integrated with the system or coupled to the system by a connection means. Preferably, the connection means include cable and / or wireless connections.

[0055] In one embodiment of the invention, the system further includes a temperature sensor configured to sense the temperature of the scleral surface, preferably a thermocouple and / or an infrared thermometer. The controller is configured to control the ultrasonic emission event such that the temperature rise of the scleral surface does not exceed 1°C within the time interval TA.

[0056] Heating of the scleral surface is a key aspect of ultrasound-enhanced drug delivery to target sites within the intraocular space. In one embodiment of the invention, the heating of the sclera is measured. This heating can be measured using various methods known to those skilled in the art.

[0057] In one embodiment of the invention, an infrared thermometer is used to measure the heating of the scleral region subjected to ultrasound during the duration of ultrasound application. In another embodiment of the invention, a thermocouple is used to measure the heating of the scleral region subjected to ultrasound during the duration of ultrasound application.

[0058] In embodiments of the invention, the parameters of the application cycle are controlled such that, during the duration of ultrasound application, the heating of the scleral region to which ultrasound is applied does not exceed 1°C, advantageously, it does not exceed 0.5°C. Preferably, the intensity and / or application time TA are controlled to control the heating of the sclera.

[0059] The present invention further relates to a method for delivering a drug to a target site in the intraocular space using a system described in any of the foregoing aspects and embodiments of the invention. In one aspect of the invention, a method for delivering a drug to a target site in the intraocular space includes the steps of: providing a drug applicator and / or system according to any of the foregoing aspects and / or embodiments, coupling the drug applicator to a scleral surface, and applying at least one ultrasound application cycle, wherein the application cycle includes an ultrasound application having a duration TA and a waiting period having a duration TW.

[0060] In an embodiment of the invention, the step of coupling the system to the eye includes applying pressure to the drug applicator and pressing the drug applicator against the scleral surface.

[0061] In an embodiment of the invention, the drug applicator is formed of a soft, elastic material. To couple the drug applicator to the eye, the user and / or physician can press the drug applicator against the eye. The drug applicator elastically deforms upon contact with the scleral surface, thereby forming an interface between the drug applicator and the scleral surface. The size of this interface preferably increases with increasing pressure. The material of the drug applicator must be adapted to not cause discomfort to the eye. Preferably, adaptation includes any of the following: adaptation to elasticity, adaptation to temperature, and / or adaptation to structure.

[0062] In embodiments of the invention, the step of coupling the system to the eye further includes applying an ultrasound coupling agent to the drug applicator and / or the scleral surface before pressing the drug applicator to the scleral surface. In embodiments of the invention, applying an ultrasound coupling agent to the drug applicator and / or the scleral surface before pressing the drug applicator to the scleral surface improves the transmission of ultrasound signals to the scleral tissue.

[0063] In embodiments of the present invention, the step of providing a drug applicator and / or system further includes the step of loading a drug into the drug applicator.

[0064] In one embodiment, the drug applicator is designed to be attached to a cartridge of the system.

[0065] In an embodiment of the invention, the drug applicator does not permanently hold the drug. The drug is loaded into the drug applicator prior to the application of ultrasound. The loading can be performed using any of the methods described above, including injection needles, port structures, and / or direct filling methods.

[0066] In embodiments of the invention, the step of providing a drug applicator and / or system additionally or alternatively includes the step of replacing an empty drug applicator with a pre-loaded drug applicator.

[0067] In an embodiment of the invention, the drug applicator is pre-loaded with the drug. Before ultrasonic application, an empty or blank drug applicator and / or an empty previously used drug applicator are removed from the system, and a pre-loaded drug applicator is coupled to the system.

[0068] In an embodiment of the invention, the method further includes the step of determining a plurality of parameters of the application cycle by receiving information about the drug from the information sending and / or receiving unit, the parameters including at least the number of application cycles, duration TA, and duration TW.

[0069] In an embodiment of the present invention, the user manually inputs multiple parameters of the application cycle, including at least the number of application cycles, duration TA, and duration TW.

[0070] In an embodiment of the invention, the temperature of the scleral surface is measured during the application time TA, and the controller controls the ultrasonic emission such that the temperature of the scleral surface rises by no more than 1°C, advantageously, by no more than 0.5°C.

[0071] An aspect of the present invention relates to an apparatus for delivering at least one drug to a target side of the intraocular space of the eye, wherein the apparatus comprises: an ultrasound generating device configured to generate ultrasound, the ultrasound being delivered to a desired site of the eye; and an interface configured to couple the apparatus to a drug applicator containing the at least one drug without the use of tools, wherein the drug applicator is configured to facilitate the delivery of the ultrasound to the desired site of the eye, wherein the apparatus has a diameter of less than 2500 cm. 3 The volume.

[0072] In an embodiment of the present invention, when the drug applicator is coupled through the interface, the device and the drug applicator have a distance of less than 3000 cm. 3 The volume. In an embodiment of the invention, the device has a volume of less than 1000 cm³. 3 The volume of the device is less than 25 cm in some embodiments of the invention. In some embodiments of the invention, when the drug applicator is coupled via the interface, the device and the drug applicator have a maximum size of less than 30 cm. In some embodiments of the invention, the device has a maximum size of less than 15 cm. In some embodiments of the invention, the device has a weight of less than 9 kg. In some embodiments of the invention, the device and the drug applicator have a total weight of less than 10 kg.

[0073] In an embodiment of the invention, the device further includes a housing that at least partially surrounds the ultrasound generating unit. In an embodiment of the invention, the device further includes a signal generating unit in communication with the ultrasound generating unit. In an embodiment of the invention, the signal generating unit includes a controller configured to control the signal generating unit and an amplifier configured to generate an ultrasound signal. In an embodiment of the invention, the device is a handheld device. In an embodiment of the invention, the device is a wearable device. In an embodiment of the invention, the device is configured to be worn on a user's head, at least partially above the user's eyes.

[0074] In an embodiment of the invention, the ultrasonic generator is configured to operate at a frequency of 20 kHz to 100 kHz. According to the apparatus of claim 30, the ultrasonic generator operates at a frequency of less than 30V. RMS The ultrasonic generator operates under an excitation voltage. In an embodiment of the invention, the ultrasonic generator includes a curved transducer. In an embodiment of the invention, the ultrasonic generator weighs less than 200g. In an embodiment of the invention, the ultrasonic generator has a maximum dimension of less than 3cm.

[0075] In embodiments of the invention, the interface allows for repeatable coupling and decoupling of the drug applicator from the device. In embodiments of the invention, the drug applicator is configured to hold at least 100 μl of the at least one drug. In embodiments of the invention, the device is powered by an onboard power supply. In embodiments of the invention, the power supply comprises a primary battery.

[0076] Another aspect of the invention relates to a method for generating instructions to deliver at least one drug to a target site in the intraocular space of the eye, the method comprising: obtaining a signal indicating the identity of at least one drug to be delivered or an identifier of a treatment plan for the eye; and generating instructions for operating an ultrasound generating device by means of one or more processors based on the signal indicating the identity of the at least one drug to be delivered or the identifier of the treatment plan for the eye.

[0077] The method may further include applying ultrasound using the ultrasound generator according to the instructions to deliver the at least one drug to a target site in the intraocular space of the eye. In embodiments of the invention, the signal is provided in response to user input identifying the at least one drug or an identification of the treatment plan for the eye. In embodiments of the invention, the at least one drug is contained in a drug applicator operatively coupled to the ultrasound generator. In embodiments of the invention, the drug applicator is removably coupled to the ultrasound generator. In embodiments of the invention, the drug applicator is removably coupled to the ultrasound generator. In embodiments of the invention, the signal is provided in response to a label on the drug applicator indicating the at least one drug to be delivered or an identification of the treatment plan for the eye. In embodiments of the invention, the drug applicator is pre-loaded with the at least one drug.

[0078] In embodiments of the invention, determining the instruction includes selecting the instruction from a plurality of instruction options for various drugs or treatment plans. In embodiments of the invention, the one or more processors are carried on a device including the ultrasound generator. In embodiments of the invention, the instruction includes the frequency of the ultrasound. In embodiments of the invention, the instruction includes a mechanical index. In embodiments of the invention, the instruction includes the number of ultrasound generation cycles and the time.

[0079] In embodiments of the invention, the generation of ultrasound allows fluid to drain from the eye to reduce intraocular pressure. In embodiments of the invention, the drainage of the fluid occurs simultaneously with the delivery of the at least one drug. In embodiments of the invention, the drainage of the fluid occurs before the delivery of the at least one drug. In embodiments of the invention, the drainage of the fluid occurs after the delivery of the at least one drug. In embodiments of the invention, the ultrasound operates at a frequency below 1 MHz when the fluid is drained from the eye. In embodiments of the invention, the temperature of the eye rises by no more than 2°C when the fluid is drained from the eye. In embodiments of the invention, the drainage of the fluid occurs during treatment to reduce intraocular pressure. In embodiments of the invention, the drainage of the fluid occurs during treatment for glaucoma.

[0080] In an embodiment of the present invention, the identifier of the treatment plan for the eye includes an identifier of the disease to be treated.

[0081] Another aspect of the invention relates to an apparatus for delivering at least one drug to a target side of the intraocular space of the eye, wherein the apparatus comprises: an ultrasound generating device configured to generate ultrasound, the ultrasound being delivered to a desired site of the eye; and an interface configured to repeatedly couple the apparatus to a drug applicator containing the at least one drug, wherein the drug applicator is configured to facilitate the delivery of the ultrasound to the desired site of the eye, wherein the interface includes a coupling medium, the thickness of which is a multiple of the propagation speed of the coupling medium at a resonant frequency.

[0082] In embodiments of the invention, the coupling is achieved without the use of tools. In embodiments of the invention, the thickness of the coupling medium is an odd multiple of the propagation speed of the coupling medium at four times its resonant frequency. In embodiments of the invention, the coupling medium is configured to optimize impedance matching between the ultrasound generator and the drug applicator. In embodiments of the invention, the coupling medium is a solid. In embodiments of the invention, the coupling medium is a liquid, suspension, or gel.

[0083] In an embodiment of the invention, the ultrasound generator is configured to be at least partially inserted into a drug applicator cartridge. In an embodiment of the invention, the ultrasound generator includes a pin configured to slide through a slot in the cartridge to allow the ultrasound generator to lock into the cartridge. In an embodiment of the invention, the drug applicator is configured to be at least partially inserted into the ultrasound generator cartridge. In an embodiment of the invention, the interface includes a first fastener configured to engage with a second fastener mounted on the drug applicator. In an embodiment of the invention, the first and second fasteners are configured to be threaded together. In an embodiment of the invention, the first and second fasteners are configured to be snap-fit ​​together. In an embodiment of the invention, the interface allows for a magnetic connection between the ultrasound generator and the drug applicator.

[0084] In embodiments of the invention, the drug applicator has an attenuation coefficient of 5 dB / MHz / cm or lower. In embodiments of the invention, the interface provides coupling loss of less than 10%. In embodiments of the invention, the ultrasound generator is configured to operate at a frequency of 20 kHz to 100 kHz. In embodiments of the invention, the ultrasound generator operates at less than 30V. RMS The device operates under an excitation voltage. In an embodiment of the invention, the ultrasonic generator includes a curved transducer.

[0085] According to a further aspect of the invention, an apparatus is provided for delivering at least one drug to a target side of the intraocular space of the eye. The apparatus may include: an ultrasound generating device configured to generate ultrasound, the ultrasound being delivered to a desired site of the eye; a light source configured to generate light, the light being delivered to the desired site of the eye; and an interface configured to couple the apparatus to a drug applicator containing the at least one drug, wherein the drug applicator is configured to assist in the delivery of the ultrasound to the desired site of the eye and is configured to allow light from the light source to be delivered to the desired site of the eye.

[0086] In embodiments of the present invention, the light source is configured to generate UV light. In embodiments of the present invention, the light source is configured to emit light of UV-A wavelength. In embodiments of the present invention, the light from the light source is configured to cause cross-linking of the at least one drug when the at least one drug is exposed to the light. In embodiments of the present invention, the at least one drug comprises a photosensitive molecule. In embodiments of the present invention, the at least one drug comprises riboflavin.

[0087] In an embodiment of the invention, the ultrasonic generator and the light source are enclosed within a housing. In an embodiment of the invention, the light source is coupled to the ultrasonic generator. In an embodiment of the invention, the light source has a fixed position relative to the ultrasonic generator. In an embodiment of the invention, the ultrasonic generator includes an internal space in which the light source is located. In an embodiment of the invention, the ultrasonic generator has a circular cross-section with a free space in the middle forming the internal space. In an embodiment of the invention, the internal space also includes optical elements that modify the light emitted by the light source. In an embodiment of the invention, the ultrasonic generator includes an internal space in which a data collection device is located. In an embodiment of the invention, the recording device is a camera or a microphone.

[0088] In an embodiment of the invention, the weight of the ultrasound generating device is less than 200g. In an embodiment of the invention, the ultrasound generating device has a maximum size of less than 3cm. In an embodiment of the invention, the light source is configured to guide light through the drug applicator when the drug applicator is coupled to the device.

[0089] Furthermore, aspects of the invention may relate to a drug applicator for delivering at least one drug to a target site in the intraocular space of the eye, wherein the drug applicator comprises: a first portion formed of an opaque material configured to at least partially define at least one space configured to hold the at least one drug; a second portion formed of a material at least partially transparent to light of a selected wavelength configured to allow light of the selected wavelength to pass from one side of the drug applicator to the other side of the drug applicator; and an interface configured to couple the drug applicator to an ultrasound generator configured to generate ultrasound delivered to a desired site of the eye via the drug applicator.

[0090] In an embodiment of the invention, the ultrasound generating device is operatively coupled to a light source configured to provide light of a selected wavelength. In an embodiment of the invention, the light source is configured to generate UV light. In an embodiment of the invention, light from the light source is configured to cause cross-linking of the at least one drug when the at least one drug is exposed to the light. In an embodiment of the invention, the at least one drug includes riboflavin. In an embodiment of the invention, the ultrasound generating device and the light source are enclosed within a housing. In an embodiment of the invention, the ultrasound generating device includes an internal space in which the light source is located.

[0091] In an embodiment of the invention, the at least one space is a single continuous space. In an embodiment of the invention, the at least one space comprises a plurality of discontinuous spaces. In an embodiment of the invention, the plurality of discontinuous spaces include holes.

[0092] In an embodiment of the invention, the first portion includes an outer surface coated with a material that reflects light of the selected wavelength. In an embodiment of the invention, the material is configured to reflect UV light to reduce any UV exposure to the external environment. In an embodiment of the invention, the first portion includes a target side configured to contact a desired site of the eye. In an embodiment of the invention, the target side is formed of a soft, biocompatible material. In an embodiment of the invention, the target side is configured to deliver an agent that improves the delivery of the at least one drug to the target site.

[0093] In an embodiment of the invention, the first portion is formed of an elastic material. In an embodiment of the invention, the second portion is transparent to ultraviolet light. In an embodiment of the invention, the second portion is surrounded by the first portion.

[0094] In embodiments of the invention, the drug applicator is configured to be pre-loaded with the at least one drug. In embodiments of the invention, the drug applicator includes a sealing material configured to prevent contamination. In embodiments of the invention, the drug applicator is configured to receive in-situ loading of the at least one drug.

[0095] An aspect of the present invention provides a method for delivering at least one drug to a target site in the intraocular space of the eye, the method comprising: applying a drug retention cover containing the at least one drug to a surface of the eye, wherein the drug retention cover is configured to allow closure of the eye when the drug retention cover is applied to the surface; positioning an ultrasound generator at a desired site of the eye; and generating ultrasound using the ultrasound generator and applying the ultrasound to the desired site, wherein the generation of the ultrasound delivers the at least one drug to the target site in the intraocular space of the eye without damaging the tissues of the eye.

[0096] In embodiments of the present invention, the drug-holding cover is a contact lens or membrane. In embodiments of the present invention, the drug-holding cover is formed of a porous material. In embodiments of the present invention, the drug-holding cover is formed of a hydrophilic material, a hydrophobic material, an amphiphilic material, or a sterile material. In embodiments of the present invention, the at least one drug is encapsulated in the drug-holding cover. In embodiments of the present invention, the at least one drug is attached to the surface of the drug-holding cover. In embodiments of the present invention, the drug-holding cover has an attenuation coefficient of 5 dB / MHz / cm or lower.

[0097] In one embodiment of the invention, the ultrasound generator is positioned above the eyelid. In another embodiment, the ultrasound generator is positioned on the sclera of the eye. In yet another embodiment, the ultrasound generator is positioned on the cornea of ​​the eye. In yet another embodiment, the ultrasound generator maintains contact with the covering material containing the medication.

[0098] The method may further include providing a drug applicator operatively coupled to the ultrasound generator. In one embodiment of the invention, the drug applicator is positioned above the eyelid. In another embodiment of the invention, the drug applicator is positioned above the sclera of the eye. In yet another embodiment of the invention, the drug applicator is positioned above the cornea of ​​the eye.

[0099] The invention also relates to an apparatus for delivering at least one drug to a target side of the intraocular space of the eye, the apparatus comprising: an eye-worn frame including at least one extension configured to extend behind the wearer's ear when the apparatus is worn by the wearer; and one or more ultrasound generating devices supported by the eye-worn frame, wherein each ultrasound generating device is configured to generate ultrasound for delivery to a desired site of the eye when the apparatus is worn by the wearer, wherein the generation of ultrasound delivers the at least one drug to a target site in the intraocular space of the eye without damaging the tissues of the eye.

[0100] The device may further include a drug applicator supported by the eye-worn frame, the drug applicator containing the at least one drug. In embodiments of the invention, the drug applicator is operatively coupled to the one or more ultrasound generating devices. In embodiments of the invention, the drug applicator is positioned to at least partially cover the eye when the device is worn by the wearer.

[0101] In an embodiment of the invention, the eye-wearing frame includes a lens frame. In an embodiment of the invention, the eye-wearing frame forms goggles. In an embodiment of the invention, the eye-wearing frame forms a helmet including a portion covering at least one eye.

[0102] In an embodiment of the invention, the ultrasound generating device is adhered to the eyeglass frame. In an embodiment of the invention, the ultrasound generating device is removable from the eyeglass frame. In an embodiment of the invention, the ultrasound generating device is movable from one part of the eyeglass frame to another part of the eyeglass frame. In an embodiment of the invention, the ultrasound generating device is positioned to at least partially cover the eye when the device is worn by the wearer.

[0103] According to an aspect of the invention, a method is provided for delivering at least one drug to a target site in the intraocular space of the eye. The method may include: positioning an ultrasound generating device and a drug applicator relative to a desired site on the sclera of the eye, wherein the drug applicator contains the at least one drug; and generating ultrasound using the ultrasound generating device and applying the ultrasound to the desired site on the sclera at a frequency of about 30 to 60 kHz and a mechanical coefficient of 0.1 to 0.3, wherein the generation of the ultrasound delivers the drug at a concentration of at least 1.3 μg / ml and a mechanical coefficient of at least 90 μm. 2 Delivered at a rate of / s to the target site in the intraocular space of the eye without damaging the eye's tissues.

[0104] The method may further include at least partially enclosing the ultrasound generator within a housing. In embodiments of the invention, the housing allows the ultrasound generator to be held in the hand. In embodiments of the invention, the housing allows the ultrasound generator to be worn. The method may further include providing communication from a signal generating unit to the ultrasound generating unit. In embodiments of the invention, the signal generating unit includes a controller configured to control the signal generating unit and an amplifier configured to generate an ultrasound signal.

[0105] In an embodiment of the present invention, the ultrasonic generator operates at less than 30V. RMS The device operates under an excitation voltage. In an embodiment of the invention, the ultrasonic generator includes a curved transducer. In an embodiment of the invention, the ultrasonic generator weighs less than 200g. In an embodiment of the invention, the ultrasonic generator has a maximum dimension of less than 3cm. In an embodiment of the invention, the drug applicator and the ultrasonic generator are configured to be coupled and decoupled from each other.

[0106] In an embodiment of the invention, the drug applicator is positioned to contact the eye at the desired site. In an embodiment of the invention, the drug applicator is positioned to contact a portion of the eye other than the desired site. In an embodiment of the invention, the drug applicator is configured to hold at least 100 μl of the at least one drug. In an embodiment of the invention, the drug delivered to the target site comprises molecules of at least 70 kDa. In an embodiment of the invention, the ultrasound generation lasts for a duration of less than 300 s.

[0107] Furthermore, aspects of the present invention may relate to a method for ultrasound-enhanced delivery of at least one drug to a target site in the intraocular space of the eye, the method comprising: positioning an ultrasound generating device and a drug applicator relative to a desired site on the sclera of the eye, wherein the drug applicator contains the at least one drug; and generating ultrasound using the ultrasound generating device and applying the ultrasound to the desired site on the sclera with a mechanical coefficient of 0.1 to 0.3, wherein the generation of the ultrasound delivers the drug at a concentration of at least 1.3 μg / ml and a particle size of at least 90 μm. 2 Delivered at a rate of / s to the target site in the intraocular space of the eye without damaging the eye tissues, and the temperature of the tissues does not rise by more than 1°C.

[0108] The method may further include at least partially enclosing the ultrasound generator within a housing. In embodiments of the invention, the housing allows the ultrasound generator to be held in the hand. In embodiments of the invention, the housing allows the ultrasound generator to be worn.

[0109] The method may further include providing communication from the signal generating unit to the ultrasound generating unit. In an embodiment of the invention, the signal generating unit includes a controller configured to control the signal generating unit and an amplifier configured to generate an ultrasound signal.

[0110] In an embodiment of the present invention, the ultrasonic generator operates at less than 30V. RMS The device operates under an excitation voltage. In an embodiment of the invention, the ultrasonic generator includes a curved transducer. In an embodiment of the invention, the ultrasonic generator weighs less than 200g. In an embodiment of the invention, the ultrasonic generator has a maximum dimension of less than 3cm. In an embodiment of the invention, the drug applicator and the ultrasonic generator are configured to be coupled and decoupled from each other.

[0111] In an embodiment of the invention, the drug applicator is positioned to contact the eye at the desired site. In an embodiment of the invention, the drug applicator is positioned to contact a portion of the eye other than the desired site. In an embodiment of the invention, the drug applicator is configured to hold at least 100 μl of the at least one drug. In an embodiment of the invention, the drug delivered to the target site comprises molecules of at least 70 kDa. In an embodiment of the invention, the drug delivered to the target site comprises small molecules of less than 900 Da. In an embodiment of the invention, the drug delivered to the target site comprises large molecules of less than 250 kDa. In an embodiment of the invention, the ultrasound generation duration is less than 300 s.

[0112] Other aspects and advantages of this disclosure will become apparent to those skilled in the art from the following detailed description, which shows and describes only illustrative embodiments thereof. It will be understood that this disclosure is capable of other different embodiments, and that several details thereof can be modified in various obvious ways without departing from this disclosure. Therefore, the drawings and descriptions are to be considered illustrative in nature and not restrictive.

[0113] Incorporation

[0114] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the extent that each individual publication, patent, or patent application is specifically and individually identified as incorporated by reference. If any publication, patent, or patent application incorporated by reference contradicts the disclosure contained in this specification, the specification is intended to supersede and / or take precedence over any such contradictory material. Attached Figure Description

[0115] The novel features of the invention are specifically set forth in the appended claims. A better understanding of the features and advantages of the invention will be obtained by referring to the following detailed description and accompanying drawings (also referred to herein as “Figures”) illustrating exemplary embodiments in which the principles of the invention are utilized, in which:

[0116] Figure 1 An embodiment of a system for ultrasound-enhanced drug delivery is shown;

[0117] Figure 2 An example of an implementation of the delivery unit is shown;

[0118] Figure 3 Another example of an implementation of the delivery unit is shown;

[0119] Figures 4A to 4C An example of coupling between a drug applicator and an ultrasound generator is shown;

[0120] Figures 5A to 5B An example is shown of how a drug applicator and an ultrasound generator can be coupled to each other;

[0121] Figures 6A to 6D Various embodiments of the drug applicator are shown;

[0122] Figures 7A to 7B An example of the drug loading mechanism of a drug applicator is shown;

[0123] Figure 8 An illustration shows a configuration of a drug applicator for application to the eye;

[0124] Figure 9 A perspective view showing an implementation of the system's application head;

[0125] Figure 10 A perspective view of an embodiment according to one aspect of the present invention is shown;

[0126] Figure 11 A perspective view of a wearable embodiment of a system according to one aspect of the present invention is shown;

[0127] Figure 12 A perspective view of a wearable embodiment of a system according to one aspect of the present invention is shown;

[0128] Figure 13 An example of a delivery unit including a light source is shown;

[0129] Figures 14A to 14G Examples of various configurations of the delivery unit are shown;

[0130] Figure 15 An example of using a drug-holding covering applied to the surface of the eye is shown;

[0131] Figures 16A to 16B An example of additional application of medication to maintain the covering is shown;

[0132] Figure 17 An example of a process for generating instructions to operate an ultrasound generator is shown;

[0133] Figures 18A to 18C Examples of ultrasound being applied according to various treatment plans are shown;

[0134] Figure 19 An example of drug penetration into a target site within the intraocular space of the eye is shown;

[0135] Figure 20 The effects of various mechanical indices are shown;

[0136] Figure 21 This demonstrates how various frequencies affect intracellular binding;

[0137] Figure 22 The additional effects of various mechanical indices and frequencies are shown; and

[0138] Figure 23 Further examples of the effects of various mechanical indices are shown. Detailed Implementation

[0139] While various embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Many variations, modifications, and substitutions will occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed.

[0140] Applying ultrasound to the surface of the eye can aid in drug delivery. The system may include an ultrasound generator that can be coupled to a drug applicator. Ultrasound can help allow drugs to penetrate to a target site within the intraocular space. The drug applicator may hold one or more deliverable drugs. Ultrasound is delivered to the eye via the drug applicator. In some embodiments, the drug applicator may be detachable from the device. The drug applicator may be formed of a material and have a design that allows for the delivery of low-attenuation ultrasound to the eye while providing a comfortable connection with the eye. The drug applicator may be pre-loaded with drug, or the drug may be loaded in situ.

[0141] Figure 1 An embodiment of a system for ultrasound-enhanced drug delivery is shown. The system may include a delivery unit 200, a signal generation unit 300, and / or an input and control unit 400.

[0142] Delivery unit 200, generating unit 300, and input and control unit 400 can be operatively interconnected via communication links 501, 503, and 504. The communication links can include wired and wireless communication. Preferred communication mechanisms may include direct communication links, such as WiFi, infrared, optical, radio, or Bluetooth communication links. Preferred communication links may also include wired communication, such as any type of bus connection.

[0143] The delivery unit 200, generating unit 300, and input and control unit 400 are preferably integrated together into a single housing and / or optionally arranged as a functional group and integrated into multiple housings. The single housing may partially or completely enclose the delivery unit, generating unit, and / or input and control unit. The housing may include or exclude one or more internal spaces within which the delivery unit, generating unit, and / or input and control unit can be provided. The delivery unit, generating unit, and / or input and control unit may or may not share one or more internal spaces. In some cases, the units may be separate from each other. The housing may or may not be fluid-tight (e.g., hermetically tight, watertight). The housing may protect one or more internal components from dust, particles, light, or other external environmental conditions. Similarly, the housing may or may not prevent emissions (e.g., light) or substances from leaving the housing.

[0144] The delivery unit, generating unit, and / or input and control unit may share a common support. The common support can support the weight of the delivery unit, generating unit, and / or input and control unit. The common support allows the delivery unit, generating unit, and / or input and control unit to move together. The common support can maintain a fixed position between the delivery unit, generating unit, and / or input and control unit. The common support may or may not be a housing.

[0145] Optionally, the delivery unit, generating unit, and input and control unit may be formed as part of the housing of the handheld device. The individual units may be integrated into different parts of the handheld device. The individual units may or may not be removable or detachable from the handheld device.

[0146] In one example, the input and control unit 400 may be configured as a handheld device including display and input means; the delivery unit 200 is preferably configured as a small, optional handheld device, which is ergonomically positioned in front of the eyes 100 and is also configured to contact surfaces (e.g., scleral surface, corneal surface, limbus); and the signal generation unit 300 is preferably formed in a robust housing, preferably having a form factor compatible with the frame.

[0147] The various units can form a drug delivery device. For example, a drug delivery device may include a delivery unit, a generating unit, and / or an input and control unit. A drug delivery device may include a housing. A drug delivery device may or may not include an integral or partial drug delivery unit. A drug delivery device may or may not include a drug applicator. A drug delivery device may be reusable. A drug applicator may or may not be reusable. For example, a drug applicator may be reusable when refilled with the same or a different drug. A drug applicator may be disposable. In some embodiments, a drug applicator may be a single-use, disposable item.

[0148] The signal generating unit 300 may include a controller 302 and a signal generator and / or amplifier 301. The controller 302 may be operatively connected to the signal amplifier 301. The signal generator and / or amplifier 301 is operatively connected to the ultrasonic transducer 202 via a communication link 501. The signal generator and / or amplifier 301 and the controller 302 may be arranged in a common housing 303 of the signal generating unit 300. The housing of the signal generating unit may be separate from the housing of the delivery unit 200. Alternatively or additionally, the signal generating unit and the delivery unit may share a common housing.

[0149] In embodiments of the invention, controller 302 may be configured to control signal generator and / or amplifier 301 to generate an ultrasonic signal. The controller may include one or more processors that can generate instructions sent to the signal generator and / or amplifier to generate a desired ultrasonic signal. The controller may determine desired ultrasonic characteristics, as described in more detail elsewhere herein. Alternatively or optionally, signal generator and / or amplifier 301 is configured to amplify the ultrasonic signal. The emitted ultrasonic signal may have any desired characteristics. Examples of controllable characteristics include waveform, frequency, and / or mechanical index. In one example, the emitted ultrasound may have a sinusoidal waveform and a center frequency of 20 kHz to 100 kHz, more preferably 40 kHz. Any other waveform, frequency, and / or mechanical index may be provided, as described elsewhere herein.

[0150] In embodiments of the invention, the emitted ultrasonic signal may comprise a pulse wave with a duty cycle preferably in the range of 30% to 70%, and a preferred pulse repetition rate between 1 Hz and 100 Hz. Various examples of emitted ultrasonic signal profiles are provided in more detail elsewhere herein.

[0151] In embodiments of the invention, the mechanical index of the emitted ultrasonic signal does not exceed 0.2 to avoid severe effects caused by the emitted ultrasonic signal, such as cavitation and / or tissue damage. In some embodiments, the mechanical index of the emitted ultrasound is about 0.2. In some embodiments, the mechanical index may be less than or equal to about 0.01, 0.05, 0.1, 0.12, 0.15, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.25, 0.27, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or 0.9. In some cases, the mechanical index may be greater than or equal to any of the provided values, or fall within a range between any two of the provided values. The mechanical index predicts cavitation activity during ultrasound application with a specific combination of frequency and intensity. Preferably, the mechanical index is controlled by controlling the frequency and / or intensity of the emitted ultrasonic signal.

[0152] In an embodiment of the present invention, the emitted ultrasonic signal has a strength of less than 4 W / cm². 2 Spatial average time-averaged intensity. The preferred intensity is 0.005 W / cm². 2 Up to 1W / cm 2 In some implementations, the spatially averaged temporal average intensity may be less than or equal to approximately 0.001, 0.003, 0.005, 0.01, 0.03, 0.05, 0.07, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.7, 0.8, 0.9, 0.95, 1, 2, 3, 4, or 5 W / cm². 2 The strength can be greater than any of the provided values, or it can fall within the range of any two provided values.

[0153] The controller 302, the signal generator and / or amplifier 301, and the ultrasonic transducer 202 can be collectively referred to as an ultrasonic device.

[0154] The display and control unit 400 may also include a display and a user interaction device. The display and control unit 400 is operatively connected to the ultrasound device and the information transmitting and / or receiving unit 203 via communication links 501, 503, 504. The communication links may include cable and / or wireless connections, or any other type of connection, as described in more detail elsewhere herein. The display and control unit may include a housing separate from the ultrasound device, or may share a common housing.

[0155] In embodiments of the present invention, the display and control unit 400 can be implemented as an application on a tablet computer, laptop computer, desktop computer, smartphone, or personal digital assistant. Alternatively or additionally, the display and control unit 400 can be designed as a stand-alone device that optionally includes a battery.

[0156] One or more parts of the drug delivery device may be powered by an onboard power source. For example, the delivery unit, signal generation unit, and / or display and control unit may be powered by an onboard power source. The power source may include one or more batteries. For example, the power source may include one or more primary batteries. The power source may include one or more rechargeable batteries. The power source may be used to power an ultrasound generator. The power source may be located within the housing of the drug delivery device. The power source may or may not be removable or detachable from the drug delivery device.

[0157] In some embodiments, the delivery unit 200 may include multiple parts that can be coupled to each other. For example, the delivery unit may include a drug applicator and an ultrasound generator. In some embodiments, the ultrasound generator may be part of the drug delivery device. The drug applicator may or may not be part of the drug delivery device. In some embodiments, the drug applicator may be provided separately from the drug delivery device. The drug applicator may be coupled to the drug delivery device. In some embodiments, the drug applicator may be coupled to the drug delivery device in a separable and / or repeatable manner.

[0158] Details of one embodiment of the delivery unit 200 are shown below Figure 2 The delivery unit 200 includes a drug applicator 201, an ultrasound generating device such as an ultrasound transducer 202, and preferably an information transmitting and receiving unit 203. The drug applicator 201 includes at least one space 800 for holding the drug. The term ultrasound transducer 202 includes any hardware for generating ultrasound signals.

[0159] In embodiments of the present invention, the drug applicator 201 is formed of a low-ultrasonic-attenuation material. The low-ultrasonic-attenuation material may be at least one selected from the following list: epoxy resin, polyurethane rubber, polycarbonate, nylon 6-6, polyvinyl chloride, polyester, ultra-high molecular weight polyethylene, polypropylene, Teflon, polystyrene, chloroprene rubber, polyvinyl alcohol, polydimethylsiloxane, silicone rubber, silicone hydrogel, and silicone rubber. Additionally or alternatively, the drug applicator 201 may be formed of silicone rubber doped with at least one of the following materials: nickel, silver, palladium, tungsten, gold, platinum, silicon dioxide, titanium dioxide, aluminum oxide, barium sulfate, iron oxide, zirconium dioxide, cerium oxide, bismuth oxide, ytterbium oxide, lutetium oxide, and hafnium oxide.

[0160] The drug applicator may be formed of, or may include, a low-ultrasound-attenuation material having an ultrasonic attenuation of less than or equal to about 20, 15, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, or 0.1 dB / (MHz cm). The drug applicator may have an ultrasonic attenuation greater than any of the provided values, or fall within a range between any two provided values. Low ultrasonic attenuation can advantageously facilitate the transport of ultrasound from the ultrasound generator to the drug applicator and ultimately to the target site. If the attenuation is too high, energy may be lost during ultrasound transmission, and the acoustic output at the delivery site may be low, which may hinder the drug delivery process or reduce its efficiency.

[0161] The drug applicator 201 can be configured to couple to the surface of the eye. In embodiments of the invention, the drug applicator 201 is configured to couple to the scleral surface with low ultrasonic loss at a surface 601b facing the eye 100. In some embodiments, the drug applicator can be configured to couple to the corneal surface. Any description of the scleral surface of the eye herein can be applied to any other part of the eye surface, such as the corneal surface. In some embodiments, to enhance ultrasonic coupling, a substance can be applied to surface 601b and / or the scleral surface of the eye 100. This substance fills an optional gap 601a between the drug applicator 201 and the scleral surface of the eye 100. This substance can be, for example, an ultrasonic coupling agent. The substance can be in gel or liquid form. The ultrasonic coupling agent can have an acoustic impedance between the drug applicator and the eye surface (e.g., the scleral surface, corneal surface, etc.). The acoustic impedance of the ultrasonic coupling agent can fall between the acoustic impedance value of the drug applicator and the acoustic impedance value of the eye surface to which the ultrasonic coupling agent is configured to contact.

[0162] In embodiments of the invention, the coupling between the drug applicator 201 and the surface of the eye, such as the sclera, can be improved through the design of the drug applicator 201. The drug applicator 201 can be formed of an elastic material with a Young's modulus less than 10 GPa. The drug applicator can be formed of an elastic material with a Young's modulus less than or equal to 20 GPa, 15 GPa, 12 GPa, 10 GPa, 9 GPa, 8 GPa, 7 GPa, 6 GPa, 5 GPa, 4 GPa, 3 GPa, 2 GPa, 1.5 GPa, 1 GPa, 0.5 GPa, or 0.1 GPa. In some cases, the Young's modulus of the drug applicator can be greater than any of the provided values, or fall between any two of the provided values. When the drug applicator 201 is made of a sufficiently elastic material, the drug applicator can press against the eye 100, and upon application of pressure, the drug applicator 201 will deform and adapt to the specific shape of each eye 100. The pressure can be uniformly distributed on the scleral surface, improving the user experience. In some embodiments, the pressure change on the scleral surface at the point of contact between the drug applicator and the eye can be less than 5 MPa, 4 MPa, 3 MPa, 2 MPa, 1 MPa, 500 kPa, 300 kPa, 200 kPa, 100 kPa, 50 kPa, 30 kPa, 20 kPa, 15 kPa, 10 kPa, 7 kPa, 5 kPa, 3 kPa, 2 kPa, 1 kPa, 0.5 kPa, 0.1 kPa, 0.05 kPa, or 0.01 kPa. Furthermore, the gap 601a between the scleral surface and the drug applicator 201 is minimized, and ultrasonic coupling is improved.

[0163] In some embodiments, the drug applicator can directly contact the surface of the eye. The drug applicator can contact the eye surface without the need for intermediate devices or substances. In some embodiments, to enhance the contact between the drug applicator and the eye surface, the drug applicator can be shaped or formed to provide a larger contact area with the eye surface. For example, the drug applicator can be shaped or formed to have at least 0.1 mm of space between the drug applicator and the eye surface, such as the sclera of the eye. 2 0.5mm 2 1mm 2 1.5mm 2 2mm 2 3mm 2 5mm 2 7mm 2 10mm 2 15mm 2 20mm 2 30mm 2 40mm 2 50mm 2 75mm 2 1cm2 1.5cm 2 2cm 2 or 3cm 2 The contact area.

[0164] The advantage of this invention over the prior art is that the delivery performance is not affected by the spacing distance d of the drug applicator 201. Therefore, deformation of the drug applicator 201 is possible without hindering the drug delivery performance.

[0165] In embodiments of the invention, a drug applicator 201 is configured to be mechanically coupled to a drug delivery system. In one embodiment, the drug applicator 201 is configured to be coupled to an ultrasonic transducer 202. The coupling may include mechanical coupling, and the drug applicator 201 may be held in a fixed position relative to the ultrasonic transducer 202, preferably at a fixed position of the ultrasonic transducer 202. The coupling may also include low-loss ultrasonic coupling between the drug applicator 201 and the ultrasonic transducer 202. Low-loss ultrasonic coupling is preferably improved by using a material at the interface 602 between the drug applicator 201 and the ultrasonic transducer 202. This material is preferably an ultrasonic coupling agent. The mechanical coupling is preferably a releasable mechanical coupling designed to couple different drug applicators 201 to the ultrasonic transducer 202. The different drug applicators 201 preferably have different sizes and / or different form factors. Other examples of coupling between drug applicators and ultrasonic transducers are provided in more detail elsewhere herein.

[0166] Any description of the ultrasonic transducer 202 herein is applicable to any type of ultrasonic generating device, and vice versa. The ultrasonic transducer can be designed based on a bending vibration mode. Bending transducers can advantageously produce desired ultrasonic frequencies and / or intensities, and have relatively low excitation voltage, low weight, and / or small size. In alternative embodiments, an ultrasonic transducer with a stacked ceramic design can be used.

[0167] Ultrasonic transducers can generate any ultrasonic frequency. For example, ultrasonic transducers can generate frequencies less than or equal to about 1 kHz, 5 kHz, 10 kHz, 20 kHz, 25 kHz, 30 kHz, 35 kHz, 37 kHz, 39 kHz, 40 kHz, 41 kHz, 43 kHz, 45 kHz, 50 kHz, 55 kHz, 60 kHz, 65 kHz, 70 kHz, 80 kHz, 90 kHz, 100 kHz, 120 kHz, 150 kHz, 200 kHz, 300 kHz, 400 kHz, 500 kHz, 600 kHz, 700 kHz, 800 kHz, 900 kHz, 1 MHz, 1.5 MHz, 2 MHz, 3 MHz, or 5 MHz. Ultrasonic transducers can generate frequencies greater than any of the frequency values ​​provided herein, or frequencies falling within the range of any two values ​​provided herein.

[0168] Ultrasonic transducers can produce ultrasonic intensities of any magnitude. For example, ultrasonic transducers can produce intensities less than or equal to approximately 0.001, 0.005, 0.01, 0.03, 0.05, 0.07, 0.1, 0.11, 0.12, 0.13, 0.14, 0.15, 0.17, 0.2, 0.25, 0.3, 0.35, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.2, 1.5, 2, 2.5, 3, 5, or 10 W / cm². 2 The intensity. Ultrasonic transducers can produce intensities greater than any intensity value provided herein, or within a range between any two values ​​provided herein.

[0169] In some embodiments, the ultrasonic transducer may have a voltage of less than about 0.1, 0.5, 1, 3, 5, 10, 15, 20, 22, 25, 27, 30, 33, 35, 40, 45, 50, 60, 70, 80, 90, 100, 120, 150, 200, 300, or 500 V. RMS The excitation voltage can be less than any of these values, while allowing the ultrasonic transducer to operate at frequency values ​​or intensity values ​​as provided herein. In some embodiments, the excitation voltage can be greater than any of the values ​​provided herein, or fall within a range between any two values ​​provided herein.

[0170] Ultrasonic transducers can have a relatively small weight. For example, the weight of an ultrasonic transducer can be less than 1g, 5g, 10g, 20g, 30g, 40g, 50g, 60g, 70g, 80g, 90g, 100g, 110g, 120g, 130g, 150g, 170g, 200g, 225g, 250g, 300g, 350g, 400g, 500g, 600g, 700g, 800g, 1kg, 2kg, 3kg, or 5kg. The weight of the ultrasonic transducer can be less than any of these values ​​while allowing the ultrasonic transducer to operate at frequency values ​​or intensity values ​​as provided herein. In some embodiments, the weight can be greater than any of the values ​​provided herein, or fall within the range of any two values ​​provided herein.

[0171] Ultrasonic transducers can have a small size. For example, an ultrasonic transducer can have a maximum dimension (e.g., length, width, height, diagonal, or diameter) less than 1 mm, 3 mm, 5 mm, 7 mm, 10 mm, 12 mm, 15 mm, 17 mm, 20 mm, 22 mm, 25 mm, 27 mm, 30 mm, 35 mm, 40 mm, 45 mm, 50 mm, 60 mm, 70 mm, 80 mm, 90 mm, 100 mm, 120 mm, 150 mm, 175 mm, 200 mm, 250 mm, or 300 mm. An ultrasonic transducer can have a maximum dimension smaller than any of these values ​​while allowing the ultrasonic transducer to operate at frequency values ​​or intensity values ​​as provided herein. In some embodiments, the maximum dimension can be greater than any of the values ​​provided herein, or fall within a range between any two values ​​provided herein.

[0172] In some implementations, the ultrasonic transducer can have a diameter of less than 0.1 cm. 3 0.5cm 3 1cm 3 1.5cm 3 2cm 3 2.5cm 3 3cm 3 4cm 3 5cm 3 6cm 3 7cm 3 8cm 3 9cm 3 10cm 3 12cm 3 15cm 3 17cm 3 20cm 3 25cm 3 30cm 3 35cm3 40cm 3 50cm 3 70cm 3 100cm 3 120cm 3 150cm 3 200cm 3 250cm 3 300cm 3 400cm 3 500cm 3 750cm 3 Or 1000cm 3 The volume. Ultrasonic transducers can have a volume smaller than any of these values ​​while allowing the ultrasonic transducer to operate at frequency values ​​or intensity values ​​as provided herein. In some embodiments, the volume can be larger than any of the values ​​provided herein, or fall within a range between any two values ​​provided herein.

[0173] Providing an ultrasound transducer with any of these characteristics can advantageously allow for its use in medical applications for the eye and other soft tissues. A small size and / or weight can allow for its use in portable drug delivery devices.

[0174] Ultrasonic transducers can have any shape factor. In some cases, ultrasonic transducers can have a shape factor that allows a drug applicator to mate with the transducer at an interface. The interface can be indirect contact with the drug applicator, or within a distance where the interface can contact air, gas, water, gel, or other low-ultrasonic-attenuation materials, thereby preventing ultrasonic attenuation. In some examples, the ultrasonic transducer can have a shape factor at the interface that is triangular, square, circular, annular, or other shapes (such as those provided elsewhere herein). The interface of the ultrasonic transducer can be formed by one or more ultrasonic transducers, and the interface can be adjusted as needed to achieve a desired shape. In some cases, the desired shape may include a circle or any other shape, as provided elsewhere herein. The desired shape may have an internal space. The internal space may be provided in the middle.

[0175] The internal space allows for the combination of the ultrasonic transducer with additional features. For example, additional features within the internal space can be coupled to the ultrasonic transducer 202 at interface 202c within the transducer to connect it for energy, control, or data transmission. Additional features 202c-e may include emitting devices, such as wavelength emitting devices 202c like LED lights, UV lights, or bulbs; wavelength recording devices, such as cameras 202d or microphones 202e. Additional features can be used in conjunction with lenses 202f that can adjust the wavelength. For example, the emitted wavelength can be adjusted (e.g., focusing, concentrating, diffraction, filtering, reflection, separation, etc.). The measured wavelength can also be adjusted (e.g., amplification, focusing, diffraction, filtering, reflection, separation, etc.). Additional features of the ultrasonic transducer can be used in a variety of applications, such as inducing chemical reactions like UV crosslinking, and / or illuminating a target area with video recording using a camera, as described in more detail elsewhere herein. This allows practitioners to examine the eyes before, during, and / or after treatments such as corneal crosslinking (CXL) via UV light or VEGF drug delivery for diabetic retinopathy or macular degeneration.

[0176] In embodiments of the invention, the information transmitting and / or receiving unit 203 is arranged and configured such that it can retrieve information about the drug applicator 201 and / or the drug when the drug applicator is coupled to the application head. To be able to identify the drug applicator 201, the information transmitting and / or receiving unit 203 includes a reading means configured to read information relating to the drug applicator 201. The reading means preferably includes a reader for human-readable tags or machine-readable tags and / or RFID tags.

[0177] Figure 3 Another example of an embodiment of the delivery unit according to an embodiment of the present invention is shown. The delivery unit 200 may include a drug applicator 201 and an ultrasound generating device such as an ultrasound transducer 202. The delivery unit may also include an information transmitting and receiving unit 203. The drug applicator 201 includes at least one space 800 for holding the drug. The delivery unit may be configured to contact the eye 100. The surface 601b of the drug delivery unit may be configured to face the eye and / or deliver ultrasound to the eye. The surface may optionally be configured for delivering the drug to the eye. A gap 601a may or may not be provided between the eye-facing surface 601b of the delivery unit and the surface of the eye, such as the sclera or cornea.

[0178] The drug applicator 201 may or may not be removable from the ultrasound generator 202. The drug applicator can have any type of shape for the desired application. In some embodiments, different drug applicators with different shape factors can be switched back and forth. Different drug applicators with different properties (e.g., size, shape, material, elasticity, retention of different drugs, attenuation properties) can be interchanged with each other. For example, a first drug applicator having a first set of properties can be coupled to the ultrasound generator. The first drug applicator can be removed. A second drug applicator having a second set of properties can be coupled to the ultrasound generator. The first set of properties and the second set of properties can be different from each other. The first set of properties and the second set of properties can share or not share one or more of the same properties.

[0179] The information transmitting and / or receiving unit 203 may be operatively coupled to the drug applicator and / or the ultrasound generator. The information transmitting and / or receiving unit may receive information about the drug applicator. The information transmitting and / or receiving unit may be able to sense, by means of one or more sensors, when the drug applicator is coupled to the ultrasound generator and / or when the drug applicator is not coupled to the ultrasound generator. The presence and / or absence of the drug applicator may be detected. The information transmitting and / or receiving unit may be able to detect information about the drug applicator coupled to the ultrasound generator. This information may include the type of drug applicator, one or more characteristics of the drug applicator, and / or an identifier or other information about the specific drug applicator (e.g., serial number, batch number, drug name, manufacturing date, etc.).

[0180] The information transmitting and / or receiving unit may include sensors that can capture information about the presence and / or absence of a drug applicator, or that can collect information about the drug applicator (e.g., reading a tag on the drug applicator, measuring characteristics of the drug applicator, or receiving information emitted by the drug applicator). Examples of sensor types may include visual sensors (e.g., imaging devices capable of detecting visible, infrared, or ultraviolet light, such as cameras), proximity sensors (e.g., ultrasonic sensors, radar, time-of-motion cameras), inertial sensors (e.g., accelerometers, gyroscopes, inertial measurement units (IMUs)), pressure sensors (e.g., barometers), audio sensors (e.g., microphones), or field sensors (e.g., magnetometers, electromagnetic sensors). Any suitable number and combination of sensors may be used, such as one, two, three, four, five, or more sensors. Optionally, data may be received from different types of sensors (e.g., two, three, four, five, or more types). Different types of sensors may measure different types of signals or information (e.g., images, sounds, signals, positions, proximity, pressure, etc.) and / or utilize different types of measurement techniques to obtain data. For example, the sensor may include any suitable combination of active sensors (e.g., sensors that generate and measure energy from their own source) and passive sensors (e.g., sensors that detect available energy). In some implementations, multiple types of sensors may be used to detect information about the drug applicator. In one example, an optical sensor may read visual markings on the drug applicator. Examples of visual markings may include labels, words, numbers, characters, shapes, symbols, icons, barcodes, QR codes, sequences of one or more flashlights, or any other type of visual marking. In another example, the drug applicator may be an RFID reader that can read RFID information from the drug applicator. In yet another example, the drug applicator may include an infrared reader that can read infrared information emitted by the drug applicator. In some implementations, the information sending and / or receiving unit may include a communication unit that can receive information from individual sensors or from the drug applicator.

[0181] Alternatively or additionally, to capture information about the drug applicator, the information transmitting and / or receiving unit may capture information related to the ultrasound generator. The information transmitting and / or receiving unit (and any of its sensors) may be located immediately adjacent to the drug applicator and / or ultrasound transducer. The information transmitting and / or receiving unit can assist in measuring and regulating input cycle information. Information about a specific ultrasound cycle, such as, but not limited to, single cycle time, cycle repetition, ultrasound intensity, ultrasound frequency, and possible additional characteristics, can be transmitted from the signal generating unit 300. Information can be transmitted from the signal amplifier 301 to the ultrasound generator 202 via the communication link 501. The signal transmitting and / or receiving unit 203 can measure the output of the ultrasound generator 202 and send the information back to the controller 302, which can then adjust the signal generator and / or amplifier 301. After general regulation of the ultrasound output and input, the information transmitting and / or receiving unit 203 may include sensors, such as any sensors described above. For example, one or more sensors may measure temperature, ultrasound frequency, and / or intensity. Additional sensors and / or devices may include cameras, electrodes, tonometers, timers, scanning devices, or lights. Signal generator and / or amplifier 301 can receive signals from any sensor and / or device. Signal generator and / or amplifier 301 can send information to signal generation unit 300 and / or display and control unit 400 that can read and adjust parameters.

[0182] The information transmitting and / or receiving unit may or may not include one or more processors on its surface. The information transmitting and / or receiving unit may or may not process information acquired by sensors. The information transmitting and / or receiving unit may determine the presence or absence of a drug applicator and / or information about the drug applicator. The information transmitting and / or receiving unit may or may not transmit raw or formatted data to another part of the drug delivery device to be processed.

[0183] The information transmitting and / or receiving unit can be located anywhere on the drug delivery unit. In some embodiments, the information transmitting and / or receiving unit can be located on or near the ultrasound generating device. The information transmitting and / or receiving unit can be located on or near an interface of the ultrasound generating device configured for coupling with the drug applicator. The information transmitting and / or receiving unit can be located on or at one side of the ultrasound generating device, which side is configured for coupling with the drug applicator. The information transmitting and / or receiving unit can be located on or within the surface of the ultrasound generating device. The information transmitting and / or receiving unit can be embedded in the ultrasound generating device. The information transmitting and / or receiving unit or a portion thereof may or may not be provided on the drug applicator.

[0184] Information transmitting and / or receiving unit 203 may be operatively coupled to communication link 502. The communication link may be a wired or wireless communication mechanism. The transmitting and / or receiving unit may transmit information about the drug applicator to another part of the drug delivery device via communication through the link; this information may include the presence or absence of the drug applicator. The information transmitting and / or receiving unit may or may not receive information via the communication link. In some embodiments, instructions may be sent to the information transmitting and / or receiving unit that may affect the operation of the information transmitting and / or receiving unit.

[0185] Figures 4A to 4C A schematic example of a coupler 701 between a drug applicator 201 and an ultrasound generator 202 according to an embodiment of the present invention is shown. The drug applicator can be coupled to the ultrasound generator before the drug delivery device is operated. The coupler can be an interface between the drug applicator and the ultrasound generator. For example, the drug applicator can directly contact the ultrasound generator via an interface, which can be the coupler. In other cases, the coupler can be an intermediate component. The drug applicator can contact the ultrasound generator via an intermediate component.

[0186] The coupler can have any form or configuration between the ultrasound generator and the drug applicator. A schematic diagram is provided to illustrate the relationship between the ultrasound generator and the drug applicator, and the coupler shown therein is not limited to the depiction provided. The ultrasound generator is operatively coupled to the drug applicator via this coupler.

[0187] Figure 4A A schematic example of a coupler 701 between a drug applicator 201 and an ultrasound generator 202 is shown. In some cases, the coupler may have a large surface area contact with the ultrasound generator and / or the drug applicator. For example, the surface area contact may be maximized. For example, the coupler may have a cross-sectional area greater than or equal to the cross-sectional area of ​​the ultrasound generator and / or the surface area of ​​the drug applicator. The coupler may have a matching or larger surface area compared to the surface area of ​​the ultrasound generator in contact with the coupler and / or the surface area of ​​the drug applicator in contact with the coupler. The increased surface area can allow the ultrasound signal from the ultrasound generator to be delivered to the drug applicator in an increased manner. This may be desirable when less attenuation from the ultrasound generator to the drug applicator and / or the surface of the eye is desired.

[0188] Figure 4BA further schematic example of a coupler 701 between a drug applicator 201 and an ultrasound generator 202 is shown. In some cases, the coupler may have a smaller surface area contact with the ultrasound generator and / or the drug applicator. For example, the surface area contact may be smaller than the total surface area of ​​the ultrasound generator and / or the drug applicator. For example, the cross-sectional area of ​​the coupler may be less than or equal to the cross-sectional area of ​​the ultrasound generator and / or the surface area of ​​the drug applicator. The coupler may have a matching or smaller surface area compared to the surface area of ​​the ultrasound generator in contact with the coupler and / or the surface area of ​​the drug applicator in contact with the coupler. The reduced surface area allows ultrasound signals from the ultrasound generator to be delivered to the drug applicator in a controlled manner. In some embodiments, the size of the coupling mechanism may be selected to allow a desired level of ultrasound attenuation. In some cases, the coupling mechanism may be selected to provide a desired form factor of the device. The desired form factor may depend on a design that allows the drug applicator to be attached to or detached from the ultrasound generator in an easy and repeatable manner.

[0189] Figure 4C A schematic example of a coupler 701 between a drug applicator 201 and an ultrasound generator 202 is shown. In some cases, the ultrasound generator can be coupled to the drug applicator by being inserted into the housing 201d of the drug applicator. The coupler can be provided within the housing of the drug applicator. For example, surface area contact may or may not be maximized. In some embodiments, the drug applicator can be inserted into the housing of the ultrasound generator. The coupler can be provided within the housing of the ultrasound generator.

[0190] The coupler may be formed of or may include a coupling medium. A coupling medium may be provided at the interface between the drug applicator and the ultrasonic transducer. The coupling medium may be in the form of a solid, liquid, suspension, and / or gel. The coupler may be formed of a rigid, semi-rigid, or elastic material. The coupling medium may be formed of a low-attenuation material.

[0191] The coupling medium can have a thickness d. The thickness can be a multiple of λ, where λ is the wavelength. The thickness can be a multiple of λ / 4. The thickness can be an odd multiple of λ / 4. Odd multiples can be odd integers (e.g., 1, 3, 5, 7...). This can improve or optimize the impedance matching between the ultrasound generator (e.g., an ultrasound transducer) and the drug applicator, thereby allowing ultrasound waves to be transmitted from the transducer to the target site.

[0192] The wavelength λ can be calculated as follows:

[0193] λ=c / f r

[0194] Where c is the propagation speed in the coupling medium, and f rThis is the resonant frequency. The propagation speed *c* can depend on the material type of the coupling medium. The propagation speed can depend on one or more physical properties of the coupling medium. For example, the propagation speed can depend on the elasticity, density, or temperature of the coupling medium. Therefore, the thickness of the coupling medium can be proportional to the wavelength. The thickness of the coupling medium can be directly proportional to the wavelength. The thickness of the coupling medium can be linearly proportional to the wavelength. The thickness of the coupling medium can be proportional to the propagation speed (e.g., directly proportional, linearly proportional). The thickness can be proportional to the resonant frequency. The thickness can be inversely proportional to the resonant frequency. The thickness can be linearly inversely proportional to the resonant frequency.

[0195] The interface between the drug applicator and the ultrasound generator may include a coupling medium, the thickness of which is a multiple of the propagation velocity of the coupling medium at its resonant frequency. The thickness of the coupling medium may be an odd multiple of the propagation velocity of the coupling medium at four times its resonant frequency.

[0196] In some embodiments, the spacing between the drug applicator and the ultrasound generator may depend on the thickness. The spacing between the drug applicator and the ultrasound generator may depend on the design of the drug applicator housing. Alternatively or additionally, the spacing between the drug applicator and the ultrasound generator may depend on the design of the ultrasound generator housing. The spacing may depend on the thickness of any component that connects the drug applicator and the ultrasound generator.

[0197] Coupling between the drug applicator and the ultrasound generator can be performed manually. Manual attachment and / or detachment between the drug applicator and the ultrasound generator is possible. Coupling may require the use of two hands, or it may be accomplished with only one hand. Coupling between the drug applicator and the ultrasound generator can be achieved without the use of tools. Coupling between the drug applicator and the ultrasound generator can include a simple release mechanism (e.g., a quick-release mechanism). A simple release mechanism can include one, two, three, four, five, or six manual actions. Examples of a single manual action can include twisting, pulling, pushing, moving a lever, pressing a button, pressing a switch, or any other simple action. Each action can be in a single direction (e.g., axial, lateral, vertical, rotational, etc.). One or more actions or all actions can be performed manually without the use of tools. The user may not need to apply any excessive force when performing any action. Easy manual attachment and detachment between the drug applicator and the ultrasound generator allows for the use of disposable drug applicators via drug delivery devices. Various drug applicators can be switched back and forth as needed. The drug applicator can be easily attached to a drug delivery device for use and then disassembled when the drug applicator has been used and is no longer needed. This also advantageously allows for the use of different types of drug applicators with the same drug delivery device.

[0198] Figures 5A to 5B An example of how a drug applicator and an ultrasound generator can be coupled to each other is shown. In one example, at least one of the drug applicator or the ultrasound generator can be at least partially inserted into each other. The drug applicator cartridge is at least partially inserted into the ultrasound generator, and vice versa.

[0199] For example, drug applicator 201 may include drug applicator cartridge 201d. The drug applicator may be coupled to ultrasound generator 202. The ultrasound generator may be at least partially inserted into the drug applicator cartridge.

[0200] The ultrasound generator may include one or more pins 202g. The pins may protrude from the outer surface of the ultrasound generator. The pins may be positioned such that they can engage in a lock 201e of the drug applicator cartridge 201d. In some embodiments, the lock may include one or more slots, notches, grooves, or other mechanisms that can receive the pins. The lock may have a shape that allows the pins to lock into the lock. The lock may guide the pins in at least two different directions. The lock may terminate at a round or hook-like point, which may help hold the ultrasound generator together with the drug applicator. Any description of the pins herein may apply to any protrusion in the lock that may be received into the drug applicator cartridge. In other embodiments, the opposite may be provided, wherein the ultrasound generator may include one or more slots, notches, grooves, or other mechanisms that can receive protrusions such as pins from the drug applicator cartridge. In some embodiments, the pins from the drug applicator cartridge may be formed on the inner surface of the drug applicator cartridge, so that when the ultrasound generator is inserted into the drug applicator cartridge, the pins may form a lock on the ultrasound generator.

[0201] In another example, the ultrasound generating device 202 may include an ultrasound generating device housing. The ultrasound generating device may be coupled to a drug applicator. The drug applicator may be at least partially inserted into the ultrasound generating device housing.

[0202] A drug applicator may include one or more pins. The pins may protrude from the outer surface of the drug applicator. The pins may be positioned such that they can engage with a locking mechanism in an ultrasound generator housing. In some embodiments, the locking mechanism may include one or more slots, notches, grooves, or other mechanisms that can receive the pins. The locking mechanism may have a shape that allows the pins to lock into the locking mechanism. The locking mechanism may guide the pins in at least two different directions. The locking mechanism may terminate at a round or hook-like point, which may help hold the ultrasound generator housing together with the drug applicator. Any description of the pins herein may apply to any protrusion in a locking mechanism that can be received into an ultrasound generator housing. In other embodiments, the opposite may be provided, where the drug applicator may include one or more slots, notches, grooves, or other mechanisms that can receive protrusions such as pins from the ultrasound generator housing. In some embodiments, the pins from the ultrasound generator housing may be formed on the inner surface of the ultrasound generator housing, so that when the drug applicator is inserted into the ultrasound generator housing, the pins may form a locking mechanism for the drug applicator.

[0203] Alternatively or additionally, the interface of the ultrasound generator may include a first fastener configured to engage with a second fastener carried on the drug applicator. The first and second fasteners may be configured to be threaded together. The ultrasound generator or drug applicator may be threadedly connected to each other. In one example, the ultrasound generator or drug applicator may be threaded together via a lock (e.g., a lock on a drug applicator housing or ultrasound generator housing) and a pin (e.g., a pin on the ultrasound generator or drug applicator). Threading together allows for direct or tight contact between the drug applicator and the ultrasound generator. In some embodiments, the first and second fasteners may be configured to snap together. Any interlocking or snap-fit ​​mechanism may be used to connect the ultrasound generator and the drug applicator. The lock and / or pin may or may not be used with a snap-fit ​​mechanism. The engagement between the first and second fasteners may or may not include a rotating component. The rotating component may include rotation about an axis extending along the length of the drug applicator and / or the length of the ultrasound generator. Axial rotation may be performed about an axis extending through the drug applicator and the ultrasound generator.

[0204] In some embodiments, the additional interface 602 may have direct contact between the drug applicator 201 and the ultrasonic generator 202, or it may be filled with an ultrasonic attenuating material, such as, but not limited to, air, water, gel, and / or hydrogel, to prevent any reduction in ultrasonic intensity and facilitate ultrasonic transfer to the drug applicator. Improved ultrasonic transfer to the drug applicator can result in improved ultrasonic transfer to the delivery site 100.

[0205] The drug applicator and the ultrasonic generator can be fastened together. In some embodiments, the drug applicator can be fastened to the ultrasonic generator, and vice versa. They can be fastened together by means of mechanical features. Various shapes that can facilitate fastening together can be provided, such as interlocking or mating shapes. In some embodiments, a magnet can facilitate coupling between the drug applicator and the ultrasonic generator. In one example, a magnet can be placed on the ultrasonic generator, while a suitable metal or alloy is loaded on the drug applicator. Alternatively or additionally, a magnet can be placed on the drug applicator, while a suitable metal or alloy is loaded on the ultrasonic generator. This can allow the ultrasonic generator and the drug applicator to be held together by means of magnetic force. This can be provided as an alternative or addition to any other connection mechanism described elsewhere herein. This can be provided as an alternative or addition to any kind of lock, screw, clip, or adhesive that can help couple the drug applicator to the ultrasonic generator.

[0206] Various coupling mechanisms can be provided between the drug applicator and the ultrasound generator. As previously described, such a mechanism can allow manual coupling and decoupling between the drug applicator and the ultrasound generator. Coupling can allow repeatable coupling and decoupling between the drug applicator and the ultrasound generator. Coupling can allow low ultrasound attenuation from the ultrasound generator to the drug applicator. Coupling can allow low ultrasound attenuation from the ultrasound generator to the delivery site. Low ultrasound attenuation can have any value or characteristic, as described elsewhere herein.

[0207] A drug applicator can be loaded with one or more drugs. Drugs can be stored within or on the drug applicator in any manner.

[0208] For example, a drug may be provided on the surface of a drug applicator. In some embodiments, the entire surface of the drug applicator may be coated with a drug. In some embodiments, only a portion of the surface of the drug applicator may be coated with a drug. For example, a portion of the surface of the drug applicator configured to contact the surface of the eye may be coated with a drug. The interface 601a between the delivery site on the eye and the drug applicator may be filled with a reagent or material that can improve drug delivery to the target site. This can be done by coating the drug and / or reagent onto the surface of the drug applicator. Alternatively or additionally, the interface may be filled with the drug itself for delivery to the delivery site on the eye. In some embodiments, the reagent or material that can improve drug delivery to the target site may include microspheres, micelles, nanoparticles, proteins, molecules, or chemicals that can be adsorbed or absorbed on their surface. The reagent may include any reagent described elsewhere herein.

[0209] In another example, the drug can be incorporated into a porous material. For example, the drug can be soaked, encapsulated, adhered to, or adsorbed onto the porous material. Examples of porous materials may include, but are not limited to, sponges or polymer matrices. The porosity of the porous material can be at least 3%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, or 99%. The porosity of the porous material can be less than any of the provided values, or fall within a range between any two of the provided values. The drug can be delivered within the pores of the porous material.

[0210] The medication may be contained within a compartment of the drug applicator. The medication may be completely contained within the compartment. Seals or caps may be removed to provide access to the medication during use with a subject. In some embodiments, the application of ultrasound may allow the medication to pass through the walls or portions of the drug applicator, thereby delivering it to a delivery site on the subject's eye.

[0211] In some implementations, the drug can be delivered within a compartment of the drug applicator having an open or sealed end. During use on a subject, the sealed end may be removed, broken, or punctured.

[0212] A drug applicator can be loaded with a single type of drug. Alternatively, a drug applicator can be loaded with multiple types of drugs. Multiple types of drugs can be loaded into a common space. Alternatively, multiple types of drugs can be loaded into different spaces or chambers. Multiple types of drugs can be in fluid communication with each other. Alternatively, when loaded onto a drug applicator, multiple types of drugs can be fluidly isolated from each other. When using a drug delivery device, multiple types of drugs may or may not be delivered to the same site of the eye.

[0213] Any description of a drug in this article may also apply to any reagent or material that may aid in drug delivery. Reagents or materials that may aid in drug delivery may be stored with the drug or may be stored separately from the drug.

[0214] Figures 6A to 6D Different embodiments of a drug applicator 201 according to an embodiment of the present invention are shown. The drug applicator may include an internal space 800 which can hold the drug to be delivered. The internal space may be a single continuous internal space. The internal space may have any geometry, such as substantially spherical, cylindrical, conical, prismatic, or any other shape. Alternatively, the internal space may include multiple chambers or sections. The internal space may include multiple discontinuous internal spaces. In some embodiments, the internal space may include one or more holes or channels.

[0215] The drug applicator may include one or more walls 201a or solid portions that may partially or completely surround the internal space. The walls may be solid and non-porous. Alternatively, one or more portions of the walls may be porous. The walls may be impermeable to the drug contained within the internal space. Alternatively, one or more portions of the walls may be permeable to the drug contained within the internal space. In some embodiments, under certain conditions (e.g., temperature, light, applied ultrasonic vibration, or pressure), one or more portions of the walls may be permeable to the drug contained within the internal space.

[0216] In some preferred embodiments, the drug held in the drug receiving space 800 may be sealed towards the external space, i.e., the surrounding environment, to protect the drug from contamination by any foreign substances or gases. This protection may be particularly desirable during the production, transport, and / or storage of the drug applicator 201 or system. Immediately before use, the seal may be broken to allow the drug in space 800 to be delivered.

[0217] Figure 6A An embodiment is shown in which the drug applicator 201 can be sealed on all surfaces. During the manufacturing process of the drug applicator 201, the space 800 for holding the drug within the drug applicator 201 of this embodiment can be filled with the drug. The sealed drug applicator can be delivered and / or used by a drug delivery device.

[0218] Figure 6B An embodiment is shown in which a drug applicator 201 is sealed on all surfaces and includes a port structure 201c. The port structure 201c is configured to allow the space 800 to be filled and / or refilled with a drug. The port structure allows drug passage only when a filling device is inserted into the port. When the drug applicator is only supplying drug, the port structure may optionally prevent drug leakage from the drug applicator. The port structure can be resealed when not in use. The port may allow the drug applicator to be filled and / or refilled during the manufacturing stage, after delivery of the drug applicator, and / or immediately before use of the drug applicator. Drug can be delivered into the internal space when the drug applicator is attached to a drug delivery device or when the drug applicator is detached from the drug delivery device.

[0219] like Figure 6CAs shown, the drug applicator 201 may optionally have at least one opening on a surface pointing toward the surface of the eye (e.g., the scleral surface, the corneal surface). The opening may be provided on a surface opposite to the surface configured to couple with the drug delivery device. In some embodiments, the drug receiving space 800 may be configured to be filled through at least one opening on the surface pointing toward the scleral surface. The drug receiving space may be filled during the manufacture of the drug applicator, after delivery of the drug applicator, and / or immediately before use of the drug applicator. Drug can be delivered through the opening when the drug applicator is attached to the drug delivery device or when the drug applicator is detached from the drug delivery device.

[0220] Figure 6D An embodiment of a drug applicator is shown, having at least one opening at a surface pointing toward the eye and having a port structure 201c. The port structure 201c is configured to allow filling and / or refilling of the space 800 with a drug. This may include any features, or may be used in any manner as described elsewhere herein.

[0221] In these embodiments, a surface, preferably the surface pointing towards the eye 100, is preferably configured to have a removable cap (e.g., a peel-off cap, a break-off cap, a twist-off cap) and / or may be configured to be permeable to a drug held in the space 800. In some embodiments, the surface may be impermeable to a drug under some conditions, but permeable to a drug under other conditions (e.g., certain temperatures, light ranges, ultrasonic transmission, plus certain other conditions).

[0222] In embodiments of the invention, the drug receiving space 800 is configured to receive a volume of drug. The volume of the drug is preferably from 10 μL to 1 mL. In some embodiments, the volume of the drug may be greater than 1 μL, 5 μL, 10 μL, 20 μL, 30 μL, 50 μL, 75 μL, 100 μL, 150 μL, 200 μL, 300 μL, 400 μL, 500 μL, 700 μL, 1 mL, 1.5 mL, 2 mL, 3 mL, or 5 mL. The volume of the drug may be less than any value provided herein, or may fall within the range of any two values ​​provided herein. Additionally or optionally, other substances may be inserted into the drug receiving space 800 to improve drug delivery and / or improve at least one chemical, physical, and / or pharmaceutical property of the drug. Examples of such other substances may include, but are not limited to, deionized water, buffer solutions (e.g., phosphate-buffered saline), or surfactants capable of dissolving hydrophobic drug molecules (e.g., benzyl alcohol).

[0223] In an embodiment of port structure 201c, the port structure is configured to be punctured by an injection needle, such as Figure 7AAs shown. The injection needle allows liquid communication between the drug receiving space 800 and the drug reservoir or container 201f coupled to the injection needle. Preferably, the drug is inserted into the drug receiving space 800 from the drug reservoir or container by applying pressure. Preferably, the port structure 201c is self-sealing after the injection needle is removed.

[0224] Figure 7B An example of another drug filling mechanism is shown. Port structure 201c can be coupled to a drug delivery mechanism, such as tube 201g. Flow control regulator 201h can be used to control the delivery of drug to or from internal space 800. The flow control regulator can be a binary regulator, which only controls whether drug flow is permitted or not permitted. The flow control regulator can control the amount / rate of drug that can flow. In some embodiments, drug can be pumped from a drug reservoir into the internal space. Positive pressure from outside the reservoir can be used to "push" the drug into the internal space. In some cases, negative pressure from within the internal space can be used to "pull" the drug into the internal space. In some embodiments, both positive and negative pressure can be used to deliver drug into the internal space.

[0225] These loading mechanisms can be used for in-situ loading. In-situ loading can be performed manually by a healthcare practitioner or other user. Examples of healthcare practitioners may include, but are not limited to, physicians, nurses, clinicians, or individuals employed by a hospital, clinic, or site that owns or operates the drug delivery device. Individuals using the device to administer medication to subjects may or may not have received training on the use of the device. Individuals using the device may administer the device to other individuals or may self-administer it. Individuals using the device may manually load the device in situ. The drug applicator may be loaded with medication before medication is administered. The drug applicator may be loaded with medication before or simultaneously with attaching the drug applicator to the drug delivery device. The drug applicator may be loaded with medication within 24 hours, 12 hours, 6 hours, 4 hours, 3 hours, 2 hours, 1 hour, 45 minutes, 30 minutes, 15 minutes, 10 minutes, 5 minutes, 3 minutes, 2 minutes, 1 minute, 30 seconds, or 15 seconds after the drug delivery device is used on a subject. The drug applicator may be loaded with medication when the subject is present, or while the subject is on-site. The subject may be a human subject or an animal subject. The subject may be a patient receiving treatment using the device.

[0226] The drug can be pre-loaded into the drug applicator during the manufacturing process. The benefit of loading the drug into the open space of the drug applicator during production can be optimized or increased volume or concentration under aseptic conditions. Interface 601b can be sealed with a sealing material to prevent contamination of the drug prior to administration. The sealing material can include a biocompatible membrane. The sealing material can be a stopper or other type of cap. The drug applicator can be coupled to the drug delivery device before treating the subject. The sealed interface can be opened by hand or with the aid of a removal device. In some embodiments, the seal can include a porous membrane or film that can directly face the delivery site on the eye. The drug can penetrate the membrane or film under certain conditions. For example, the drug can penetrate the porous membrane or film when ultrasound is applied.

[0227] Figure 8 A schematic diagram of a drug applicator 201 configured for application to an eye 100 is shown. The eye may include a target site for drug delivery. The target site may be on the surface of the eye or within the intraocular space of the eye. It is desirable for the drug to penetrate into the intraocular space of the eye to be delivered to the target site. Delivery of the drug to the target site can aid in the treatment of the eye. The target site may be at any depth within the eye. For example, the target site may be at least 0 mm, 0.1 mm, 0.3 mm, 0.5 mm, 0.7 mm, 1 mm, 1.2 mm, 1.5 mm, 1.7 mm, 2 mm, 2.5 mm, 3 mm, 3.5 mm, 4 mm, 4.5 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 1 cm, 1.1 cm, 1.2 cm, 1.3 cm, 1.5 cm, 1.7 cm, 2 cm, 2.5 cm, or 3 cm within the eye. The depth of the target site may be less than any of the provided values, or fall within a range between any two provided values.

[0228] The eye may include a delivery site, which can be configured to initially contact the drug. The delivery site can be the area where the drug applicator contacts the eye. The delivery site can be the site where ultrasound is delivered to the eye. The delivery site can be provided on the surface of the eye. The delivery site can be on the sclera of the eye. The delivery site can be on the cornea of ​​the eye. The delivery site can be on the cornea or on the anterior region of the eye surrounding the cornea. The delivery site can be the corneal surface, the limbus, the pars plana scleral surface, and / or the posterior scleral surface. The delivery site can be on the upper region of the eye. The delivery site can be on the lower region of the eye. The delivery site can be on the right or left side of the eye. The delivery site can be selected based on the target site for drug delivery. The delivery site can be selected based on the type of drug being administered. For example, a first delivery site can be selected for a Class I drug, and a second delivery site different from the first delivery site can be selected for a Class II drug that is different from the Class I drug. The delivery site can depend on the disease or ocular condition being treated. For example, a first delivery site can be selected for a first disease or eye condition, and a second delivery site different from the first delivery site can be selected for a second disease or eye condition different from the first delivery site.

[0229] The systems and methods provided herein can be used to deliver drugs to the eye. The systems and methods provided herein can be used to deliver drugs to target sites in the eye. The systems and methods provided herein can allow for the delivery of drugs transscleral and / or transcorneal to target sites in the eye. This can be used to treat ocular diseases or conditions such as, but not limited to, prevention of central retinal vein occlusion, branch retinal vein occlusion, central serous retinopathy, cytomegalovirus retinitis, retinoblastoma, intraocular lymphoma, ocular melanoma, giant cell arteritis, histoplasmosis, ischemic optic neuropathy, macular folds, macular telangiectasia, uveitis, choroidal neovascularization, age-related macular degeneration, diabetic retinopathy, glaucoma, retinitis pigmentosa, macular edema, macular degeneration, multiple recurrent pterygium, ocular toxoplasmosis, proliferative vitreoretinopathy (PVR), Stevens-Johnson syndrome, ocular cicatricial pemphigoid, ocular degenerative conditions, postoperative conditions, or any other diseases or conditions as described elsewhere herein. This can be used to treat the eyes, even relatively healthy ones, such as by delivering vitamins or other substances beneficial to the eyes. It can also be used for eye diagnostics, by delivering substances that can aid in imaging or measuring eye characteristics.

[0230] The chosen target site and / or delivery site may depend on soft human or animal tissue. Subjects, such as human or animal subjects, may have protective layers, such as the epidermis or dermis, to protect the body from environmental influences. Directional ultrasound can more easily penetrate or stimulate more soft tissue layers. Any applications described herein for delivery to the eye can be applied to other targets of the subject, such as, but not limited to, the tongue, oral mucosa, nasal mucosa, vaginal tissue, anal tissue, or other parts of the subject's body. Indirectly accessible targets may include, but are not limited to, the brain or muscles, bones, or other tissues.

[0231] As described elsewhere herein, a drug applicator can have any shape factor. For example, a drug applicator can have an end-shaped format, a ring-shaped format, or any other format. In some embodiments, a drug applicator can have a substantially spherical, hemispherical, cylindrical, conical, truncated conical, annular, elliptical, prismatic, or any other form. The drug applicator may optionally have a concave surface that can adapt to the curvature of the eyeball. The surface of a drug applicator configured to contact the eyeball can have a raised, flat, or recessed shape.

[0232] The drug applicator can be formed of a stretchable material that conforms to the curvature of the eyeball. The drug applicator can be formed of a conformable material to provide increased contact surface area between the drug applicator and the eyeball. The drug applicator can be configured to contact any portion of the ocular surface, such as the corneal surface, limbus, pars plana scleral surface, and / or posterior scleral surface. The drug applicator can be configured or not configured to conform to various curvatures or characteristics of the eye. The drug applicator can be configured or not configured to conform to various areas on the ocular surface.

[0233] The drug applicator can have any size. In one example, the drug applicator 201 can have an outer diameter 201h or at least 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 1 cm, 1.1 cm, 1.2 cm, 1.3 cm, 1.5 cm, 1.7 cm, 2 cm, 2.2 cm, 2.5 cm, or 3 cm. The outer diameter can be less than or equal to any of the provided values, or fall within the range of any two values ​​provided herein. The drug applicator 201 can have an inner diameter 201j or at least 0.1 mm, 0.5 mm, 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 1 cm, 1.1 cm, 1.2 cm, 1.3 cm, 1.5 cm, 1.7 cm, 2 cm, 2.2 cm, or 2.5 cm. The inner diameter can be less than or equal to any of the provided values, or fall within the range of any two values ​​provided herein. In one example, the drug applicator 201 may have an external height 201i or at least 0.5 mm, 0.8 mm, 0.9 mm, 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 6 mm, 7 mm, 1 cm, 1.2 cm, 1.5 cm, 1.7 cm, 2 cm, 2.2 cm, 2.5 cm, 3 cm, 3.5 cm, 4 cm, 4.5 cm, 5 cm, 5.5 cm, 6 cm, 7 cm, 10 cm, 12 cm, 15 cm, 20 cm, 25 cm, or 30 cm. The external height may be less than or equal to any of the values ​​provided, or fall within the range between any two values ​​provided herein. In one example, the drug applicator 201 may have an internal height 201k or at least 0.1mm, 0.3mm, 0.5mm, 0.8mm, 0.9mm, 1mm, 2mm, 3mm, 4mm, 5mm, 6mm, 7mm, 1cm, 1.2cm, 1.5cm, 1.7cm, 2cm, 2.2cm, 2.5cm, 3cm, 3.5cm, 4cm, 4.5cm, 5cm, 7cm, 10cm, 12cm, 15cm, 20cm, or 25cm. The external height may be less than or equal to any of the values ​​provided, or fall within the range between any two values ​​provided herein.

[0234] The size of the drug applicator can be selected to hold a desired volume of drug. The drug volume within various drug applicators can vary depending on the treatment plan in which the drug applicator is used. In some embodiments, the drug applicator can be configured to hold a volume from 100 μL to 5 mL. The drug applicator can be configured to hold any volume of drug, as described elsewhere herein.

[0235] The size of the drug applicator can depend on the desired delivery site on the eye. For example, depending on the delivery site, different sizes or shape factors of the drug applicator can be used to deliver the drug. In one example, a drug applicator configured to deliver drug to the cornea with an average diameter of 11 mm could result in a minimum applicator tip inner diameter of 12 mm and a radius of 6 mm, which could result in an internal height of 0.884 mm–44 mm to hold volumes of 100 μL–5 mL, respectively. A drug applicator configured to deliver drug to the sclera could have an inner diameter of less than 12 mm, with a similarly chosen volume for that space. A drug applicator configured to deliver drug to the limbus could have an inner diameter of 1–2 mm. In some embodiments, for stable and precise targeting of the delivery area, a minimum inner diameter of at least 5 mm is required, which would result in internal heights of 5 mm–254.71 mm and volumes of 100 μL–5 mL, respectively.

[0236] The internal space 800 of the drug applicator can determine the volume of drug that the drug applicator can hold. The internal space can be defined by an inner diameter and an internal height. The internal space can have a cylindrical shape. Alternatively, the internal space can have any other shape or configuration (e.g., spherical, hemispherical, elliptical, prismatic, conical, truncated conical, porous), as described elsewhere herein.

[0237] Figure 9 A perspective view of one embodiment of the application head 205 of the system is shown. The application head may include a delivery unit 200. The application head 205 may be configured to receive an ultrasonic transducer 202. Additionally and / or optionally, the application head 205 is also configured to allow mechanical and ultrasonic coupling between the drug applicator 201 and the ultrasonic transducer 202.

[0238] The appearance of the applicator head 205 may be defined by an outer housing. The outer housing may partially or completely surround the ultrasonic transducer. The outer housing may or may not partially or completely surround the drug applicator. In some embodiments, the drug applicator may be removable from the ultrasonic transducer and may not be surrounded within the housing. The housing may be formed from a single piece. Alternatively, the housing may be formed from multiple pieces. For example, the outer housing may include a first housing portion 205a and a second housing portion 205b. In one example, the first housing portion may be an upper housing portion, and the second housing portion may be a lower housing portion. The first and second housing portions, individually or in combination with additional housing portions, may surround the ultrasonic transducer. The housing may or may not surround additional portions, such as the signal generation unit 300 and / or the display and / or the input unit 400.

[0239] The drug delivery device may include an ultrasonic transducer. The drug delivery device may include a housing. The drug delivery device may or may not include a signal generating unit and / or a display and / or an input unit. The drug delivery device may have a relatively small size. In some embodiments, the drug delivery device may have a size less than or equal to about 1, 5, 10, 50, 75, 100, 150, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1250, 1500, 1750, 2000, 2250, 2500, 2750, 3000, 3250, 3500, 4000, 5000, 6000, or 7000 cm². 3 The volume of the drug delivery device may be greater than or equal to any value provided herein or fall within the range of any two values ​​provided herein. The housing of the drug delivery device may have a volume less than any value provided herein, greater than any value provided herein, or fall within the range of any two values ​​provided herein. In some embodiments, when a drug applicator is coupled to the drug delivery device, both the drug delivery device and the drug applicator may have volumes less than any value provided herein, greater than any value provided herein, or fall within the range of any two values ​​provided herein.

[0240] In some embodiments, the drug delivery device may have a maximum dimension less than or equal to about 0.1 mm, 0.5 mm, 1 mm, 1.5 mm, 2 mm, 3 mm, 4 mm, 5 mm, 7 mm, 1 cm, 1.5 cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, 10 cm, 12 cm, 15 cm, 17 cm, 20 cm, 22 cm, 25 cm, 30 cm, 35 cm, 40 cm, 45 cm, 50 cm, 55 cm, 60 cm, or 70 cm. The maximum dimension may be the dimension of the device with the maximum length. The maximum dimension may be the length, width, height, diagonal, or diameter of the device. The drug delivery device may have a maximum dimension greater than or equal to any value provided herein or falling within the range of any two values ​​provided herein. The housing of the drug delivery device may have a maximum dimension less than any value provided herein, greater than any value provided herein, or falling within the range of any two values ​​provided herein. In some implementations, when the drug applicator is coupled to the drug delivery device, the drug delivery device and the drug applicator may have a maximum size that is less than any value provided herein, greater than any value provided herein, or falls within a range of any two values ​​provided herein.

[0241] The drug delivery device may have a weight less than or equal to about 0.1g, 0.5g, 1g, 5g, 10g, 50g, 75g, 100g, 150g, 200g, 250g, 300g, 350g, 400g, 450g, 500g, 600g, 750g, 1kg, 2kg, 3kg, 4kg, 5kg, 6kg, 7kg, 8kg, 9kg, 10kg, 11kg, 12kg, 13kg, 15kg, 20kg, 25kg, 30kg, 35kg, 40kg, or 50kg. The drug delivery device may have a weight greater than or equal to any value provided herein or falling within the range of any two values ​​provided herein. The housing of the drug delivery device may have a weight less than any value provided herein, greater than any value provided herein, or falling within the range of any two values ​​provided herein. In some embodiments, when the drug applicator is coupled to the drug delivery device, the drug delivery device and the drug applicator may have a weight less than any value provided herein, greater than any value provided herein, or falling within a range of any two values ​​provided herein.

[0242] The device can be small enough to be handheld. It can be configured to be carried by a single hand. It can be configured to be operated using a single hand. It can also be carried or operated using two hands. The device may include a gripping area configured for gripping by a single hand. The gripping area can optionally have a contour for being grasped by the hand. The contour can allow individual fingers of the hand to be received on the handle. The contour can allow the device to be held ergonomically while the device is used to administer ultrasound to a subject.

[0243] The device can be configured as a wearable device. It can be worn on any part of the subject's body. For example, it can be worn on the subject's head, face, neck, torso, arms, hands, legs, or feet. The device can be worn to at least partially cover one or more of the subject's eyes. The device can be supported on the subject's head. In some embodiments, the device can be supported by at least the top portion of the head. In some embodiments, the device can be supported by the subject's forehead. The device can be supported by one or both of the subject's ears. Examples of wearable configurations are provided in more detail elsewhere herein.

[0244] Figure 10A perspective view of an embodiment of a system according to one aspect of the invention is shown. The system may include an application head 205, a drug applicator 201, and an additional housing and holding portion 700a. The additional housing and holding portion preferably houses all components of the system. Alternatively, some components of the system may be housed in at least one additional housing (not shown). A signal generating unit 300 may or may not be incorporated as part of the additional housing and holding portion. A display and / or input unit 400 may or may not be incorporated as part of the additional housing and holding portion. The drug applicator may or may not be removable from the application head. The application head may or may not be removable from the additional housing and holding portion. The application head may be coupled or decoupled from the additional housing and holding portion in a repeatable manner.

[0245] The additional housing and holding portion 700a can be configured to receive a patient's head. For receiving the patient's head, a chin rest and / or forehead rest are preferably provided. In one embodiment of the invention, the application head 205 is attached to a flexible arm, thereby allowing adjustment of the application head 205 and the drug applicator 201 relative to the rest of the additional housing and holding portion 700a. For example, the height of the application head 205 can be adjusted relative to the patient's eyes when the patient's head rests on the chin rest and forehead rest. Adjustment of the application head height allows for adaptation to various facial features, sizes, and shapes. The application head can be adjusted to reach a desired position relative to the patient's eyes. The flexible arm can extend and / or retract to adjust the height of the application head. In some embodiments, the flexible arm may include one or more telescopic components that allow adjustment of the arm's length. The length of the flexible arm can be adjusted manually or by means of one or more actuators that can enable one or more portions of the arm to move relative to each other in response to a signal or command. The chin rest and forehead rest allow the patient's eyes to remain in a substantially stationary position while allowing the application head to reach the desired location relative to the eyes. The curved arm also optionally allows for further lateral movement of the application head and / or closer proximity to the eye. This allows the application head to reach the desired location relative to the eye for delivery of ultrasound and / or medication.

[0246] As previously described, the drug delivery device can have any shape factor, such as a wearable shape factor. The drug delivery device can be configured to be worn on the subject's head. The drug delivery device can be configured to cover at least a portion of the subject's face. The drug delivery device can be configured to cover one or both eyes of the subject. The drug delivery device can be configured to at least partially cover the subject's eyes. The drug delivery device can be configured to at least partially surround the subject's head.

[0247] In some embodiments, the drug delivery device may be supported by the top of the subject's head. For example, the drug delivery device may be in the form of a hat or helmet. The hat or helmet may cover at least a portion of the top of the subject's head. A portion of the drug delivery device may extend downward from the hat or helmet to cover one or both eyes of the subject. For example, the downwardly extending portion may have a brim, goggles, or eyeglasses shape factor. The drug delivery device may have a brim, headband, or other shape factor that may completely or partially encircle the subject's head without necessarily covering the top of the subject's head. One or more straps that may partially or completely encircle the subject's head may be used to support the device on the subject's head. The drug delivery device may have a goggles or eyeglasses shape factor. The drug delivery device may be supported at least partially by one or both ears of the subject. For example, the drug delivery device may include a portion that extends past the subject's ears. The portion extending past the subject's ears may include an eyeglasses portion that may partially wrap around behind the ears, or may include a goggles or headband portion that may extend beyond the ears, or may include a hat or helmet portion that may extend beyond the ears. For example, the drug delivery device may include temples and / or earpieces that extend to and / or wrap around behind the ears. The drug delivery device can have any shape factor of any type of eyeglasses. The drug delivery device may include an eye-worn frame that includes at least one extension configured to extend behind the subject's ear when the subject wears the device.

[0248] Figure 11 A perspective view of an embodiment of a system according to one aspect of the present invention is shown. Figure 12 A perspective view of another embodiment of the system according to one aspect of the invention is shown. The application head 205 and the system can be integrated into a device that resembles a pair of glasses or other types of eye-wearing or wearable devices. Any description of glasses herein is applicable to any other type of eye-wearing or wearable device.

[0249] Directions such as front, left, and right originate from the directions during normal use of the eyeglasses device. An application head 205 may be formed on the front of the eyeglasses device. A drug applicator 201 may be attached to the application head 205 at a position in front of the left and / or right eye. An additional housing and holding portion 700b preferably forms the frame and / or yoke of the eyeglasses device. The housing and holding portion may or may not include a signal generating unit 300 and / or a display and / or an input unit 400.

[0250] The application head may be supported by an eye-worn frame. The eye-worn frame may support one or more ultrasound generating devices. Each ultrasound generating device may be configured to generate ultrasound when the subject wears the device, which is delivered to a desired site in the eye. In some embodiments, a single ultrasound generating device may be supported by the eye-worn frame on a single eye. The ultrasound generating device may be positioned on the eye-worn frame to at least partially cover the eye when the subject wears the device. For example, the ultrasound generating device may be configured to deliver ultrasound only to the left eye or only to the right eye. In some embodiments, the ultrasound generating device may be fixed to the eye-worn frame and may not move relative to the eye-worn frame.

[0251] In some implementations, the ultrasound generator is movable relative to the eyeglass frame. For example, the ultrasound generator can be configured to slide left or right to cover the desired eye. For example, the ultrasound generator can be positioned above the left eye to deliver ultrasound to the left eye. When it is desired to deliver ultrasound to the right eye, the ultrasound generator can be moved to be positioned above the right eye. The ultrasound generator can be moved along the eyeglass frame without being removed or detached from it. Alternatively, the ultrasound generator can be detached from the eyeglass frame in a first position and reattached to it in a second position. In some implementations, the position relative to the left and / or right eye can be adjustable. This can be useful for accommodating different users with different facial shapes and sizes. In some cases, the position relative to the left and / or right eye can be locked. This can be advantageous when the device is worn by repeated subjects. The position can be set for a specific subject, and measurements can be fixed for that specific subject each time the subject undergoes a treatment period to place the ultrasound generator in the same position relative to the eye.

[0252] The generation of ultrasound can lead to the delivery of at least one drug to a target site in the eye without damaging the eye's tissues. In some embodiments, the eye-worn frame can support two ultrasound generators corresponding to each eye of the subject. In some embodiments, a single ultrasound generator can be used to deliver ultrasound to both target eyes. The ultrasound generator can generate ultrasound that can be delivered to both eyes via a low-attenuation material. In some embodiments, the ultrasound generator can be coupled to two drug applicators that can deliver ultrasound to both eyes.

[0253] The ultrasound generator may or may not be in direct contact with the eye. In some embodiments, a drug applicator may be coupled to the ultrasound generator. The drug applicator may be supported by an eyeglass frame. The drug applicator may be supported by a corresponding ultrasound generator. The drug applicator may be in contact with the eye. When a subject wears the device, the drug applicator may be positioned to at least partially cover one or more of the subject's eyes. The drug applicator may be coupled and / or decoupled from the ultrasound generator in a repeatable manner. If the ultrasound generator is movable or detachable from the eyeglass frame, the drug applicator may move and / or detach from the ultrasound generator. In some embodiments, the drug applicator may be fixed to the eyeglass frame, while the ultrasound generator may be detachable or movable. In some embodiments, the drug applicator may be movable or detachable relative to the eyeglass frame independently of the ultrasound generator.

[0254] The drug applicator can be positioned relative to the eyeglass frame to contact the surface of the eye or the eyelid. The ultrasound generator and / or drug applicator can be moved laterally along the eyeglass frame. The ultrasound generator and / or drug applicator can be moved closer to or further away from the eye surface (e.g., forward and backward). The drug applicator can be configured to deliver a drug to the surface of the eye. The drug applicator can be configured to deliver ultrasound from the ultrasound generator to the eye.

[0255] The advantages of a wearable design can include improved usability, particularly an enhanced user experience during application. A wearable design can also allow the drug applicator and / or ultrasound to be easily aligned with the desired site on the eye. In some embodiments, the subject may wear the device. The position of the drug applicator and / or ultrasound generator can then be adjusted for the subject to allow for the delivery of ultrasound and / or medication in the desired manner. The subject may wear the device during treatment. In some embodiments, there may be a treatment plan requiring the subject to wear the device at different times of the day or over a course of treatment lasting several days, weeks, or months. Each time the subject wears the device, components such as the ultrasound generator and / or drug applicator can be readjusted. Alternatively, the previous positions of the eyeglass components may be retained, and adjustments may not be required or may require very minor adjustments when the subject wears the eyeglasses again.

[0256] Figure 13 An example of a delivery unit including a light source according to an embodiment of the present invention is shown. In some embodiments, it may be useful to apply light to a drug delivered to the eye to produce a desired effect. Examples of desired effects may include initiating a chemical reaction of the drug, such as cross-linking of the drug, altering the properties of the drug to improve penetration, or achieving the desired delivery effect.

[0257] In some cases, light can be provided to the desired site of the eye after drug and ultrasound have been delivered to it. In some cases, light can be provided before, simultaneously with, and / or after drug delivery to the desired site of the eye. Light can be provided from a source external to the drug delivery device. Alternatively, light can be provided from the drug delivery device itself. In one example, the application head may include an onboard light source.

[0258] The drug delivery device may include an ultrasound generator and a light source configured to generate light to be delivered to a desired site of the eye. The drug delivery device may be configured to couple with a drug applicator that assists in delivering ultrasound to the desired site of the eye and allows light from a light source mounted on the drug delivery device to be delivered to the desired site of the eye.

[0259] The drug delivery device may include a housing. A light source may be provided within the housing. An ultrasound generator and a light source may be provided within a common housing. The housing may prevent light from the light source from escaping the device in an undesirable manner. The light source may have a fixed position relative to the ultrasound generator. The light source may be coupled to the ultrasound generator.

[0260] An ultrasound generating device may include an internal space in which a light source is located. In one example, the ultrasound generating device may have a geometric cross-section in which the free space forming the internal space is substantially in the middle. For example, the ultrasound generating device may have a circular cross-section with free space forming the internal space at or near the center. The light source may be provided within the free space and may illuminate the drug delivery device directly. The internal space or another part of the drug delivery device may optionally include optical elements that can modify the light emitted by the light source. Examples of optical elements may include lenses, filters, condensers, diffractors, prisms, mirrors, dichroic mirrors, beam splitters, or any other type of optical element. The optical elements may alter the path of light, focus light, diffuse light, separate light, reflect light, filter out one or more wavelengths of light, or modify light in any other way.

[0261] The light source can be of any type. The light source can emit light along any wavelength of the electromagnetic spectrum. The light source can emit visible light, ultraviolet (UV) light, infrared light, microwave light, or any other type of light. In some embodiments, the light source can emit UV light. The light source can be a UV lamp that emits light along the UV-A wavelength. In some embodiments, the light source can emit light along UV-B and / or UV-C wavelengths. The light source can emit light with wavelengths in the range of 10 nm to 400 nm. The light source can emit light with wavelengths between 315 and 400 nm. The light source can emit light with wavelengths less than 10, 30, 50, 100, 150, 200, 250, 280, 300, 315, 325, 350, 400, 450, or 500 nm. The light source can emit light with wavelengths greater than any of these values ​​or falling within the range of any two of these values. The light source may include one or more LEDs. The light source may include one or more lasers.

[0262] In one example, a drug delivery device and / or drug applicator can be used for UV (e.g., UV-A) treatment of a target site. The drug applicator 201 may include an inlet 201a facing a gap 601a and / or an ultrasonic transducer 202. The ultrasonic transducer may be coupled to a light source (e.g., a UV lamp) 202c. The light source may be supported by a support structure 202b. The light source and / or support structure may be within the internal space 202a of the ultrasonic transducer. The light source may be partially or completely located within the internal space. The light source may or may not protrude from the internal space. In some embodiments, the light source may protrude completely from the internal space.

[0263] The emitted wavelength from the light source can pass through the inlet 201a of the drug applicator, whereby the outer shell 201b of the drug applicator can be opaque and formed or coated with a material that prevents light from escaping through the drug applicator shell. For example, if the light from the light source includes UV light, the drug applicator may include a shell formed or coated with a UV-reflective material to prevent any UV exposure to the external environment. The only exit for the UV light may be through the side facing the delivery site (e.g., the surface of the eye). In some embodiments, less than 20%, 10%, 5%, 3%, 2%, 1%, 0.5%, or 0.1% of the emitted light may escape through the housing of the ultrasonic generator and / or the outer shell of the drug applicator.

[0264] Therefore, a drug applicator may include a first portion formed of an opaque material configured to at least partially define a space configured to hold a drug, and a second portion formed of a material at least partially transparent to light of a selected wavelength, configured to allow light to pass from one side of the drug applicator to the other. The space configured to hold the drug may be a single continuous space. Alternatively, the space configured to hold the drug may include multiple discontinuous spaces. These discontinuous spaces may include apertures. The first portion may be configured such that light from a light source cannot penetrate into the space to hold the drug. This can be used to prevent reactions (e.g., crosslinking) that may be induced by the light source until the drug is delivered to the desired site. The first portion may include a surface coated with a material that reflects light of a selected wavelength. For example, if the light from the light source is UV light, the coating may reflect UV light. The coating may be provided on the outer surface of the drug applicator. This can reduce any UV exposure to the external environment. The coating may be provided on the inner surface of the drug applicator. This can reduce any UV exposure to the drug within the space of the first portion. In some embodiments, the material forming the first region may reflect selective wavelengths (e.g., UV wavelengths).

[0265] The first portion may include a target side, which may be configured to contact a desired site on the eye. The target side may contact the eyelid or ocular surface, such as the sclera, cornea, and / or limbus. In some embodiments, the target side may be formed of a soft, biocompatible material. Soft materials can allow for comfortable contact with the eye and / or increase the surface area between the drug applicator and the eye, which can allow for improved ultrasound delivery to the eye. The target side may be configured to deliver an agent that can improve drug delivery to the target side. Further description of this is provided elsewhere in this document. In some embodiments, the first portion may be formed of an elastic material. The first portion may have any of the material properties described elsewhere in this document for drug applicators. The first portion can allow for soft, comfortable contact with the eye without requiring a separate layer at the target side. The material used throughout the first portion may be the same, or a different material may be provided on the target side. The material provided on the target side may be softer than the rest of the material.

[0266] In some embodiments, the material used for the first part of the drug applicator may be formed of an opaque elastic material such as a polymer or silicone.

[0267] The second portion of the drug applicator may be transparent to light of a selected wavelength. For example, the second portion of the drug applicator may be transparent to at least a subset of the light emitted by the light source. In some cases, the second portion of the drug applicator may be transparent to the entire wavelength range of the light emitted by the light source. The second portion of the drug applicator may be transparent to UV light (e.g., UV-A, UV-B, and / or UV-C light). The second portion may be at least partially surrounded by the first portion. In some embodiments, the first portion may surround an internal space. The second portion may occupy a portion or all of the internal space. In some embodiments, one or more drugs may be provided within the internal space, and the second portion may occupy a portion of the internal space to help contain the drug. The second portion may include solid, liquid, gel, and / or other types of materials.

[0268] The drug held in the drug applicator can be any type of drug that can be delivered to the eye. In some embodiments, a light source can be configured to trigger a reaction in the drug. For example, the light source can be configured to trigger cross-linking of the drug. In one example, the drug can be riboflavin. In some embodiments, light from the light source can be used to cross-link collagen at the delivery site.

[0269] In one embodiment, UV wavelengths can be generated by a light source at an ultrasound generator. The light can penetrate the transparent applicator inlet 201a and space 800. This space can be used to hold the medication. The light can reach the delivery site 100 without scattering through the drug applicator outer shell 201b. This may result in specifically focused UV light for potential treatment of keratoconus and / or LASIK / SMILE-related corneal ectasia. This can occur by crosslinking riboflavin or any other crosslinking agent at the delivery site and causing it to undergo corneal crosslinking CXL.

[0270] For safety reasons, the combination of opaque and transparent materials used in the drug applicator can be configured to allow UV irradiation in a selected area and reduce overexposure in two other areas.

[0271] The drug applicator can have any shape factor, as described elsewhere herein. For example, the drug applicator can be, but is not limited to, circular, cylindrical, conical, elliptical, triangular, square, or rectangular. The drug applicator surfaces facing the gap 601a and / or the target site 100 can have the same or different shapes. They can have the same or different shapes relative to each other or relative to the rest of the drug applicator. The target-facing surfaces can be coated with a biocompatible material that can contact the target surface. This material can cover or enclose the space 800 of the drug applicator to prevent drug contamination. The material also prevents spillage and loss during handling of the drug applicator.

[0272] Figures 14A to 14G Examples of various configurations of the delivery unit or a portion thereof are shown. An ultrasonic generator 202 may be provided.

[0273] Figure 14A An example of an ultrasonic generator 202 is shown. The ultrasonic generator may include a transducer that may not require internal space.

[0274] Figure 14B An example of an ultrasound generator 202 is shown, which may include an interface 602 configured to face a drug applicator. The interface allows coupling between the ultrasound generator and the drug applicator. The interface may be provided on the eye-facing side of the ultrasound generator. The ultrasound generator may include an internal space 202a.

[0275] Figure 14C A cross-section of the ultrasonic generator 202 having an internal space 202a can be shown. The ultrasonic generator can have any cross-sectional shape. For example, the ultrasonic generator can have a circular, elliptical, triangular, square, rectangular, trapezoidal, pentagonal, hexagonal, octagonal, or any other cross-section. The internal space can have any cross-sectional shape. For example, the internal space can have a circular, elliptical, triangular, square, rectangular, trapezoidal, pentagonal, hexagonal, octagonal, or any other cross-section. The internal space can have any cross-sectional shape. The ultrasonic generator and the internal space can be arranged concentrically. The ultrasonic generator and the internal space can each include an axis extending through their respective lengths. The axis can pass through the center of their respective portions. The axes of each of these portions can be parallel to each other. The axes of each of these portions can directly overlap each other.

[0276] In some implementations, a transmitter, such as a light source, may be provided within the interior space. Alternatively or additionally, a data collection device may be provided. The data collection device may include one or more sensors capable of collecting data. For example, the data collection device may include one or more cameras, microphones, infrared detectors, UV detectors, radar, or any other type of data collection device.

[0277] Figure 14EAn example of a light source 202c that can be located within the internal space 202a of an ultrasonic generator is shown. The light source may be supported by a support structure 202b. The support structure may provide a connection between the light source and a power source, such as one or more batteries as described elsewhere herein. In some cases, the support structure itself may include a power source, such as a battery, that can directly supply power to the light source. The ultrasonic generator and the light source may or may not be powered by the same power source. They may be powered by different power sources. In some embodiments, the support structure may be formed of a highly ultrasonic attenuating material, which can reduce the effect of ultrasound on the light source. In some embodiments, it may be necessary for the support structure to provide active or passive damping for the ultrasound generated by the ultrasonic generator. This may allow the light source to experience a smaller or no ultrasonic signal. Any description of the support structure for the light source herein can be applied to the support structure for any other object provided within the internal space, such as a transmitting device or a data collection device.

[0278] Figure 14G Another example of a light source 202c that can be located within the internal space 202a of an ultrasound generating device is shown. The light source can be supported by a support structure. One or more optical elements 202f can be provided. The one or more optical elements can modify the emitted light. Alternatively or additionally, one or more optical elements can be provided in a drug applicator. In some cases, one or more adjustment mechanisms 202f can be provided, which can be provided for the emitting device or data collecting device. The adjustment mechanism can be an optical element or other type of adjustment mechanism. The adjustment mechanism can change the emission from the device within the internal space, or the emission entering the internal space from outside the internal space.

[0279] Figure 14D An example of a data collection device, such as camera 202d, is shown. The camera may be supported on a support structure 202b. The camera can be used to image the delivery site. The camera can be used to capture still or moving images. The camera may be a video camera capable of capturing streaming images. The camera can be used to collect data about the delivery site and how treatment is performed. A transparent portion of the drug applicator may allow the camera to image the delivery site through the drug applicator. In some embodiments, the camera may be used in conjunction with a light source. The light source can be used to illuminate the area being imaged. In some embodiments, the light source may be a reaction that triggers the drug, which can be imaged.

[0280] Figure 14F Another example of a data collection device is shown, such as microphone 202e. The microphone can be supported on support structure 202b. The microphone can be used to collect acoustic data from a delivery site. In some embodiments, the microphone can be used to collect ultrasonic data. In some embodiments, the microphone can be used in conjunction with a light source.

[0281] In some implementations, one or more modules can be switched within the internal space of the ultrasound generator. For example, the light source can be switched with different light sources or data collection devices. A single module can be housed within the internal space, or multiple modules can be housed within the internal space. For example, both the light source and the data collection device, or multiple types of data collection devices, can be housed within the internal space.

[0282] A drug applicator can be used to deliver drugs to a delivery site on the eye. A drug applicator can also be used to deliver ultrasound to a delivery site on the eye. Alternatively or additionally, a drug retention cover can be used to deliver drugs to a delivery site on the eye. The drug retention cover can be configured to contact the surface of the eye. The drug retention cover can be positioned on the surface of the eye and / or can be at least partially adhered to the eye.

[0283] Medication retention covers can be configured to allow eye closure when applied to a surface. The medication retention cover may have a small profile that prevents it from protruding more than 5 mm, 4 mm, 3 mm, 2.5 mm, 2 mm, 1.5 mm, 1.3 mm, 1.2 mm, 1 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.3 mm, 0.1 mm, 0.05 mm, or 0.01 mm from the eye. In some embodiments, the medication retention cover may be a contact lens, film, membrane, layer, or sheet. The medication retention cover may be formed of a flexible material. The medication retention cover may be stretchable or bendable to conform to the shape of the eye surface.

[0284] Medication retainer covers can have any shape. For example, a medication retainer cover can be substantially circular. Medication retainer covers can also be oval, rectangular, triangular, crescent-shaped, ring-shaped, or any other shape. When in its natural state, a medication retainer cover can be substantially curved, similar to the curved surface of the eye. Alternatively, a medication retainer cover can be flat when in its natural state.

[0285] The drug retention cover can be formed of a porous material. The porous material allows the drug retention cover to retain at least one drug within its pores. The drug retention cover can be formed of hydrophilic, hydrophobic, amphiphilic, and / or sterile materials. In some cases, the drug retention cover may include a microporous foam. In one example, the drug retention cover may include a hydrophilic microporous foam adjacent to a hydrophobic barrier membrane. The drug retention cover may include a polymeric material, such as a polymer membrane. The drug retention cover can be formed of a low-attenuation material. Any properties of low-attenuation materials as described elsewhere herein may be applicable to the drug retention cover. For example, the attenuation coefficient of the drug retention cover may be less than 20, 15, 12, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, 0.5, or 0.1 dB / (MHz cm).

[0286] At least one drug may be encapsulated in a drug-retaining cover. At least one drug may be adhered to or applied to the surface of the drug-retaining cover.

[0287] Methods for delivering at least one drug may include applying a drug-holding cover to the surface of the eye. An ultrasound generator may be positioned relative to a desired site on the eye. Ultrasound may be generated by means of the ultrasound generator and applied to the desired site.

[0288] Figure 15 An example of the application of a drug retention cover 901 on the surface of an eye 100 according to an embodiment of the present invention is shown. An ultrasound generator 1000 may be positioned on the eyelid 102 of the eye. In some embodiments, the drug retention cover may be positioned on the surface of the eye below the eyelid. The drug retention cover may be positioned directly below the portion of the eyelid that contacts the ultrasound generator. Alternatively, the drug retention cover may be positioned below a portion of the eyelid different from the portion that contacts the ultrasound generator. The ultrasound generator may contact a portion of the eyelid when delivering ultrasound. When the ultrasound generator contacts the eyelid, the drug retention cover may or may not be directly below the ultrasound generator. In some embodiments, the drug retention cover may be provided at a completely different location on the eye. However, the ultrasound signals that can be provided to the eye can still help deliver the drug from the drug retention cover.

[0289] When an ultrasound generator delivers ultrasound to the eyelids, the eyes can be completely or partially closed.

[0290] Optionally, the drug applicator may be operatively coupled to an ultrasound generator. The drug applicator may be positioned on the eyelid. The drug applicator may be formed of a low-attenuation material, which allows ultrasound to be transmitted to the eyelid. A drug retention cover may or may not be directly below the drug applicator. In some embodiments, a drug retention cover may be provided on different areas of the eye.

[0291] Figures 16A to 16B An example of an additional application of the drug-retaining cover 901 according to an embodiment of the present invention is shown. The ultrasound generator 1000 may be positioned above the drug-retaining cover, such as... Figure 16A As shown, or when the medication keeps the covering on different parts of the eye, it can be positioned directly on the surface of the eye 100, such as... Figure 16B As shown. In some embodiments, the drug retention cover can be positioned on any part of the surface of the eye. For example, the drug retention cover can be positioned on the sclera, cornea, or limbus of the eye. When delivering ultrasound, the ultrasound generating device can come into contact with the drug retention cover. When the ultrasound generating device contacts the drug retention cover, the drug retention cover can be located directly below the ultrasound generating device. The ultrasound generating device can be positioned above the sclera, cornea, or limbus of the eye. The drug retention cover can be formed of a low-attenuation material, which allows ultrasound from the device to be transmitted to the surface of the eye. This can help deliver medication from the drug retention cover to the target site of the eye.

[0292] In some embodiments, the drug retention cover can be provided on a completely different part of the eye. The ultrasound generator can be in direct contact with the surface of the eye. For example, the ultrasound generator can be in direct contact with the sclera, cornea, or limbus of the eye. However, the ultrasound signals that can be provided to the eye can still help deliver the drug from the drug retention cover. The ultrasound generator can deliver ultrasound to a part of the eye's surface that is different from the part of the eye where the drug cover is provided. The ultrasound generator can deliver ultrasound to a part of the eye's surface that is different from the part of the eye that receives the drug.

[0293] The eyes can be open when the ultrasound generator delivers ultrasound.

[0294] Optionally, the drug applicator may be operatively coupled to an ultrasound generating device. In some embodiments, the drug applicator may be positioned above a drug holding cover. Alternatively, the drug applicator may directly contact the surface of the eye, and the drug holding cover may be located in a different part of the eye. The drug applicator may be formed of a low-attenuation material, which allows ultrasound to be transmitted to the drug holding cover and / or the surface of the eye. The drug holding cover may or may not be directly below the drug applicator. In some embodiments, the drug holding cover may be provided on a different area of ​​the eye than the applicator.

[0295] In some implementations, for a particular treatment plan, it may be desirable to use a drug retention cover placed at a desired site on the eye. The drug retention cover can optionally be placed for an extended period, which allows for prolonged drug delivery. The application of ultrasound can provide enhanced delivery. Ultrasonic delivery can be provided for the entire duration of the time the drug retention cover is provided to the eye. Alternatively, ultrasonic delivery can be provided only for a subset of the time the drug retention cover is provided to the eye.

[0296] Alternatively or additionally, ultrasound may be desired to provide drainage from the eye or the drainage system around the eye. For example, in certain conditions, it may be necessary to reduce elevated intraocular pressure. In one example, for treating diseases such as glaucoma where elevated pressure due to potential obstruction of fluid drainage can damage a part of the eye (e.g., the optic nerve), ultrasound can be used to help drain fluid from the eye. Ultrasound can be used in combination with medications. For example, for treating uveal efflux or reducing aqueous humor production, improved drug delivery to the target site can aid in fluid drainage and pressure relief. Medications (such as, but not limited to, prostaglandin analogs, beta-blockers, adrenergic drugs, miotics, carbonic anhydrase inhibitors, or any other medications described elsewhere herein) can be delivered to the desired site. Preferably, they can be delivered via a drug applicator to reduce drug loss due to tears, blinking, or eye movements (e.g., compared to eye drops). Ultrasound can be applied, which can aid in the delivery of these medications. In some cases, these medications can be delivered through a drug-holding cover. Ultrasound stimulation can help clear obstructed drainage systems, which may include the scleral venous system, aqueous humor veins, Schlemm's canals, and / or trabecular meshwork.

[0297] The generation of ultrasound allows for the drainage of fluid from the eye to reduce intraocular pressure. Fluid drainage can occur simultaneously with the delivery of one or more medications. Fluid drainage can occur before the delivery of one or more medications. Fluid drainage can occur after the delivery of one or more medications. In some embodiments, ultrasound can be operated at a desired frequency during fluid drainage from the eye. The desired frequency can have any value as provided elsewhere herein. In some cases, the desired frequency may be below 1 MHz. In some embodiments, fluid drainage can be performed without causing any permanent damage to the eye. Optionally, fluid drainage can be performed by disrupting the intracellular structures of the eye. In some cases, eye drainage can occur without significantly increasing the eye temperature. In some cases, eye drainage can occur without raising the eye temperature by more than 0.1°C, 0.5°C, 1°C, 1.2°C, 1.5°C, 1.7°C, 2°C, 2.5°C, 3°C, 4°C, 5°C, 7°C, or 10°C. In some implementations, the eye temperature does not exceed 33°C, 34°C, 35°C, 36°C, 37°C, 38°C, 39°C, 40°C, 41°C, 42°C, 43°C, 44°C, or 45°C. Fluid drainage may be useful during treatments to lower intraocular pressure. For example, fluid drainage may be useful during glaucoma.

[0298] In one example, ultrasound-mediated glaucoma drug delivery can reach the trabecular meshwork and Schlem's canals. Ultrasound-mediated glaucoma drug delivery can occur through the limbal region. Alternatively, the drug can be delivered through other areas, such as the sclera or cornea. Delivery of drugs for treating glaucoma can occur simultaneously with a reduction in aqueous humor production or an increase in fluid outflow. Ultrasound can temporarily disrupt the trabecular meshwork and Schlem's canals and promote fluid outflow, thereby lowering intraocular pressure. In some embodiments, high-intensity ultrasound (e.g., 1 to 20 MHz) can be applied to lower intraocular pressure. In some embodiments, the systems and methods provided herein can use lower-intensity ultrasound, such as less than 1 MHz, 900 kHz, 800 kHz, 700 kHz, 600 kHz, 500 kHz, 400 kHz, 300 kHz, 250 kHz, 200 kHz, 150 kHz, 100 kHz, 80 kHz, 60 kHz, 50 kHz, 40 kHz, 30 kHz, or 20 kHz, to lower intraocular pressure. In other embodiments, low-intensity ultrasound (e.g., with 2-4 W / cm) can be provided. 2 ).

[0299] Drug delivery devices can assist in delivering medications and / or ultrasound to desired sites on the eye. This allows medications to be delivered to target sites on the eye, which may include target sites within the intraocular space of the eye. In some embodiments, different parameters can be provided for the operation of the ultrasound generator of the drug delivery device, depending on the medication to be delivered or the treatment plan to be followed. Instructions for operating the ultrasound generator can be generated based on the identification of the medication or the treatment plan for the eye.

[0300] Figure 17 An example of a process for generating instructions to operate an ultrasound generator is shown. The method for generating instructions to deliver a drug may include obtaining a signal 1701 indicating an identifier of at least one drug to be delivered or an identifier of a treatment plan for the eye. The method may further include generating instructions to operate the ultrasound generator 1702 based on the signal indicating the drug or treatment plan. Ultrasound can be applied according to the instructions, which can achieve drug delivery 1703.

[0301] A signal 1701 indicating an identifier of at least one drug to be delivered or an identifier of a treatment plan for the eye can be obtained. The signal can be received at a drug delivery device, a display and / or an input device, or a separate device. In some embodiments, the signal can be provided in response to user input. User input can be input of a drug identifier (e.g., the name of the drug, a drug selection from a variety of drugs, the batch number or other identifier of the drug, the type of drug). User input can be input of an identifier of a treatment plan for the eye. The identifier of the treatment plan can include an identifier of the disease or condition for which the eye is being treated (e.g., glaucoma, macular degeneration, diagnosis, vitamin delivery, prevention, or any other disease or condition as described elsewhere herein). The identifier of the treatment plan can include a specific treatment plan identifier (e.g., plan name, an alphanumeric string identifying the plan, plan type), which may or may not be unique for a particular subject or subject type. A specific treatment plan for the subject can be generated with the assistance of the physician treating the subject. A specific treatment plan for the subject can be generated by means of one or more processors based on certain input regarding the subject's condition.

[0302] In some implementations, the user can access settings for the disease / condition to be treated, ultrasound intensity, ultrasound frequency, cycle time, start, stop, and / or timer. The user can input or view patient information and / or a biography. For example, the patient's name, medical history, disease / condition, treatment stage, and images can be accessed. In some cases, user input may only be a patient identifier, and disease and / or treatment identifiers can be extracted from the patient's records. In some cases, user input may only be a disease and / or treatment identifier, and the device or system can automatically generate operating parameters for the ultrasound generator. Alternatively, the user can manually adjust operating parameters of the ultrasound generator, such as frequency, mechanical index, intensity, cycle time, number of cycles, waiting period, etc.

[0303] User input can be provided via a user interface. The user interface can be contained within the drug delivery device. For example, a user can directly input the identifier of the medication and / or treatment plan into the drug delivery device. In another example, a user can interact with a display and / or input device, which can be part of the drug delivery device or provided separately from it. In some cases, the display and / or input unit can communicate with the drug delivery device. User input can be provided from any other external device. For example, a user can provide input to a device that can communicate with the drug delivery device, such as a computer, tablet, or smartphone.

[0304] In some implementations, signals indicating the identification of a drug or a treatment plan can be provided from one or more processors. The drug identification or treatment plan identification can be provided on a label on a drug applicator that can be coupled to the device. The drug applicator may be pre-loaded with at least one drug. The drug applicator may be removably coupled to the device. When the drug applicator is coupled to the device, a sensor can be used to read the label on the drug applicator. Further details of reading the label from the drug applicator are provided elsewhere herein. The label may provide information such as the identification of the drug, the volume of the drug, the identification of the treatment plan, the duration of the treatment plan, the details of the treatment plan, the disease to be treated, the identification of the subject, the batch, the manufacturing time, the manufacturing location, the manufacturer ID, the expiration date, or other information related to the drug applicator and / or the drug. The information may be provided directly by the label, or the label may allow the drug delivery device to access memory where the information can be stored. For example, if a treatment plan identifier is provided, the drug delivery device may access memory storage on-device or memory storage not on-device. The memory storage may have additional information associated with the treatment plan identifier.

[0305] In some implementations, the drug applicator can "push" information such as the identifier of the drug or treatment plan to the drug delivery device. For example, the drug applicator can broadcast information, such as the identifier of the drug or treatment plan, which can be read by the communication unit of the drug delivery device.

[0306] One or more processors can be used to generate instructions 1702 to operate the ultrasound generator based on signals indicating a drug or treatment plan. The processor may be carried on a drug delivery device. Alternatively, the processor may not be carried on a drug delivery device. The processor may optionally be carried on a display and / or input device. The processor may be provided at a separate device. The processor may be provided as part of a cloud computing infrastructure.

[0307] The generated instructions can include selecting from multiple instruction options for various medications or treatment plans. For example, a first set of instruction options can be provided for a first medication or treatment plan. A second set of instructions, different from the first set of options, can be provided for a second medication or treatment plan. A preset range of instruction sets can be provided. Based on the identified medication or treatment plan, the appropriate instruction set corresponding to the identified medication or treatment plan can be selected.

[0308] In other cases, instructions can be generated from scratch instead of selecting from an existing instruction pool. Instructions can be generated based on known parameters of the drug and / or treatment plan. Instructions can be generated based on the subject's identification or characteristics. For example, instructions may differ if the subject is a 40-year-old woman from those for a 60-year-old man. Any known interactions between the subject and the drug may also affect the instructions. For example, person A may be more sensitive to drug A than person B.

[0309] Instructions can define the operation of the ultrasound generating device. This can include determining the frequency of the ultrasound, the mechanical properties of the ultrasound, the timing information of the ultrasound (e.g., the duration of ultrasound (TA), the waiting period of ultrasound (TW), the number of duty cycles of ultrasound, the length of the treatment plan of ultrasound), the waveform of the ultrasound, and / or the intensity of the ultrasound.

[0310] Ultrasound 1703 can be generated according to instructions. The generation of ultrasound can enable drug delivery to the target site. In some embodiments, ultrasound can be applied before, simultaneously with, and / or after the drug applicator comes into contact with the eye.

[0311] Other embodiments of the invention relate to integrating a system according to one aspect of the invention into existing treatment devices for eye diseases. The system is preferably combined with and / or integrated with other diagnostic and / or therapeutic devices.

[0312] Figures 18A to 18C Examples of ultrasound being applied according to various treatment plans are shown.

[0313] Figure 18A An example of ultrasound that can be applied according to a treatment plan is shown. The ultrasound can be delivered in pulses that turn on and off. The system can operate at least one application cycle. Each application cycle includes at least one ultrasound emission event with a duration TA and a subsequent waiting period with a duration TW. During the ultrasound emission event, the ultrasound device operates, while during the waiting period, the ultrasound device does not operate. Throughout the full duration of at least one application cycle, the drug applicator can contact the surface of the eye, such as the scleral surface, corneal surface, or limbus.

[0314] Depending on the physical, chemical, and pharmaceutical properties of the drug, different parameters for application cycles are required. In one embodiment of the invention, the system is configured to control parameters selected from the following list.

[0315] At least one parameter (preferred subset): the duration TA of the ultrasonic emission event, the ultrasonic emission...

[0316] The duration of the waiting period after the emission event (TW), the number of applied cycles, the intensity of the ultrasonic emission event, the center frequency of the ultrasonic emission event, the mechanical index of the ultrasonic emission system, and in the case of pulsed ultrasonic emission events: the repetition rate of the ultrasonic emission event and the duty cycle of the ultrasonic emission event.

[0317] Any number of application cycles can be provided. In some implementations, a preset number of application cycles can be provided. In some cases, a preset duration for the running application cycles can be provided.

[0318] Figure 18B An example of multiple application cycles that can be clustered together according to an embodiment of the present invention is shown. The cycle clusters may or may not repeat. In some embodiments, the clusters may have a time length T. C The total length of the applied loop can be approximately T. E The amount of time between clusters can be the hibernation period T. D Clusters can repeat any number of times. Clusters can repeat a predetermined number of times, or repeat for a preset duration.

[0319] Figure 18C An example is shown of how parameter P can change over time t during a treatment plan. There may or may not be a regular application cycle. In some implementations, a series of application cycles with different characteristics may or may not be repeated. For example, the ultrasound “on” time T0 may be fixed or may vary. The waiting period T during ultrasound “off”... W It can be fixed or it can vary. Similarly, the cluster length T E It can be fixed or it can change. Cluster T DThe time interval can be fixed or it can vary.

[0320] One or more parameters can be fixed for a specific application cycle. One or more parameters can be fixed for the entire cluster. One or more parameters can be fixed for the entire treatment plan. Alternatively, one or more parameters can be changed during the treatment plan. One or more parameters can be changed during the cluster. One or more parameters can be changed during the application cycle. Any parameter can be changed, including but not limited to the intensity of the ultrasound emission event, the center frequency of the ultrasound emission event, or the mechanical index of the ultrasound emission system.

[0321] For any given time (e.g., TA, TW, TC, TD, TE), the time unit can be on the order of microseconds, milliseconds, seconds, tens of seconds, minutes, or larger. For example, the duration of ultrasound generation can be less than or equal to approximately 0.001 s, 0.005 s, 0.01 s, 0.05 s, 0.1 s, 0.5 s, 1 s, 3 s, 5 s, 10 s, 15 s, 20 s, 30 s, 45 s, 60 s, 90 s, 120 s, 150 s, 180 s, 210 s, 240 s, 270 s, 300 s, 360 s, 420 s, 480 s, 540 s, 600 s, 1000 s, 2000 s, 3000 s, or 6000 s. The duration of ultrasound generation can be greater than any value provided herein or fall within the range between any two values ​​provided herein. Similarly, waiting periods less than or equal to any duration provided herein may be provided for the duration. Waiting periods may be longer than any duration provided herein, or fall within a range of any duration provided herein. Any other time associated with the ultrasound treatment profile (e.g., TC, TD, TE) may have a duration less than, greater than, or fall between any two durations provided herein. In some implementations, the entire treatment plan may span on the order of seconds, minutes, hours, days, weeks, months, or years. Patients may receive ultrasound treatment at different points in time, and the drug delivery system may be re-evaluated as needed.

[0322] Different ultrasound profiles may be provided over time for different medications and / or treatment plans.

[0323] Figure 19 An example of a drug penetrating to a target site within the intraocular space of the eye, according to an embodiment of the invention, is shown. An ultrasound generator 202 and a drug applicator 201 can deliver the drug and ultrasound to the eye 100. The ultrasound generator can advantageously allow the drug to penetrate a distance d within the eye.

[0324] In some embodiments, it is desirable for the drug to penetrate to the posterior part of the eye. For example, for diseases such as diabetic retinopathy or macular degeneration, the drug can be delivered to the posterior part of the eye. In some embodiments, the drug may be a corticosteroid or an anti-VEGF drug. Some drugs may include, but are not limited to, triamicolone marketed under the names Aristocort, Kencaort, or Kenalog, or anti-VEGF drugs marketed under the names Lucentis, Eylea, or Avastin. The drug can be delivered to the posterior part of the eye, i.e., the retina, via ultrasound treatment as described herein. The concentration of the drug that can be delivered may be the same as that provided during intravitreal injection, or at least 50%, 60%, 70%, 80%, 90%, 95%, 97%, or 99% of that concentration, without requiring such invasive techniques.

[0325] The drug can penetrate to a depth d of at least 4 cm, 3.5 cm, 3 cm, 2.5 cm, 2 cm, 1.5 cm, 1 cm, 0.8 cm, 0.7 cm, 0.6 cm, 0.5 cm, 0.4 cm, 0.3 cm, 0.2 cm, or 0.1 cm. This distance can be penetrated when ultrasound is operated at any frequency value, such as less than or equal to 1 MHz, 900 kHz, 800 kHz, 700 kHz, 600 kHz, 500 kHz, 400 kHz, 300 kHz, 250 kHz, 200 kHz, 150 kHz, 120 kHz, 100 kHz, 90 kHz, 80 kHz, 70 kHz, 60 kHz, 50 kHz, 40 kHz, 30 kHz, 20 kHz, or 10 kHz. This distance can also be penetrated when ultrasound is operated at a frequency value greater than any of the provided values ​​or falling within the range of any two of the provided values. Ultrasound can penetrate such distances when operating at any mechanical index, such as less than or equal to 0.01, 0.05, 0.1, 0.13, 0.15, 0.17, 0.18, 0.19, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.7, 0.8, or 0.9. Ultrasound can also penetrate such distances when operating at a mechanical index greater than any of the provided values ​​or falling within the range of any two provided values. Ultrasound can also penetrate such distances when operating at any intensity, such as less than or equal to 10, 9, 8, 7.5, 7, 6.5, 6, 5.5, 5, 4.5, 4, 3.5, 3, 2.5, 2, 1.5, 1, 0.5, or 0.1 W / cm². 2During operation, the drug can penetrate such a distance. This distance is possible when ultrasound is operated with a mechanical index greater than any provided value or falling within the range of any two provided values. The drug can penetrate to any indicated depth within 600 seconds, 480 seconds, 420 seconds, 360 seconds, 300 seconds, 240 seconds, 180 seconds, 120 seconds, 90 seconds, 60 seconds, 30 seconds, 20 seconds, 15 seconds, 10 seconds, 5 seconds, 3 seconds, 2 seconds, 1 second, 0.5 seconds, or 0.1 seconds. The drug can penetrate to such depth within any indicated time value of the applied ultrasound. The drug can penetrate to such depth within any indicated time value of contact between the drug applicator and the ocular surface. The drug can penetrate to the maximum depth to which it can travel within any provided time value.

[0326] The drug can be formulated to penetrate the target site at any concentration. In some embodiments, the drug can be delivered to the vitreous humor and retina of the eye at any concentration. The drug can be delivered to the target site at concentrations greater than or equal to 0.01, 0.05, 0.1, 0.3, 0.5, 0.7, 1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 2, 2.5, 3, 3.5, 4, 5, 7, 10, 12, 15, 17, 20, 25, 30, 35, 40, 50, 60, 70, 80, 100, 150, 200, 250, 300, 400, 500, 700, 1000, 1200, 1500, 2000, 2500, 3000, 3500, 4000, 5000, 7000, and 10000 μg / mL. The drug can also be delivered at concentrations lower than any of the provided values ​​or within a range between any two of the provided values. The drug can penetrate at any speed. The drug can penetrate at a speed of at least 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 150, 175, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, and 1000 μm. 2 Delivery speed of / s.

[0327] Drugs capable of penetrating to such depths can be any type of molecule. Drugs can penetrate to such depths at such ultrasonic frequencies, intensities, or mechanical indices. Drugs can penetrate at any such concentration or at any such rate. Drugs can penetrate to such depths within a specified time period. Such penetration can occur without damaging ocular tissues (e.g., sclera, retina, cornea, limbus). Such penetration can occur without permanently damaging ocular tissues. Such penetration can occur without raising the eye temperature by more than 0.1°C, 0.5°C, 1°C, 1.5°C, 2°C, 2.5°C, 3°C, 3.5°C, 4°C, 5°C, 6°C, 7°C, 8°C, 9°C, or 10°C, or any other temperature value provided elsewhere herein. Such penetration can occur without causing the eye temperature to rise above 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44 or 45 degrees Celsius.

[0328] Drug molecules can be small organic molecules, proteins, monoclonal antibodies, antibody fragments, or nanoparticles. Molecules of any size can be delivered to the target site. In some embodiments, the size of the molecule can be less than or equal to about 10 Da, 50 Da, 100 Da, 300 Da, 500 Da, 700 Da, 900 Da, 1 kDa, 2 kDa, 3 kDa, 5 kDa, 7 kDa, 10 kDa, 20 kDa, 30 kDa, 40 kDa, 50 kDa, 60 kDa, 70 kDa, 80 kDa, 90 kDa, 100 kDa, 120 kDa, 150 kDa, 170 kDa, 200 kDa, 220 kDa, 250 kDa, 280 kDa, 300 kDa, 350 kDa, 400 kDa, 450 kDa, 500 kDa, 600 kDa, 700 kDa, 800 kDa, 900 kDa, or 1 MDa. In some cases, the size of the molecule can be larger than any of the sizes provided herein. The size of the molecule can fall within the range between any two sizes provided herein.

[0329] The size of the molecules constituting the drug to be delivered can be important for the parameters of the applied cycle. For relatively small molecules, preferably smaller than 70 kDa, the drug delivery rate is primarily controlled by the duration of the sonic emission event (TA). For relatively large molecules, preferably larger than 70 kDa, the drug delivery rate is primarily controlled by the duration of the waiting period (TW) following the sonic emission event.

[0330] Since the optimal set of parameters for application cycles varies for different drugs and / or different users, the system preferably includes one or more processors for assisting in setting the parameters for the application cycles. An information sending and / or receiving unit 203 can be used to retrieve information about the drug from the drug applicator 201. A display and input unit 400 may be provided to allow changes to preset parameters.

[0331] In embodiments of the invention, the system is connected to a central database, and the database manages information regarding the optimal set of parameters for applying the cycle. The database may be provided on a cloud computing infrastructure. One or more drug delivery devices may be able to communicate with the database. For example, the drug delivery device may receive instructions regarding the optimal set of parameters for a specific treatment plan, drug, and / or patient. The drug delivery device may send information about the drug, treatment plan, and / or patient to the database, and the database may return the optimal set of parameters. Alternatively or additionally, the optimal set of parameters for applying the cycle is stored on / in the drug applicator and is preferably retrieved by the information sending and / or receiving unit 203. In some embodiments, the optimal set of parameters is carried on the drug delivery device. The optimal set of parameters may be updated periodically or in response to events from the central database.

[0332] In an embodiment of the invention, the system includes an input device configured to manually set parameters for applying the loop.

[0333] A system according to one aspect of the invention is configured to perform a method according to other aspects of the invention. Preferred embodiments of the method for ultrasound-enhanced delivery of a drug are described below. Those skilled in the art will recognize that some of the above-described embodiments of the system relate to certain embodiments of the method described below.

[0334] In an embodiment of the invention, the drug to be delivered is stored in a drug applicator 201. Prior to the delivery operation, the drug applicator 201 is coupled to an application head 205. Before coupling, the used drug applicator 201 needs to be removed. Before or after coupling, the drug applicator 201 is prepared for the delivery operation. Preparing for the delivery operation preferably includes removing a peel-off seal and / or removing a protective cap.

[0335] In an alternative embodiment, the drug is stored in a container holding several doses of the drug. The drug applicator 201 is preferably permanently coupled to the application head 202, and / or the drug applicator 201 is coupled to the application head 202. Optionally, the drug applicator 201 is cleaned before loading the drug into it. After optional cleaning, the drug is loaded into the drug receiving space 800 in the drug applicator 201. Loading can be performed simultaneously with or without the drug applicator 201 being attached to the application head 205.

[0336] In embodiments of the invention, the preparation system is used for the delivery operation after the drug applicator 201 has been prepared for the delivery operation. In alternative embodiments of the invention, the preparation system is used for the delivery operation before the drug applicator 201 is prepared for the delivery operation. The preparation system for the delivery operation preferably includes setting an optimal set of parameters for the application cycle and / or adjusting the parameters of the application cycle. Before setting and / or adjusting the parameters of the application cycle, information about the drug and / or information about the drug applicator 201 is preferably retrieved via the information sending and / or receiving unit 203.

[0337] In an embodiment of the invention, the system is positioned such that the drug applicator contacts the scleral surface after the system and / or drug applicator 201 has been prepared for the delivery process. In an alternative embodiment, the system is positioned before the system and / or drug applicator is prepared.

[0338] Positioning the system preferably includes applying an ultrasonic transmission gel to the interface 601b between the drug applicator 201 and the scleral surface. Alternatively or additionally, positioning the system includes pressing the drug applicator 201 against the scleral surface.

[0339] In an embodiment of the invention, at least one application cycle is performed after the system has been positioned. During the application cycle, the drug applicator 201 remains in contact with the scleral surface.

[0340] In embodiments of the invention, the temperature of the scleral surface is measured using a measuring means during at least one application cycle. The measuring means preferably includes a thermocouple and / or an infrared thermometer. Preferably, the temperature of the scleral surface does not rise by more than 1°C during at least one application cycle. The system is preferably configured to control ultrasonic emission events to prevent overheating of the scleral tissue.

[0341] In embodiments of the invention, after at least one application cycle, an additional waiting period is required to deliver the drug most efficiently.

[0342] In embodiments of the invention, the drug applicator 201 is removed from the scleral surface after at least one application cycle. According to embodiments of the invention, the drug applicator 201 is preferably configured for reuse at a later time or is configured as a single-use drug applicator 201. According to embodiments of the invention, the drug applicator 201 is removed from the application head 205 after at least one application cycle, and / or remains on the application head 205 for subsequent use.

[0343] Figure 20The effects of various mechanical indices according to embodiments of the present invention are illustrated. For example, different diffusivity is provided for each mechanical index (e.g., D of BSA). 声学混合 Such values ​​are provided during a 30s period of 40kHz ultrasound application with N>=3. An error bar is provided, representing the standard deviation of the fitted diffusivity values. The highest degree of diffusivity can be provided with a mechanical index of 0.2.

[0344] Figure 21 This illustrates how various frequencies affect intracellular binding according to embodiments of the invention. For example, using 20 kHz ultrasound with a mechanical index of 0.2 allows drug molecules (e.g., any type of molecule having any of the characteristics or parameters provided elsewhere herein) to be delivered to the surface of the eye (e.g., the sclera, cornea, limbus) and / or the suprachoroidal space, but not across the retina. Drug molecules can be delivered at any velocity, any value as described elsewhere herein, without damaging ocular tissues.

[0345] The study provides stained images showing tight junctions, demonstrating that at 20 kHz, ultrasound does not disrupt the tight junctions of retinal epithelial cells. At 40 kHz, ultrasound disrupts all intercellular junctions. Because the intercellular junctions remain intact, drug molecules cannot pass through the epithelial cell layer and are thus retained in the suprachoroidal space.

[0346] Figure 22 Further effects of the various mechanical indices according to embodiments of the present invention are illustrated. The concentration of BSA in the receiving chamber is shown for each mechanical index and frequency.

[0347] Figure 23 Further examples of the effects of various mechanical indices according to embodiments of the present invention are shown. Different variations in BSA partitioning relative to a control can be provided under each mechanical index. In some embodiments, mechanical indices with different cavitation mechanisms can be provided. For example, lower mechanical index values ​​may correspond to stable cavitation, and higher mechanical indices may correspond to transient cavitation.

[0348] Drug delivery systems or their components may be provided as kits containing instructions for use. For example, a kit containing a drug delivery device may include instructions for use. A drug applicator may be provided with the drug delivery device or separately. A kit containing a drug applicator may include instructions for use. The kit may contain information about the drug loaded onto the drug applicator. One or more settings for using the drug delivery device and / or the drug applicator for a specific drug may be provided in the instructions. In some embodiments, the drug delivery device may be reusable. The drug applicator may be coupled to the drug delivery device. The drug applicator may be reusable or disposable. Optionally, the drug applicator may be refilled or loaded with drug. In some cases, the drug applicator may be discarded after a single use.

[0349] Throughout this application, the terms "drug," "therapeutic agent," and the more general term "molecule" are considered interchangeable, and their respective use depends on the technical context. The use of a particular term does not imply limitation of the scope of the subject matter sought for protection. For example, a therapeutic agent may include a drug and / or a drug may include a molecule.

[0350] As used herein, the term "medicine" refers to a pharmaceutical preparation containing at least one pharmaceutically active compound. In one embodiment of the invention, the pharmaceutically active compound has a molecular weight of up to 70 kDa and / or comprises antibodies, biological conjugates, protein drug conjugates, corticosteroid drug conjugates, nanoparticles encapsulating a drug, conjugated drug nanoparticles, protein drugs, biological agents, corticosteroid drugs, nonsteroidal anti-inflammatory drugs, charged molecules, uncharged molecules, or mixtures of the above pharmaceutically active compounds. In alternative embodiments of the invention, the pharmaceutically active compound has a molecular weight greater than 70 kDa and / or comprises antibodies, biological conjugates, protein drug conjugates, corticosteroid drug conjugates, nanoparticles encapsulating a drug, conjugated drug nanoparticles, protein drugs, biological agents, corticosteroid drugs, nonsteroidal anti-inflammatory drugs, charged molecules, uncharged molecules, or mixtures of the above pharmaceutically active compounds. In some cases, a medicine may include any compound or molecule that can be used to treat eye diseases or conditions, for diagnosis, or to promote the health of the eye or any other part of the body.In some embodiments, examples of drugs may include, but are not limited to: prostaglandins or analogues, such as xalatan, lumigan, and travatan, which increase uveal-scleral outflow of aqueous humor; topical β-adrenergic receptor antagonists such as timolol, betagan, and betalol, which reduce aqueous humor production by the ciliary body; α2-adrenergic agonists such as brimonidine, which increase aqueous humor outflow through a dual mechanism—reducing aqueous humor production and increasing uveal-scleral outflow; low-selectivity sympathomimetic drugs such as adrenaline and propine, which increase aqueous humor outflow through the trabecular meshwork and possibly through the uveal-scleral outflow pathway; miotics (parasympathomimetic drugs) such as pilocarpine, which act by constricting the ciliary muscle, tightening the trabecular meshwork, and allowing increased aqueous humor outflow; and carbonic anhydrase inhibitors. Drugs such as drolidine (Trusopt), brinzolidine (Azopt), and acetazolamide (Diamox) can reduce aqueous humor production by inhibiting carbonic anhydrase in the ciliary body; β-blockers; bevacizumab (Avastin); ranibizumab (Lucentis); triamcinolone (Kenalog) (Triesence / Trivaris); intravitreal ganciclovir; intravitreal foscarnet; cidofovir; fomvirsen; methotrexate; vancomycin; ceftazidime; amikacin; amphotericin B; voriconazole; dexamethasone; riboflavin; Nesvacumab or other monoclonal antibodies that may target the protein angiopoietin 2 (ANG2) or other pro-angiogenic cytokines; or aptamers such as Fovisa, Zimura, or others that can bind specifically and with affinity to targets such as platelet-derived growth factor (PDGF).

[0351] In the embodiments, the pharmaceutically active compound can be used to treat and / or prevent central retinal vein occlusion, branch retinal vein occlusion, central serous retinopathy, cytomegalovirus retinitis, retinoblastoma, intraocular lymphoma, ocular melanoma, giant cell arteritis, histoplasmosis, ischemic optic neuropathy, macular folds, macular telangiectasia, uveitis, choroidal neovascularization, age-related macular degeneration, diabetic retinopathy, glaucoma, retinitis pigmentosa, macular edema, cystoid macular edema, macular degeneration, multiple recurrent pterygium, ocular toxoplasmosis, proliferative vitreoretinopathy (PVR), Stevens-Johnson syndrome, ocular cicatricial pemphigoid, endophthalmitis, ocular degenerative conditions, or postoperative conditions requiring delivery of the drug into the intrascleral space.

[0352] The scope of protection of this invention is not limited to the examples given above. This invention is embodied in each novel feature and each combination of features, particularly including every combination of any feature recited in the claims, even if such feature or combination of features is not expressly stated in the claims or examples.

[0353] While preferred embodiments of the invention have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. The specific examples provided in the specification are not intended to limit the invention. Although the invention has been described with reference to the foregoing description, the description and illustration of embodiments herein are not intended to be construed as limiting. Many variations, alterations, and substitutions will now occur to those skilled in the art without departing from the invention. Furthermore, it should be understood that all aspects of the invention are not limited to the specific descriptions, configurations, or relative proportions set forth herein, but depend on a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in the practice of the invention. Therefore, the invention is also contemplated to cover any such alternatives, modifications, variations, or equivalents. The following claims are intended to define the scope of the invention and thereby cover the methods and structures within the scope of these claims and their equivalents.

Claims

1. A drug applicator for a system for ultrasound-enhanced delivery of at least one drug to a target site in the intraocular space, the system comprising: A signal generation unit and a controller are operably connected to the ultrasonic transducer. The drug applicator mentioned above: (a) Includes at least one drug receiving space for maintaining the drug, (b) Made of low ultrasonic attenuation material, (c) Configured to provide low-loss ultrasonic coupling between the system and the sclera or cornea, and (d) is configured to be mechanically coupled to the system and further configured to be coupled to the ultrasonic transducer with low ultrasonic loss; and The signal generating unit and / or the ultrasonic transducer are configured to emit ultrasonic waves in at least one application cycle, the application cycle comprising at least one ultrasonic emission event having a duration TA and a wait period having a duration TW, and When the drug comprises a molecule with a size of 70 kDa or smaller, the controller is configured to control the duration TA between 30 s and 300 s, and the drug applicator is configured to deliver the drug through the sclera during the duration TA. And / or When the drug comprises molecules larger than 70 kDa, the controller is configured to control the duration TW between 60 s and 600 s, and the drug applicator is configured to deliver the drug through the sclera during the duration TW.

2. A system for ultrasonically enhanced transscleral delivery of at least one drug to a target site in the intraocular space, the system comprising a signal generating unit operatively connected to an ultrasonic transducer, a drug applicator, and a controller. The drug applicator mentioned above: (a) Includes at least one drug receiving space for maintaining the drug, (b) Made of low ultrasonic attenuation material, (c) Configured to provide low-loss ultrasonic coupling between the system and the sclera or cornea, and (d) is configured to be mechanically coupled to the system and further configured to be coupled to the ultrasonic transducer with low ultrasonic loss; and The signal generating unit and / or the ultrasonic transducer are configured to emit ultrasonic waves in at least one application cycle, the application cycle comprising at least one ultrasonic emission event having a duration TA and a wait period having a duration TW, and When the drug comprises a molecule with a size of 70 kDa or smaller, the controller is configured to control the duration TA between 30 s and 300 s, and the drug applicator is configured to deliver the drug through the sclera during the duration TA. And / or When the drug comprises molecules larger than 70 kDa, the controller is configured to control the duration TW between 60 s and 600 s, and the drug applicator is configured to deliver the drug through the sclera during the duration TW.

3. The drug applicator of claim 1, wherein the drug applicator includes at least one opening on a surface pointing toward a desired site of the eye, and wherein an ultrasonic coupling agent fills the gap between the drug applicator and the desired site of the eye.

4. The drug applicator of claim 1, wherein the drug applicator is configured to be replaceable and / or designed for single-use applications.

5. The drug applicator of claim 1, wherein the at least one drug receiving space is substantially sealed at a surface designated for coupling with a desired site of the eye, and the seal is configured to allow drug penetration.

6. The drug applicator of claim 1, wherein the at least one drug receiving space is substantially open at a surface designated for coupling with the sclera.

7. The drug applicator of claim 1, wherein the drug applicator is configured to be filled and / or refilled, and wherein the drug applicator receives 10 µL to 1.5 mL of the drug.

8. The drug applicator according to claim 1, wherein the drug applicator is made of an elastic material with a Young's modulus less than or equal to 20 GPa.

9. The drug applicator according to claim 1, wherein the drug applicator is made of at least one of the following materials: Epoxy resin, polyurethane rubber, polycarbonate, nylon 6-6, polyvinyl chloride, polyester, ultra-high molecular weight polyethylene, polypropylene, Teflon, polystyrene, chloroprene rubber, polyvinyl alcohol, silicone rubber, and silicone hydrogel.

10. The drug applicator of claim 1, wherein the drug applicator is made of polydimethylsiloxane.

11. The drug applicator of claim 1, wherein the drug applicator is made of silicone rubber.

12. The drug applicator according to claim 1, wherein the drug applicator is made of silicone rubber doped with at least one of the following materials: nickel, silver, palladium, tungsten, gold, platinum, silicon oxide, titanium oxide, aluminum oxide, barium sulfate, iron oxide, zirconium dioxide, cerium oxide, bismuth oxide, ytterbium oxide, lutetium oxide, and hafnium oxide.

13. The drug applicator of claim 1, wherein the controller is configured to control at least one of a plurality of parameters of the application cycle, the plurality of parameters of the application cycle being selected from the following: (a) The duration TA of the ultrasonic emission event, (b) The duration TW of the waiting period following the ultrasonic emission event. (c) The number of loops applied, (d) The intensity of the ultrasonic emission event, (e) The center frequency of the ultrasonic emission event, (f) The mechanical properties of the ultrasonic transmission system, and In the case of pulsed ultrasound emission events: (g) The repetition rate of the ultrasonic emission events, and (h) The duty cycle of the ultrasonic emission event.

14. The drug applicator according to claim 1, further comprising an information receiving and / or transmitting unit, The information receiving and / or transmitting unit is configured to receive and / or transmit information related to the drug; and The information receiving and / or transmitting unit is operatively connected to the signal generating unit and / or the controller, or the information receiving and / or transmitting unit is operatively connected to the signal generating unit and / or the controller, and the controller is configured to control at least one of a plurality of parameters of the application cycle based on the information related to the drug.

15. The drug applicator of claim 1, wherein the system further comprises a display and / or a manual input unit configured to display and / or manually set at least one of a plurality of parameters of the application cycle.

16. The drug applicator of claim 1, wherein the system further comprises a temperature sensor configured to sense the temperature of the sclera or corneal surface, and The controller is configured to control the ultrasonic emission event such that the temperature of the sclera or corneal surface does not rise by more than 1°C during the time TA.

17. The drug applicator of claim 1, wherein the drug applicator is configured to be coupled to a surface of a desired site of the eye, and The signal generating unit and / or the ultrasonic transducer are configured to apply at least one ultrasonic application cycle, the ultrasonic application cycle including an ultrasonic application with a duration TA and a waiting period with a duration TW.

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