Multi-dose ocular fluid delivery system

Abstract

To provide a multi-dose ocular fluid delivery device.SOLUTION: Aspects of the fluid delivery device include a fluid package and an actuator. The fluid package includes a reservoir 406 of an ophthalmic formulation, an aperture 402, and a valve member 404 for sealing the aperture when fluid is not being expelled through the aperture. The actuator is configured to operate the valve member to at least reduce, if not prevent, entry of external substances or contaminants into the reservoir such that the ophthalmic drug present in the reservoir does not require a preservative (e.g., such as when a preservative-free ophthalmic drug is present in the reservoir). Also provided are methods of using the devices in fluid delivery applications, and kits containing components of the devices.SELECTED DRAWING: Figure 4

Description

[Technical Field]

[0001] The present invention relates to the delivery of fluids to the eye of a patient. [Background technology]

[0002] There are many instances where eye drops are used to treat diseases of the eye and other parts of the body. Depending on the disease, these may include, but are not limited to, steroids, antihistamines, and sympathomimetics. , beta-receptor blockers, parasympathomimetic prostaglandins, nonsteroidal anti-inflammatory drugs A variety of different active agents, such as nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, antifungals, or local anesthetics Eye drops may contain no medication, but this is because they act as a lubricant or tear substitute. It is something that becomes matter.

[0003] Generally, eye droppers are used to deliver eye drops. Current eye droppers often tilt the subject's head back, have the subject lie down, pull the subject's lower eyelid downward, or Or you need to combine pulling on the subject's lower eyelid and tilting their head. This is because the delivery mechanism for using medications usually relies on gravity. It is not only difficult to get the medicine into the eye without hitting it, It requires the subject to steadily lose awkwardness, gain flexibility, and control their body. It is essential.

[0004] Additionally, current eye dropper bottles can cause physical damage to the user's eye if they are struck by the bottle. Furthermore, contact with the eye can lead to bacterial contamination of the tip. Therefore, the subject may contaminate the medicine in the eye dropper bottle, which may then lead to bacterial infection in the eye. There is a risk of this happening.

[0005] A typical medical eye dropper dispenses droplets of approximately 50 μL. The eye can normally only hold 7 μL of liquid on the corneal surface, so if too much is dropped, the liquid will be absorbed from the surface of the eye. The medicine will spill out and most of it will be lost. If the amount is too large (50 μL), most of the delivered liquid will be lost from the cornea due to the blinking reflex. In addition, discomfort can lead to poor compliance. This results in inaccuracy and waste. Furthermore, the technology used for this method of administration limits the amount of medicine dispensed. do not provide a satisfactory method for controlling the amount of medication expelled, and are not designed to actually reach and infect the eye. It also doesn't offer a way to guarantee they'll stay.

[0006] Most multi-dose containers of ophthalmic preparations today generally contain antibacterial and They contain preservatives that serve multiple functions, including preventing the degradation of active ingredients in the formulation. Examples of preservatives found in formulations include benzalkonium chloride (BAR), chlorobutanol, and perfluorooctyl alcohol. These include sodium borate and stabilized oxychloro complex (SOC). While providing benefits, preservatives also have significant cytotoxic effects on patients receiving the formulation. This can have consequences.

[0007] Therefore, there is a continuing need for improved ophthalmic formulation delivery devices. A multi-dose delivery device that can precisely deliver small amounts of preservative-free ophthalmic preparations to the eye. We found that the development of equipment was particularly important. Summary of the Invention [Means for solving the problem]

[0008] A multi-dose ocular fluid delivery device is provided. Embodiments of the fluid delivery device include a fluid package. The fluid package includes a reservoir that holds the ophthalmic formulation. an opening, and a valve for sealing the opening when fluid is not being discharged through the opening. The actuator includes a member. The actuator is configured to detect whether the ophthalmic formulation present in the reservoir requires a preservative. without preservatives (e.g., when a preservative-free ophthalmic preparation is present in the reservoir). The reservoir is designed to at least reduce, if not prevent, the ingress of foreign matter or contaminants into the reservoir. The valve member is configured to operate the device in a fluid delivery application. Methods for using the method and kits containing the device components are also provided. [Brief explanation of the drawings]

[0009] [Figure 1] FIG. 1 is a perspective view of one embodiment of the present invention. [Figure 2] 2 is a side view of the example of FIG. 1, and a diagram showing its electronic circuitry. FIG. [Figure 3] FIG. 3 is an exploded view of the example of FIGS. 1 and 2, showing the ampoule and the electromagnetic transducer separately. [Figure 4] 10A-10C are enlarged cross-sectional views illustrating aperture configurations suitable for use in embodiments of the present invention. [Figure 5A] 5A and 5B are diagrams illustrating the operating principle of the aperture configuration of FIG. 4. [Figure 5B] 5A and 5B are diagrams illustrating the operating principle of the aperture configuration of FIG. 4. DETAILED DESCRIPTION OF THE INVENTION

[0010] A multi-dose ocular fluid delivery device is provided. Embodiments of the fluid delivery device include a fluid package. The fluid package includes a reservoir of ophthalmic formulation, an opening, and a valve member for sealing the opening when fluid is not being discharged through the opening. The actuator may impart mechanical vibrations to the bail member and / or reservoir wall. and configured to expel the ophthalmic preparation through the opening.

[0011] This approach allows the ophthalmic formulation present in the reservoir to be used without the need for preservatives ( For example, if a preservative-free ophthalmic preparation is present in the reservoir, The ingress of harmful substances or contaminants can be at least reduced, if not prevented.

[0012] Also included are methods of using the device in fluid delivery applications and device components. Kits are also available.

[0013] To further describe various embodiments of the present invention, we first provide more detailed information about the fluid delivery device. This is followed by various methods of using the device and kits that include the device or its components. We will explain about this.

[0014] fluid delivery device

[0015] As summarized above, aspects of the present invention include the use of ophthalmic formulations, such as preservative-free ophthalmic formulations. a plurality of eyepieces configured to eject the eyepiece into a target position in the subject's eye, i.e., a target eye position. The fluid delivery device may optionally be configured to deliver fluid to a target location of a user, For example, it is configured so that the user can administer it themselves to a target location in the eye. Thus, the device of such an embodiment does not require any assistance from others, such as medical personnel. This allows the user to administer fluid to their own target location without receiving a needle.

[0016] The characteristics of the fluid delivery device may vary, but in some cases the device may be a handheld device. A handheld device is one that can be comfortably held in the hand of an average adult. In some embodiments of a handheld device, the device has dimensions and weight such that 10~500mm, for example 20~250mm, 50~100mm, for example 70~85 The longest dimension including mm and 10-1000g e.g. 25-500g e.g. 40-100g It has a weight of

[0017] The fluid delivery devices described herein include a fluid package having a reservoir and an opening; an actuator member configured to expel fluid through the port; and It may include a valve member configured to seal the opening when not being evacuated. In addition, additional components may be present. Here, each component will be described in detail. .

[0018] Fluid Package

[0019] The fluid package members of the device of the present invention are configured to hold a quantity of fluid. a body container, e.g., operably connected to an actuator, as described in more detail below. The container may have any convenient shape and may be made of any convenient material, e.g. They may be made of glass or plastic. The containers may contain single delivery doses or multiple doses. For example, the container may be configured to hold multiple delivery doses. and the reservoir is a multi-dose reservoir. Thus, the amount of liquid formulation that the container is configured to hold may vary. In some cases, the volume may be 100 μL to 10 mL, for example, 120 to 800 μL. The volume may be in the range of 100 to 2000 μL.

[0020] The container may include a reservoir configured to hold a quantity of fluid, such as those described above, and a and one or more openings therein for discharging fluid from the reservoir member. The number of openings in the page may vary, and in some cases the number of openings may be between 1 and 5, e.g. For example, the range is 1-20, such as 1-10, including 1-4, 1-3, and 1-2. In some embodiments, the fluid package includes one opening. In some embodiments, the fluid package includes The dimensions of a given opening may vary as desired. In this case, the opening is in the range of 10 to 500 μm, for example, 50 to 450 μm, for example, 75 to 350 μm. In some embodiments, the opening has a length dimension, e.g., a diameter, of 80 to 120 μm (e.g., For example, 80-100 μm), or 150-350 μm (for example, 200-350 μm, for example Optionally, the openings have a diameter in the range of at least For example, the antibacterial material may be included in a part of the valve member when the valve member is in a sealed state. The inner surface of the opening may be partially or entirely made of an antibacterial material. Examples of antimicrobial materials that may include, but are not limited to, antimicrobial metals, e.g., silver, copper and antimicrobial coatings, such as parylene polymers, chlorhexidine, and prota Some of these are based on amine sulfate compositions.

[0021] The container may have any convenient configuration, but in some embodiments the container may be a reservoir. and configured to operably couple to an actuator. and a neck portion including one or more openings. , and is configured to be disposable.

[0022] As outlined above, the fluid package also has a function to prevent fluid from being discharged through the opening. The valve member is configured to seal the opening when the valve member is not in use. is configured to seal the opening when fluid is not being discharged from the opening, The valve is configured not to seal the opening when the body is being expelled from the opening. The material is designed to allow external materials and contaminants to enter through the openings when fluid is not being discharged through them. This prevents the ingress of antiseptics into the reservoir. There may be ophthalmic formulations that are free of the agent.

[0023] In some embodiments, the valve member may include a distal end configured to mate with the opening to seal the opening. The tip may have any convenient shape. In some embodiments, the tip is a cone. In such a case, the conical tip has a height of 0.5 to 5.0 mm, for example. 0.75~1.5mm, bottom diameter 0.4~4.0mm, for example 1.5~2.5mm In other embodiments, the tip may have a rounded sealing structure. In some embodiments, the diameter of the bottom surface is in the range of 0.4 to 4.0 mm, for example, 1.5 to 2.5 mm. The sphere may have a hemispherical structure.

[0024] In some embodiments, the fluid package may be configured to, for example, In order to ensure uniform discharge of the fluid, a discharge hole (ven) for introducing gas into the reservoir is provided. The vent may include a vent for allowing microorganism-free air to escape from the exterior of the package. Any convenient drain hole configuration may be employed. Examples of such drain holes include holes in the neck region that are located at the farthest point from the neck region. A lumen is included that extends to a location within the reservoir around the end of the fluid package. The length of the lumen may vary, and in some cases, the length of the lumen may be 5.0 to 20 mm, for example, 12 to 18mm, and the inner diameter is 0.5 to 2.0mm, for example 0.7 to 1.0mm. Lumenal holes in the fluid package allow, for example, microorganisms, such as bacteria and other unwanted pathogens, to enter the fluid package. In such an instance, the cover may be It may have antimicrobial properties, e.g., the cover is designed to prevent the passage of microorganisms, e.g., bacteria. In the case of a porous membrane having a pore size configured as above, the pore size is 0.22 μm or less, for example For example, it may be 0.2 μm or less, for example, 0.15 μm or less. The cover may include, but is not limited to, one or more antimicrobial agents, including antimicrobial metals. , e.g., silver, copper, etc., antibacterial coatings, e.g., parylene polymers, chlorhexidine, and and protamine sulfate compositions.

[0025] In some embodiments, the extension region of the fluid package is separable from the neck region, e.g. For example, if the two components are not manufactured as a single, integral structure. In such cases, the extension area may be a standard ophthalmic bottle. The length of a suitable ophthalmic bottle may be in the range of 25 to 45 mm, for example 30 to 35 mm. The inner diameter of a standard ophthalmic bottle is 5.0-30mm, for example, 13-20mm. The internal volume of a standard ophthalmic bottle is 2.0 to 14.0 mL, e.g., 2.0 to 5.0 The diameter of the hole in a standard ophthalmic bottle can vary and can range from 4 mL. The bottle may be in the range of 0.0 to 13.0 mm, for example 8.0 to 11.0 mm. It may be made from any material, including any convenient material such as glass or polymer.

[0026] In such cases, the neck region may fit onto a standard ophthalmic bottle, and the neck region The neck region may include, for example, an opening, a valve member, and a drain hole, as described above. It may be fitted to the bottle using any convenient configuration, for example, press fit, threaded fit, etc.

[0027] Actuator

[0028] In addition to the fluid package, the device may be operably coupled to the fluid package and configured to an adapter configured to expel fluid from a reservoir of the adapter through one or more openings to a target location; In some embodiments, the actuator further comprises a actuator member. The member is configured to provide vibration, and the vibration frequency may be varied. In some cases, the frequency is in the audible range, e.g., 20-20,000 Hz, e.g., 500 In some embodiments, the vibration frequency is between 50 and 10,000 Hz, including up to 1,000 Hz. Sound wave frequency, in some cases 10-1000KHz, e.g. 20-800KHz , the range including 20 to 35 KHz.

[0029] In some embodiments, the actuator generates a pressure fluctuation in the fluid within the fluid package. The fluid is configured to be expelled from the reservoir through the opening by the opening. The actuator is then actuated by the fluid through a displacement induced on the outer surface of the fluid package. The actuator generates a pressure fluctuation. Vibrations at audio or ultrasonic frequencies applied to the exterior surface of the package (see above) causing acoustic pressure cycles in the fluid held by the fluid package, resulting in one or more The fluid is discharged from the top opening.

[0030] In some embodiments, the fluid is delivered as a stream by an actuator from the fluid package. A stream is a continuous flow of liquid (i.e., not composed of individual droplets) a non-continuous flow of liquid, e.g., a collimated flow of individual droplets A discontinuous fluid stream may be a series of small particles separated by a relatively short time. It may be a long glob of fluid. Also, as the distance between the ejected fluid and the opening increases, The composition of the stream may change over time. If so, the diameter of the stream may vary, for example, from 0.05 to 0.3 mm, e.g., 0.05 ~0.2mm, for example, 0.05~0.15mm, for example, in the range of 0.070~0.130mm If the stream is a discontinuous flow of individual droplets, the The volume may vary, from 50 to 1500 pL, e.g., from 100 to 1000 pL. Depending on the embodiment, the width of the stream may be continuous, discontinuous, or with continuous components. It has discontinuous components but is substantially constant along the length of the stream and has one or more The variation in the width of the stream from the opening to the target position should be less than 5%, e.g., less than 2%. The duration of delivery of the streams during a given administration may vary. , selected to provide a desired delivery dose. The duration, i.e., the duration of administration, is 10-3000 milliseconds, e.g., 100-2000 milliseconds, including 400-600 milliseconds, for example, in the range of 250-1000 milliseconds. The duration of viable administration of the be.

[0031] The nature of the actuator member may vary, and in some cases, the actuator portion In some embodiments, the electromagnetic actuator may be In this case, a low frequency vibration amplitude within the audible range (for example, 20 to 20,000 Hz) is applied. Therefore, the electromagnetic actuator operates at frequencies in the audible range, but with low noise levels below 30 dB. At the same time, the device ejects fluid from a sufficiently large nozzle at a sufficiently low velocity. This minimizes the discomfort associated with topical fluid delivery to the eye.

[0032] Illustrative Embodiments

[0033] An embodiment of the present invention is illustrated in FIGS. 1 to 3. 1, which shows an electromagnetic dispensing device (100). The electromagnetic dispensing device (100) includes an ampoule ( The electromagnetic dispensing device (100) further includes an electromagnetic transducer (113). The electromagnetic transducer (113) vibrates the ampoule (103) to The sample (103) is configured to dispense fluid from an opening (116) in the bottom of the sample (103).

[0034] The electromagnetic transducer (113) is made up of a base plate (101), an electromagnet (115), and , and a permanent magnet (109). The electromagnet (115) includes a ferromagnetic core (electromagnet core pin, core ) (110) and a coil (108) wound around the ferromagnetic core (110). The permanent magnet (109) is disposed adjacent to the electromagnet core pin (110), and the flexible cantilever (106) is supported by the magnetic field generated by the coil (108). The permanent magnet (109) and the flexible cantilever beam (106) that supports it are subjected to magnetic force and mechanical vibration. The cantilever (106) supports the cantilever (106) and The device includes a fixed part (107) that transmits the vibration of the ampoule (103) to the base (106). Spacer support pins extending from the base plate (101) and supporting the cantilever beam (106) It further includes a cantilever support (102).

[0035] In the illustrated embodiment, the permanent magnet (109) is positioned at a distance (d 2) A fixed portion (106) is disposed at the free end of the cantilever (106) and supports the ampoule. The portion (107) is disposed at a distance (d1) from the cantilever support portion (102). In this way, the advantage of the leverage is taken and the pressure applied to the ampoule (103) The force applied to the permanent magnet (109) is amplified by the ratio of the distance d2 / d1. In the illustrated embodiment, the ampoule (103) contains 1 mL of aqueous solution, approximately 1 gm (gram). Therefore, the ampoule (103) is vibrated with an amplitude of about 20 to 60 mm. The force required to cause the contact is about 0.2 N to 1 N. In the illustrated embodiment, the distance d2 is 1 3.5 mm, and the distance d1 is 1.35 mm. The ratio of d2 / dl is about 10, and the vibration The amplitude is 20 μm to 60 μm depending on the input voltage. The diameter of the opening ranges from 200 to 350 μm, and such a large opening allows for large vibration amplitudes. Discharges fluid only at

[0036] In the illustrated embodiment, the ferromagnetic core (110), the base plate (101), and the spacer (104) are The support pin (102) is made of a soft magnetic material such as 4750 alloy, but the compensation force Other alloys with low .DELTA. and low magnetic hysteresis may also be used.

[0037] The ampoule (103) is attached to the discharge nozzle (116) in the direction of the vibration amplitude of the cantilever beam (106). This vibration causes pressure fluctuations in the ampoule (103). This causes the fluid to be ejected from the nozzle (116), as indicated by the arrow (105).

[0038] The permanent magnet (109) is made of neodymium N35, N38, N42, samarium cobalt, etc. It is preferable that it is made of rare earth magnetic material. Non-rare earth alloys such as iron, nickel, and cobalt may also be used.

[0039] Referring to FIG. 2, this shows a magnetic transducer (100), which may also be used in conjunction with a battery cell or the like. Also included is a diagram of an electrical circuit that generates an alternating electrical signal from a DC source.

[0040] The electromagnetic transducer (100) generates an alternating current that is fed to a coil (108). The coil (100A) generates a magnetic force that vibrates the permanent magnet (109). 108) defines two separate magnetic coils, the first of which is the primary coil (108 A) and the second coil is the detection coil (108B). Both of the detection coils (108B) are wound around the iron core (110). DC voltage When the primary coil (108A) is connected to the coil, a current flows and the generated electromagnetic force creates a permanent magnet. The stone (109) is pulled towards the core (110). A current flows through the primary coil (108A). At the same time, a temporary, time-dependent electromagnetic induction occurs, generating an electromotive force (EMF ) and a current is induced in the detection coil (108B), and this current is passed through the bipolar transistor (T r), which draws the current from the primary coil (108A) to ground (130). As a result, the magnetic force returns to zero and the permanent magnet (109) operates normally. Then the primary coil (108A) turns on again, pulling the magnet back. As shown in the figure, an AC magnetic field is generated using a DC input voltage from a DC battery. In this case, the transistor (Tr) is a general-purpose NPN transistor such as the Fairchild model 2N3904. This circuit also includes a Zener diode (D1) to regulate the voltage. The magnetic coils (108A) and (108B) have an inductance in the range of 1 to 10 mH. and configured to generate a magnetic field for vibrating the permanent magnet (109). Generally, to reduce the inertial load and increase the vibration amplitude, the mass of the permanent magnet (109) is In one embodiment, the mass of the permanent magnet (109) is 0.075 gm ( The cantilever beam (106) has a thickness of 0.2 mm, a width of 5 mm, and a free length of 13.5 mm. In the illustrated embodiment, the cantilever beam (106) is made of stainless steel alloy 304. , has a natural frequency of about 523 Hz, while the driving frequency of the magnetic oscillator is about 1100 Hz. be.

[0041] FIG. 3 shows an exploded perspective view of the electromagnetic dispensing device (100), and shows the ampoule (103) and The ampoule (103) and the electromagnetic transducer (113) are shown separately. and a pin member (301) inserted into the fixed portion (107) with a tight interference fit. In this way, the vibration generated by the electromagnetic transducer (113) It is transferred to the ampoule (103).

[0042] In Figures 1-3, the valve member that seals the opening when no fluid is being dispensed is too small. The scale is not clear. Therefore, Figure 4 shows a fluid that operates according to the above principles. 4 is an enlarged cross-sectional view of the discharge device (400) showing the valve member. It has a similar principle of operation to the above, but differs in some of the details of its construction.

[0043] Here, (402) is an opening, (404) is a valve member, and the liquid to be discharged is supplied from a reservoir (40 6) (only partially shown here), and (408) is the valve member (404) (410) is a solenoid for an electromagnetic actuator. id, and (412) is a metal cylinder with a conical end. (412) is made of an electromagnetic iron alloy, so the magnetic field generated by the solenoid (410) The member (414) is attracted by the magnetic flux generated by the valve member (404). ) / diaphragm (408). The combination of solenoid (410) and (412) This paper provides an electromagnetic actuator with the above-mentioned operating principle. The movement of the fluid ejection device caused by the actuator causes the valve member (404) to open and close the opening (4 The vibrations are caused by the engagement and disengagement of the diaphragm (408) and the vibrations of the diaphragm (408). More generally, mechanical vibration of the valve member and / or reservoir As generally explained above, the valve The member and / or the opening may include an antimicrobial material.

[0044] The diaphragm (408) engages the valve member (404) with the opening (402) to allow fluid The opening (402) is sealed except when the fluid is being discharged. The mechanical stiffness of the diaphragm (408) is selected to provide the appropriate amount of mechanical force for this engagement. may be provided.

[0045] The fluid is introduced by vibrating the valve member (404) and / or sealing the opening. By creating a pressure fluctuation within the fluid sufficient to break down the condition, it may be evacuated. As in this example, one vibration actuator can achieve both physical effects. .

[0046] 5A-B show these two physical effects in a simplified manner. In the example of FIG. 5A, The first process (block arrow pointing to the left) of discharging fluid from port (502) is shown by the valve section. This is caused by vibrating the tip of the material (504) to engage and disengage with the opening (502). This vibration of the valve member (504) is shown diagrammatically by the open double arrow. The second process of discharging fluid from the valve member (502) is when the fluid overcomes the valve member (504). This is due to the force exerted as a result of the pressure fluctuations in the fluid, which is sufficient to expel the fluid. The forces arising from pressure fluctuations in such a fluid are shown schematically by the black solid double-headed arrows. In the example of FIG. 4, such pressure fluctuations are caused by vibrations and / or vibrations of the diaphragm (408). This is due to the movement of the valve member (404). However, the rounded portion engages with the opening (506) to seal the opening (506) except when discharging fluid. The valve member vibration and fluid pressure fluctuations are the same as those of the valve member. or any combination thereof is expected to contribute to the evacuation of fluid.

[0047] method

[0048] As summarized above, aspects of the present disclosure involve administering an active agent to a target location, such as an ocular location, of a subject. The target location of the eye may be the corneal region, the conjunctival region, or a combination of the corneal and conjunctival regions. "Ocular surface" refers to a region (i.e., area or domain) of the ocular surface, such as a region containing a component. In some embodiments, the target location of the eye is a location or region offset relative to the optical axis of the eye. In some embodiments, the target location in the eye is either the conjunctiva of the globe or tarsus, or the conjunctival vestibule. In other words, the target local eye position is located at the center of the pupil or the center of the iris. The magnitude of the displacement / displacement distance may vary, depending on the implementation. The size of the particles may be 1 to 20 mm, for example, 2 to 20 mm, for example, 5 to 10 mm. The size of the targeted local eye location can vary, but ranges from ~15 mm. In some embodiments, the targeted local eye size is 15 mm 2 is less than or equal to 1 to 15 mm 2 , for example, 3 to 9 mm 2 2.5 to 12 mm (including 2 The range is.

[0049] Aspects of this method embodiment include delivering a dose of a liquid formulation of an active agent to a target location. In some embodiments, the delivered dose is absorbed by the tear film at the targeted local ocular location. The volume of the dose that can be completely accommodated by the tear film at the targeted local eye location. is the film attached to the target local ocular location. Thus, the tear film, e.g. , a film or layer of tear fluid present on the ocular surface at the targeted local ocular location as described above. The delivered dose is completely contained by the tear film at the targeted local ocular location. The volume can be fully accommodated on the ocular surface, including the targeted local eye location. "Completely contained on the ocular surface" means that, upon delivery, the delivered dose However, excess fluid does not flow from the surface of the eye and passes over the eyelid, and the administered eye surface The above means the amount that can be retained in the form of tears, for example. Depending on the embodiment, the amount may be in the range of 1 to 15 μL, for example, 5 to 10 μL.

[0050] In some embodiments, the delivered dose is contained in the tear film at the targeted local ocular location. In such cases, the amount of the drug that is administered exceeds the amount required for the standard dose. The reference dose is otherwise the same as the delivered dose except for the amount. The concentration of active agent in the reference dose is the same as the concentration of active agent in the delivered dose. The amount of the dose may exceed the amount of the delivered dose, for example by two-fold or more, for example by three-fold or more. In some embodiments, the reference dose is in the range of 25-60 μL, such as 30-50 μL. In some embodiments, the reference dose is the dose delivered by a standard eye dropper device. do.

[0051] The delivered dose of the liquid formulation of the active agent is delivered as a stream to a targeted local ocular location. The stream may be a continuous flow of liquid (i.e., from individual droplets) It may be a discontinuous flow of liquid, e.g., a non-structured flow, or a discontinuous flow of liquid, e.g., individual liquids. A collimated stream of droplets, or a stream containing both continuous and discontinuous components If the stream is a continuous flow of liquid, the diameter of the stream may vary. In some embodiments, the thickness is 0.05 to 0.15 mm, for example, 0.070 to 0.130 mm. m. If the stream is a discontinuous flow of individual droplets, the individual The volume of the droplets may vary, ranging from 50 to 1500 pL, for example, from 100 to 1000 pL. The velocity of the stream may vary, and in some embodiments, the aperture The minimum exit velocity of the fluid from the NR Lindblad and J. MScheider, "Production of unif defined in a scientific paper entitled "Ultra-large liquid droplets" (Equation 2), which is incorporated herein by reference. , the exit velocity is 20% or more faster than the minimum exit velocity, and in some embodiments, 3% or more faster than the minimum exit velocity. For example, if the aperture size is 125 microns, the minimum speed The velocity is 194 cm / sec, but the selected velocity is at least 30% higher, i.e., 252 The duration of the stream delivery during a given administration may vary, e.g., as described above. Ideally, the duration of the stream is chosen to provide the desired dose. The time between each call should be less than the blink response time, i.e., less than 150 milliseconds. , the duration of administration may be extended to 250 milliseconds or up to 1000 milliseconds. In some instances, the duration is 100 milliseconds or more.

[0052] The delivered dose can be administered using any convenient protocol to target localized ocular In some embodiments, the delivered dose may be administered to a location by an individual other than the subject. The dose delivered may be administered to a targeted local ocular location, e.g., by a physician or nurse. It may be administered by any medical professional. In other embodiments, the delivered dose is For example, if a subject administers a dose to a targeted local ocular location in one of their eyes, , self-administered by the subject.

[0053] The fluids present in the fluid package may vary as desired. In this case, the fluid present in the fluid delivery package is a liquid formulation of an active agent. The terms "drug," "compound," and "drug" are used interchangeably to refer to a localized target A molecule or molecules that exert a physiological effect upon contact with a subject through administration to a target site. Examples of active agents that may be present in the liquid formulation include, but are not limited to: Anti-infectives (including but not limited to antibiotics, antivirals, anti-inflammatory agents (including but not limited to steroids and non-steroidal anti-inflammatory drugs (NSAIDS), anti-allergy drugs (including but not limited to anti-inflammatory drugs), antihistamines and mast cell stabilizers), antifungals, cholinergics, long-acting Anticholinergics, including both long-acting and short-acting anticholinergics (e.g., atropine, tropicamide, etc.) ), vasoconstrictors, biological agents (e.g., proteins, artificial proteins, etc.), small molecules, Anesthetics, analgesics, ocular hypotensives (including but not limited to prostaglandin analogs, These include ROK inhibitors, beta blockers, carbonic anhydrase inhibitors, and alpha agonists. ), lubricants (including but not limited to saline, polymer solutions, proteoglycans, Glycosaminoglycans, carbohydrates, etc.), mydriatics (pupil dilators), myotonic agents (pupil dilators) Pore ​​shrinkers), iodine derivatives, etc., and / or various combinations thereof. The concentration of the cholinergic agent in a given volume of liquid formulation may vary. The concentration of cholinergic agonists in microdose liquid formulations is 50 ng / mL to 100 mg / mL. It is a range.

[0054] In addition to the active agent, the liquid formulation comprises an aqueous delivery vehicle, e.g., a pharmaceutically acceptable aqueous vehicle. In addition to water, aqueous delivery vehicles may include, but are not limited to: Contains multiple additional ingredients such as salts, buffers, preservatives, solubility enhancers, viscosity modifiers, and colorants. Suitable aqueous vehicles include sterile distilled or purified water, isotonic sodium chloride, isotonic solutions such as ammonium or boric acid solutions, phosphate buffered saline (PBS), propylene glycol Other suitable vehicle components include glycerol and butylene glycol. , phenylmercuric nitrate, sodium sulfate, sodium sulfite, sodium sulfite, sodium phosphate Other suitable vehicle components include sodium phosphate and sodium phosphate. Additional examples include alcohols, oils and fats, polymers, surfactants, fatty acids, and silicone oils. , moisturizers, humectants, viscosity adjusters, emulsifiers and stabilizers. Auxiliaries such as pH adjusters such as ammonium, hydrochloric acid, and sulfuric acid, and viscosity increasers such as methylcellulose As summarized above, the ophthalmic formulation present in the reservoir may contain preservatives. "Preservative-free" includes, but is not limited to, the following: , benzalkonium chloride (BAK), chlorobutanol, sodium perborate, stabilized Contains antibacterial agents such as hydroxyl complex (SOC), and preservatives such as paraban and organic mercury compounds. This means that they have not.

[0055] Exemplary final compositions are sterile, preservative-free, essentially free of foreign matter, and suitable for patient comfort. A balance is struck between the pH that provides sensitivity and acceptability and the pH desired for optimal drug stability. An exemplary "pharmaceutically acceptable vehicle" is an "ophthalmically acceptable vehicle" as used herein. The compound is a "vehicle for administration to a patient," and is any substance or mixture that is non-reactive with the compound and suitable for administration to a patient. In an exemplary embodiment, the vehicle is a topical agent or combination of agents that is delivered to the patient's eye. In various embodiments, the vehicle is an aqueous vehicle suitable for various applications. It may further contain other ingredients that may be desirable for use in pharmaceutical compositions, such as antibacterial agents, preservatives, etc. , co-solvents, surfactants, viscosity builders.

[0056] As used herein, the terms "host," "subject," "individual," and "patient" refer to The terms are used interchangeably and refer to any individual in need of such treatment according to the disclosed methods. "mammals" refers to any mammal of any kind. Such mammals include, for example, humans, sheep, cattle, horses, and rabbits. In certain embodiments, the mammalian species includes cats, dogs, cats, non-human primates, mice, and rats. In some embodiments, the subject is a non-human mammal. In some embodiments, the subject is a domestic animal. In some embodiments, the subject is a pet. In some embodiments, the subject is a mammal. In this study, the subjects are humans. Other subjects include pets kept at home (dogs, cats, etc.). livestock (cattle, pigs, goats, horses, etc.), rodents (mice, guinea pigs, rats, etc.) animal models of disease, such as mice, and even non-human primates (chimpanzees, monkeys, etc.) ) are mentioned.

[0057] In some embodiments of the subject methods, the methods include administering a therapeutically effective amount of a compound to treat a predetermined condition, e.g., a disease condition, in a subject. In such an embodiment, the results of the measurements can be more quickly For example, 2 weeks ago, 1 month ago, 2 months ago, 3 months ago, 6 months ago, 1 year ago, 2 years ago , and results from studies conducted on the same individuals five, ten, or more years ago. The assessment may vary depending on the nature of the condition being treated. In some embodiments, the subject methods include diagnosing an individual as having a given condition. Further includes:

[0058] The above method is used in a variety of applications. For some applications, see the "Utilities" section below. This is explained in detail in the section on "Security."

[0059] Utilities

[0060] The subject devices and methods are used in a variety of applications, including both therapeutic and diagnostic / testing applications. As used herein, "treating" or "treatment" refers to The term "food" refers to the treatment of a disease or injury to a subject or patient, such as a mammal (e.g., a human). (a) means to treat or cure the onset of a disease or condition, including the prophylactic treatment of a subject; (b) eliminating or reversing a disease or condition in a patient; (c) ameliorating the disease or condition, e.g., by administering the inhibiting the disease or condition by slowing or halting its progression, and and (d) alleviating the disease or condition in the patient.

[0061] An example of a disease that can be treated using the methods / devices of the present invention is glaucoma. optic nerve damage is a group of disorders characterized by progressive visual field loss due to damage to the optic nerve. It is the leading cause of blindness in the country, affecting 1-2% of individuals aged 60 and over. There are many risk factors for developing glaucoma (age, race, myopia, family history, and trauma). Elevated intraocular pressure, also known as ocular hypertension, is the only condition associated with disease reduction in glaucomatous optic neuropathy. In glaucoma with elevated intraocular pressure, the source of resistance to outflow is the trabecular meshwork. The trabecular meshwork allows aqueous fluid to enter the Schlemm's canal and penetrate the posterior wall of the canal. The aqueous humor flows into the collecting channels of the eye and then into the aqueous veins. Aqueous humor is a clear fluid that fills the area between the cornea and the lens. Because it is constantly secreted by the body, the flow of aqueous humor from the ciliary body to the anterior chamber of the eye is continuous. Intraocular pressure is determined by the production of aqueous humor and its exit through the trabecular meshwork (the main route) or the uveal vein. The balance of the outlet (accessory pathway) via the scleral outflow is determined by the trabecular meshwork, which is located at the outer edge of the iris. The trabecular meshwork adjacent to Schlemm's canal is located between the inner periphery of the cornea and the cornea. It causes most of the resistance to outflow (juxta-Schlemm's canal trabecular meshwork).

[0062] In embodiments where the methods and devices are used to treat glaucoma, the dose delivered is The "intraocular pressure adjusting agent" may include a drug, and may be any of the following: or equivalents, derivatives or analogs thereof, including, for example, antiglaucoma drugs. (e.g., adrenergic agonists, adrenergic antagonists (β-blockers)), carbonic anhydrase inhibitors ( CAI, systemic and local), prostaglandins, prostaglandin precursors, etc. medications, including beta-blockers such as timolol, betaxolol, levobunolol, and atenolol Antiglaucoma drugs (e.g., as described in U.S. Pat. No. 4,952,581), apraclonidin Adrenergic agonists, including clonidine derivatives such as brimonidine or clonidine (e.g., (described in Patent No. 5,811,443), and bimatoprost, travo and prostaglandin analogues such as prostaglandin, tafluprost, and latanoprost. In some embodiments, a therapeutic agent is already commercially available for glaucoma and the commercially available formulation is used. Additional therapeutic agents include acetazolamide, dorzolamide, brinzolamide, Carbonic anhydrase inhibitors such as methazolamide, dichlorphenamide, and diamox are used. This may be done.

[0063] Diagnostic and examination applications include, but are not limited to, examining the retina and other deep structures of the eye. It can be used for such purposes as dilating the pupils. Suitable mydriatic agents include, but are not limited to, the following: atropine, atropine sulfate, atropine hydrochloride, atropine methyl bromide, atropine methyl Methyl nitrate, atropine hyperduri c), atropine N-oxide, phenylfurine, phenylfurine hydrochloride, hydroxya Amphetamine, hydroxyamphetamine methyl bromide, hydroxyamphetamine hydrochloride , hydroxyamphetamine iodide, cyclopentolate, cyclopentolate hydrochloride , homatropine, homatropine hydrobromide, homatropine hydrochloride, homatropine methyl bromide scopolamine, scopolamine hydrobromide, scopolamine hydrochloride, scopolamine me Scopolamine hydrobromide, scopolamine methylnitrate, scopolamine N-oxide, tropicamine Tropicamide, tropicamide hydrobromide, tropicamide hydrochloride, etc.

[0064] kit

[0065] Also provided are kits for use in practicing the methods described above. The term refers to a packaged delivery device or a component thereof, such as an amplifier as described above. In addition to the components described above, the kit may also include instructions for using the components of the kit, e.g. For example, the package may further include instructions for practicing the subject method. The instructions are recorded on a suitable recording medium. For example, the instructions may be written on a substrate such as paper or plastic. In this way, the instructions are included in the kit as part of the package contents. or the container of the kit or a component thereof (i.e., package or subpackage) In other embodiments, the instructions may be included on a label (such as that accompanying the package). CD-ROM, floppy disk, hard disk drive (HDD), portable Electronically stored data files on a suitable computer-readable storage medium such as a flash drive In yet other embodiments, the physical instructions are not provided with the kit. However, there are methods available to obtain instructions remotely via the Internet, etc. Examples of formats include a web address where the manual can be viewed or a Web page where the manual can be downloaded. The kit includes a b address. As well as the instructions, means for obtaining the instructions are also included. Recorded on a suitable substrate.

Claims

1. 1. A device for delivering a fluid to an eye of a patient, comprising: a reservoir configured to hold the fluid; an opening; and a passage through which the fluid passes. a valve member configured to seal the opening when the fluid is not being discharged; The package and By subjecting the valve member and / or the wall of the reservoir to mechanical vibration, an actuator configured to expel the fluid through the opening.

2. The actuator oscillates the tip of the valve member into engagement with the opening. and configured to discharge the fluid from the opening by moving the nozzle or the nozzle from the opening.

10. The device of claim 1 .

3. The actuator passes through the valve member to expel the fluid from the opening. The apparatus of claim 1 , configured to generate a pressure fluctuation in the fluid sufficient to

4. The device of claim 1 , wherein the fluid is a preservative-free eye drop.

5. The device of claim 1 , wherein the reservoir is a multi-dose reservoir.

6. 10. The device of claim 1, wherein the front valve member has a conical tip that engages the opening.

7. 2. The valve member of claim 1, wherein the valve member has a rounded tip that engages the opening. The device.

8. the valve member has a tip that engages the opening, the tip comprising an antimicrobial material. Item 1. The device described in item 1.

9. The device of claim 1 , wherein the opening comprises an antimicrobial material.

10. The actuator is disposed on an outer surface of the reservoir and contacts at least one of the walls of the reservoir.

10. The method of claim 1, further comprising: Equipment.

11. The actuator vibrates to cause pressure fluctuations in the fluid, thereby The device of claim 10 configured to expel the fluid from a mouth.

12. The fluid package is configured to: a resilient diaphragm configured to engage and hold the tip of the lubricant member in the opening; 10. The apparatus of claim 1 .

13. 10. The device of claim 1 configured to deliver a dose of 1 to 15 μL.

14. 10. The device of claim 1, configured to deliver medication at 150 mm / sec or less.

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