Topical ocular delivery device and method using the same

Abstract

To provide a topical ocular delivery device with significantly reduced discomfort.SOLUTION: Provided is a topical ocular delivery device. An aspect of the device includes a transducer configured to vibrate with an amplitude and a frequency for discharging a flow at such a speed that discomfort during topical ocular delivery is the minimum. Also provided is a method using the device, for example, a use method of the device for the purpose of ocular delivery.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a topical intraocular delivery device and methods of using the same. This application claims priority under 35 U.S.C.§ 119(e) to U.S. Provisional Patent Application No. 62 / 693,818, filed on Jul. 3, 2018, the entire disclosure of which is incorporated herein by reference and made a part hereof.

Background Art

[0002] For example, it is often desirable to administer liquid formulations to the surface of the eye for treatment of ocular conditions such as disease states, alleviation of discomfort such as dry eye, improvement of appearance such as eye redness and any improvement in appearance, and for diagnostic purposes, among many situations. Administration of liquid formulations to the surface of the eye is generally achieved by instilling one or more drops of the liquid formulation directly onto the surface of the eye from a small container or bottle ( e.g., a conventional eye dropper). In such an embodiment, the instillation of the liquid formulation is self-administered or administered by another person such as a healthcare provider or caregiver.

[0003] Conventional eye droppers have dispensed droplets on the order of 30 - 50 μL. However, since the human eye can typically hold only about 7 μL of liquid on the corneal surface, if the amount instilled is large, the drug will overflow from the surface of the eye and most of it will be lost. Also, large droplets on the order of 30 μL or 50 μL cause blinking reflexes and remove most of the body fluid on the eye surface, which at the same time causes discomfort and reflexive tearing. Due to these factors, administration of eye drops from conventional eye droppers (whether self-administered or administered by others) can pose problems For example, conventional eye droppers may not be able to administer accurate and known dosages of liquid formulations and active agents to the eye It cannot be done. Furthermore, in the administration using a conventional eye dropper, a significant amount of waste occurs. In addition, in the administration using a conventional eye dropper, there is a possibility of giving discomfort to the patient.

[0004] Many types of ultrasonic fluid ejection devices that eject a liquid in a mist form have been developed conventionally. These nebulizers utilize a sealed chamber, and this chamber further includes a perforated membrane or pinhole membrane as the front wall of the chamber and means for vibrating the membrane, and this means typically vibrates the membrane by a piezoelectric transducer attached to the end of the membrane. As a result, an acoustic pressure wave is generated in the liquid, and the liquid droplets of the fluid are forced to pass through the open pinhole.

[0005] Such devices are described in publications such as US Patent Application Publication No. 2014 / 0187969 and US Patent Nos. 3,812,854, 4,159,803, 4,30 0,546, 4,334,531, 4,465,234 , 4,632,311, 4,338,576 and 4,8 50,534, etc. Ultrasonic fluid ejection devices configured for the delivery of a topical solution to the surface of the eye have also been developed. For example, see US Patent Application Publication Nos. 2 014 / 03336618 and 2013 / 017283(A1) as well as US Patent Nos. 8,684,980, 8,733,935 and 9,087,145. With the development of ultrasonic delivery devices as described above, while the administration of fluids such as eye drops has been improved, the discharge from these ultrasonic delivery devices Since the fluid is relatively fast, it may cause discomfort in the eye during delivery. Thus, there is a continuing need for improvement. SUMMARY OF THE INVENTION MEANS FOR SOLVING THE PROBLEM

[0006] A topical intraocular delivery device is provided. As a side of the device, a transducer configured to vibrate at an amplitude and frequency for discharging a fluid at a speed that minimizes discomfort during topical intraocular delivery is included. In some embodiments, the transducer is configured to vibrate at a greater amplitude and a lower frequency compared to the ultrasonic fluid ejection device described above, such that the speed of the stream of fluid discharged from the nozzle is substantially slower compared to the speed of the fluid flowing from the ultrasonic ejection device. As a result, the impact of the fluid on the eye is reduced and the discomfort

[0007]

Figure 1

Figure 2

Figure 3

Figure 4

[0008] A fluid ejection device for delivering a topical eye drop to the surface of the eye is provided. A side of the present invention discharges a low-speed stream that comprising a transducer configured as such. Methods of using the device, such as for local intraocular delivery are also provided.

[0009] Before explaining the present invention in more detail, it should be understood that the present invention is, of course, not limited to the specific embodiments described. The terms used in this specification are for the sole purpose of describing the specific embodiments and the scope of the present invention is limited only by the appended claims, so it should also be understood that no limitation is intended. When a range of values is provided, unless the context clearly indicates otherwise, each intervening value between the upper and lower limits of that range and other stated values or intervening values within that range to one tenth of the unit of the lower limit is understood to be included within the scope of the present invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges and are also included within the scope of the present invention, subject to any restrictions clearly excluded within the stated range. When the stated range includes one or both of the limiting values, ranges excluding one or both of the included limiting values are also included in the present invention. Specific ranges herein are preceded by the term "about" in front of the numerical values. In this specification, the term "about" is used to provide literal support for not only the exact number that the term precedes, but also for numbers that are close to or approximate the number that the term precedes. When determining whether a number is close to or approximate to a specifically recited number, an unrecited number may be a number that provides a substantial equivalent of the specifically recited number in the context in which it is presented.

[0010]

[0011]

[0012] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Any methods and materials similar to or equivalent to those described herein can also be used in the practice or testing of the present invention, but representative, exemplary methods and materials are described herein. All publications and patents cited herein are hereby incorporated by reference as if each individual publication or patent were specifically and individually indicated to be incorporated by reference, to disclose and describe the methods and / or materials relevant to the citation of the publications. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention has the right to antedate such publication on the basis of prior invention. Also, the provided publication dates may be different from the actual publication dates and may require individual verification.

[0013]

[0014] As used in this specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. It should be further noted that the claims may be drafted to exclude any element. Therefore, this specification is not intended to function as a prior basis for using exclusive terms such as "solely", "only", etc. in relation to the recitation of claim elements, or for using "negative" limitations.

[0015] ​​​​​​​​​​​​​​​Upon reading this disclosure, it will be apparent to those skilled in the art that each of the individual embodiments described and illustrated herein can be separated or combined with features of any of the other several embodiments without departing from the scope or spirit of the invention. Any of the recited methods can be performed in the order of the recited events or in any other order that is logically possible. As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein can be separated or combined with features of any of the other several embodiments without departing from the scope or spirit of the invention. It has separate members and features that can be readily separated or combined with features of any of the other several embodiments without departing from the scope or spirit of the invention. As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein can be separated or combined with features of any of the other several embodiments without departing from the scope or spirit of the invention. Any of the recited methods can be performed in the order of the recited events or in any other order that is logically possible. As will be apparent to those skilled in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein can be separated or combined with features of any of the other several embodiments without departing from the scope or spirit of the invention. Any of the recited methods can be performed in the order of the recited events or in any other order that is logically possible.

[0016] The apparatus and method of the present invention are described, or are to be described, with functional descriptions for reasons of grammatical fluidity. However, unless the claims are expressly formulated under 35 U.S.C. § 112, the claims should not be construed as necessarily limited in any way by the recitation of "means" or "step" limitations, but should be given the full scope of the meaning and equivalents provided by the claims under the doctrine of equivalents, and where the claims are expressly formulated under 35 U.S.C. § 112, it is expressly understood that full statutory equivalents should be given under 35 U.S.C. § 112. The apparatus and method of the present invention are described, or are to be described, with functional descriptions for reasons of grammatical fluidity. However, unless the claims are expressly formulated under 35 U.S.C. § 112, the claims should not be construed as necessarily limited in any way by the recitation of "means" or "step" limitations, but should be given the full scope of the meaning and equivalents provided by the claims under the doctrine of equivalents, and where the claims are expressly formulated under 35 U.S.C. § 112, it is expressly understood that full statutory equivalents should be given under 35 U.S.C. § 112. The apparatus and method of the present invention are described, or are to be described, with functional descriptions for reasons of grammatical fluidity. However, unless the claims are expressly formulated under 35 U.S.C. § 112, the claims should not be construed as necessarily limited in any way by the recitation of "means" or "step" limitations, but should be given the full scope of the meaning and equivalents provided by the claims under the doctrine of equivalents, and where the claims are expressly formulated under 35 U.S.C. § 112, it is expressly understood that full statutory equivalents should be given under 35 U.S.C. § 112. The apparatus and method of the present invention are described, or are to be described, with functional descriptions for reasons of grammatical fluidity. However, unless the claims are expressly formulated under 35 U.S.C. § 112, the claims should not be construed as necessarily limited in any way by the recitation of "means" or "step" limitations, but should be given the full scope of the meaning and equivalents provided by the claims under the doctrine of equivalents, and where the claims are expressly formulated under 35 U.S.C. § 112, it is expressly understood that full statutory equivalents should be given under 35 U.S.C. § 112. The apparatus and method of the present invention are described, or are to be described, with functional descriptions for reasons of grammatical fluidity. However, unless the claims are expressly formulated under 35 U.S.C. § 112, the claims should not be construed as necessarily limited in any way by the recitation of "means" or "step" limitations, but should be given the full scope of the meaning and equivalents provided by the claims under the doctrine of equivalents, and where the claims are expressly formulated under 35 U.S.C. § 112, it is expressly understood that full statutory equivalents should be given under 35 U.S.C. § 112. The apparatus and method of the present invention are described, or are to be described, with functional descriptions for reasons of grammatical fluidity. However, unless the claims are expressly formulated under 35 U.S.C. § 112, the claims should not be construed as necessarily limited in any way by the recitation of "means" or "step" limitations, but should be given the full scope of the meaning and equivalents provided by the claims under the doctrine of equivalents, and where the claims are expressly formulated under 35 U.S.C. § 112, it is expressly understood that full statutory equivalents should be given under 35 U.S.C. § 112. The apparatus and method of the present invention are described, or are to be described, with functional descriptions for reasons of grammatical fluidity. However, unless the claims are expressly formulated under 35 U.S.C. § 112, the claims should not be construed as necessarily limited in any way by the recitation of "means" or "step" limitations, but should be given the full scope of the meaning and equivalents provided by the claims under the doctrine of equivalents, and where the claims are expressly formulated under 35 U.S.C. § 112, it is expressly understood that full statutory equivalents should be given under 35 U.S.C. § 112. The apparatus and method of the present invention are described, or are to be described, with functional descriptions for reasons of grammatical fluidity. However, unless the claims are expressly formulated under 35 U.S.C. § 112, the claims should not be construed as necessarily limited in any way by the recitation of "means" or "step" limitations, but should be given the full scope of the meaning and equivalents provided by the claims under the doctrine of equivalents, and where the claims are expressly formulated under 35 U.S.C. § 112, it is expressly understood that full statutory equivalents should be given under 35 U.S.C. § 112.

[0017] To further illustrate the various aspects of the present invention, embodiments of the apparatus are first described, and then embodiments of methods of using the apparatus, for example, methods for local intraocular delivery applications, are described. To further illustrate the various aspects of the present invention, embodiments of the apparatus are first described, and then embodiments of methods of using the apparatus, for example, methods for local intraocular delivery applications, are described. To further illustrate the various aspects of the present invention, embodiments of the apparatus are first described, and then embodiments of methods of using the apparatus, for example, methods for local intraocular delivery applications, are described.

[0018] Fluid delivery device

[0019] As summarized above, aspects of the present invention include a fluid delivery device configured to eject an ophthalmic formulation to a target location in a subject's eye, i.e., a target eye location. The fluid delivery device is an embodiment As summarized above, aspects of the present invention include a fluid delivery device configured to eject an ophthalmic formulation to a target location in a subject's eye, i.e., a target eye location. The fluid delivery device is an embodiment Depending on the state, it is configured to enable a user to self-administer a fluid to a target position of the user, for example, a target eyeball position. Therefore, the device of such an embodiment can administer an amount of fluid to the target position of the user without assistance from other individuals such as medical practitioners. Although the nature of the fluid delivery device may vary, in some embodiments, the device is a handheld device. By a handheld device, it means that the device has dimensions and a weight such that it can be comfortably held by the hand of an average adult human. In some embodiments of the handheld device, the device has a maximum dimension including 50-100 mm such as 10-500 mm, for example 20-250 mm, for example 70-85 mm, and has a weight such as 10-1000 g, for example 25-500 g, for example 40-100 g. The fluid delivery device described herein may include a fluid package that includes a reservoir and an opening, and a transducer (i.e., actuator) member configured to discharge fluid from the reservoir through the opening. Additional members may be arranged. Each of these members will be described in more detail below.

[0020] The fluid package member of the device of the present invention is configured to hold an amount of fluid and is, for example, a fluid container configured to be operably coupled to an actuator, as will be described in more detail below. The container may have any convenient shape and may be made of any convenient material, for example, glass or plastic. The container may be for a single delivery

[0021]

[0022] Fluid Package

[0023] ​​​​​​​​​​​​​​ It may be configured to hold a dose or multiple delivery doses. For example, the container contains a liquid formulation in an amount sufficient to provide multiple delivery doses, where the reservoir is made to be a reservoir for multiple doses. Thus, the volume of the liquid formulation that the container is configured to hold may, in some cases, vary in the range of 100 μL to 10 mL, for example 120 to 800 μL, including 100 to 2000 μL. The container includes, for example, a reservoir member configured to hold an amount of fluid as described above, and one or more openings through which the fluid is discharged from the reservoir member during use. The number of openings in a given fluid package may vary, but in some embodiments, the number of openings is in the range of 1 to 20, such as 1 to 10, including 1 to 5, for example 1 to 4, 1 to 3, and 1 to 2. In some embodiments, the fluid package includes a single opening. In some embodiments, the fluid package includes one or more openings. The dimensions of a given opening may vary as desired. In some embodiments, the opening has a longest dimension, such as a diameter, in the range of 10 to 500 μm, for example 50 to 450 μm, for example 75 to 350 μm. Here, in some embodiments, the opening has a diameter in the range of 80 to 120 μm (for example 80 to 100 μm), or 150 to 350 μm (for example 200 to 350 μm, for example 250 to 300 μm). Optionally, the opening may contain an antibacterial material corresponding to at least a part of it, for example, a part or all of the inner surface of the opening configured to fit with a closure when in a sealed state. Examples of antibacterial materials that may be included are antibacterial metals, such as silver, copper, etc.

[0024] Antibacterial coatings, such as parylene polymers, chlorhexidine, and protamine sulfate compositions, etc., are included, but not limited to these. Although examples include, but are not limited to, these.

[0025] The container may have any convenient configuration, but in some embodiments, it includes a reservoir that is extended, for example, includes a valve and a neck portion configured to be operably coupled to an actuator and includes one or more openings. The fluid package may be configured to be disposable in some embodiments. The fluid package found for use in embodiments of the present invention is further described in International Application PCT / US2018 / 014211, published as WO2018 / 136618, the disclosure of which is incorporated herein by reference. Although the fluid disposed in the fluid package may be changed as desired. In some embodiments, the fluid disposed in the fluid delivery package is a liquid formulation of an active agent. As used herein, the terms "agent," "compound," and "drug" are used interchangeably to refer to a molecule or combination of molecules that have a physiological effect when contacted with a subject via administration to a target local site of the subject. Examples of active agents that may be disposed in the liquid formulation include, but are not limited to, the following. Anti-infective drugs (including, but not limited to, antibiotics, antiviral drugs, etc.), anti-inflammatory agents (including, but not limited to, steroids and non-steroidal anti-inflammatory drugs (NSAIDs)), anti-allergy agents (including, but not limited to, antihistamines and mast cell stabilizers), antifungal agents, cholinergic agents, anti-cholinergic agents including both long-acting and short-acting Although the fluid disposed in the fluid package may be changed as desired. In some embodiments, the fluid disposed in the fluid delivery package is a liquid formulation of an active agent. As used herein, the terms "agent," "compound," and "drug" are used interchangeably to refer to a molecule or combination of molecules that have a physiological effect when contacted with a subject via administration to a target local site of the subject. Examples of active agents that may be disposed in the liquid formulation include, but are not limited to, the following. Anti-infective drugs (including, but not limited to, antibiotics, antiviral drugs, etc.), anti-inflammatory agents (including, but not limited to, steroids and non-steroidal anti-inflammatory drugs (NSAIDs)), anti-allergy agents (including, but not limited to, antihistamines and mast cell stabilizers), antifungal agents, cholinergic agents, anti-cholinergic agents including both long-acting and short-acting Although the fluid disposed in the fluid package may be changed as desired. In some embodiments, the fluid disposed in the fluid delivery package is a liquid formulation of an active agent. As used herein, the terms "agent," "compound," and "drug" are used interchangeably to refer to a molecule or combination of molecules that have a physiological effect when contacted with a subject via administration to a target local site of the subject. Examples of active agents that may be disposed in the liquid formulation include, but are not limited to, the following. Anti-infective drugs (including, but not limited to, antibiotics, antiviral drugs, etc.), anti-inflammatory agents (including, but not limited to, steroids and non-steroidal anti-inflammatory drugs (NSAIDs)), anti-allergy agents (including, but not limited to, antihistamines and mast cell stabilizers), antifungal agents, cholinergic agents, anti-cholinergic agents including both long-acting and short-acting Although the fluid disposed in the fluid package may be changed as desired. In some embodiments, the fluid disposed in the fluid delivery package is a liquid formulation of an active agent. As used herein, the terms "agent," "compound," and "drug" are used interchangeably to refer to a molecule or combination of molecules that have a physiological effect when contacted with a subject via administration to a target local site of the subject. Examples of active agents that may be disposed in the liquid formulation include, but are not limited to, the following. Anti-infective drugs (including, but not limited to, antibiotics, antiviral drugs, etc.), anti-inflammatory agents (including, but not limited to, steroids and non-steroidal anti-inflammatory drugs (NSAIDs)), anti-allergy agents (including, but not limited to, antihistamines and mast cell stabilizers), antifungal agents, cholinergic agents, anti-cholinergic agents including both long-acting and short-acting

[0026] The fluid disposed in the fluid package may be changed as desired. In some embodiments, the fluid disposed in the fluid delivery package is a liquid formulation of an active agent. As used herein, the terms "agent," "compound," and "drug" are used interchangeably to refer to a molecule or combination of molecules that have a physiological effect when contacted with a subject via administration to a target local site of the subject. Examples of active agents that may be disposed in the liquid formulation include, but are not limited to, the following. Anti-infective drugs (including, but not limited to, antibiotics, antiviral drugs, etc.), anti-inflammatory agents (including, but not limited to, steroids and non-steroidal anti-inflammatory drugs (NSAIDs)), anti-allergy agents (including, but not limited to, antihistamines and mast cell stabilizers), antifungal agents, cholinergic agents, anti-cholinergic agents including both long-acting and short-acting Although the fluid disposed in the fluid package may be changed as desired. In some embodiments, the fluid disposed in the fluid delivery package is a liquid formulation of an active agent. As used herein, the terms "agent," "compound," and "drug" are used interchangeably to refer to a molecule or combination of molecules that have a physiological effect when contacted with a subject via administration to a target local site of the subject. Examples of active agents that may be disposed in the liquid formulation include, but are not limited to, the following. Anti-infective drugs (including, but not limited to, antibiotics, antiviral drugs, etc.), anti-inflammatory agents (including, but not limited to, steroids and non-steroidal anti-inflammatory drugs (NSAIDs)), anti-allergy agents (including, but not limited to, antihistamines and mast cell stabilizers), antifungal agents, cholinergic agents, anti-cholinergic agents including both long-acting and short-acting Although the fluid disposed in the fluid package may be changed as desired. In some embodiments, the fluid disposed in the fluid delivery package is a liquid formulation of an active agent. As used herein, the terms "agent," "compound," and "drug" are used interchangeably to refer to a molecule or combination of molecules that have a physiological effect when contacted with a subject via administration to a target local site of the subject. Examples of active agents that may be disposed in the liquid formulation include, but are not limited to, the following. Anti-infective drugs (including, but not limited to, antibiotics, antiviral drugs, etc.), anti-inflammatory agents (including, but not limited to, steroids and non-steroidal anti-inflammatory drugs (NSAIDs)), anti-allergy agents (including, but not limited to, antihistamines and mast cell stabilizers), antifungal agents, cholinergic agents, anti-cholinergic agents including both long-acting and short-acting Although the fluid disposed in the fluid package may be changed as desired. In some embodiments, the fluid disposed in the fluid delivery package is a liquid formulation of an active agent. As used herein, the terms "agent," "compound," and "drug" are used interchangeably to refer to a molecule or combination of molecules that have a physiological effect when contacted with a subject via administration to a target local site of the subject. Examples of active agents that may be disposed in the liquid formulation include, but are not limited to, the following. Anti-infective drugs (including, but not limited to, antibiotics, antiviral drugs, etc.), anti-inflammatory agents (including, but not limited to, steroids and non-steroidal anti-inflammatory drugs (NSAIDs)), anti-allergy agents (including, but not limited to, antihistamines and mast cell stabilizers), antifungal agents, cholinergic agents, anti-cholinergic agents including both long-acting and short-acting Although the fluid disposed in the fluid package may be changed as desired. In some embodiments, the fluid disposed in the fluid delivery package is a liquid formulation of an active agent. As used herein, the terms "agent," "compound," and "drug" are used interchangeably to refer to a molecule or combination of molecules that have a physiological effect when contacted with a subject via administration to a target local site of the subject. Examples of active agents that may be disposed in the liquid formulation include, but are not limited to, the following. Anti-infective drugs (including, but not limited to, antibiotics, antiviral drugs, etc.), anti-inflammatory agents (including, but not limited to, steroids and non-steroidal anti-inflammatory drugs (NSAIDs)), anti-allergy agents (including, but not limited to, antihistamines and mast cell stabilizers), antifungal agents, cholinergic agents, anti-cholinergic agents including both long-acting and short-acting Although the fluid disposed in the fluid package may be changed as desired. In some embodiments, the fluid disposed in the fluid delivery package is a liquid formulation of an active agent. As used herein, the terms "agent," "compound," and "drug" are used interchangeably to refer to a molecule or combination of molecules that have a physiological effect when contacted with a subject via administration to a target local site of the subject. Examples of active agents that may be disposed in the liquid formulation include, but are not limited to, the following. Anti-infective drugs (including, but not limited to, antibiotics, antiviral drugs, etc.), anti-inflammatory agents (including, but not limited to, steroids and non-steroidal anti-inflammatory drugs (NSAIDs)), anti-allergy agents (including, but not limited to, antihistamines and mast cell stabilizers), antifungal agents, cholinergic agents, anti-cholinergic agents including both long-acting and short-acting Although the fluid disposed in the fluid package may be changed as desired. In some embodiments, the fluid disposed in the fluid delivery package is a liquid formulation of an active agent. As used herein, the terms "agent," "compound," and "drug" are used interchangeably to refer to a molecule or combination of molecules that have a physiological effect when contacted with a subject via administration to a target local site of the subject. Examples of active agents that may be disposed in the liquid formulation include, but are not limited to, the following. Anti-infective drugs (including, but not limited to, antibiotics, antiviral drugs, etc.), anti-inflammatory agents (including, but not limited to, steroids and non-steroidal anti-inflammatory drugs (NSAIDs)), anti-allergy agents (including, but not limited to, antihistamines and mast cell stabilizers), antifungal agents, cholinergic agents, anti-cholinergic agents including both long-acting and short-acting Although the fluid disposed in the fluid package may be changed as desired. In some embodiments, the fluid disposed in the fluid delivery package is a liquid formulation of an active agent. As used herein, the terms "agent," "compound," and "drug" are used interchangeably to refer to a molecule or combination of molecules that have a physiological effect when contacted with a subject via administration to a target local site of the subject. Examples of active agents that may be disposed in the liquid formulation include, but are not limited to, the following. Anti-infective drugs (including, but not limited to, antibiotics, antiviral drugs, etc.), anti-inflammatory agents (including, but not limited to, steroids and non-steroidal anti-inflammatory drugs (NSAIDs)), anti-allergy agents (including, but not limited to, antihistamines and mast cell stabilizers), antifungal agents, cholinergic agents, anti-cholinergic agents including both long-acting and short-acting Although the fluid disposed in the fluid package may be changed as desired. In some embodiments, the fluid disposed in the fluid delivery package is a liquid formulation of an active agent. As used herein, the terms "agent," "compound," and "drug" are used interchangeably to refer to a molecule or combination of molecules that have a physiological effect when contacted with a subject via administration to a target local site of the subject. Examples of active agents that may be disposed in the liquid formulation include, but are not limited to, the following. Anti-infective drugs (including, but not limited to, antibiotics, antiviral drugs, etc.), anti-inflammatory agents (including, but not limited to, steroids and non-steroidal anti-inflammatory drugs (NSAIDs)), anti-allergy agents (including, but not limited to, antihistamines and mast cell stabilizers), antifungal agents, cholinergic agents, anti-cholinergic agents including both long-acting and short-acting Although the fluid disposed in the fluid package may be changed as desired. In some embodiments, the fluid disposed in the fluid delivery package is a liquid formulation of an active agent. As used herein, the terms "agent," "compound," and "drug" are used interchangeably to refer to a molecule or combination of molecules that have a physiological effect when contacted with a subject via administration to a target local site of the subject. Examples of active agents that may be disposed in the liquid formulation include, but are not limited to, the following. Anti-infective drugs (including, but not limited to, antibiotics, antiviral drugs, etc.), anti-inflammatory agents (including, but not limited to, steroids and non-steroidal anti-inflammatory drugs (NSAIDs)), anti-allergy agents (including, but not limited to, antihistamines and mast cell stabilizers), antifungal agents, cholinergic agents, anti-cholinergic agents including both long-acting and short-acting Mydriatics (e.g., atropine, tropicamide, etc.), vasoconstrictors, biological agents (e.g., proteins, artificial proteins, etc.), small molecules, anesthetics, analgesics, intraocular pressure lowering agents (prostag landin analogs, ROK inhibitors, beta blockers, carbonic anhydrase inhibitors, alpha a gonists, etc., but not limited to these), lubricants (physiological saline, polymer solutions, proteoglycans, glycosaminoglycans, carbohydrates, etc., but not limited to these ), mydriatics (pupil dilators), miotics (pupil constrictors), iodine derivatives, anti-inflammatory agents / immune modulators / immunosuppressants, e.g., cyclosporine such as cyclosporine A and its derivatives , FK-506, rapamycin, buspirone, spiperone, and / or their derivatives , lifitegrast (Xiidra), etc., and / or various combinations thereof are.

[0027] Additional drugs and agents that can be used with the described device are incorporated herein by reference from U.S. Patent Publication No. 2017 / 0344714 and U.S. Patent No. 9,087, 145, which disclose any number of agents in more detail. The concentration of cholinergic agents in a trace amount of a given liquid formulation may be varied. In some embodiments, the concentration of cholinergic agents in a trace amount of a liquid formulation is in the range of 50 ng / mL to 100 mg / mL .

[0028] In addition to the active agent, the liquid formulation may include an aqueous delivery vehicle, e.g., a pharmaceutically acceptable aqueous vehicle. In addition to water, the aqueous delivery vehicle includes one or more additional ingredients including, but not limited to, salts, buffers, preservatives, solubilizers, viscosity modifiers, colorants, etc. It may contain additives. Suitable aqueous vehicles include sterilized distilled water or purified water, isotonic solutions such as aqueous sodium chloride solution or aqueous boric acid solution, phosphate buffered saline (PBS ), propylene glycol, butylene glycol, and the like. Other suitable vehicle components include phenylmercuric nitrate, sodium sulfate, sodium sulfite, sodium sulfite, sodium phosphate, and phosphate - sodium. Additional examples of other suitable vehicle components include alcohols, oils and fats, polymers, surfactants, fatty acids, silicone oil, humidifiers, moisturizers, viscosity modifiers, emulsifiers, and stabilizers. Further, the composition may contain auxiliary substances, for example, pH adjusters such as sodium hydroxide, hydrochloric acid or sulfuric acid, and viscosity increasing agents such as methyl cellulose.

[0029] Transducer

[0030] In addition to the fluid package, the device further includes a transducer (i.e., actuator) member operably coupled to the fluid package and configured to eject fluid from a reservoir of the fluid package to a target location through one or more openings. In some embodiments the transducer is a member configured to impart vibrations to the contents of the container, and the vibration frequency of the vibration may vary. In some embodiments the frequency may be in the audible range, for example from 20 to 20000 Hz, for example from 50 to 10000 Hz, for example from 100 to 3000 Hz including 50 to 50000 Hz, for example 500 to 3000 Hz, where in some embodiments the frequency is from 800 to 1200 Hz, for example from 900 to 1100 Hz, for example 1 000 Hz range. In some embodiments, the transducer is configured to achieve a desired fluid velocity ​ configured to operate with a vibration amplitude sufficient to provide, where, according to an embodiment the vibration amplitude is in the range of 1 to 10 μm, for example in the range of 2 to 10 μm, for example in the range of 1 to 5 μm in the range of, for example in the range of 1.5 to 4.5 μm, for example in the range of 2 to 4 μm, for example in the range of 2 to 3 μm including the range of. According to some embodiments, the transducer operates, for example, at an acoustic intensity of 50 dB or less, for example 40 dB or less, for example including 30 dB or less, for example 25 dB or less, for example 20 dB or less, with a weak acoustic intensity.

[0031] According to some embodiments, the transducer is configured to cause pressure fluctuations in the fluid within the fluid package so as to discharge fluid from the reservoir through an opening. According to an embodiment the transducer is configured to cause pressure fluctuations in the fluid by displacement induced on the outer surface of the fluid package. The transducer on the fluid package, and the audible frequency vibrations (such as those described above) applied to the outer surface of the fluid package in some embodiments generate cycles of sound pressure in the fluid held by the fluid package, and as a result, fluid is discharged from one or more openings.

[0032] According to some embodiments, the fluid is discharged from the fluid package as a stream by an actuator, where the stream is a continuous flow of liquid (i.e., a flow not composed of individual droplets) or a discontinuous flow of liquid, for example, a collimated flow of individual droplets, or a series of streams, etc. The stream may be continuous or discontinuous and may be collimated, so in certain embodiments, a liquid formulation ​​​​​​​​contacts a limited portion of the outer surface of the eyeball before spreading to a greater portion of the ocular surface, and this Here, the limited contact portion includes 50% or less, such as 40% or less, 30% or less, for example 25% or less, 20% or less, 15% or less, including 10%, for example 5% or less.

[0033] Embodiments of the present invention provide for the accurate delivery of a stream to a defined position such that the stream is accurately administered to a desired position on the ocular surface. The stream may be delivered as a collimated flow, so in such an example, substantially all, if not all, of the liquid formulation released from the device is delivered to the ocular surface. This is in contrast to other delivery modes such as a mist or aerosol where not all of the fluid released from the device reaches the ocular surface, but instead at least a portion is applied to the surrounding periorbital surface. If the stream is a continuous flow of liquid, the diameter of the stream may be variable and, in embodiments, is in the range of 0.05 - 0.50 mm, such as 0.070 - 0.130 mm. In some embodiments, the diameter of the flow is substantially constant along the length from its origin to the local eye position, such that the magnitude of the difference in diameter is, in some cases, 0.5 mm or less, such as 1 mm or less, for example 0.25 mm or less. In such a case, the stream may be collimated so as to spread minimally, if at all, as it propagates from the opening of the device to the ocular surface.

[0034] If the stream is a discontinuous flow of individual droplets, the volume of the individual droplets is varied in some embodiments in the range of 50 - 1500 pL, such as 100 - 1000 pL. ​​​​​​​​​​This is also acceptable. When droplets are administered, the diameter of a given droplet may, depending on the embodiment, be changed within a range of 20 to 10 00 μm, for example, within a range of 50 to 750 μm including 100 to 500 μm This is possible. The duration of the delivery of the stream during a given administration may vary and is, for example as described above, selected to provide the desired delivered microdose. In some embodiments the duration of the delivery of the stream, i.e., the duration of the administration, is 20 to 2000 milli seconds, for example 50 to 1000 milliseconds, 75 to 500 milliseconds, for example 100 to 150 milliseconds and is within a range of 50 to 200 milliseconds. The amount delivered can be varied as a function of the pulse duration and the pulse duration may be fixed or variable

[0035] As summarized above, the actuator is configured to eject the fluid at a speed that minimizes discomfort to the user during administration. The speed of the stream being administered can vary and, for example, as will be described in more detail below, generally exceeds the minimum exit velocity of the fluid from the opening of the device used to administer the stream The "minimum exit velocity" is as defined in Linblad and Scheider, "Production of uniform-size liquid droplets", J. Sci entific Instruments(1965)42:635 (see Equation 2 described therein). In some embodiments, the exit velocity may be more than 20% greater than the minimum exit velocity, and in some embodiments may be 300% or less of the minimum exit velocity For example, for an opening size of 150 microns, the minimum exit is as defined in Linblad and Scheider, "Production of uniform-size liquid droplets", J. Scientific Instruments(1965)42:635 (see Equation 2 described therein). In some embodiments, the exit velocity may be more than 20% greater than the minimum exit velocity, and in some embodiments may be 300% or less of the minimum exit velocity velocity. In some embodiments, the exit velocity may be more than 20% greater than the minimum exit velocity, and in some embodiments may be 300% or less of the minimum exit velocity For example, for an opening size of 150 microns, the minimum exit The mouth velocity is 194 cm / sec, but the selected velocity is at least 30% higher, i.e., , it may be at least 252 cm / sec. In some embodiments, the velocity ranges from 10 to 500 cm / sec, for example 20 - 250 cm / sec, including 50 - 150 cm / sec.

[0036] The properties of the transducer member may vary, but in some embodiments, the transducer member is an electromagnetic actuator. In some embodiments, the electromagnetic transducer provides a low - frequency vibration amplitude, optionally within the audible range (e.g., 20 - 20,000 Hz). In some embodiments, the electromagnetic transducer operates within the audible range of frequencies but generally generates a low audible sound of 30 dB or less. At the same time, the device ejects fluid from a sufficiently large nozzle at a sufficiently small velocity to minimize the discomfort associated with local delivery to the eye. The electromagnetic transducers vary, but in some embodiments, the electromagnetic transducer includes a configuration that amplifies the vibration force applied to the drug package. In some embodiments , the electromagnetic transducer includes a cantilever beam with one end fixed and a permanent magnet disposed at the other end, and this cantilever beam is attached near the end (fixed end) to which the drug package is fixed, as illustrated and described in more detail below.

[0037] Exemplary embodiments

[0038] As described above, the minimum flow rate required to form the stream ejected from the aperture is inversely proportional to its diameter (N R Lindblad and J M Schneider 19 65 J. Sci. Instrum. 42 635 Production of uniform-sized liquid droplets). Embodiments of the present invention In the case of, a nozzle diameter of about 0.2 mm is at least twice as large as that described in the prior art ophthalmic delivery systems as disclosed in U.S. Patent Nos. 5,630,793, 9, 087,145 and 8,684,980. A larger diameter nozzle was selected to reduce the velocity of the fluid affecting the surface of the eyeball . A larger diameter flow at a lower velocity exerts a lower pressure (force per unit area) on the target surface, which may be more comfortable for the patient. . The minimum vibration amplitude required to eject fluid from such a large nozzle is relatively large , about 3 μm. Such an amplitude is difficult to generate at ultrasonic frequencies, such as 20,000 Hz or higher

[0039] . However, it can be easily realized even at low frequencies, such as less than 3,000 Hz, and even 1,000 Hz. The present invention operates in the audible frequency range and will describe a transducer, such as an electromagnetic transducer (i.e., an actuator), that generates a small audible sound that is in some cases 30 dB or less . At the same time, the device releases fluid from a sufficiently large nozzle at a sufficiently low speed to minimize the discomfort associated with topical delivery to the eye . Furthermore, because of the large diameter of the opening, the device can supply the required amount in a shorter time. In some embodiments, the device of the present invention can deliver about 5 - 10 μL within 500 milliseconds, such as within 250 milliseconds . Furthermore, due to the large diameter of the opening, the device can supply the required amount in a shorter time. In some embodiments, the device of the present invention can deliver about 5 - 10 μL within 500 milliseconds, such as within 250 milliseconds . Furthermore, due to the large diameter of the opening, the device can supply the required amount in a shorter Due to the large diameter of the orifice, the device can discharge a viscous fluid in the range of, for example, 1 to 20 centipoise. It can do so.

[0040] In an embodiment of the present invention, the diameter of the opening is, in some cases, 200 μm or more. Returning to the description cited above, the minimum exit velocity required to form an injection is inversely proportional to the nozzle diameter. Returning to the description cited above, the minimum exit velocity required to form an injection is inversely proportional to the nozzle diameter. .

[0041]

Number

[0042] Here, V is the minimum exit velocity. T is the surface tension of water at 25 °C, T = 72 dyn e / cm, D is the nozzle diameter, and ρ is the density of water, ρ = 1 gm / cm 3 is .

[0043] Therefore, for example, as defined in the prior art, such as U.S. Patent Nos. 5,630,793, 9,087,145, and 8,684,980, when the diameter of the nozzle is 100 μm, the possible minimum velocity based on Equation 1 is approximately 1.82 m / sec. However, when the nozzle diameter is 200 μm, the flow velocity is 1.29 m / sec. Therefore, due to (1) the decrease in flow velocity and (2) the four-fold increase in the injection area, the impact pressure of the fluid on the surface of the eyeball decreases proportionally. Therefore, due to (1) the decrease in flow velocity and (2) the four-fold increase in the injection area, the impact pressure of the fluid on the surface of the eyeball decreases proportionally. The impact pressure of the fluid on the surface of the eyeball decreases proportionally.

[0044] One embodiment of the present invention is illustrated in FIGS. 1 to 3. Referring to FIG. 1 showing the electromagnetic ejection device (100) of the present invention. The electromagnetic ejection device (100) includes an ampoule (103) containing the fluid to be dispensed, and the fluid is discharged through an opening (116) at the lower part of the ampoule. It further includes an electromagnetic transducer (113) configured to vibrate the ampoule.

[0045] The electromagnetic transducer (113) includes a base plate (101), an electromagnet (115), and a permanent magnet (109). The electromagnet (115) includes a ferromagnetic core pin (110) and a coil (108) wound around the core pin. The permanent magnet (109) is disposed close to the electromagnetic core pin (ferromagnetic core pin, iron core) (110) and is supported by a flexible cantilever beam (106) having a free end and a fixed end. The dimensions of the cantilever beam (106) may be variously changed. Here, in some embodiments, the cantilever beam (106) has a width in the range of 3 to 7 mm, including 2 to 8 mm, for example 4 to 6 mm (for example 5 mm), and a length in the range of 15 to 20 mm, including 15 to 25 mm, for example 16 to 18 mm (for example 17 mm). Here, in some embodiments, the dimensions of the beam are selected according to the vibration amplitude in order to provide a device that operates with a small sound, for example 30 dB or less as described above. The alternating magnetic field generated by the coil (108) generates mechanical vibrations of the permanent magnet (109) and the flexible cantilever beam (106) that supports it. The cantilever beam (106) includes a fixing portion (107) that supports the cantilever beam (106) and transmits the vibration to the ampoule. The cantilever beam (106) having a fixed end and a free end enables the electromagnetic transducer (113) to generate sufficient force to swing the drug package.

[0046] In the illustrated embodiment, the magnet is attached to the free end, but the drug package is close to the fixed end, for example within 2 mm, including within 5 mm or less, for example within 1 mm or less.

[0047] ​ is mounted within the range. In this way, the vibration force applied to the drug package is amplified by the lever principle provided by the cantilever configuration that enables the electromagnetic transducer (113) to apply sufficient force to the drug package. Further, the high-amplitude vibration of the magnet at the free end is fed back to the circuit (by the magnetic field). In some embodiments, the circuit operates at its natural frequency. This configuration provides a device that is very economical while providing an effective approach for delivering drugs to the surface of the eye. This device further includes a stand-off support pin (102) that extends from the base plate (101), supports the cantilever (106), and functions as a spacer. In still other configurations, the oscillator often does not operate at its natural frequency.

[0048] In the illustrated embodiment, the permanent magnet (109) is disposed at the free end of the cantilever (106) at a position separated by (d2) from the stand-off support pin (102), while the ampoule support fixing portion (107) is disposed at a position separated by (d1) from the stand-off support pin (102). In this way, the benefit of the lever principle is obtained, and the force applied to the ampoule (103) is further amplified by the ratio of the distance d2 / d1 to the force applied to the permanent magnet (109). In the illustrated embodiment, the ampoule (103) contains 1 mL of aqueous solution and has a mass of about 1 gm. Therefore, the force required to vibrate the ampoule (103) at an amplitude of about 20 - 60 mm is about 0.2 N - 1 N. In the illustrated embodiment, the distance d2 is 13.5 mm and the distance d1 is 1.35 mm. The ratio d2 / d1 is about 10, and the vibration ​​​​​​​​​​​​​​​​The amplitude is between 20 μm and 60 μm according to the input voltage. In the illustrated embodiment, the diameter of the discharge opening (116) ranges from 200 to 350 μm, and such a large opening ( discharge nozzle) (116) discharges only at a high vibration amplitude.

[0049] In the illustrated embodiment, the ferromagnetic core (110), the base plate (101), and the stand-off support pins (102) are made of a soft magnetic material such as 4750 alloy, or other alloys with low coercive force and minimal magnetic hysteresis. The ampoule (103) is oriented such that the vibration amplitude and position of the discharge nozzle (116) match those of the cantilever beam (106). This vibration generates pressure fluctuations within the ampoule, and fluid is discharged from the discharge nozzle (116) as shown by the arrow (105). The permanent magnet (109) may be made of a rare-earth magnetic material such as neodymium N35, N38, N42, samarium cobalt, etc. Non-rare-earth alloys such as iron, nickel, cobalt, etc. may also be used.

[0050] Referring now to FIG. 2, this figure shows the electromagnetic discharge device (100) and further includes a diagram of an electric circuit that generates alternating electrical signals from a DC source such as a battery cell. The electromagnetic discharge device (100) includes a circuit (100A) that generates an alternating current supplied to the coil (108) to generate a magnetic force that vibrates the permanent magnet (109). The coil (108) defines two separate magnetic coils, where the first coil is the primary coil (which may be referred to as the driver coil) (108A), and the second coil is the detection coil (which may be referred to as the sensor coil) (108B). Both the coils (108A) and (108B) are wound around the iron core (1 It is wound around the periphery of (10). When a DC voltage is connected to the primary coil (108A), , a current flows, and the permanent magnet (109) is pulled towards the iron core (110) by the generated electromagnetic force. At the same time, the current in the primary coil (108A) generates a transient and time-dependent electromagnetic induction that induces the electromotive force (EMF) and the current in the detection coil (108B). That current is supplied to the bipolar transistor (Tr) that turns off by pulling the current from the primary coil (108A) to the ground (130). As a result, the magnetic force returns to zero, and the magnet (10 9) returns to its normal position. Subsequently, the primary coil (108A) turns on again, pulling back the magnet (1 09). In this way, an alternating magnetic field is generated using the DC input voltage from the DC battery. The transistor (Tr) used is an NPN general-purpose amplifier such as 2N3904 made by Fairchild. This circuit further includes a Zener diode (D1) for adjusting the voltage. The magnetic coils (108A) and (108B) have an inductance in the range of 1 to 10 mH and are configured to generate a magnetic field for vibrating the permanent magnet (109). Generally, the mass of the magnet (190) is small to reduce the inertial load and increase the vibration amplitude. In one embodiment, the mass of the permanent magnet (109) is 0.075 gm. The cantilever beam (1 06) is made of stainless steel alloy 304 with 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) has a natural frequency of approximately 523 Hz, and the driving frequency of the magnetic oscillator is approximately 1100 Hz.

[0051] Figure 2 shows the coaxial primary coil (108A) (i.e., the driver) and the detection coil (10 8B) (i.e., the sensor) shows an oscillator based on a coil, but other configurations may be used. For example, in some embodiments, only the primary coil or the driver coil is arranged, and the detection coil or the sensor coil is not arranged. In such a case, the direction of the current in the primary coil can be reversed to obtain the desired oscillation frequency. In other words, the current may be switched from positive to negative at the desired frequency to obtain the desired number of oscillations. The direction of the current in the primary coil or the driver coil may be operatively coupled to the primary coil or the driver coil using any convenient approach, such as a frequency generator, an oscillator, a microprocessor, etc., and may be switched, for example, using a square bridge circuit or the like.

[0052] FIG. 3 shows an exploded perspective view of the electromagnetic ejection device (100), showing the ampoule (103) and the electromagnetic transducer (113) separately. The ampoule (103) can be seen to include a pin member (302) that is inserted into the fixing member (107) with a tight interference fit. In this way, the vibration generated by the transducer is transmitted to the ampoule.

[0053] Optionally, the fluid delivery device may include one or more additional components, as described below, for example.

[0054] Alignment system

[0055] Embodiments of the fluid delivery devices described herein may also include an image-based alignment system configured to align the fluid ejected through one or more openings of the fluid package to a target position, such as a target eye position (e.g., the details below). The alignment system may be configured to align the fluid ejected through one or more openings of the fluid package to a target position, such as a target eye position (e.g., the details below). The alignment system may be configured to align the fluid ejected through one or more openings of the fluid package to a target position, such as a target eye position (e.g., the details below). The alignment The fluid delivery system is configured to allow a user, such as a subject to whom the fluid is to be administered, to administer the fluid that is dispensed upon actuation of the device. and aligning one or more openings to a target location such that the fluid is delivered to the target location. In some embodiments, the alignment system is a system that enables Following user alignment, for example, the protocol described in more detail below Thus, the device is configured to allow a user to self-administer fluid.

[0056] As summarized above, the alignment system is an image-based alignment system. An “image-based” alignment system is one that aligns the delivery device with respect to the target location. The matching may include capturing an image of a subject, e.g., a user, to whom fluid is to be delivered during a self-administration protocol. , for example, is meant to include visualization of an image or reflection.

[0057] Lenticular Print Image-Based Alignment System

[0058] In some embodiments, the image-based alignment system includes one or more lenticules. Lenticular printing is a system that includes one or more printing images. The lens may include an image and an array of linear lenses or focusing elements that superimpose the images. Or due to the optical properties of the focusing element, some parts of the printed image are only desired from certain angles. In one embodiment, the fluid delivery device and the lenticular printer form a composite visible image. The device is configured to deliver a stream of light from the delivery device to a target, such as the surface of the eye, when the image is visible to the user. The alignment system is arranged so that the first pair of linear lenses a lenticular print disposed perpendicular to the second pair of linear lenses; This is also acceptable. In this way, rotation or angular alignment is achieved according to two axes perpendicular to the line of sight or the optical axis of the eye.

[0059] In one embodiment, the alignment system includes two pairs of lenticular prints. The first pair of prints has an array of vertical linear lenses, and the second pair of prints has an array of horizontal linear lenses. The pair of vertical prints are arranged at a predetermined distance from each other, and the horizontal pair of prints are arranged at a predetermined distance from each other. In this way, the desired image can be made visible to the user only from a certain distance and in a certain direction. The ejection device and the lenticular prints may be arranged in positions relative to each other such that when the desired image is visible to the user, the stream ejected from the ejection device reaches a target position, such as the target eyeball position. In some embodiments, when the delivery device is arranged at about 50-100 mm from the target position, the target image is displayed. In other embodiments, the lens or focusing element is designed to collectively form an image or a specific desired pattern only from a predetermined distance and orientation from an array of lenses or focusing elements and one or more apertures, and includes or is formed from an array or pattern designed to do so in an image forming system. In some embodiments, when the delivery device is arranged at about 50-100 mm from the target position, the target image is displayed. In other embodiments, the lens or focusing element is designed to collectively form an image or a specific desired pattern only from a predetermined distance and orientation from an array of lenses or focusing elements and one or more apertures, and includes or is formed from an array or pattern designed to do so in an image forming system. distance and orientation from an array of lenses or focusing elements and one or more apertures, and includes or is formed from an array or pattern designed to do so in an image forming system. distance and orientation from an array of lenses or focusing elements and one or more apertures, and includes or is formed from an array or pattern designed to do so in an image forming system. configured.

[0060] Any convenient lenticular system as described above can be employed, and examples of such lenticular systems include, but are not limited to, those described in U.S. Patent Nos. 6,065,623, 8,1 44,399 and International Patent Publication No. WO1994020875, and these disclosures are incorporated herein by reference. are included, but not limited thereto, and these disclosures are incorporated herein by reference. It is incorporated into the book.

[0061] Reflector image-based alignment system

[0062] Another type of image-based alignment system that may be disposed in the fluid delivery device of the present invention The tosist system is a reflector (i.e., mirror) image-based alignment system, such a system includes one or more reflectors or mirrors, and in some cases, includes a single reflector or mirror. In some embodiments, the reflector has a curved shape that defines a focal point, i.e., includes a concave mirror.

[0063] Typically, the most visible parts of the eye when viewed through the mirror are the iris, conjunctiva, sclera (through the conjunctiva) , and the cornea. The eye tissue on the focal plane of the concave spherical mirror appears to be in focus with the mirror placed at a focal distance (F) from that tissue. When the mirror is placed, the focus (P) appears to be in focus. The focus (P) is the intersection of the focal plane and the optical axis of the mirror. One way to deliver fluid to the target area generally involves positioning a reflector having a curved shape in proximity to the target area located on the surface of the eye until the reflection of the eye on the reflector appears to be in focus on the subject, where the focal plane defined by the reflector coincides with the eye when the reflection appears to be in focus. Once placed, this method may include operating the fluid delivery assembly to eject fluid from one or more openings such that the fluid is delivered to the target location on the eye. The focal plane defined by the reflector coincides with the eye when the reflection appears to be in focus. Once placed, this method may include operating the fluid delivery assembly to eject fluid from one or more openings such that the fluid is delivered to the target location on the eye. It may be included.

[0064] In some embodiments, the reflector defines one or more openings therethrough. In such a system, fluid is also ejected from one or more openings that are aligned with the one or more openings. from one or more openings that are aligned with the one or more openings. It may include a fluid delivery assembly configured as a sea urchin, where the system is configured to eject fluid through one or more openings, towards the focus, or in proximity to the focus. In some embodiments, the fluid delivery assembly is configured to eject fluid from one or more openings that are aligned with one or more openings defined through a reflective surface such that the fluid is directed towards or in proximity to the target area towards the focal plane. In another aspect, a system for aligning a fluid delivery assembly relative to a target area of a subject's eye may generally include a concave mirror having a reflective surface, where the mirror defines a focal plane and one or more openings through which fluid is delivered, and includes a fluid delivery assembly configured to eject fluid from one or more openings aligned with the one or more openings such that the fluid is ejected towards or in proximity to the focal plane through the one or more openings. Instead of a concave mirror, the reflective image assembly may include, for example, a planar mirror coupled with an appropriate lens that allows for alignment by the user, as will be described in more detail above and below. Regardless of whether the reflective surface is curved or flat, the alignment system may be configured to focus on an image of the eye that includes the target position when the user aligns the fluid delivery device in a self - administration protocol where the target position is on the surface of the eyeball. In this way, the same eye that includes the target eye position is employed by the user, for example, by focusing and centering the eye in the mirror of the alignment system to align the position of the fluid delivery device. It may include a fluid delivery assembly configured as a sea urchin, where the system is configured to eject fluid through one or more openings, towards the focus, or in proximity to the focus. In some embodiments, the fluid delivery assembly is configured to eject fluid from one or more openings that are aligned with one or more openings defined through a reflective surface such that the fluid is directed towards or in proximity to the target area towards the focal plane. In another aspect, a system for aligning a fluid delivery assembly relative to a target area of a subject's eye may generally include a concave mirror having a reflective surface, where the mirror defines a focal plane and one or more openings through which fluid is delivered, and includes a fluid delivery assembly configured to eject fluid from one or more openings aligned with the one or more openings such that the fluid is ejected towards or in proximity to the focal plane through the one or more openings. Instead of a concave mirror, the reflective image assembly may include, for example, a planar mirror coupled with an appropriate lens that allows for alignment by the user, as will be described in more detail above and below. Regardless of whether the reflective surface is curved or flat, the alignment system may be configured to focus on an image of the eye that includes the target position when the user aligns the fluid delivery device in a self - administration protocol where the target position is on the surface of the eyeball. In this way, the same eye that includes the target eye position is employed by the user, for example, by focusing and centering the eye in the mirror of the alignment system to align the position of the fluid delivery device. It may include a fluid delivery assembly configured as a sea urchin, where the system is configured to eject fluid through one or more openings, towards the focus, or in proximity to the focus. In some embodiments, the fluid delivery assembly is configured to eject fluid from one or more openings that are aligned with one or more openings defined through a reflective surface such that the fluid is directed towards or in proximity to the target area towards the focal plane. In another aspect, a system for aligning a fluid delivery assembly relative to a target area of a subject's eye may generally include a concave mirror having a reflective surface, where the mirror defines a focal plane and one or more openings through which fluid is delivered, and includes a fluid delivery assembly configured to eject fluid from one or more openings aligned with the one or more openings such that the fluid is ejected towards or in proximity to the focal plane through the one or more openings. Instead of a concave mirror, the reflective image assembly may include, for example, a planar mirror coupled with an appropriate lens that allows for alignment by the user, as will be described in more detail above and below. Regardless of whether the reflective surface is curved or flat, the alignment system may be configured to focus on an image of the eye that includes the target position when the user aligns the fluid delivery device in a self - administration protocol where the target position is on the surface of the eyeball. In this way, the same eye that includes the target eye position is employed by the user, for example, by focusing and centering the eye in the mirror of the alignment system to align the position of the fluid delivery device. It may include a fluid delivery assembly configured as a sea urchin, where the system is configured to eject fluid through one or more openings, towards the focus, or in proximity to the focus. In some embodiments, the fluid delivery assembly is configured to eject fluid from one or more openings that are aligned with one or more openings defined through a reflective surface such that the fluid is directed towards or in proximity to the target area towards the focal plane. In another aspect, a system for aligning a fluid delivery assembly relative to a target area of a subject's eye may generally include a concave mirror having a reflective surface, where the mirror defines a focal plane and one or more openings through which fluid is delivered, and includes a fluid delivery assembly configured to eject fluid from one or more openings aligned with the one or more openings such that the fluid is ejected towards or in proximity to the focal plane through the one or more openings.

[0065] Instead of a concave mirror, the reflective image assembly may include, for example, a planar mirror coupled with an appropriate lens that allows for alignment by the user, as will be described in more detail above and below. Regardless of whether the reflective surface is curved or flat, the alignment system may be configured to focus on an image of the eye that includes the target position when the user aligns the fluid delivery device in a self - administration protocol where the target position is on the surface of the eyeball. In this way, the same eye that includes the target eye position is employed by the user, for example, by focusing and centering the eye in the mirror of the alignment system to align the position of the fluid delivery device. It may include a fluid delivery assembly configured as a sea urchin, where the system is configured to eject fluid through one or more openings, towards the focus, or in proximity to the focus. In some embodiments, the fluid delivery assembly is configured to eject fluid from one or more openings that are aligned with one or more openings defined through a reflective surface such that the fluid is directed towards or in proximity to the target area towards the focal plane. In another aspect, a system for aligning a fluid delivery assembly relative to a target area of a subject's eye may generally include a concave mirror having a reflective surface, where the mirror defines a focal plane and one or more openings through which fluid is delivered, and includes a fluid delivery assembly configured to eject fluid from one or more openings aligned with the one or more openings such that the fluid is ejected towards or in proximity to the focal plane through the one or more openings.

[0066] Instead of a concave mirror, the reflective image assembly may include, for example, a planar mirror coupled with an appropriate lens that allows for alignment by the user, as will be described in more detail above and below. Regardless of whether the reflective surface is curved or flat, the alignment system may be configured to focus on an image of the eye that includes the target position when the user aligns the fluid delivery device in a self - administration protocol where the target position is on the surface of the eyeball. In this way, the same eye that includes the target eye position is employed by the user, for example, by focusing and centering the eye in the mirror of the alignment system to align the position of the fluid delivery device. It may include a fluid delivery assembly configured as a sea urchin, where the system is configured to eject fluid through one or more openings, towards the focus, or in proximity to the focus. In some embodiments, the fluid delivery assembly is configured to eject fluid from one or more openings that are aligned with one or more openings defined through a reflective surface such that the fluid is directed towards or in proximity to the target area towards the focal plane. In another aspect, a system for aligning a fluid delivery assembly relative to a target area of a subject's eye may generally include a concave mirror having a reflective surface, where the mirror defines a focal plane and one or more openings through which fluid is delivered, and includes a fluid delivery assembly configured to eject fluid from one or more openings aligned with the one or more openings such that the fluid is ejected towards or in proximity to the focal plane through the one or more openings. Instead of a concave mirror, the reflective image assembly may include, for example, a planar mirror coupled with an appropriate lens that allows for alignment by the user, as will be described in more detail above and below. Regardless of whether the reflective surface is curved or flat, the alignment system may be configured to focus on an image of the eye that includes the target position when the user aligns the fluid delivery device in a self - administration protocol where the target position is on the surface of the eyeball. In this way, the same eye that includes the target eye position is employed by the user, for example, by focusing and centering the eye in the mirror of the alignment system to align the position of the fluid delivery device. It may include a fluid delivery assembly configured as a sea urchin, where the system is configured to eject fluid through one or more openings, towards the focus, or in proximity to the focus. In some embodiments, the fluid delivery assembly is configured to eject fluid from one or more openings that are aligned with one or more openings defined through a reflective surface such that the fluid is directed towards or in proximity to the target area towards the focal plane. In another aspect, a system for aligning a fluid delivery assembly relative to a target area of a subject's eye may generally include a concave mirror having a reflective surface, where the mirror defines a focal plane and one or more openings through which fluid is delivered, and includes a fluid delivery assembly configured to eject fluid from one or more openings aligned with the one or more openings such that the fluid is ejected towards or in proximity to the focal plane through the one or more openings.

[0067] The dimensions of the reflective surfaces of such an image-based alignment system may be varied as desired. In some embodiments, the reflective surface may be 10-30 mm in its longest dimension, e.g., diameter. In some embodiments, the dimensions are in the range of 0.01 mm to 0.05 mm. In such cases, the longest dimension, e.g., diameter, is 10-15 m. m, for example, in the range of 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, or 15 mm It may be an enclosure.

[0068] housing

[0069] In some embodiments, the fluid delivery device may include, for example, various components of the device, as described above. The housing may be of any convenient configuration, and may Some have a longest dimension in the range of 50-100 mm, e.g., 70-85 mm. The housing may be of any convenient shape, where advantageous shapes are those in which the device In some embodiments, the housing includes The housing has a generally rectangular cuboid shape. The housing may be made of any material, such as plastic or metal. It may be manufactured from any convenient material.

[0070] The various components of the device may be associated with the housing components in any convenient manner. In some embodiments, the fluid package and actuator components may be housed in a housing. and at least a portion of the image-based alignment system is disposed within the image base during use. The alignment system of the base is visible to the user, e.g. on the surface of the housing. is associated with. In some embodiments, the housing includes a movable cover that covers, for example, an opening and / or an alignment system when the device is not in use. The cover can be configured to move between a closed position and an open position, and when the cover is moved from the closed position to the open position, the device transitions to a configuration where fluid delivery can occur. In some embodiments, when the cover is moved from the closed position to the open position, the device may transition from an inactive state to an active state. For example, moving the cover from the closed position to the open position may activate an actuator member. In some embodiments, the device includes one or more illumination sources. Any convenient illumination source can be employed, such as, but not limited to, light emitting diodes (LEDs). When arranged, the illumination source may be in a variety of different configurations. For example, it may be different from other components of the device, such as an alignment system. Alternatively, it may be associated with another component of the device. For example, it can be associated with the alignment system of the device, such as at least partially defining a boundary even if it does not completely bound the alignment system of the device. When arranged, the illumination source can perform various different functions, such as illuminating a target position within a reflective surface of the alignment system, indicating that the device is aligned with the target position, indicating that the device is within a predetermined distance of the target position, indicating that the device is ready to deliver fluid, indicating the amount of fluid in a fluid package (e.g., full, partially full, empty), etc. configured to move between a closed position and an open position, and when the cover is moved from the closed position to the open position, the device transitions to a configuration where fluid delivery can occur. In some embodiments, when the cover is moved from the closed position to the open position, the device may transition from an inactive state to an active state. For example, moving the cover from the closed position to the open position may activate an actuator member. In some embodiments, the device includes one or more illumination sources. Any convenient illumination source can be employed, such as, but not limited to, light emitting diodes (LEDs).

[0071] Illumination source

[0072] When arranged, the illumination source may be in a variety of different configurations. For example, it may be different from other components of the device, such as an alignment system. Alternatively, it may be associated with another component of the device. For example, it can be associated with the alignment system of the device, such as at least partially defining a boundary even if it does not completely bound the alignment system of the device. When arranged, the illumination source can perform various different functions, such as illuminating a target position within a reflective surface of the alignment system, indicating that the device is aligned with the target position, indicating that the device is within a predetermined distance of the target position, indicating that the device is ready to deliver fluid, indicating the amount of fluid in a fluid package (e.g., full, partially full, empty), etc. For example, it can be associated with the alignment system of the device, such as at least partially defining a boundary even if it does not completely bound the alignment system of the device. When arranged, the illumination source may be in a variety of different configurations. For example, it may be different from other components of the device, such as an alignment system. Alternatively, it may be associated with another component of the device. When arranged, the illumination source can perform various different functions, such as illuminating a target position within a reflective surface of the alignment system, indicating that the device is aligned with the target position, indicating that the device is within a predetermined distance of the target position, indicating that the device is ready to deliver fluid, indicating the amount of fluid in a fluid package (e.g., full, partially full, empty), etc. When arranged, the illumination source can perform various different functions, such as illuminating a target position within a reflective surface of the alignment system, indicating that the device is aligned with the target position, indicating that the device is within a predetermined distance of the target position, indicating that the device is ready to deliver fluid, indicating the amount of fluid in a fluid package (e.g., full, partially full, empty), etc.

[0073] Distance sensor

[0074] In some embodiments, the device includes one or more distance sensors. A distance sensor is a component configured to determine the distance between the device and a target position. Any convenient distance sensor may be arranged, and such sensors include, but are not limited to, infrared (IR) sensors, radar sensors, etc. In embodiments where the device includes a distance sensor, the device may be further configured to provide a signal such as an audible signal or a visual signal when the determined distance between the device and the target position is within a predetermined range. For example, the device may be configured to activate an illumination source when the device is within a predetermined range of the target position determined by the distance sensor, as in the example described above. In some embodiments, the device is configured to be activated when the determined distance between the device and the target position is within a predetermined distance. In the above embodiments, the predetermined range may vary and, in some cases, is between 1 mm and 250 mm, for example, 10 mm to 100 mm. a member configured to determine the distance between the device and the target position. Any convenient distance sensor may be arranged, and such sensors include, but are not limited to, infrared (IR) sensors, radar sensors, etc. In embodiments where the device includes a distance sensor, the device may be further configured to provide a signal such as an audible signal or a visual signal when the determined distance between the device and the target position is within a predetermined range. For example, the device may be configured to activate an illumination source when the device is within a predetermined range of the target position determined by the distance sensor, as in the example described above. In some embodiments, the device is configured to be activated when the determined distance between the device and the target position is within a predetermined distance. In the above embodiments, the predetermined range may vary and, in some cases, is between 1 mm and 250 mm, for example, 10 mm to 100 mm. etc., but are not limited thereto. In embodiments where the device includes a distance sensor, the device may be further configured to provide a signal such as an audible signal or a visual signal when the determined distance between the device and the target position is within a predetermined range. For example, the device may be configured to activate an illumination source when the device is within a predetermined range of the target position determined by the distance sensor, as in the example described above. In some embodiments, the device is configured to be activated when the determined distance between the device and the target position is within a predetermined distance. In the above embodiments, the predetermined range may vary and, in some cases, is between 1 mm and 250 mm, for example, 10 mm to 100 mm. etc., but are not limited thereto. In embodiments where the device includes a distance sensor, the device may be further configured to provide a signal such as an audible signal or a visual signal when the determined distance between the device and the target position is within a predetermined range. For example, the device may be configured to activate an illumination source when the device is within a predetermined range of the target position determined by the distance sensor, as in the example described above. In some embodiments, the device is configured to be activated when the determined distance between the device and the target position is within a predetermined distance. In the above embodiments, the predetermined range may vary and, in some cases, is between 1 mm and 250 mm, for example, 10 mm to 100 mm. is within a predetermined range. For example, the device may be configured to activate an illumination source when the device is within a predetermined range of the target position determined by the distance sensor, as in the example described above. In some embodiments, the device is configured to be activated when the determined distance between the device and the target position is within a predetermined distance. In the above embodiments, the predetermined range may vary and, in some cases, is between 1 mm and 250 mm, for example, 10 mm to 100 mm. such as a visual signal. For example, the device may be configured to activate an illumination source when the device is within a predetermined range of the target position determined by the distance sensor, as in the example described above. In some embodiments, the device is configured to be activated when the determined distance between the device and the target position is within a predetermined distance. In the above embodiments, the predetermined range may vary and, in some cases, is between 1 mm and 250 mm, for example, 10 mm to 100 mm. As in the example above, when the device is within a predetermined range of the target position determined by the distance sensor, the device may be configured to activate an illumination source. In some embodiments, the device is configured to be activated when the determined distance between the device and the target position is within a predetermined distance. In the above embodiments, the predetermined range may vary and, in some cases, is between 1 mm and 250 mm, for example, 10 mm to 100 mm. is within a predetermined distance, the device is configured to be activated. In the above embodiments, the predetermined range may vary and, in some cases, is between 1 mm and 250 mm, for example, 10 mm to 100 mm. In the above embodiments, the predetermined range may vary and, in some cases, is between 1 mm and 250 mm, for example, 10 mm to 100 mm. In some cases, it is between 1 mm and 250 mm, for example, 10 mm to 100 mm.

[0075] FIG. 4 is a diagram showing an embodiment of a fluid delivery device according to the present invention. As shown in FIG. 4, the device (400) includes a housing (410) having a slide cover (420). For example, as in the example described above, a fluid delivery package and a transducer are arranged within the housing. As shown, the device (400) includes an actuator button (430) at the top of the housing. The device also includes a concave mirror image-based alignment system (440) as described above, and the concave mirror (450) discharges from the opening during fluid delivery. As shown in FIG. 4, the device (400) includes a housing (410) having a slide cover (420). For example, as in the example described above, a fluid delivery package and a transducer are arranged within the housing. For example, as in the example described above, a fluid delivery package and a transducer are arranged within the housing. As shown, the device (400) includes an actuator button (430) at the top of the housing. The device also includes a concave mirror image-based alignment system (440) as described above, and the concave mirror (450) discharges from the opening during fluid delivery. It includes an opening (460) through which the dispensed fluid can flow. Surrounding the concave mirror (450) or defining the boundary is a circular LED (470). An IR sensor (480) is also shown therein.

[0076] Further details regarding various embodiments of the above components are described in U.S. Patent Application No. 1 4 / 992,975, filed on January 1, 2016, published as U.S. Patent Publication No. 2016 / 0199225; U.S. Patent Application No. 15 / 094,849, filed on April 8, 2016, published as U.S. Patent Publication No. 2016 / 0296367; U.S. Patent Application No. 15 / 874,377, filed on January 18, 2018, published as U.S. Patent Publication No. 2018 / 0207030; International Application No. PCT / US2018 / 064529, filed on December 7, 2018; U.S. Provisional Patent Application No. 62 / 656,552, filed on April 12, 2018; and U.S. Provisional Patent Application No. 62 / 693,818, filed on July 3, 2018, which are hereby incorporated by reference into this specification.

[0077] Method

[0078] As summarized above, aspects of the present disclosure include methods of administering a liquid formulation of an ophthalmic agent to a local ocular position of a subject's eye. The local ocular position refers to an area on the outer surface of the eye (i.e., a region or domain), such as a region of the cornea, a region of the conjunctiva, or a region including components of both the cornea and the conjunctiva. In some embodiments, the local ocular position is a position or region offset relative to the optical axis of the eye. In some embodiments, the local ocular position is the conjunctiva of the eyeball or tarsal plate, ​​​​​​Or it is in either the conjunctiva or the vestibule. In other words, the local eye position is displaced from the center of the pupil or the center of the iris. The magnitude of the displacement / drift may vary but, in some embodiments, the magnitude is in the range of 1 to 30 mm, such as 2 to 20 mm, such as 5 to 15 mm, including 5 to 10 mm. The size of the targeted local eye position may vary but, in some embodiments, the size of the targeted local eye position is 2.5 to 1 2, such as 3 to 9 mm 2 and is in a range such as this.

[0079] Aspects of the present invention include delivering a dose or amount of a liquid ophthalmic formulation that can be completely contained by the local eye tear film. The tear film at the eye position is a film related to the local eye position. Thus, the tear film is, for example, as described above, a film or layer of tear fluid on the eye surface where the local eye position is located. Also, since the delivery amount of the liquid formulation is an amount that can be completely contained by the tear film at the local eye position, it may be an amount that can be completely contained on the ocular surface including the local eye position. "Completely contained on the ocular surface" means that, upon delivery, the delivered amount can be held, for example, in the form of tears, on the eye surface where it is administered without excessive liquid flowing out from the eye surface and passing over the eyelid. The predetermined amount to be delivered may vary, but in some cases, this amount is in the range of 1 to 15 μL, such as 3 to 10 μL, including 5 to 10 μL. In some embodiments the amount of the liquid formulation administered to the eye surface does not cause a blink reflex. Thus, the delivery of the liquid volume according to embodiments of the present invention does not induce reflex tears, eyelid spasms / blinks and does not cause any discomfort to the patient. "Completely contained on the surface of the eyeball" means that at the time of delivery, the delivered amount can be held on the surface of the eye where it is administered, for example, in the form of tears, without excessive liquid flowing out from the surface of the eye and passing over the eyelid. The predetermined amount to be delivered may vary, but in some cases, this amount is in the range of 1 to 15 μL, such as 3 to 10 μL, including 5 to 10 μL. According to some embodiments the amount of the liquid formulation administered to the eye surface does not cause a blink reflex. Therefore, the delivery of the liquid volume according to embodiments of the present invention does not cause reflex tears, eyelid spasms / blinks and does not cause any discomfort to the patient. According to some embodiments, the amount of the liquid formulation administered to the eye surface does not cause a blink reflex. Thus, the delivery of the liquid volume according to embodiments of the present invention does not induce reflex tears, eyelid spasms / blinks Without triggering, this enables the delivery of an accurate known amount of the active agent to a local position in the present embodiment. to be possible.

[0080] An advantage of the embodiments of the present invention is that an accurate known amount of an ophthalmic agent is delivered to a local eye position because the amount of the liquid preparation accurately administered to the surface of the eye can be completely contained on the eye surface. As outlined above, the amount of the liquid preparation is delivered in a manner that minimizes these, even if it does not exclude the reflex tears and loss of the amount of the liquid preparation. Thus, in the administration of a given liquid preparation, a certain fraction of the liquid administered is accurately retained on the surface of the eye. Therefore, the method of the present invention enables the delivery of an accurately known dose of a given ophthalmic agent. In other words, the delivery of an accurate amount of an ophthalmic agent to the surface of the eye is in contrast to other administration protocols where delivery, prediction, or measurement of an accurate known amount is not possible due to one or more losses such as loss due to reflex blinking or tears, loss due to the entire dose not reaching the surface of the eye (such as occurs in mist or aerosol delivery). In the method of the present invention, the amount (mass) of the ophthalmic agent delivered to the surface of the eye is equal to the mass of the dose multiplied by the concentration of the ophthalmic agent in the administered liquid. For example, if a given dose is 10 microliters of a 1% ophthalmic agent (10 mg / mL) solution, the known mass of the ophthalmic agent delivered to the surface of the eye is 0.1 mg. Similarly, when delivering 4 microliters of a 2% ophthalmic agent (20 mg / mL) solution according to the present invention, the known mass of the ophthalmic agent delivered to the surface of the eye is 0.08 mg. This ability to know the mass of the ophthalmic agent delivered to the local surface of the eye is, for example, in contrast to conventional dropwise administration where the amount of the agent reaching the eye surface is highly variable and difficult to accurately control due to factors such as reflex blinking, evaporation, and uneven distribution on the eye surface. In the method of the present invention, the amount (mass) of the ophthalmic agent delivered to the surface of the eye is equal to the mass of the dose multiplied by the concentration of the ophthalmic agent in the administered liquid. For example, if a given dose is 10 microliters of a 1% ophthalmic agent (10 mg / mL) solution, the known mass of the ophthalmic agent delivered to the surface of the eye is 0.1 mg. Similarly, when delivering 4 microliters of a 2% ophthalmic agent (20 mg / mL) solution according to the present invention, the known mass of the ophthalmic agent delivered to the surface of the eye is 0.08 mg. This ability to know the mass of the ophthalmic agent delivered to the local surface of the eye is, for example, in contrast to conventional dropwise administration where the amount of the agent reaching the eye surface is highly variable and difficult to accurately control due to factors such as reflex blinking, evaporation, and uneven distribution on the eye surface.

[0081] This ability to know the mass of the ophthalmic agent delivered to the local surface of the eye is, for example, in contrast to conventional Using an eye protocol or an aerosol / mist delivery device presents distinct advantages compared to other methods of delivering an active agent to a local eye location. For example, with a conventional 40 microliter volume of eye drops, (1) it is not possible to retain 40 microliters on the surface of the eyeball, (2) most of the eye drops spill over the edge of the eyelid and are wiped away by the tissue, (3) additional amounts of eye drops are lost through the tear system, (4) reflex tearing is caused as a result of the large volume of eye drops, leading to dilution of the drug concentration, etc. Thus, it is not precisely clear exactly how much of the active agent or drug is delivered to and retained on the surface of the eyeball. Regarding devices that deliver a formulation in the mist / aerosol form, it is not possible to guarantee that all of the discharged formulation adheres to the cornea or the eye surface without any remaining on the surrounding periorbital surface.

[0082] The mass of a given ophthalmic agent delivered to a local eye location according to an embodiment of the present invention may vary depending on many considerations including the nature of the agent, the condition being treated, the age of the subject, etc.

[0083] Aspects of the present invention include delivering a microdose of an ophthalmic agent to a local eye location. In some embodiments, the microdose delivered has an efficacy comparable to a reference dose having a volume that exceeds the volume of the local tear film of the targeted eye. The reference dose in such cases is the same as the administered dose except for the volume. Thus, in the reference dose, The concentration of the active agent is the same as the concentration of the active agent in the delivered dose. The amount of the reference dose is , more than twice the amount of the delivered dose, for example more than three times. Depending on the embodiment , the reference dose has a volume in the range of 25 - 60 μL, such as 30 - 50 μL. Depending on the embodiment , the reference dose is the dose delivered by a standard eye drop device.

[0084] The microdoses of the embodiments of the present invention are effective, for example, in treating the condition of the eye to which they are administered, at least reducing side effects, and in some embodiments, substantial side effects, such as side effects that may require additional medications to counteract, and / or side effects that may lead to a decrease in patient compliance. Thus, the magnitude of the side effects caused by the administration of the microdoses is reduced and is sufficiently minimized such that no intervention is required to improve the side effects, which, for example, does not require the administration of additional active agents to improve the side effects. In some cases, the subject does not experience side effects after microadministration. The microdoses of the embodiments of the present invention are effective in treating the condition of the eye administered without substantial side effects, and thus, in some embodiments, the ophthalmic agent is the only active agent present in the microdose, and such microdoses do not contain any other active agents that improve any side effects of the ophthalmic agent for the condition being treated. For example, when pilocarpine is administered in a microdose according to an embodiment of the present invention, the microdose may not contain an agent that improves the side effects of pilocarpine, and such agents include vasoconstrictors such as oxymetazoline, naphazoline, tetrahydrozoline, and alpha agonists (e.g., brimonidine). For example, when pilocarpine is administered in a microdose according to an embodiment of the present invention, the microdose may not contain an agent that improves the side effects of pilocarpine, and such agents include vasoconstrictors such as oxymetazoline, naphazoline, tetrahydrozoline, and alpha agonists (e.g., brimonidine). For example, when pilocarpine is administered in a microdose according to an embodiment of the present invention, the microdose may not contain an agent that improves the side effects of pilocarpine, and such agents include vasoconstrictors such as oxymetazoline, naphazoline, tetrahydrozoline, and alpha agonists (e.g., brimonidine).

[0085] ​​​ The ability to deliver an accurately known amount in accordance with the present invention allows for the delivery of the same dosage or amount of an active agent using a variety of different regimens (the term "regimen" is used in its conventional meaning to refer to a schedule of administration of an active agent that includes the time between administrations, the duration of treatment, and the amount administered each time), where for a given subject, a single regimen may be used repeatedly or a number of different regimens may be employed over a given course of treatment. Thus, the methods and devices described herein provide the same dosage of an active agent delivered by a plurality of different regimens. For example, with respect to a first micro-dose in which a predetermined amount of a formulation having a predetermined active agent concentration is administered, the amount of the formulation and the concentration of the active agent in the formulation can be varied to obtain micro-doses that administer the same dosage, but micro-doses administered by different regimens can be obtained. For example, even though the exact dosage of the active agent administered, as determined by the weight in micrograms, milligrams, or grams of the pharmaceutical active ingredient, is the same between a first regimen and a second regimen, the volume of the active formulation delivered may be increased and the concentration of the active agent in the delivery fluid may be decreased to such an extent that the tolerability and effectiveness of the second regimen are superior to those of the first regimen.

[0086] As used herein, the terms "host", "subject", "individual", and "patient" are used interchangeably and refer to any mammalian animal in need of such treatment in accordance with the disclosed methods. Such mammalian animals include, for example, humans, sheep, cows, horses, pigs, dogs, cats, non-human primates, mice, and rats. In certain embodiments, the subject is non- ​​​​​​​​​​​​​​​​​ The subject is a human mammal. In some embodiments, the subject is a domestic animal. In other embodiments, the subject is a pet. In some embodiments, the subject is a mammal. In some embodiments, the subject is a human being. Other subjects may include household pets (e.g., dogs and cats), domestic animals (e.g., cows, pigs, goats, horses, etc.), rodents (e.g., mice, guinea pigs, and rats, such as in a disease animal model), and non-human primates (e.g., chimpanzees and monkeys). It may also be included.

[0087] In some aspects of the subject method, the method further includes the step of measuring the effectiveness of a predetermined condition, such as a disease state, in the subject. In some such embodiments, the determination is made by comparing with results obtained on the same individual at an earlier time, such as 2 weeks ago, 1 month ago ago, 2 months ago, 3 months ago, 6 months ago, 1 year ago, 2 years ago, 5 years ago, or 10 years ago, or results obtained at a time more than that ago. The evaluation may vary depending on the nature of the condition being treated. In some embodiments, the subject method further includes diagnosing the individual as having a predetermined condition.

[0088] Utility

[0089] The apparatus of the subject method is used for various different purposes, including both treatment and diagnostic / inspection applications. As used herein, the term "treating" or "treatment" means treating or treating a disease or medical condition in a subject or test subject, such as a mammal (such as a human), and this term includes (a) preventing the occurrence of a disease or medical condition, such as prophylactic treatment of a test subject, and (b) improving a disease or medical condition of the test subject, and (c) relieving the symptoms of a disease or medical condition of the test subject. such as causing removal or regression of a patient's disease or medical condition (c) in a patient inhibiting a disease or medical condition, such as delaying or arresting the development of a disease or medical condition in a patient, or (d) alleviating the symptoms of a patient's disease or medical condition. Examples of conditions that can be treated using the methods / apparatus of the present invention include glaucoma. Glaucoma

[0090] is a collection of disorders characterized by progressive visual field loss due to damage to the optic nerve. This is the leading cause of blindness in the United States and affects 1-2% of individuals over the age of 60. There are many risk factors (age, race, myopia, family history, trauma) associated with the development of glaucoma, but elevated intraocular pressure, also known as ocular hypertension, is correlated with the reduction of glaucomatous optic neuropathy and is the only risk factor that has been successfully manipulated. In glaucoma associated with elevated intraocular pressure, the resistance to outflow is in the trabecular meshwork. The tissue of the trabecular meshwork allows "aqueous" to enter Schlemm's canal, and then the posterior wall of Schlemm's canal becomes the aqueous collector channel and flows into the aqueous veins. Aqueous or aqueous humor is a clear liquid that fills the region between the cornea and the lens in the front of the eye. Aqueous humor is constantly secreted from the ciliary body surrounding the lens, so the flow of aqueous humor from the ciliary body to the anterior chamber of the eye is continuous without interruption. Intraocular pressure is determined by the balance between the production of aqueous humor and the outlet via the trabecular meshwork (main pathway), or the outlet via the uveoscleral outflow (secondary pathway). The trabecular meshwork is located between the outer edge of the iris and the inner circumference of the cornea. The portion of the trabecular meshwork adjacent to Schlemm's canal causes most of the resistance to the outflow of aqueous humor ( juxtacanalicular trabecular meshwork). is a collection of disorders characterized by progressive visual field loss due to damage to the optic nerve. This is the leading cause of blindness in the United States and affects 1-2% of individuals over the age of 60. There are many risk factors (age, race, myopia, family history, trauma) associated with the development of glaucoma, but elevated intraocular pressure, also known as ocular hypertension, is correlated with the reduction of glaucomatous optic neuropathy and is the only risk factor that has been successfully manipulated. In glaucoma associated with elevated intraocular pressure, the resistance to outflow is in the trabecular meshwork. The tissue of the trabecular meshwork allows "aqueous" to enter Schlemm's canal, and then the posterior wall of Schlemm's canal becomes the aqueous collector channel and flows into the aqueous veins. Aqueous or aqueous humor is a clear liquid that fills the region between the cornea and the lens in the front of the eye. Aqueous humor is constantly secreted from the ciliary body surrounding the lens, so the flow of aqueous humor from the ciliary body to the anterior chamber of the eye is continuous without interruption. Intraocular pressure is determined by the balance between the production of aqueous humor and the outlet via the trabecular meshwork (main pathway), or the outlet via the uveoscleral outflow (secondary pathway). The trabecular meshwork is located between the outer edge of the iris and the inner circumference of the cornea. The portion of the trabecular meshwork adjacent to Schlemm's canal causes most of the resistance to the outflow of aqueous humor ( juxtacanalicular trabecular meshwork). is the leading cause of blindness in the United States and affects 1-2% of individuals over the age of 60. There are many risk factors (age, race, myopia, family history, trauma) associated with the development of glaucoma, but elevated intraocular pressure, also known as ocular hypertension, is correlated with the reduction of glaucomatous optic neuropathy and is the only risk factor that has been successfully manipulated. In glaucoma associated with elevated intraocular pressure, the resistance to outflow is in the trabecular meshwork. The tissue of the trabecular meshwork allows "aqueous" to enter Schlemm's canal, and then the posterior wall of Schlemm's canal becomes the aqueous collector channel and flows into the aqueous veins. Aqueous or aqueous humor is a clear liquid that fills the region between the cornea and the lens in the front of the eye. Aqueous humor is constantly secreted from the ciliary body surrounding the lens, so the flow of aqueous humor from the ciliary body to the anterior chamber of the eye is continuous without interruption. Intraocular pressure is determined by the balance between the production of aqueous humor and the outlet via the trabecular meshwork (main pathway), or the outlet via the uveoscleral outflow (secondary pathway). The trabecular meshwork is located between the outer edge of the iris and the inner circumference of the cornea. The portion of the trabecular meshwork adjacent to Schlemm's canal causes most of the resistance to the outflow of aqueous humor ( juxtacanalicular trabecular meshwork). There are many risk factors (age, race, myopia, family history, trauma) associated with the development of glaucoma, but elevated intraocular pressure, also known as ocular hypertension, is correlated with the reduction of glaucomatous optic neuropathy and is the only risk factor that has been successfully manipulated. In glaucoma associated with elevated intraocular pressure, the resistance to outflow is in the trabecular meshwork. The tissue of the trabecular meshwork allows "aqueous" to enter Schlemm's canal, and then the posterior wall of Schlemm's canal becomes the aqueous collector channel and flows into the aqueous veins. Aqueous or aqueous humor is a clear liquid that fills the region between the cornea and the lens in the front of the eye. Aqueous humor is constantly secreted from the ciliary body surrounding the lens, so the flow of aqueous humor from the ciliary body to the anterior chamber of the eye is continuous without interruption. Intraocular pressure is determined by the balance between the production of aqueous humor and the outlet via the trabecular meshwork (main pathway), or the outlet via the uveoscleral outflow (secondary pathway). The trabecular meshwork is located between the outer edge of the iris and the inner circumference of the cornea. The portion of the trabecular meshwork adjacent to Schlemm's canal causes most of the resistance to the outflow of aqueous humor ( juxtacanalicular trabecular meshwork). There are many risk factors (age, race, myopia, family history, trauma) associated with the development of glaucoma, but elevated intraocular pressure, also known as ocular hypertension, is correlated with the reduction of glaucomatous optic neuropathy and is the only risk factor that has been successfully manipulated. In glaucoma associated with elevated intraocular pressure, the resistance to outflow is in the trabecular meshwork. The tissue of the trabecular meshwork allows "aqueous" to enter Schlemm's canal, and then the posterior wall of Schlemm's canal becomes the aqueous collector channel and flows into the aqueous veins. Aqueous or aqueous humor is a clear liquid that fills the region between the cornea and the lens in the front of the eye. Aqueous humor is constantly secreted from the ciliary body surrounding the lens, so the flow of aqueous humor from the ciliary body to the anterior chamber of the eye is continuous without interruption. Intraocular pressure is determined by the balance between the production of aqueous humor and the outlet via the trabecular meshwork (main pathway), or the outlet via the uveoscleral outflow (secondary pathway). The trabecular meshwork is located between the outer edge of the iris and the inner circumference of the cornea. The portion of the trabecular meshwork adjacent to Schlemm's canal causes most of the resistance to the outflow of aqueous humor ( juxtacanalicular trabecular meshwork). In the embodiments where the methods and apparatus are used for the treatment of glaucoma, the administered dose to be delivered is for intraocular pressure regulation The resistance to outflow is in the trabecular meshwork. The tissue of the trabecular meshwork allows "aqueous" to enter Schlemm's canal, and then the posterior wall of Schlemm's canal becomes the aqueous collector channel and flows into the aqueous veins. Aqueous or aqueous humor is a clear liquid that fills the region between the cornea and the lens in the front of the eye. Aqueous humor is constantly secreted from the ciliary body surrounding the lens, so the flow of aqueous humor from the ciliary body to the anterior chamber of the eye is continuous without interruption. Intraocular pressure is determined by the balance between the production of aqueous humor and the outlet via the trabecular meshwork (main pathway), or the outlet via the uveoscleral outflow (secondary pathway). The trabecular meshwork is located between the outer edge of the iris and the inner circumference of the cornea. The portion of the trabecular meshwork adjacent to Schlemm's canal causes most of the resistance to the outflow of aqueous humor ( juxtacanalicular trabecular meshwork). The tissue of the trabecular meshwork allows "aqueous" to enter Schlemm's canal, and then the posterior wall of Schlemm's canal becomes the aqueous collector channel and flows into the aqueous veins. Aqueous or aqueous humor is a clear liquid that fills the region between the cornea and the lens in the front of the eye. Aqueous humor is constantly secreted from the ciliary body surrounding the lens, so the flow of aqueous humor from the ciliary body to the anterior chamber of the eye is continuous without interruption. Intraocular pressure is determined by the balance between the production of aqueous humor and the outlet via the trabecular meshwork (main pathway), or the outlet via the uveoscleral outflow (secondary pathway). The trabecular meshwork is located between the outer edge of the iris and the inner circumference of the cornea. The portion of the trabecular meshwork adjacent to Schlemm's canal causes most of the resistance to the outflow of aqueous humor ( juxtacanalicular trabecular meshwork). Aqueous or aqueous humor is a clear liquid that fills the region between the cornea and the lens in the front of the eye. Aqueous humor is constantly secreted from the ciliary body surrounding the lens, so the flow of aqueous humor from the ciliary body to the anterior chamber of the eye is continuous without interruption. Intraocular pressure is determined by the balance between the production of aqueous humor and the outlet via the trabecular meshwork (main pathway), or the outlet via the uveoscleral outflow (secondary pathway). The trabecular meshwork is located between the outer edge of the iris and the inner circumference of the cornea. The portion of the trabecular meshwork adjacent to Schlemm's canal causes most of the resistance to the outflow of aqueous humor ( juxtacanalicular trabecular meshwork). Aqueous humor is constantly secreted from the ciliary body surrounding the lens, so the flow of aqueous humor from the ciliary body to the anterior chamber of the eye is continuous without interruption. Intraocular pressure is determined by the balance between the production of aqueous humor and the outlet via the trabecular meshwork (main pathway), or the outlet via the uveoscleral outflow (secondary pathway). The trabecular meshwork is located between the outer edge of the iris and the inner circumference of the cornea. The portion of the trabecular meshwork adjacent to Schlemm's canal causes most of the resistance to the outflow of aqueous humor ( juxtacanalicular trabecular meshwork). Intraocular pressure is determined by the balance between the production of aqueous humor and the outlet via the trabecular meshwork (main pathway), or the outlet via the uveoscleral outflow (secondary pathway). The trabecular meshwork is located between the outer edge of the iris and the inner circumference of the cornea. The portion of the trabecular meshwork adjacent to Schlemm's canal causes most of the resistance to the outflow of aqueous humor ( juxtacanalicular trabecular meshwork). The trabecular meshwork is located between the outer edge of the iris and the inner circumference of the cornea. The portion of the trabecular meshwork adjacent to Schlemm's canal causes most of the resistance to the outflow of aqueous humor ( juxtacanalicular trabecular meshwork). The trabecular meshwork is located between the outer edge of the iris and the inner circumference of the cornea. The portion of the trabecular meshwork adjacent to Schlemm's canal causes most of the resistance to the outflow of aqueous humor ( juxtacanalicular trabecular meshwork). The portion of the trabecular meshwork adjacent to Schlemm's canal causes most of the resistance to the outflow of aqueous humor ( juxtacanalicular trabecular meshwork).

[0091] In the embodiments where the methods and apparatus are used for the treatment of glaucoma, the administered dose to be delivered is for intraocular pressure regulation It can contain a medicinal preparation. The "intraocular pressure regulator" can contain drugs, such as anti-glaucoma drugs (for example, adrenergic agonists, adrenergic antagonists (β-blockers), etc.), and can be any of the following or their equivalents, derivatives or analogs. For example, carbonic anhydrase inhibitors (CAI, systemic and topical agents), timolol, betaxolol, levobunolol, atenolol, etc. Prostaglandins containing anti-glaucoma drugs including β-blockers, prostaglandin precursors, etc. (for example, as described in U.S. Patent No. 4,952,581), adrenergic agonists containing clonidine derivatives such as apraclonidine or brimonidine (for example, those as described in U.S. Patent No. 5,811,443), and prostaglandin analogs such as bimatoprost, travoprost, tafluprost, latanoprost, etc. Depending on the examples, the therapeutic agent is already commercially available for glaucoma, and its commercially available formulation can be used. Further therapeutic agents include carbonic anhydrase inhibitors such as acetazolamide, dorzolamide, brinzolamide, methazolamide, dichlorphenamide, diamox, etc.

[0092] Other diseases that can be treated by the methods and devices of the present invention include those described in U.S. Patent Publication No. 2017 / 0344714 and U.S. Patent No. 5,059,059, but are not limited thereto, and the disclosures thereof are incorporated herein by reference.

[0093] For diagnostic / inspection uses, for example, in order to enable inspection of the retina and other deep structures of the eye, It includes, but is not limited to, mydriatic uses in which the pupil is dilated. For use in such applications Mydriatics that can be used include, but are not limited to, the following. For example, atropine , atropine sulfate, atropine hydrochloride, atropine methyl bromide, atropine me thyl nitrate, atropine biurate, atropine N-oxide, phenylephrine, phenyl ephrine hydrochloride, hydroxyamphetamine, hydroxyamphetamine hydrobromide, h ydroxyamphetamine hydrochloride, hydroxyamphetamine iodide, cyclopentolate , cyclopentolate hydrochloride, homatropine, homatropine hydrobromide, homatropi ne hydrochloride, homatropine methyl hydrobromide, scopolamine, scopolamine hydrobromide , scopolamine methyl hydrobromide, scopolamine methyl nitrate, scopolamine N-ox ide, tropicamide, tropicamide hydrobromide, tropicamide hydrochloride, and the like.

[0094] Kit

[0095] Also provided are kits for practicing embodiments of the methods as described above. The term "kit" refers to a packaged delivery device or its components, e.g., the ampoules as described above. In addition to the above components, the kit may further include, for example, instructions for using the components of the kit to practice the subject method. The instructions are typically recorded on a suitable recording medium. For example, the instructions may be printed on a substrate such as paper or plastic . Thus, the instructions may be included in the kit as a package insert, or on the kit container or its components (i.e., ​​​The labeling may be in the labeling of the package or subpackage. In this state, the manual is stored on a CD-ROM, a floppy disk, or a hard disk drive (HD D) electronically recorded on a suitable computer-readable storage medium, such as a portable flash drive; In yet another embodiment, the actual instructions are stored in the kit. does not have a means for obtaining instructions from a remote source, e.g., provided via the Internet An example of this embodiment may include a display that displays instructions and / or a display that displays instructions. The kit includes a web address where the kit can be downloaded. This means for obtaining the certificate is recorded on a suitable substrate.

[0096] Notwithstanding the claims appended hereto, the disclosure is also defined by the following clauses.

[0097] (Clause 1) 1. A fluid delivery device comprising: (a) A fluid package comprising: (i) a reservoir containing an ophthalmic formulation; (ii) the fluid package having an opening; (b) removing the fluid from the reservoir at a rate that minimizes discomfort during localized intraocular delivery; an electromagnetic transducer configured to vibrate at a frequency sufficient to eject fluid through the and, 16. A fluid delivery device comprising:

[0098] (Clause 2) The electromagnetic transducer is adapted to expel fluid from the reservoir through the opening. 2. The fluid delivery device of claim 1, configured to generate a pressure variation in the fluid. Place.

[0099] (Clause 3) The electromagnetic transducer generates pressure fluctuations in the fluid due to displacement induced on the outer surface of the fluid package. The fluid delivery device according to clause 2.

[0100] (Clause 4) The fluid delivery device according to any of the preceding clauses, wherein the electromagnetic transducer vibrates at an audible frequency.

[0101] (Clause 5) The fluid delivery device according to clause 4, wherein the audible frequency range is in the range of 50 to 5000 Hz.

[0102] (Clause 6) The fluid delivery device according to clause 5, wherein the audible frequency range is 800 to 1200 Hz.

[0103] (Clause 7) The fluid delivery device according to any of the preceding clauses, wherein the electromagnetic transducer is configured to operate with a vibration amplitude in the range of 2 to 3 μm.

[0104] (Clause 8) The fluid delivery device according to clause 7, wherein the electromagnetic transducer includes an electromagnet and a permanent magnet that are operably close to each other.

[0105] (Clause 9) The fluid delivery device according to clause 8, wherein the permanent magnet is disposed in the first region of the cantilever beam.

[0106] (Clause 10) The electromagnetic transducer is disposed in the second region of the cantilever beam, and the electromagnetic transducer further includes a fixing portion disposed in the second region of the cantilever beam, and is configured to transmit a vibration displacement force to the outer surface of the drug package. The fluid delivery device according to clause 9. Delivery device.

[0107] (Article 11) The fluid delivery device according to any of the preceding paragraphs, wherein the electromagnetic transducer is reusable. Delivery device.

[0108] (Article 12) The fluid delivery device according to any of the preceding paragraphs, wherein the fluid package includes an extended region including a reservoir and a neck region including an opening. Delivery device.

[0109] (Article 13) The fluid delivery device according to any of the preceding paragraphs, wherein the opening has a diameter in the range of 200 to 350 μm. Delivery device.

[0110] (Article 14) The fluid delivery device according to any of the preceding paragraphs, wherein the reservoir is a multi-dose reservoir.

[0111] (Article 15) The fluid delivery device according to any of the preceding paragraphs, wherein the fluid package is disposable.

[0112] (Article 16) The fluid is discharged through the opening as a flow having a velocity in the range of 50 to 150 cm / second, and the fluid delivery device according to any of the preceding paragraphs is configured to do so. Delivery device.

[0113] (Article 17) The fluid delivery device according to any of the preceding paragraphs, further comprising an image-based alignment system configured to align the fluid discharged through the opening with a target position of the eye. Delivery device. Delivery device according to any of the preceding paragraphs.

[0114] (Article 18) The fluid delivery device according to Article 17, wherein the image-based alignment system includes a reflective surface. Delivery device.

[0115] (Article 19) wherein the fluid package and the electromagnetic transducer are disposed within a housing A fluid delivery device according to any of the preceding clauses

[0116] (Article 20) wherein the housing includes a cover disposed along the housing, the cover being configured to assume an open position in which one or more of the openings are exposed and a closed position in which one or more of the openings are not exposed, A fluid delivery device according to clause 19

[0117] (Article 21) A fluid delivery device according to clause 20, wherein the cover includes a sliding cover structure

[0118] (Article 22) wherein the electromagnetic transducer is configured to operate when the cover is in the open position A fluid delivery device according to clause 21

[0119] (Article 23) wherein the electromagnetic transducer is configured to be deactivated when the cover is in the closed position A fluid delivery device according to clause 22

[0120] (Article 24) A fluid delivery device according to any of the preceding clauses, including a light source

[0121] (Article 25) wherein the device further includes a distance sensor configured to determine a distance between the device and the target location A fluid delivery device according to any of the preceding clauses

[0122] (Article 26) A method of delivering fluid to a target location of a subject, comprising (A) A step of aligning the fluid delivery device with the target position, wherein the fluid delivery device comprises (1) A fluid package comprising (a) A reservoir containing an ophthalmic preparation, and (b) An opening, and the fluid package having the same, and (2) An electromagnetic transducer configured to vibrate at a frequency sufficient to discharge fluid from the reservoir through the opening at a rate that minimizes discomfort during topical intraocular delivery. The step includes and (B) A step of operating the electromagnetic transducer to discharge fluid from the reservoir through the opening at a rate that minimizes discomfort during topical intraocular delivery to the target position. The method includes and

[0123] (Clause 27) The method according to clause 26, wherein the electromagnetic transducer is configured to generate pressure fluctuations of the fluid and discharge the fluid from the reservoir through the opening described above.

[0124] (Clause 28) The method according to clause 27, wherein the electromagnetic transducer generates pressure fluctuations in the fluid by displacement induced on the outer surface of the fluid package.

[0125] (Clause 29) The method according to any one of clauses 26 to 28, wherein the electromagnetic transducer is configured to vibrate at an audible frequency.

[0126] (Clause 30) The method according to clause 29, wherein the audible frequency ranges from 50 to 5000 Hz.

[0127] (Clause 31) The method according to clause 30, wherein the audible frequency ranges from 800 to 1200 Hz.

[0128] (Article 32) The electromagnetic transducer is configured to operate with a vibration amplitude in the range of 2 to 3 μm , the method according to any one of Articles 26 to 31.

[0129] (Article 33) The electromagnetic transducer includes an electromagnet and a permanent magnet that are operably close to each other , the method according to any one of Articles 26 to 32.

[0130] (Article 34) The method according to Article 33, wherein the permanent magnet is disposed in a first region of the cantilever beam

[0131] (Article 35) The electromagnetic transducer is disposed in a second region of the cantilever beam and further includes a fixing portion configured to transmit a configured vibration displacement force to the outer surface of the drug package, the method according to Article 34 method.

[0132] (Article 36) The method according to any one of Articles 26 to 35, wherein the electromagnetic transducer is reusable method.

[0133] (Article 37) The fluid package includes an extended region including the reservoir and a neck region including the opening , the method according to any one of Articles 26 to 36.

[0134] (Article 38) The method according to any one of Articles 26 to 37, wherein the opening has a diameter in the range of 200 to 350 μm described method.

[0135] (Article 39) The method according to any one of Articles 26 to 38, wherein the reservoir is a multi-dose reservoir

[0136] (Clause 40) The method according to any one of Clauses 26 to 39, wherein the fluid package is disposable.

[0137] (Clause 41) The method according to any one of Clauses 26 to 40, wherein the device is configured to discharge a fluid through the opening as a flow having a velocity in the range of 50 to 150 m / s.

[0138] (Clause 42) The method according to any one of Clauses 26 to 41, further comprising an image-based alignment system configured to align the fluid discharged through the opening with the position of the target eye.

[0139] (Clause 43) The method according to Clause 42, wherein the image-based alignment system includes a reflecting surface.

[0140] (Clause 44) The method according to any one of Clauses 26 to 43, wherein the fluid package and the electromagnetic transducer are disposed within a housing.

[0141] (Clause 45) The method according to Clause 44, wherein the housing includes a cover disposed along the housing, the cover being configured to take an open position in which one or more openings are exposed and a closed position in which one or more openings are not exposed.

[0142] (Clause 46) The method according to Clause 45, wherein the cover includes a sliding cover structure.

[0143] (Clause 47) The method according to Clause 45, wherein the transducer is configured to operate when the cover is in the open position. ​​​​​​​The method according to clause 46.

[0144] (Clause 48) The method according to clause 47, wherein the electromagnetic transducer is deactivated when the cover is in the closed position. The method according to clause 47, which is configured as such.

[0145] (Clause 49) The method according to any one of clauses 26 to 48, wherein the device includes a light source.

[0146] (Clause 50) The method according to any one of clauses 26 to 49, wherein the device further comprises a distance sensor configured to determine the distance between the device and the target position. The method according to any one of clauses 26 to 49, which further includes such a component.

[0147] (Clause 51) The method according to any one of clauses 26 to 50, wherein the target position is the position of the eye.

[0148] (Clause 52) The method according to clause 51, wherein the position of the eye includes the position of the cornea / conjunctiva.

[0149] (Clause 53) The method according to clause 52, wherein the position of the eye includes a region in the range of 2.5 to 12 μm 2 The method according to clause 52, which includes such a region.

[0150] (Clause 54) The method according to any one of clauses 26 to 53, which is executed by a subject.

[0151] (Clause 55) The method according to any one of clauses 26 to 54, wherein the method is a method for treating a subject with respect to the state of the eye. The method according to any one of clauses 26 to 54, which is described as such.

[0152] (Clause 56) A kit comprising a fluid delivery device or a member thereof according to any one of clauses 1 to 25.

[0153] In at least some of the foregoing embodiments, one or more elements used in the embodiments can be interchangeably used in other embodiments, unless such substitution is technically infeasible. It will be understood by those skilled in the art that various other omissions, additions, and modifications can be made to the above methods and structures without departing from the scope of the claimed subject matter. All such modifications and changes are intended to fall within the scope of the subject matter as defined by the appended claims. Generally, the terms used herein, particularly in the appended claims (e.g., the body of the appended claims), are generally "open" terms (e.g., the term "comprising" should be interpreted as "comprising but not limited to", the term "having" should be interpreted as "having at least", the term "including" should be interpreted as "including but not limited to", etc.). If a specific number of recited claims is intended, such intent is explicitly recited in the claim, and in the absence of such recitation, it will be further understood by those in the art that no such intent exists. For example, for purposes of illustration, the following appended claims include the use of introductory phrases "at least one" and "one or more" to introduce a listing of claims. However, the use of such phrases should not be construed to mean that the introduction of a claim by the indefinite article "a" or "an" limits a particular claim containing such introduced claim recitation to an embodiment containing only one such recitation.

[0154]

[0155] ​​​​​​​​​​​​​​​​ However, the use of such terms should not be construed to mean that the introduction of a claim recitation by the indefinite article "a" or "an" limits any particular claim containing such introduced claim recitation to an embodiment containing only one such recitation. The same applies to the use of definite articles used to introduce an implicit claim. Further, even if a specific number of the introduced claims is explicitly recited, one of ordinary skill in the art will recognize that such recitation should be construed to mean at least the recited number (e.g., "two recitations" recited alone. In the absence of other qualifying language, at least two recitations, or two or more recitations). Even when the same claim contains an introductory phrase of "one or more" or "at least one" and an indefinite article such as "a" or "an" (e.g., "a" and / or "an" should be construed to mean "at least one" or "one or more"), the same applies. In addition, when a similar convention such as "at least one of A, B, C, etc." is used, generally, such a construction is intended to have a meaning that can be understood by one of ordinary skill in the art (e.g., "a system having at least one of A, B, and C" includes, but is not limited to, a system having only A, only B, only C, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). When a similar convention such as "at least one of A, B, or C" is used, generally, such a construction is intended to have a meaning that can be understood by one of ordinary skill in the art.

[0156] Furthermore, when a similar convention such as "at least one of A, B, C, etc." is used, generally, such a construction is intended to have a meaning that can be understood by one of ordinary skill in the art (e.g., "a system having at least one of A, B, and C" includes, but is not limited to, a system having only A, only B, only C, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). When a similar convention such as "at least one of A, B, or C" is used, generally, such a construction is intended to have a meaning that can be understood by one of ordinary skill in the art. (e.g., "a system having at least one of A, B, or C" includes, but is not limited to, a system having only A, only B, only C, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). In general, such a construction is intended to have a meaning that can be understood by one of ordinary skill in the art. For example, a "system having at least one of A, B, or C" includes, but is not limited to, systems having A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). Those skilled in the art will understand that in any of the specification, claims, or drawings, any disjunctive and / or phrase presenting substantially two or more alternative terms should be considered to potentially include either one of the terms, either one of the terms, or both terms. For example, the phrase "A or B" will be understood to include the possibilities of "A" or "B" or "A and B". Furthermore, when a disclosed feature or aspect is described with respect to a Markush group, one of ordinary skill in the art will recognize thereby that the disclosure also describes the same with respect to any individual element or subgroup of elements of the

[0157] Markush group. As will be understood by those skilled in the art, from the perspective of providing a written description, all ranges disclosed in this specification also include any and all possible subranges and combinations of those subranges. Each of the recited ranges can be

[0158] readily recognized as being fully described and can be decomposed into at least equal halves, thirds, fourths, fifths, tenths, etc. of the same range. By way of non-limiting example, each range discussed in this specification can be readily decomposed into lower thirds, middle thirds, and upper thirds, etc. As will also be understood by those skilled in the art, words such as "up to", "at least", "greater than", "more than", etc. ​​All languages such as "small" include the recited numbers and, as described above, then refer to the scope that can be decomposed into subranges. Finally, as will be understood by those skilled in the art, a range includes the individual elements. Thus, for example, a group having clauses 1 to 3 refers to a group having 1, 2, or 3 clauses. Similarly, a group having clauses 1 to 5 refers to a group having 1, 2, 3, 4, or 5 clauses, etc. As will be understood by those skilled in the art, a range includes the individual elements. Thus, for example, a group having clauses 1 to 3 refers to a group having 1, 2, or 3 clauses. Similarly, a group having clauses 1 to 5 refers to a group having 1, 2, 3, 4, or 5 clauses, etc. As will be understood by those skilled in the art, a range includes the individual elements. Thus, for example, a group having clauses 1 to 3 refers to a group having 1, 2, or 3 clauses. Similarly, a group having clauses 1 to 5 refers to a group having 1, 2, 3, 4, or 5 clauses, etc. As will be understood by those skilled in the art, a range includes the individual elements. Thus, for example, a group having clauses 1 to 3 refers to a group having 1, 2, or 3 clauses. Similarly, a group having clauses 1 to 5 refers to a group having 1, 2, 3, 4, or 5 clauses, etc. As will be understood by those skilled in the art, a range includes the individual elements. Thus, for example, a group having clauses 1 to 3 refers to a group having 1, 2, or 3 clauses. Similarly, a group having clauses 1 to 5 refers to a group having 1, 2, 3, 4, or 5 clauses, etc.

[0159] The foregoing invention has been described in some detail in an illustrative and exemplary manner for purposes of facilitating understanding, but it will be readily apparent to those of ordinary skill in the art that certain changes and modifications can be made without departing from the spirit or scope of the appended claims in light of the teachings of the invention. The foregoing invention has been described in some detail in an illustrative and exemplary manner for purposes of facilitating understanding, but it will be readily apparent to those of ordinary skill in the art that certain changes and modifications can be made without departing from the spirit or scope of the appended claims in light of the teachings of the invention. The foregoing invention has been described in some detail in an illustrative and exemplary manner for purposes of facilitating understanding, but it will be readily apparent to those of ordinary skill in the art that certain changes and modifications can be made without departing from the spirit or scope of the appended claims in light of the teachings of the invention. The foregoing invention has been described in some detail in an illustrative and exemplary manner for purposes of facilitating understanding, but it will be readily apparent to those of ordinary skill in the art that certain changes and modifications can be made without departing from the spirit or scope of the appended claims in light of the teachings of the invention.

[0160] Therefore, the foregoing merely illustrates the principles of the invention. It will be understood by those skilled in the art that, although not explicitly described or shown herein, various arrangements embodying the principles of the invention and falling within its spirit and scope can be devised. Further, all of the examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to the advancement of the art and are to be construed as not being limited to such specifically recited examples and conditions. Additionally, all descriptions in this specification that recall the principles, aspects, and embodiments of the invention, as well as any specific examples, are intended to encompass their structural and functional equivalents. Further, such equivalents include both currently known equivalents and equivalents developed in the future. Therefore, the foregoing merely illustrates the principles of the invention. It will be understood by those skilled in the art that, although not explicitly described or shown herein, various arrangements embodying the principles of the invention and falling within its spirit and scope can be devised. Further, all of the examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to the advancement of the art and are to be construed as not being limited to such specifically recited examples and conditions. Additionally, all descriptions in this specification that recall the principles, aspects, and embodiments of the invention, as well as any specific examples, are intended to encompass their structural and functional equivalents. Further, such equivalents include both currently known equivalents and equivalents developed in the future. Therefore, the foregoing merely illustrates the principles of the invention. It will be understood by those skilled in the art that, although not explicitly described or shown herein, various arrangements embodying the principles of the invention and falling within its spirit and scope can be devised. Further, all of the examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to the advancement of the art and are to be construed as not being limited to such specifically recited examples and conditions. Additionally, all descriptions in this specification that recall the principles, aspects, and embodiments of the invention, as well as any specific examples, are intended to encompass their structural and functional equivalents. Further, such equivalents include both currently known equivalents and equivalents developed in the future. Therefore, the foregoing merely illustrates the principles of the invention. It will be understood by those skilled in the art that, although not explicitly described or shown herein, various arrangements embodying the principles of the invention and falling within its spirit and scope can be devised. Further, all of the examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to the advancement of the art and are to be construed as not being limited to such specifically recited examples and conditions. Additionally, all descriptions in this specification that recall the principles, aspects, and embodiments of the invention, as well as any specific examples, are intended to encompass their structural and functional equivalents. Further, such equivalents include both currently known equivalents and equivalents developed in the future. Therefore, the foregoing merely illustrates the principles of the invention. It will be understood by those skilled in the art that, although not explicitly described or shown herein, various arrangements embodying the principles of the invention and falling within its spirit and scope can be devised. Further, all of the examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to the advancement of the art and are to be construed as not being limited to such specifically recited examples and conditions. Additionally, all descriptions in this specification that recall the principles, aspects, and embodiments of the invention, as well as any specific examples, are intended to encompass their structural and functional equivalents. Further, such equivalents include both currently known equivalents and equivalents developed in the future. Therefore, the foregoing merely illustrates the principles of the invention. It will be understood by those skilled in the art that, although not explicitly described or shown herein, various arrangements embodying the principles of the invention and falling within its spirit and scope can be devised. Further, all of the examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to the advancement of the art and are to be construed as not being limited to such specifically recited examples and conditions. Additionally, all descriptions in this specification that recall the principles, aspects, and embodiments of the invention, as well as any specific examples, are intended to encompass their structural and functional equivalents. Further, such equivalents include both currently known equivalents and equivalents developed in the future. Therefore, the foregoing merely illustrates the principles of the invention. It will be understood by those skilled in the art that, although not explicitly described or shown herein, various arrangements embodying the principles of the invention and falling within its spirit and scope can be devised. Further, all of the examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to the advancement of the art and are to be construed as not being limited to such specifically recited examples and conditions. Additionally, all descriptions in this specification that recall the principles, aspects, and embodiments of the invention, as well as any specific examples, are intended to encompass their structural and functional equivalents. Further, such equivalents include both currently known equivalents and equivalents developed in the future. Therefore, the foregoing merely illustrates the principles of the invention. It will be understood by those skilled in the art that, although not explicitly described or shown herein, various arrangements embodying the principles of the invention and falling within its spirit and scope can be devised. Further, all of the examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to the advancement of the art and are to be construed as not being limited to such specifically recited examples and conditions. Additionally, all descriptions in this specification that recall the principles, aspects, and embodiments of the invention, as well as any specific examples, are intended to encompass their structural and functional equivalents. Further, such equivalents include both currently known equivalents and equivalents developed in the future. Therefore, the foregoing merely illustrates the principles of the invention. It will be understood by those skilled in the art that, although not explicitly described or shown herein, various arrangements embodying the principles of the invention and falling within its spirit and scope can be devised. Further, all of the examples and conditional language recited herein are principally intended to aid the reader in understanding the principles of the invention and the concepts contributed by the inventors to the advancement of the art and are to be construed as not being limited to such specifically recited examples and conditions. Additionally, all descriptions in this specification that recall the principles, aspects, and embodiments of the invention, as well as any specific examples, are intended to encompass their structural and functional equivalents. Further, such equivalents include both currently known equivalents and equivalents developed in the future. Both equivalents thereof, i.e., both developed elements that perform the same function regardless of structure, are intended to be included. Furthermore, what is disclosed herein is not intended to be dedicated to the public whether or not such disclosure is explicitly recited in the claims.

[0161] Accordingly, the scope of the present invention is not intended to be limited to the exemplary embodiments shown and described herein. In the claims, 35 U.S.C.§1 12(f) or 35 U.S.C.§112(6) is explicitly defined to be invoked only for limitations of the claims where the exact phrase "means" or the exact phrase "step" is recited at the beginning of such a limitation of the claims, and 35 U.S.C. §112(f) or 35 U.S.C.§112(6) is not invoked where such exact phrases are not used in the claim limitations. ​

Claims

1. 1. A fluid delivery device comprising: (a) a fluid package comprising: (i) a reservoir containing an ophthalmic formulation; (ii) the fluid package having an opening; (b) removing the opening from the reservoir at a rate that minimizes discomfort during localized intraocular delivery; an electromagnetic transducer configured to vibrate at a frequency sufficient to eject a fluid through the and, 16. A fluid delivery device comprising:

2. The electromagnetic transducer is adapted to expel fluid from the reservoir through the opening.

2. The fluid delivery system of claim 1, wherein the fluid delivery system is configured to generate pressure variations in the fluid. Device.

3. The electromagnetic transducer is actuated by a displacement induced on the outer surface of the fluid package. The fluid delivery device of claim 2 , wherein the fluid delivery device generates a pressure variation in the fluid by applying a pressure change to the fluid.

4. The electromagnetic transducer according to any one of claims 1 to 3, wherein the electromagnetic transducer vibrates at an audio frequency. The fluid delivery device.

5. 5. The fluid delivery device of claim 4, wherein the audible frequency range is 800 to 1200 Hz. Place.

6. The electromagnetic transducer is configured to operate at a vibration amplitude in the range of 2 to 3 μm. The fluid delivery device of any one of claims 1 to 5.

7. The electromagnetic transducer includes an electromagnet and a permanent magnet in operative proximity to one another. The fluid delivery device of any one of claims 1 to 6.

8. The permanent magnet is disposed on a first region of the cantilever, and the electromagnetic transducer is disposed on the front The cantilever further includes a fastener disposed in a second region thereof, the fastener being adapted to transmit a vibration displacement force to the drug package. The fluid delivery device of claim 7 , configured to communicate with an exterior surface of the fluid delivery device.

9. 9. A method according to claim 1, wherein the openings have a diameter in the range of 200 to 350 μm. The fluid delivery device as described above.

10. Discharging the fluid through the opening as a stream having a velocity in the range of 50 to 150 cm / sec. The fluid delivery device of any one of claims 1 to 9, configured to:

11. configured to direct fluid ejected through the opening to a target eye location.

11. The method according to claim 1, further comprising an image-based alignment system. The fluid delivery device of any one of claims 1 to 7.

12. the fluid package and the electromagnetic transducer are disposed within a housing; The fluid delivery device of any one of claims 1 to 11.

13. The housing includes a cover disposed along the housing, the cover comprising: an open position in which one or more of the apertures are exposed, and a closed position in which one or more of the apertures are not exposed; The fluid delivery device of claim 12 , configured to assume a position.

14. 1. A method of delivering a fluid to a target location in a subject, comprising: (a) aligning a fluid delivery device according to any one of claims 1 to 13 to the target location; Steps and (b) withdrawing the fluid from the reservoir through said opening at a rate that minimizes discomfort during localized intraocular delivery. activating an electromagnetic transducer to eject fluid at the target location; The method includes:

15. A kit comprising a fluid delivery device or component thereof according to any one of claims 1 to 13.

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