Device and method for flow control of ophthalmic preparations

Abstract

A flow control device for a compressible bottle may include a reservoir, the reservoir including an ophthalmic preparation disposed therein, the ophthalmic preparation including an ophthalmic agent and a preservative; a reservoir interface disposed at the mouth of the reservoir, the reservoir interface including one or more holes, the one or more holes in the reservoir interface fluidly connecting the interior of the reservoir and the exterior of the reservoir; a nozzle, the nozzle including an outlet and a nozzle cap, the nozzle cap including one or more holes, the one or more holes in the nozzle cap fluidly connecting the outlet and a surface of the nozzle facing the reservoir; and a rotation axis, wherein rotation of the nozzle about the rotation axis relative to the reservoir aligns the one or more holes in the reservoir interface with the one or more holes in the nozzle cap.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application No. 62 / 825,176, filed on March 28, 2019, and U.S. Provisional Application No. 62 / 993,418, filed on March 23, 2020, each of which is incorporated herein by reference in its entirety. Background Art

[0003] The present disclosure generally relates to systems and methods for removing preservatives and preservatives from fluids containing therapeutic agents.

[0004] In at least some aspects, other methods of removing preservatives from fluids containing therapeutic agents for the eye may be less than ideal. Patients with chronic diseases may instill eye drops every day, for example, for the treatment of glaucoma. To prevent bacterial growth, commercial eye drop formulations often use preservatives to address possible bacterial contamination.

[0005] Although preservative removal devices have been proposed, such methods may be less than ideal and overly complex in at least some cases. For example, the concentration of the preservative may not be stable after repeated use. Field of the Invention

[0006] The present disclosure relates to devices and methods for removing preservatives from fluids containing therapeutic agents. These devices and methods provide various advantages and improvements over other methods for removing preservatives from fluids containing therapeutic agents. For example, preservative removal devices may be overly complex and inadvertently reduce the concentration of preservatives within a formulation in a reservoir and / or remove the therapeutic agent during administration. Therefore, disclosed herein are devices and methods that provide technical solutions to address at least some of the above-mentioned shortcomings of other methods and reduce preservatives in eye drops while substantially maintaining the therapeutic agent.

[0007] The device can be constructed in a variety of ways and can include a nozzle that is configured to deliver the therapeutic agent to the eye using the nozzle. The currently disclosed method and apparatus can reduce the preservative in the eye drops while substantially maintaining the therapeutic agent, wherein the concentration of the preservative in the bottle varies very little. This can be achieved with a nozzle mounted on the end of a squeeze bottle that controls the flow of eye drops to the patient. Although reference is made to the treatment of the eye with a nozzle coupled to a container, the method and apparatus disclosed herein can be configured in a variety of ways to deliver the therapeutic agent to many locations of the body, such as using an implantable device, a syringe coupled to a needle, and intravenous drug delivery.

[0008] In one aspect, a flow control device for a compressible bottle is provided. The flow control device may include: a reservoir including an ophthalmic preparation disposed therein, the ophthalmic preparation including an ophthalmic agent and a preservative; a reservoir interface disposed at a mouth of the reservoir, the reservoir interface including one or more holes, the one or more holes in the reservoir interface fluidly connecting an interior of the reservoir and an exterior of the reservoir; a nozzle including an outlet and a nozzle cap, the nozzle cap including one or more holes, the one or more holes in the nozzle cap fluidly connecting the outlet and a surface of the nozzle facing the reservoir; and a rotation axis, wherein rotation of the nozzle about the rotation axis relative to the reservoir aligns the one or more holes in the reservoir interface with the one or more holes in the nozzle cap.

[0009] In some embodiments, the flow control device further comprises a polymer matrix disposed in the internal volume of the nozzle, the polymer matrix comprising absorbing molecules of a preservative from the ophthalmic preparation. In some embodiments, the rotation of the reservoir interface prevents the flow of the ophthalmic preparation between the interior of the nozzle and the reservoir, thereby stabilizing the concentration of the preservative in the ophthalmic preparation. In some embodiments, the flow control device further comprises a bottle cap, wherein the rotation of the bottle cap relative to the reservoir around the axis of rotation causes the nozzle to rotate relative to the reservoir around the axis of rotation. In some embodiments, the nozzle comprises one or more ridges on the surface facing the bottle cap, the first or more ridges being received by the bottle cap. In some embodiments, the bottle cap comprises one or more alignment channels on the inner surface of the bottle cap, the first or more ridges on the surface of the nozzle cap facing the bottle cap being received in the one or more alignment channels. In some embodiments, the nozzle comprises a second or more ridges on the surface facing the reservoir, the second or more ridges being received by the reservoir. In some embodiments, the reservoir comprises one or more rotation guides, and the second one or more ridges on the surface facing the reservoir are received by the one or more rotation guides. In some embodiments, the second one or more ridges on the bottle facing surface received by the rotation guide limit the rotation angle of the nozzle relative to the reservoir interface. In some embodiments, the bottle cap comprises a screw cap.

[0010] In some embodiments, the reservoir interface further comprises one or more alignment tabs, and wherein the mouth of the reservoir comprises one or more alignment channels, wherein the one or more alignment tabs are received in the one or more alignment channels, thereby rotationally fixing the orientation of the reservoir interface relative to the reservoir. In some embodiments, the nozzle cap is rotationally fixed relative to the nozzle. In some embodiments, the flow control device further comprises a filter disposed in the nozzle. In some embodiments, the polymer matrix comprises polyhydroxyethyl methacrylate (pHEMA), polyhydroxyethyl methacrylate-co-methacrylic acid or a combination thereof. In some embodiments, the polymer matrix comprises at least one monomer selected from hydroxyethyl methacrylate (HEMA), methacrylic acid (MAA), N-vinyl pyrrolidone (NVP), dimethyl acrylamide (DMA), tert-butyl methacrylate (TBM) and methacryloyloxypropyl tris(trimethylsiloxane) silane (TRIS). In some embodiments, the ophthalmic agent comprises at least one of timolol maleate, levofloxacin, dorzolamide, brimonidine tartrate, bimatoprost, tetrahydrozoline hydrochloride, or olopatadine. In some embodiments, the ophthalmic agent comprises timolol maleate and brimonidine tartrate. In some embodiments, the preservative comprises at least one of benzalkonium chloride, Sofzia or Pumite. In some embodiments, the reservoir comprises less than 100 ml of an ophthalmic preparation.

[0011] In another aspect, the present disclosure provides a method for controlling the concentration of a preservative in an ophthalmic preparation. The method comprises: receiving the bottle of any aspect or embodiment herein and rotating the nozzle or the bottle cap relative to the reservoir.

[0012] In another aspect, the present disclosure provides a method of making a flow control device as described in any aspect or embodiment herein. The method may include: filling the reservoir with the ophthalmic formulation; placing the reservoir interface on the reservoir; placing the nozzle cap on the nozzle; and placing the nozzle at the mouth of the reservoir. In some embodiments, the method further includes placing a bottle cap on the nozzle.

[0013] In another aspect, a kit includes the flow control device of any aspect or embodiment herein, and packaging is provided. In some embodiments, the kit further includes a label, wherein the label includes an indication of the contents of the ophthalmic formulation disposed within the reservoir.

[0014] In another aspect, the present disclosure provides a flow control device for delivering an ophthalmic preparation. The device may include: a reservoir including an ophthalmic preparation disposed therein, the ophthalmic preparation including an ophthalmic agent and a preservative; a nozzle including: an outlet including an internal volume of a preservative removal device, and one or more nozzle holes fluidly connecting the internal volume to the exterior of the nozzle; and a reservoir interface including one or more reservoir holes, wherein upon rotation or translation of the nozzle relative to the reservoir interface, the one or more nozzle holes are fluidly connected to the one or more reservoir holes.

[0015] In some embodiments, the preservative removal device comprises a polymer matrix comprising absorbing molecules of the preservative from the ophthalmic formulation. In some embodiments, upon rotation or translation of the nozzle, the one or more nozzle apertures are fluidly disconnected from the one or more reservoir apertures, thereby preventing flow of the ophthalmic formulation between the interior volume of the nozzle and the reservoir and stabilizing the concentration of the preservative in the ophthalmic formulation.

[0016] In some embodiments, the device further comprises a bottle cap, wherein the rotation of the bottle cap relative to the reservoir causes the nozzle to rotate or translate relative to the reservoir interface. In some embodiments, when moved to a closed state, the bottle cap produces an audible or tactile click. In some embodiments, the bottle cap comprises a closure assembly that resists manipulation by children.

[0017] In some embodiments, the nozzle comprises an outlet filter adjacent to the outlet. In some embodiments, the outlet filter comprises a mesh or screen. In some embodiments, the nozzle comprises an inlet filter adjacent to the one or more nozzle holes. In some embodiments, the inlet filter comprises a mesh or screen.

[0018] In some embodiments, the device further comprises a bottle cap, wherein when the bottle cap is removed, one or more nozzle holes are aligned with the one or more reservoir holes, and wherein when the bottle cap is coupled to the nozzle, one or more nozzle holes are not aligned with the one or more reservoir holes. In some embodiments, when the bottle cap is removed, the nozzle is in an aligned rotational position. In some embodiments, the rotation of the bottle cap relative to the reservoir around the axis of rotation causes the nozzle to rotate relative to the reservoir around the axis of rotation. In some embodiments, the nozzle includes one or more ridges on the surface facing the bottle cap, and the one or more ridges can be received by the bottle cap. In some embodiments, the bottle cap includes one or more alignment channels on the inner surface of the bottle cap, and the one or more ridges on the surface facing the bottle cap of the nozzle are received in the one or more alignment channels.

[0019] In some embodiments, the nozzle includes a second one or more ridges on the reservoir interface facing surface, and the second one or more ridges can be received by the reservoir interface. In some embodiments, the reservoir interface includes one or more rotation guides, and the second one or more ridges on the reservoir interface facing surface are received by the one or more rotation guides. In some embodiments, the second one or more ridges on the reservoir interface facing surface received by the one or more rotation guides limit the rotation angle of the nozzle relative to the reservoir interface.

[0020] In some embodiments, when the bottle cap is removed, the nozzle is in the aligned translational position. In some embodiments, a spring is disposed between the nozzle and the reservoir interface, and wherein when the bottle cap is removed, the restoring force of the spring translates the nozzle to the aligned translational position. In some embodiments, when the bottle cap is in a closed state, the nozzle is not in the aligned position. In some embodiments, when the bottle cap is in a closed state, the spring is at least partially compressed.

[0021] In some embodiments, the device further comprises a translation stop. In some embodiments, the translation stop comprises a plug configured to seal the one or more nozzle holes. In some embodiments, the translation stop comprises a rotation stop for the bottle cap.

[0022] In some embodiments, the nozzle comprises a housing configured to house the preservative removal device, wherein the housing translates relative to an outer surface of the reservoir interface. In some embodiments, a gasket provides a fluid seal between the reservoir interface and the nozzle. In some embodiments, an interference fit provides a fluid seal between the reservoir interface and the nozzle.

[0023] In another aspect, the present disclosure provides a flow control device for delivering an ophthalmic preparation. The device may include: a reservoir, the reservoir including an ophthalmic preparation disposed therein, the ophthalmic preparation including an ophthalmic agent and a preservative; a reservoir interface disposed at the mouth of the reservoir, the reservoir interface including one or more holes, the one or more holes in the reservoir interface fluidly connecting the interior of the reservoir and the exterior of the reservoir; a nozzle, the nozzle including an outlet and a nozzle seal, the nozzle seal including one or more holes, the one or more holes in the nozzle cap fluidly connecting the outlet and the surface of the nozzle oriented toward the reservoir interface; and a rotation axis, wherein rotation of the nozzle about the rotation axis relative to the reservoir aligns the one or more holes in the reservoir interface with the one or more holes in the nozzle seal.

[0024] In some embodiments, the device comprises a polymer matrix disposed in the interior volume of the nozzle, the polymer matrix comprising absorbing molecules of a preservative from the ophthalmic formulation. In some embodiments, rotation of the nozzle prevents flow of the ophthalmic formulation between the interior of the nozzle and the reservoir, thereby stabilizing the concentration of the preservative in the ophthalmic formulation.

[0025] In some embodiments, the device further comprises a bottle cap, wherein rotation of the bottle cap relative to the reservoir about an axis of rotation causes the nozzle to rotate relative to the reservoir about an axis of rotation. In some embodiments, the nozzle comprises one or more ridges on a surface facing the bottle cap, and the one or more ridges can be received by the bottle cap. In some embodiments, the bottle cap comprises one or more alignment channels on an inner surface of the bottle cap, and the one or more ridges on the surface of the nozzle seal facing the bottle cap are received in the one or more alignment channels.

[0026] In some embodiments, the nozzle includes a second one or more ridges on the surface facing the reservoir, and the second one or more ridges can be received by the reservoir. In some embodiments, the reservoir includes one or more rotation guides, and the second one or more ridges on the surface facing the reservoir are received by the one or more rotation guides. In some embodiments, the second one or more ridges on the bottle facing surface received by the rotation guide limit the rotation angle of the nozzle relative to the reservoir interface.

[0027] In some embodiments, the bottle cap comprises a screw cap. In some embodiments, the reservoir interface further comprises one or more alignment tabs, and wherein the mouth of the reservoir comprises one or more alignment channels, wherein the one or more alignment tabs are received within the one or more alignment channels, thereby rotationally fixing the orientation of the reservoir interface relative to the reservoir. In some embodiments, the nozzle seal is rotationally fixed relative to the nozzle. In some embodiments, the device further comprises a filter disposed within the nozzle.

[0028] In some embodiments, the polymer matrix includes polyhydroxyethyl methacrylate (pHEMA), polyhydroxyethyl methacrylate-co-methacrylic acid or a combination thereof. In some embodiments, the polymer matrix includes at least one monomer selected from hydroxyethyl methacrylate (HEMA), methacrylic acid (MAA), N-vinyl pyrrolidone (NVP), dimethyl acrylamide (DMA), tert-butyl methacrylate (TBM) and methacryloxypropyl tris (trimethylsiloxane) silane (TRIS). In some embodiments, the ophthalmic agent includes at least one of timolol maleate, levofloxacin, dorzolamide, brimonidine tartrate, bimatoprost, tetrahydrozoline hydrochloride, or olopatadine. In some embodiments, the ophthalmic agent includes timolol maleate and brimonidine tartrate. In some embodiments, the preservative includes at least one of benzalkonium chloride, Sofzia or Pumite. In some embodiments, the reservoir includes less than 100 ml of ophthalmic preparation.

[0029] Incorporation by reference

[0030] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. In the event that publications and patents or patent applications incorporated by reference conflict with the disclosure contained in this specification, this specification is intended to supersede and / or take precedence over any such conflicting material. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] The novel features of the present invention are particularly set forth in the appended claims. The features and advantages of the present invention will be better understood by reference to the following detailed description and the accompanying drawings, which set forth illustrative embodiments utilizing the principles of the present invention, wherein:

[0032] Figure 1 An exploded view of a flow control device according to some embodiments is illustrated.

[0033] Figure 2An external view of a flow control device integrated with a squeezable bottle according to some embodiments is illustrated.

[0034] Figure 3A and Figure 3B An exterior view and a cross-sectional view, respectively, of a flow control device in an open position according to some embodiments are illustrated.

[0035] Figure 4A and Figure 4B An exterior view and a cross-sectional view, respectively, are illustrated of a flow control device in a closed position according to some embodiments.

[0036] Figure 5A and Figure 5B An exterior view and a cross-sectional view, respectively, of a nozzle and a nozzle cap in a closed position according to some embodiments are illustrated.

[0037] Fig. 6A and Figure 6B An exterior view and a cross-sectional view, respectively, of a nozzle and a nozzle cap in an open position according to some embodiments are illustrated.

[0038] Fig. 7A and Figure 7B A ridge on a reservoir-facing surface of a nozzle received by a rotational guide on the reservoir is illustrated in an open position and a closed position, respectively, according to some embodiments.

[0039] Fig. 8A and Figure 8B An exterior view and a cross-sectional view of a nozzle and a bottle cap according to some embodiments are respectively illustrated.

[0040] Fig.9A and Fig. 9B Two views of a bottle cap according to some embodiments are illustrated.

[0041] Fig.10 Illustrated is a partially exploded view of another example flow control device in accordance with some embodiments.

[0042] Fig.11 An integrated squeezable bottle is shown according to some embodiments. Fig.10 External view of the flow control device.

[0043] Fig.12 An integrated squeezable bottle is shown according to some embodiments. Fig.10 A cross-sectional view of a flow control device.

[0044] Fig.13A and Fig. 13B An integrated squeezable bottle is shown according to some embodiments. Fig.10 Side view of the interaction between the nozzle of the flow control device and the reservoir interface.

[0045] Fig.14 Illustrated is a partially exploded view of another example flow control device in accordance with some embodiments.

[0046] Fig.15A and Fig. 15B Illustrated according to some embodiments Fig.14 External views of the flow control device with and without a cap.

[0047] Fig.16A , Fig. 16B 1 and 2 respectively illustrate a capped and uncapped Fig.14 A cross-sectional view of a flow control device.

[0048] Fig.17A , Fig. 17B According to some embodiments, Fig.14 Cross-sectional and external views of a nozzle assembly of a flow control device.

[0049] Fig.18A , Fig.18B According to some embodiments, Fig.14 Cross-sectional view and external view of the nozzle of the flow control device.

[0050] Fig.19A , Fig.19B According to some embodiments, Fig.14 External and cross-sectional views of a reservoir interface of a flow control device.

[0051] Fig. 20 Illustrated according to some embodiments Fig.14 Isomorphic view of the nozzle interface of the flow control device.

[0052] Fig.21 Illustrated according to some embodiments Fig.14 Isomorphic view of the nozzle cap of the flow control device.

[0053] Fig.22A , Fig. 22B and Fig. 22C According to some embodiments, Fig.14 Cap of the flow control device.

[0054] Fig.23A , Fig. 23B and Fig.23C According to some embodiments, Fig.14 The internal cap of the flow control device.

[0055] Fig.24A and Fig. 24B Illustrated according to some embodiments Fig.14 A variation of the nozzle design that includes an O-ring seal. DETAILED DESCRIPTION

[0056] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. All patents and publications cited herein are incorporated herein by reference.

[0057] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art to which the present invention belongs. As used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural references unless the context clearly indicates otherwise. Any reference to "or" herein is intended to include "and / or" unless otherwise indicated.

[0058] Whenever the term "at least" or "greater than" or "greater than or equal to" precedes the first value in a series of two or more values, the term "at least" or "greater than" or "greater than or equal to" applies to each value in the series. For example, greater than or equal to 1, 2, or 3 is equal to greater than or equal to 1, greater than or equal to 2, or greater than or equal to 3.

[0059] Whenever the term "not more than," "less than," or "less than or equal to" precedes the first value in a series of two or more values, "not more than," "less than," or "less than or equal to" applies to every value in the series. For example, less than or equal to 3, 2, or 1 is equal to less than or equal to 3, less than or equal to 2, or less than or equal to 1.

[0060] As used herein, and unless otherwise specified, the term "about" or "approximately" refers to an acceptable error for a particular value determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" refers to within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" refers to within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, or 0.05% of a given value or range. In certain embodiments, the term "about" or "approximately" refers to within 40.0 mm, 30.0 mm, 20.0 mm, 10.0 mm, 5.0 mm, 1.0 mm, 0.9 mm, 0.8 mm, 0.7 mm, 0.6 mm, 0.5 mm, 0.4 mm, 0.3 mm, 0.2 mm, or 0.1 mm of a given value or range.

[0061] As used herein, the terms "comprises," "comprising," or any other variations thereof, are intended to cover a non-exclusive inclusion such that a process, method, article, or apparatus that comprises a list of elements includes more than just those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.

[0062] As used herein, the terms "user", "subject" or "patient" are used interchangeably. As used herein, the term "subject" refers to animals (e.g., birds, reptiles, and mammals), mammals including primates (e.g., monkeys, chimpanzees, and humans) and non-primates (e.g., camels, donkeys, zebras, cows, pigs, horses, cats, dogs, rats, and mice). In certain embodiments, the age of the mammal is 0 to 6 months, 6 to 12 months, 1 to 5 years, 5 to 10 years, 10 to 15 years, 15 to 20 years, 20 to 25 years, 25 to 30 years, 30 to 35 years, 35 to 40 years, 40 to 45 years, 45 to 50 years, 50 to 55 years, 55 to 60 years, 60 to 65 years, 65 to 70 years, 70 to 75 years, 75 to 80 years, 80 to 85 years, 85 to 90 years, 90 to 95 years, or 95 to 100 years. In some embodiments, the subject or patient is a pig. In certain embodiments, the age of the pig is 0 to 6 months, 6 to 12 months, 1 to 5 years, 5 to 10 years, or 10 to 15 years. The natural lifespan of a pig is 10-15 years.

[0063] The term "treat" refers to any sign of successful treatment or amelioration of an injury, disease, pathology, or condition, including any objective or subjective parameter, such as ablation; remission; lessening of symptoms or making the injury, pathology, or condition more tolerable to the patient; slowing the rate of deterioration or decline; making the endpoint of deterioration less debilitating; improving the patient's physical or mental well-being. Treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation. The term "treat" and its conjugations include prevention of an injury, pathology, condition, or disease.

[0064] In some embodiments, "prevention" with respect to a disease or condition can refer to a compound that, in a statistical sample, reduces the occurrence of the disease or condition in treated samples relative to untreated control samples, or delays the onset of or reduces the severity of one or more symptoms of the disease or condition relative to untreated control samples.

[0065] The term "effective amount" is an amount of a compound sufficient to achieve a given purpose relative to the absence of the compound (e.g., to achieve the effect for which it is administered, to treat a disease, to reduce enzyme activity, to increase enzyme activity, to reduce a signaling pathway, or to reduce one or more symptoms of a disease or condition). An example of a "therapeutically effective amount" is an amount sufficient to help treat, prevent, or reduce one or more symptoms of a disease, which may also be referred to as a "therapeutically effective amount". "Reduction" of one or more symptoms (and grammatical equivalents of this phrase) refers to a decrease in the severity or frequency of the symptoms, or the elimination of the symptoms. The specific amount may depend on the purpose of the treatment and may be determined by those skilled in the art using known techniques.

[0066] The phrase "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0067] The term "substituted" refers to a portion where a substituent replaces hydrogen on one or more carbons or heteroatoms of the structure. It should be understood that "substituted" or "substituted by..." includes implicit conditions, i.e., the substitution is based on the allowed valence of the substituted atom and the substituent, and the substitution produces a stable compound, for example, it will not spontaneously undergo transformations such as rearrangement, cyclization, elimination, etc. As used herein, it is envisioned that the term "substituted" includes all allowed substituents of organic compounds. In a broad sense, allowed substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. For suitable organic compounds, allowed substituents may be one or more identical or different substituents. For the purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituents and / or any allowed substituents of organic compounds described herein that satisfy the heteroatom valence.

[0068] In the following detailed description, reference is made to the accompanying drawings, which form a part thereof. In the drawings, the same symbols generally identify the same parts unless the context indicates otherwise. The illustrative embodiments described in the detailed description, drawings, and claims are not meant to be limiting. Other embodiments may be utilized, and other changes may be made, without departing from the scope of the subject matter presented herein. It will be readily understood that aspects of the present disclosure, as generally described herein and illustrated in the drawings, can be arranged, substituted, combined, separated, and designed in a variety of different configurations, all of which are expressly contemplated herein.

[0069] Aspects of the present disclosure relate to systems, methods, devices and kits for controlling the flow of ophthalmic preparations through delivery devices. Aspects of the present disclosure can reduce, prevent or eliminate the instability of preservative concentrations over time in ophthalmic preparations. Aspects of the present disclosure can include a compressible bottle, such as an eye drop bottle, or can be used in combination with a compressible bottle.

[0070] Disclosed herein is a flow control device for delivering an ophthalmic preparation. The device may include a reservoir. The reservoir may include an ophthalmic preparation disposed with the reservoir. The ophthalmic preparation may include an ophthalmic agent and a preservative. The flow control device may include a nozzle. The nozzle may include an outlet. The nozzle may include an internal volume, the internal volume including a preservative removal device. The nozzle may include one or more nozzle holes that fluidly connect the internal volume to the exterior of the nozzle. The device may include a reservoir interface. The reservoir interface may include one or more reservoir holes. Upon rotation or translation of the nozzle relative to the reservoir interface, the one or more nozzle holes are fluidly connected to the one or more reservoir holes.

[0071] Figure 1 An exploded view of an example flow control device is illustrated in accordance with some embodiments.

[0072] Figure 1 Other views and components of example flow control devices are shown in Figure 2 , Figure 3A , Figure 3B , Figure 4A , Figure 4B , Figure 5A , Figure 5B , Fig. 6A , Figure 6B , Fig. 7A , Figure 7B , Fig. 8A , Figure 8B , Fig.9A and Fig. 9B Medium picture. Fig.10 Illustrated is a partially exploded view of another example flow control device in accordance with some embodiments. Fig.10 Other views and components of example flow control devices are shown in Fig.11 , Fig.12 , Fig.13A and Fig. 13B Medium picture. Fig.14 An exploded view of another example flow control device is illustrated in accordance with some embodiments. Fig.14 Other views and components of example flow control devices are shown in Fig.15A , Fig. 15B , Fig.16A , Fig. 16B , Fig.17A , Fig. 17B , Fig.18A , Fig.18B , Fig.19A , Fig.19B , Fig. 20 , Fig.21 , Fig.22A , Fig. 22B , Fig. 22C , Fig.23A , Fig. 23B and Fig.23C Medium picture. Fig.24A and Fig. 24B Illustrated is a cross-sectional view of another example flow control device, according to some embodiments.

[0073] Unless the context is contradictory, the various parts of the flow control device of the present disclosure can be made of various materials, such as plastic, metal, glass, etc. The plastic parts can include one or a combination of various polyolefins, polypropylene, polyethylene, etc. The parts can be molded, machined, extruded, 3D printed, cast, vacuum formed, etc., depending on the type of plastic. Alignment features, tabs, ridges, and spring elements can be optionally reinforced with polycarbonate as needed, for example as reinforcement.

[0074] The devices, systems, and methods of the present disclosure can be combined with flow dividers of various geometries, for example, as disclosed in International Publication No. WO2019 / 195734, which is incorporated herein by reference. For example, the internal volume of a nozzle as disclosed herein may include an example of a flow divider of WO2019 / 195734 disposed within the volume.

[0075] Figure 1 An exploded view of an example flow control device according to some embodiments is illustrated. The flow control device may include a nozzle 100. The reservoir may include an ophthalmic preparation disposed therein. The ophthalmic preparation may include an ophthalmic agent and a preservative as described elsewhere herein, such as in the "Ophthalmic Agents" and "Preservatives" sections. The ophthalmic preparation may include any example preparation disclosed herein, such as in the "Solutions, Emulsions, or Suspensions" section. The reservoir 100 may include a compressible bottle, such as a reservoir of a commercially available eye drop bottle. In some cases, the reservoir 100 may use a commonly available commercial bottle. In other cases, the reservoir 100 may be a special bottle designed for a specific application, such as the systems, methods, devices, and kits disclosed herein.

[0076] The reservoir of the present disclosure may include an internal volume that may include an ophthalmic preparation as disclosed herein. The reservoir may include an internal volume of about 2.5cc. The reservoir may include an internal volume of about 8cc. The reservoir may include at least about 0.2 cubic centimeters (cc), at least about 0.5cc, at least about 1cc, at least about 1.5cc, at least about 2cc, at least about 2.5cc, at least about 3cc, at least about 4cc, at least about 5cc, at least about 6cc, at least about 7cc, at least about 8cc, at least about 10cc or more internal volumes. The reservoir may include an internal volume of about 0.1cc to about 10cc, about 1cc to about 10cc, about 2cc to about 10cc, about 2.5cc to about 10cc, etc. For example, an 8cc bottle may dispense an ophthalmic preparation of about 5cc. For example, a 2.5cc bottle may dispense an ophthalmic preparation of about 2cc.

[0077] In some cases, the ophthalmic preparation can at least partially fill the internal volume of the reservoir. The ophthalmic preparation can fill at least about 1%, at least about 2%, at least about 5%, at least about 10%, at least about 20%, at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95% or more of the internal volume of the reservoir. The ophthalmic preparation can fill about 1% to about 99%, about 10% to about 98%, about 25% to about 50%, about 10% to about 50%, etc. of the internal volume of the reservoir.

[0078] The reservoir of the present disclosure may be made of plastic. The plastic may be compressible. The plastic may include one or a combination of various polyolefins, polypropylene, polyethylene, etc. The reservoir may include low-density polyethylene (e.g., Nalgene TM ). The reservoir may include a compressible bottle reservoir. The bottle may be made of a material that is soft enough to allow a person to at least partially collapse the sides of the reservoir, thereby increasing the pressure within the reservoir. The reservoir 100 may include threads 106.

[0079] The flow control device may include a reservoir interface 150, which is arranged at the mouth 108 of the reservoir. The reservoir interface may include one or more holes 152. One or more holes in the reservoir interface can fluidly connect the interior of the reservoir to the exterior of the reservoir. One or more holes may include at least 1 hole, at least 2 holes, at least about 5 holes, at least about 10 holes, at least about 20 holes, at least about 50 holes, at least about 100 holes or more. In some cases, one or more holes include the opening of the filter. One or more holes may include from about 1 to about 100, from about 1 to about 50, from about 1 to about 10, from about 5 to about 100, from about 10 to about 100, from about 2 to about 20. The number of holes.

[0080] One or more holes may include a diameter of at least about 1 micron, at least about 2 microns, at least about 5 microns, at least about 10 microns, at least about 20 microns, at least about 50 microns, at least about 100 microns, at least about 500 microns, at least about 1 mm, at least about 2 mm, at least about 5 mm, at least about 10 mm, or more. One or more holes may include a hole diameter of between about 10 microns and about 5000 microns, between about 10 microns and about 2500 microns, between about 10 microns and about 1000 microns, between about 10 microns and about 500 microns, etc.

[0081] like Figure 1 As shown, the reservoir interface 150 may include one or more alignment tabs 154. The mouth 108 of the reservoir may include one or more alignment channels 102 that may receive the one or more alignment tabs. When the alignment tabs are received in the one or more alignment channels, the orientation of the reservoir interface relative to the reservoir may be rotationally fixed.

[0082] The flow control device may include a nozzle 200. The nozzle may include at least one outlet 202 and a nozzle cap 250. The nozzle may include an internal volume that may include a preservative removal device. The preservative removal device may include any example of a preservative removal device as disclosed herein, such as a preservative removal agent and a matrix disclosed in the "preservative removal agent" section elsewhere herein. The nozzle may include an internal volume of about 0.5cc. The nozzle may include an internal volume of about 0.1cc. The nozzle may include an internal volume of about 1cc. The nozzle may include at least about 0.05 cubic centimeters (cc), at least about 0.1cc, at least about 0.2cc, at least about 0.3cc, at least about 0.4cc, at least about 0.5cc, at least about 0.6cc, at least about 0.7cc, at least about 0.8cc, at least about 1cc, at least about 1.5cc, at least about 2cc, at least about 5cc or more of the internal volume. The reservoir may include an internal volume between about 0.01 cc and about 5 cc, between about 0.1 cc and about 5 cc, between about 0.5 cc and about 1.5 cc, between about 0.5 cc and about 5 cc, or the like.

[0083] ] In some cases, the preservative removal device can at least partially fill the interior volume of the nozzle. For example, the preservative removal device can include a polymer matrix. The preservative removal device can fill at least about 1%, at least about 2%, at least about 5%, at least about 10%, at least about 20%, at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or more of the interior volume of the reservoir. The preservative removal device can fill about 1% to about 99%, about 10% to about 98%, about 25% to about 50%, about 10% to about 50%, etc. of the interior volume of the reservoir.

[0084] The nozzle 200 may include an outlet 202. The outlet may include a diameter of at least about 1 micron, at least about 2 microns, at least about 5 microns, at least about 10 microns, at least about 20 microns, at least about 50 microns, at least about 100 microns, at least about 500 microns, at least about 1 mm, at least about 2 mm, at least about 5 mm, at least about 10 mm, or more. The outlet may include a hole diameter of between about 10 and about 5000 microns, between about 10 and about 2500 microns, between about 10 and about 1000 microns, between about 10 and about 500 microns, and the like.

[0085] The nozzle cap 250 may include one or more holes 252. The one or more holes in the nozzle cap may fluidly connect the outlet 202 and the exterior of the nozzle. The one or more holes in the nozzle cap may be fluidly connected to the surface of the nozzle facing the reservoir. The one or more holes may include at least 1 hole, at least 2 holes, at least about 5 holes, at least about 10 holes, at least about 20 holes, at least about 50 holes, at least about 100 holes or more. In some cases, the one or more holes include the opening of the filter. The one or more holes may include the number of holes in the range of from about 1 to about 100, from about 1 to about 50, from about 1 to about 10, from about 5 to about 100, from about 10 to about 100, from about 2 to about 20.

[0086] One or more holes may include a diameter of at least about 1 micron, at least about 2 microns, at least about 5 microns, at least about 10 microns, at least about 20 microns, at least about 50 microns, at least about 100 microns, at least about 500 microns, at least about 1 mm, at least about 2 mm, at least about 5 mm, at least about 10 mm, or more. One or more holes may include a hole diameter of between about 10 and about 5000 microns, between about 10 and about 2500 microns, between about 10 and about 1000 microns, between about 10 and about 500 microns, etc.

[0087] In some cases, nozzle cap 250 is rotationally fixed relative to nozzle 200. In some cases, nozzle cap is rotationally fixed relative to nozzle by one or more retaining features 254. Retaining features 254 may include snap fits, interference fits, press fits, screws, etc. Rotational fixation of the nozzle cap may be assisted by glue, welding, heat sealing, etc. In some cases, the nozzle cap may be removable. The nozzle cap may help retain the preservative removal device within the interior volume of the nozzle.

[0088] In some cases, the nozzle cap may include a filter 220. The filter may include a mesh or screen. The filter may include a polyester mesh. The filter may include a paper mesh. The filter 220 may be installed in the nozzle cap 250. The filter may be installed adjacent to the nozzle cap 250. The filter may include a mesh size of about 25 microns. The filter may include a mesh size of at least about 1 micron, at least about 1 micron, at least about 2 microns, at least about 5 microns, at least about 10 microns, at least about 20 microns, at least about 50 microns, at least about 100 microns or more. The filter may include a mesh size of at most about 1 mm, at most about 500 microns, at most about 250 microns, at most about 100 microns, at most about 50 microns, at most about 25 microns or less. The filter may include a mesh size of between about 1 and about 50 microns, between about 10 and about 50 microns, between about 1 and about 30 microns, between about 20 and about 30 microns, etc.

[0089] In some embodiments, the nozzle 200 may include one or more retaining features on the outer surface of the nozzle. The retaining features 206, 208 may engage with the mouth of the reservoir to retain the nozzle in the mouth of the reservoir. The retaining features 206, 208 may include snap fits, interference fits, press fits, screws, etc. In some cases, the retaining features may allow the nozzle to rotate relative to the reservoir interface. In some cases, the nozzle may be removable. The nozzle may be removable with the nozzle cap in place.

[0090] Figure 2 An external view of a flow control device integrated with a squeezable bottle according to some embodiments is illustrated. Figure 2 The reservoir 100 and the cap 300 are illustrated. As illustrated, the cap 300 can be screwed onto or unscrewed from the threads 106 of the reservoir 100.

[0091] Figure 3A and Figure 3B An exterior view and a cross-sectional view, respectively, of a flow control device in an open position according to some embodiments are illustrated. Figure 4A and Figure 4B An exterior view and a cross-sectional view of a flow control device in a closed position according to some embodiments are illustrated, respectively. Rotation of the nozzle can prevent the ophthalmic preparation from flowing between the interior of the nozzle and the reservoir, thereby stabilizing the concentration of the preservative in the ophthalmic preparation. In some cases, the flow control device can include a rotation axis 400. Rotation of the nozzle relative to the reservoir about the rotation axis can align one or more holes 152 in the reservoir interface with one or more holes 252 in the nozzle cap. View Figure 3B The holes 152 and 252 in FIG. 1 are shown to align the two holes to allow fluid to pass between the reservoir 100 and the nozzle 200. Figure 4BThe holes 152 and 250 in FIG. 2 illustrate that the two holes are not aligned, thereby preventing fluid from passing between the reservoir 100 and the nozzle 200. Figure 3B The fluid path 425 through the device is illustrated.

[0092] Figure 3B 800 is also illustrated in the figure. The filter can include a mesh or screen. The filter can include a polyester mesh. The filter can include a paper mesh. The filter 800 can be installed in the outlet cap 850. The filter can be installed adjacent to the outlet cap 850. The filter can include a mesh size of about 25 microns. The filter can include a mesh size of at least about 1 micron, at least about 1 micron, at least about 2 microns, at least about 5 microns, at least about 10 microns, at least about 20 microns, at least about 50 microns, at least about 100 microns or more. The filter can include a mesh size of at most about 1 mm, at most about 500 microns, at most about 250 microns, at most about 100 microns, at most about 50 microns, at most about 25 microns or less. The filter can include a mesh size of between about 1 micron and about 50 microns, between about 10 microns and about 50 microns, between about 1 micron and about 30 microns, between about 20 microns and about 30 microns, etc.

[0093] The outlet filter 800 can be held in place by an outlet cap 850. In some cases, the outlet cap 250 is rotationally fixed relative to the nozzle 200. In some cases, the outlet cap is rotationally fixed relative to the nozzle by one or more retaining features. The retaining features may include snap fits, interference fits, press fits, screws, etc. The rotational fixation of the outlet cap may be assisted by glue, welding, heat sealing, etc. In some cases, the outlet cap may be removable. The outlet cap may help keep the preservative removal device within the internal volume of the nozzle. In some cases, the outlet cap 850 may be insert molded into the nozzle.

[0094] also, Figure 3B 1 is an illustration of the interaction between the retaining features 206, 208 and the mouth 108 of the reservoir to retain the nozzle in the mouth of the reservoir. The retaining features 206, 208 may include snap fits, interference fits, press fits, screws, etc. In some cases, the retaining features may allow the nozzle to rotate relative to the reservoir interface. In some cases, the nozzle may be removable. The nozzle may be removable with the nozzle cap in place. The reservoir 100 may include one or more retaining features 110 to facilitate the fit between the nozzle and the reservoir. Figure 3B An interference fit is illustrated between the reservoir 100 and the nozzle 200. The seal between the reservoir 100 and the nozzle 200 may be watertight.

[0095] Figure 5B and Figure 5BAn exterior view and a cross-sectional view, respectively, of a nozzle and a nozzle cap in a closed position according to some embodiments are illustrated. Fig. 6A and Figure 6B An exterior view and a cross-sectional view of a nozzle and a nozzle cap in an open position according to some embodiments are illustrated, respectively. In some cases, the flow control device can include a rotation axis 400. Rotation of the nozzle relative to the reservoir about the rotation axis can align one or more holes 152 in the reservoir interface with one or more holes 252 in the nozzle cap.

[0096] Figure 5A , Figure 5B , Fig. 6A and Figure 6B The interaction between the nozzle 200, the nozzle cap 250, and the reservoir interface 150 is illustrated. As illustrated, the nozzle cap 250 may be rotationally fixed relative to the nozzle 200, while the reservoir interface 150 may be free to rotate relative to the nozzle 200. In some cases, the reservoir interface 150 may be axially fixed relative to the nozzle 200 but free to rotate. In some cases, the nozzle 200, the nozzle cap 250, and the reservoir interface 150 may include portions of a nozzle assembly that may be removed from the reservoir to fill the reservoir. The nozzle cap 250 may be axially secured to the nozzle 200 by a snap fit, an interference fit, a press fit, screws, etc. In some cases, once the reservoir interface 150 is attached to the nozzle 200, it cannot be removed. The filter 220 may be disposed between the reservoir interface 150 and the nozzle 200, thereby securing the filter 220. View Figure 5B The hole 152 and nozzle cap 250 in the figure illustrate that the two holes are not aligned, thereby preventing the passage of fluid between the reservoir 100 and the nozzle 200. Figure 6B The holes 152 and 252 in FIG. 2 are shown to align the two holes to allow fluid to pass between the reservoir 100 and the nozzle 200 .

[0097] Fig. 7A and Figure 7B The ridges on the surface facing the reservoir of the nozzle received by the rotating guide on the reservoir are illustrated in an open position and a closed position, respectively, according to some embodiments. In some embodiments, the nozzle includes a second or more ridges 203 on the surface facing the reservoir, which can be received by the reservoir. In some embodiments, the reservoir includes one or more rotating guides 104, and the second or more ridges on the surface facing the reservoir are received by the one or more rotating guides. In some embodiments, the second or more ridges on the bottle-facing surface received by the rotating guide limit the rotation angle of the nozzle relative to the reservoir interface.

[0098] The interaction of the rotation guide 104 and the ridge 203 can be used to limit the angle through which the nozzle assembly can rotate. In the illustrated example, the rotation angle can be limited to approximately 30 degrees. The rotation angle can be limited based on the geometry and number of holes in the nozzle cap. For example, there may be rotation stops in the fully open and fully closed positions. For example, if the nozzle cap has 4 holes equally spaced radially about the axis of rotation, the rotation angle can be limited to 45 degrees. View Fig. 7A The position of the nozzle relative to the ridge 203 of the rotation guide 104 may be at a first rotation stop such that the nozzle is in an open position. Figure 7B Relative to the ridge 203 of the rotation guide 104, the position of the nozzle may be at a second rotation stop such that the nozzle is in a closed position.

[0099] Fig. 8A and Figure 8B The outer view and the cross-sectional view of the nozzle and the bottle cap according to some embodiments are respectively illustrated. In some embodiments, the flow control device also includes a bottle cap 300. The rotation of the bottle cap around the rotation axis 400 relative to the reservoir can make the nozzle 200 rotate around the rotation axis 400 relative to the reservoir. In some embodiments, the bottle cap includes a nut. The outside of the reservoir may include a thread 106. The inside of the bottle cap may include a thread 306. As illustrated, the ridge 204 on the cap-facing surface of the nozzle 200 can be received in the alignment channel 304 in the inside of the bottle cap 300. When the cap is screwed on, the alignment channel 304 can catch the ridge 204 so as to rotate the nozzle assembly, and the flow control device is placed in the rotation closed position. As illustrated, when the cap is fully screwed on, the cap can seal the outlet 202.

[0100] Fig.9A and Fig. 9B Two views of the bottle cap according to some embodiments are illustrated. In some embodiments, the nozzle includes one or more ridges 204 on the surface facing the bottle cap, which can be received by the bottle cap. In some embodiments, the bottle cap 300 includes one or more alignment channels 304 on the inner surface of the bottle cap, and the first one or more ridges on the surface facing the bottle cap of the nozzle cap are received in the one or more alignment channels. The bottle cap 300 can also include threads 306.

[0101] Fig.10A partially exploded view of another example flow control device according to some embodiments is illustrated. As illustrated, the flow control device may include a reservoir 100', a nozzle 200' and a cap 300'. The flow control device may include a nozzle interface 600'. As illustrated, the nozzle interface 600' may have one or more alignment guides 604'. As illustrated, one or more alignment guides 604' may be configured to be received by a thread inside the bottle cap 300' interior. When the cap 300' is screwed on, the alignment guide 604' may provide a rotation stop. The alignment guide 604' may provide guidance to allow the nozzle interface 600' to be fastened relative to the reservoir 100'. The nozzle 200' may include an outlet 202'. The nozzle 200' may have one or more ridges 204' on the cap facing side. One or more ridges 204' may be received by one or more alignment channels on the bottle cap 300' interior to rotate the nozzle relative to the reservoir 100'.

[0102] Fig.11 An integrated squeezable bottle is shown according to some embodiments. Fig.10 External view of the flow control device. Fig.11 A reservoir 100' and a cap 300' are illustrated.

[0103] Fig.12 An integrated squeezable bottle is shown according to some embodiments. Fig.10 A cross-sectional view of a flow control device.

[0104] The flow control device may include a reservoir 100'. The reservoir may include an ophthalmic preparation disposed therein. The ophthalmic preparation may include ophthalmic agents and preservatives as described elsewhere herein, such as in the "Ophthalmic Agents" and "Preservatives" sections. The ophthalmic preparation may include any of the example preparations disclosed herein, such as in the "Solutions, Emulsions, or Suspensions" section. The reservoir 100' may include a compressible bottle, such as a reservoir of a commercially available eye drop bottle. In some cases, the reservoir 100' may use a commonly available commercial bottle. In other cases, the reservoir 100' may be a dedicated bottle designed for a specific application (such as the systems, methods, devices, and kits disclosed herein).

[0105] The reservoir of the present disclosure may include an internal volume that may include an ophthalmic preparation as disclosed herein. The reservoir may include an internal volume of about 2.5cc. The reservoir may include an internal volume of about 8cc. The reservoir may include at least about 0.2 cubic centimeters (cc), at least about 0.5cc, at least about 1cc, at least about 1.5cc, at least about 2cc, at least about 2.5cc, at least about 3cc, at least about 4cc, at least about 5cc, at least about 6cc, at least about 7cc, at least about 8cc, at least about 10cc or more internal volumes. The reservoir may include an internal volume of about 0.1cc to about 10cc, about 1cc to about 10cc, about 2cc to about 10cc, about 2.5cc to about 10cc, etc. For example, an 8cc bottle may dispense an ophthalmic preparation of about 5cc. For example, a 2.5cc bottle may dispense an ophthalmic preparation of about 2cc.

[0106] In some cases, the ophthalmic preparation can at least partially fill the internal volume of the reservoir. The ophthalmic preparation can fill at least about 1%, at least about 2%, at least about 5%, at least about 10%, at least about 20%, at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95% or more of the internal volume of the reservoir. The ophthalmic preparation can fill about 1% to about 99%, about 10% to about 98%, about 25% to about 50%, about 10% to about 50%, etc. of the internal volume of the reservoir.

[0107] The reservoir of the present disclosure may be made of plastic. The plastic may be compressible. The plastic may include one or a combination of various polyolefins, polypropylene, polyethylene, etc. The reservoir may include low-density polyethylene (e.g., Nalgene TM ). The reservoir may comprise a compressible bottle reservoir. The bottle may be made of a material that is sufficiently soft to allow a person to at least partially collapse the sides of the reservoir, thereby increasing the pressure within the reservoir.

[0108] The flow control device may include a reservoir interface 500', which is arranged at the mouth of the reservoir. The reservoir interface may include one or more holes 502'. One or more holes in the reservoir interface can fluidly connect the interior of the reservoir to the exterior of the reservoir. One or more holes may include at least 1 hole, at least 2 holes, at least about 5 holes, at least about 10 holes, at least about 20 holes, at least about 50 holes, at least about 100 holes or more. In some cases, one or more holes include the opening of the filter. One or more holes may include from about 1 to about 100, from about 1 to about 50, from about 1 to about 10, from about 5 to about 100, from about 10 to about 100, from about 2 to about 20. The number of holes.

[0109] One or more holes may include a diameter of at least about 1 micron, at least about 2 microns, at least about 5 microns, at least about 10 microns, at least about 20 microns, at least about 50 microns, at least about 100 microns, at least about 500 microns, at least about 1 mm, at least about 2 mm, at least about 5 mm, at least about 10 mm, or more. One or more holes may include a hole diameter of between about 10 and about 5000 microns, between about 10 and about 2500 microns, between about 10 and about 1000 microns, between about 10 and about 500 microns, etc.

[0110] like Fig.12 As shown, the reservoir interface 500' may include one or more retaining features 510' and 518'. The mouth of the reservoir may include one or more retaining features 110', which may receive one or more retaining features 510' of the reservoir interface 500. When the reservoir interface is in place within the mouth of the reservoir, the orientation of the reservoir interface relative to the reservoir may be rotationally fixed. The retaining features 510' may include snap fits, interference fits, press fits, screws, etc. The rotational fixation of the reservoir interface may be assisted by glue, welding, heat sealing, etc. In some cases, the reservoir interface may be removable. The reservoir interface 500' may include a cavity in which the nozzle 200' may rotate.

[0111] The flow control device may include a nozzle 200'. The nozzle may include at least one outlet 202' and a nozzle cap 250'. The nozzle may include an internal volume that may include a preservative removal device. The preservative removal device may include any example of a preservative removal device as disclosed herein, such as a preservative removal agent and a matrix disclosed in the "preservative removal agent" section elsewhere herein. The nozzle may include an internal volume of about 0.5cc. The nozzle may include an internal volume of about 0.1cc. The nozzle may include an internal volume of about 1cc. The nozzle may include at least about 0.05 cubic centimeters (cc), at least about 0.1cc, at least about 0.2cc, at least about 0.3cc, at least about 0.4cc, at least about 0.5cc, at least about 0.6cc, at least about 0.7cc, at least about 0.8cc, at least about 1cc, at least about 1.5cc, at least about 2cc, at least about 5cc or more of the internal volume. The reservoir may include an internal volume between about 0.01 cc and about 5 cc, between about 0.1 cc and about 5 cc, between about 0.5 cc and about 1.5 cc, between about 0.5 cc and about 5 cc, or the like.

[0112] ] In some cases, the preservative removal device can at least partially fill the interior volume of the nozzle. For example, the preservative removal device can include a polymer matrix. The preservative removal device can fill at least about 1%, at least about 2%, at least about 5%, at least about 10%, at least about 20%, at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or more of the interior volume of the reservoir. The preservative removal device can fill about 1% to about 99%, about 10% to about 98%, about 25% to about 50%, about 10% to about 50%, etc. of the interior volume of the reservoir.

[0113] The nozzle 200' may include an outlet 202'. The outlet may include a diameter of at least about 1 micron, at least about 2 microns, at least about 5 microns, at least about 10 microns, at least about 20 microns, at least about 50 microns, at least about 100 microns, at least about 500 microns, at least about 1 mm, at least about 2 mm, at least about 5 mm, at least about 10 mm, or more. The outlet may include a hole diameter of between about 10 and about 5000 microns, between about 10 and about 2500 microns, between about 10 and about 1000 microns, between about 10 and about 500 microns, etc.

[0114] The outlet 250' may include one or more holes 252'. The one or more holes in the nozzle cap may fluidly connect the outlet 202' and the exterior of the nozzle. The one or more holes in the nozzle cap may be fluidly connected to the surface of the nozzle facing the reservoir. The one or more holes may include at least 1 hole, at least 2 holes, at least about 5 holes, at least about 10 holes, at least about 20 holes, at least about 50 holes, at least about 100 holes or more. In some cases, the one or more holes include the opening of the filter. The one or more holes may include the number of holes in the range of from about 1 to about 100, from about 1 to about 50, from about 1 to about 10, from about 5 to about 100, from about 10 to about 100, from about 2 to about 20.

[0115] One or more holes may include a diameter of at least about 1 micron, at least about 2 microns, at least about 5 microns, at least about 10 microns, at least about 20 microns, at least about 50 microns, at least about 100 microns, at least about 500 microns, at least about 1 mm, at least about 2 mm, at least about 5 mm, at least about 10 mm, or more. One or more holes may include a hole diameter of between about 10 and about 5000 microns, between about 10 and about 2500 microns, between about 10 and about 1000 microns, between about 10 and about 500 microns, etc.

[0116] In some cases, nozzle cap 250' is rotationally fixed relative to nozzle 200'. In some cases, the nozzle cap is rotationally fixed relative to the nozzle by one or more retaining features. The retaining features may include snap fits, interference fits, press fits, screws, etc. The rotational fixation of the nozzle cap may be assisted by glue, welding, heat sealing, etc. In some cases, the nozzle cap may be removable. The nozzle cap may help retain the preservative removal device within the interior volume of the nozzle.

[0117] In some cases, the nozzle cap may include a filter. The filter may include a mesh or screen. The filter may include a polyester mesh. The filter may include a paper mesh. The filter may be installed in the nozzle cap 250'. The filter may be installed adjacent to the nozzle cap 250'. The filter may include a mesh size of about 25 microns. The filter may include a mesh size of at least about 1 micron, at least about 1 micron, at least about 2 microns, at least about 5 microns, at least about 10 microns, at least about 20 microns, at least about 50 microns, at least about 100 microns or more. The filter may include a mesh size of at most about 1 mm, at most about 500 microns, at most about 250 microns, at most about 100 microns, at most about 50 microns, at most about 25 microns or less. The filter may include a mesh size of about 1 to about 50 microns, about 10 to about 50 microns, about 1 to about 30 microns, about 20 to about 30 microns, etc.

[0118] In some embodiments, the nozzle 200' can include one or more retaining features on the outer surface of the nozzle. The retaining feature 210' can abut the shelf 506' of the reservoir interface 500'. In some cases, the retaining feature can allow the nozzle to rotate relative to the reservoir interface while limiting translation of the nozzle along the rotation axis. In some cases, the nozzle can be removable. The nozzle can be removable with the nozzle cap in place.

[0119] Fig.12Also illustrated in the figure is an outlet filter 800'. The filter may include a mesh or screen. The filter may include a polyester mesh. The filter may include a paper mesh. The filter 800' may be installed in the outlet cap 850. The filter may be installed adjacent to the outlet cap. The filter may be installed adjacent to the nozzle cap. The filter may include a mesh size of about 25 microns. The filter may include a mesh size of at least about 1 micron, at least about 1 micron, at least about 2 microns, at least about 5 microns, at least about 10 microns, at least about 20 microns, at least about 50 microns, at least about 100 microns, or more. The filter may include a mesh size of at most about 1 mm, at most about 500 microns, at most about 250 microns, at most about 100 microns, at most about 50 microns, at most about 25 microns, or less. The filter may include a mesh size of between about 1 and about 50 microns, between about 10 and about 50 microns, between about 1 and about 30 microns, between about 20 and about 30 microns, and the like.

[0120] Fig.12 Also illustrated in the figure is a nozzle interface 600'. The nozzle interface 600' may include internal threads 606', which may be screwed onto the threads 106' of the reservoir 100'. When the nozzle interface 600' is screwed into place, the nozzle interface may limit axial translation of the nozzle 200' along the rotation axis 400'. When the nozzle interface 600' is screwed into place, the nozzle interface may allow rotation of the nozzle 200' along the rotation axis 400'. The nozzle interface may provide a retaining force to the retaining feature 110'. In some cases, the nozzle interface may be screwed on or off. In some cases, once the nozzle interface is screwed onto the reservoir, it may be difficult to remove the nozzle interface. Fig.12 Also illustrated is a fluid path 425' through the device.

[0121] Fig.13A and Fig. 13B The interaction between the nozzle 200' and the reservoir interface 500' is illustrated. As illustrated, the reservoir interface 500' can rotate freely relative to the nozzle 200'. In some cases, the reservoir interface 500' can be axially fixed but rotationally free relative to the nozzle 200'. In some cases, the nozzle 200' and the reservoir interface 500' may include a portion of a nozzle assembly that can be removed from the reservoir to fill the reservoir. In some cases, once the reservoir interface 500' is attached to the nozzle 200', it cannot be removed. The reservoir interface 500' may include retaining features 510' and 518'. The reservoir interface 500' may include one or more holes 502'. When the nozzle 200' rotates about the axis 400', one or more inlet holes in the nozzle 200' can be aligned with one or more holes 502' in the reservoir interface.

[0122] The one or more holes 502' in the reservoir interface can fluidly connect the inlet 202' and the exterior of the nozzle via the one or more holes 252' in the nozzle cap and the one or more inlet holes 212' in the nozzle. The one or more holes in the reservoir interface can include at least 1 hole, at least 2 holes, at least about 5 holes, at least about 10 holes, at least about 20 holes, at least about 50 holes, at least about 100 holes or more. In some cases, the one or more holes include the opening of the filter. The one or more holes can include the number of holes in the range of from about 1 to about 100, from about 1 to about 50, from about 1 to about 10, from about 5 to about 100, from about 10 to about 100, from about 2 to about 20.

[0123] The one or more holes in the reservoir interface may include a diameter of at least about 1 micron, at least about 2 microns, at least about 5 microns, at least about 10 microns, at least about 20 microns, at least about 50 microns, at least about 100 microns, at least about 500 microns, at least about 1 mm, at least about 2 mm, at least about 5 mm, at least about 10 mm, or more. The one or more holes may include a hole diameter of between about 10 and about 5000 microns, between about 10 and about 2500 microns, between about 10 and about 1000 microns, between about 10 and about 500 microns, etc.

[0124] The one or more inlet holes 212' in the nozzle 200' can include at least 1 hole, at least 2 holes, at least about 5 holes, at least about 10 holes, at least about 20 holes, at least about 50 holes, at least about 100 holes, or more. In some cases, the one or more holes include the opening of the filter. The one or more holes can include a number of holes in the range of from about 1 to about 100, from about 1 to about 50, from about 1 to about 10, from about 5 to about 100, from about 10 to about 100, from about 2 to about 20.

[0125] The one or more inlet holes 212' in the nozzle 200' may include a diameter of at least about 1 micron, at least about 2 microns, at least about 5 microns, at least about 10 microns, at least about 20 microns, at least about 50 microns, at least about 100 microns, at least about 500 microns, at least about 1 mm, at least about 2 mm, at least about 5 mm, at least about 10 mm, or more. The one or more holes may include a hole diameter of between about 10 and about 5000 microns, between about 10 and about 2500 microns, between about 10 and about 1000 microns, between about 10 and about 500 microns, etc.

[0126] Fig.13A and Fig. 13BThe rotation guide in the reservoir interface 500' is also illustrated in an open position and a closed position, respectively. In some embodiments, the nozzle includes one or more alignment features 220', which can be received in the rotation guide 520'. In some embodiments, the reservoir interface includes one or more rotation guides 520'. In some embodiments, the one or more alignment features that can be received in the rotation guide 520 limit the rotation angle of the nozzle relative to the reservoir.

[0127] The interaction of the rotation guide 520' and the alignment feature 220' can be used to limit the angle through which the nozzle assembly can be rotated. In the illustrated example, the rotation angle can be limited to approximately 20 degrees. The rotation angle can be limited based on the number and geometry of the holes in the nozzle cap. For example, there may be rotation stops in the fully open and fully closed positions. For example, in the illustrated example, there may be two equally spaced holes 212' so that the rotation angle may be less than 180 degrees. View Fig.13A The position of the nozzle relative to the alignment feature 220' of the rotation guide 520' may be at a first rotation stop such that the nozzle is in an open position. Fig. 13B The position of the nozzle may be at a second rotational stop relative to the alignment feature 220' of the rotational guide 520' such that the nozzle is in a closed position.

[0128] Fig.14 A partially exploded view of another example flow control device according to some embodiments is illustrated. As shown, the example flow control device may include a reservoir 1000, a reservoir interface 5000, a nozzle 2000, a nozzle cap 2500, a spring element 7000, a nozzle interface 6000, and a two-piece cap including an outer portion 3000 and an inner portion 3500. As shown in the illustrated example, the nozzle may translate rather than rotate to control the flow through the device. The flow control device may include a spring element 7000 that may provide a restoring force to resist compressive motion along a translation axis. The spring element may be a metal, such as alloy steel, chrome silicon, carbon steel, cobalt nickel, copper alloy, nickel alloy, stainless steel, titanium, etc.

[0129] Fig.15A and Fig. 15B illustrates, according to some embodiments, Fig.14 External view of the flow control device. Fig.15A and Fig. 15BThe reservoir 1000 and the cap 3000 are illustrated. As illustrated, the cap 3000 can be screwed onto the threads 1060 of the reservoir 1000, or unscrewed from the threads 106 of the reservoir 100. When the cap is in place, the cap 3000 can cover the outlet 2020 of the nozzle 2000. The cap 3000 can have external features 3100 that may help remove or apply the cap. In some cases, the cap 3000 includes a closure assembly that resists manipulation by children. In some cases, when moved to a closed state, the cap 3000 produces an audible or tactile click.

[0130] Fig.16A and Fig. 16B 1 and 2 respectively illustrate a capped and uncapped Fig.14 A cross-sectional view of a flow control device. Fig.16A and Fig. 16B A cross-sectional view of a flow control device in a closed position and in an open position according to some embodiments is illustrated. Translation of the nozzle can prevent the flow of the ophthalmic preparation between the interior of the nozzle and the reservoir, thereby stabilizing the concentration of the preservative in the ophthalmic preparation. In some cases, the flow control device can include a translation axis 4500.

[0131] The nozzle assembly can include a bead seal configuration. As shown, when the cap 3000 is in place, the nozzle 2000 can slide along the translation axis 4500, compressing the spring element 7000. In some cases, when the cap is fully in place, the bead seal element 2160 on the surface of the nozzle facing the reservoir interface contacts the nozzle-facing wall of the reservoir interface 5000. In some cases, when the cap is fully in place, the bead seal elements 5060, 5080 on the surface of the reservoir interface facing the nozzle contact the nozzle 2000 facing the reservoir interface wall. The bead seal elements 2160 and 5060, 5080 may include a fluid seal. In some cases, the fluid seal may include contact between the bottom surface of the nozzle cap 2500 and the surface 5160 of the reservoir interface 5000.

[0132] The translation distance 4750 is shown in Fig. 16BIn some cases, surface 5160 may include a first translation stop. In some cases, beaded sealing elements 2160 and 5060 may include a first translation stop. In some cases, the threads of cap 3000 may include a first translation stop. The second translation stop may include an interaction between the outlet 2020 and the sealing cap 3120 of the cap 3000. The second translation stop may include an interaction between the retaining feature 2100 on the surface of the nozzle 2000 facing the reservoir seal and the nozzle interface 6000. The nozzle interface 6000 may include a retaining ring. The nozzle interface 6000 may be ultrasonically welded, heat sealed, glued or bonded to the reservoir interface 5000. In some cases, the nozzle interface 6000 may be removable. In some cases, the nozzle interface 6000 may include threads, snap fits, press fits, etc. The spring element 7000 may be compressed between the retaining feature 2100 and the shelf 5200 of the reservoir interface.

[0133] Translation of the nozzle relative to the reservoir along the translation axis 4500 can fluidly connect one or more apertures 5020 in the reservoir interface 5000 with one or more apertures in the nozzle cap 2520. View Fig. 16B The holes 5020 and 2520 in FIG. 2 illustrate that the two holes are fluidly connected to allow fluid to pass between the reservoir 1000 and the nozzle 2000. Fig. 16B 5020 and the nozzle 2000 in FIG. 50 , the nozzle cap 2500 is shown abutting the bottom surface 5160 of the reservoir interface, thereby blocking the passage of fluid between the reservoir 1000 and the nozzle 2000 . Fig. 16B The fluid path 4250 through the device is illustrated.

[0134] 16B also illustrates the interaction between the reservoir interface 5000 and the reservoir 1000. The reservoir interface 5000 may include one or more retaining features 5100 and 5180. The mouth of the reservoir may include one or more retaining features 1120, which may receive one or more retaining features 5100 of the reservoir interface 5000. When the reservoir interface is in place within the mouth of the reservoir, the orientation of the reservoir interface relative to the reservoir may be rotationally fixed. The retaining features 5100, 5180 may include snap fits, interference fits, press fits, screws, etc. The rotational fixation of the reservoir interface may be assisted by glue, welding, heat sealing, etc. In some cases, the reservoir interface may be removable. The reservoir interface 5000 may include a cavity 5140 in which the nozzle 2000 may rotate.

[0135] As illustrated, the flow control device may include a reservoir 1000. The reservoir may include an ophthalmic preparation disposed therein. The ophthalmic preparation may include an ophthalmic agent and a preservative as described elsewhere herein, such as in the "Ophthalmic Agents" and "Preservatives" sections. The ophthalmic preparation may include any of the example preparations disclosed herein, such as in the "Solutions, Emulsions, or Suspensions" section. The reservoir 1000 may include a compressible bottle, such as a reservoir of a commercially available eye drop bottle. In some cases, the reservoir 1000 may use a commonly available commercial bottle. In other cases, the reservoir 1000 may be a special bottle designed for a specific application, such as the systems, methods, devices, and kits disclosed herein.

[0136] The reservoir of the present disclosure may include an internal volume that may include an ophthalmic preparation as disclosed herein. The reservoir may include an internal volume of about 2.5cc. The reservoir may include an internal volume of about 8cc. The reservoir may include at least about 0.2 cubic centimeters (cc), at least about 0.5cc, at least about 1cc, at least about 1.5cc, at least about 2cc, at least about 2.5cc, at least about 3cc, at least about 4cc, at least about 5cc, at least about 6cc, at least about 7cc, at least about 8cc, at least about 10cc or more internal volumes. The reservoir may include an internal volume of about 0.1cc to about 10cc, about 1cc to about 10cc, about 2cc to about 10cc, about 2.5cc to about 10cc, etc. For example, an 8cc bottle may dispense an ophthalmic preparation of about 5cc. For example, a 2.5cc bottle may dispense an ophthalmic preparation of about 2cc.

[0137] In some cases, the ophthalmic preparation can at least partially fill the internal volume of the reservoir. The ophthalmic preparation can fill at least about 1%, at least about 2%, at least about 5%, at least about 10%, at least about 20%, at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95% or more of the internal volume of the reservoir. The ophthalmic preparation can fill about 1% to about 99%, about 10% to about 98%, about 25% to about 50%, about 10% to about 50%, etc. of the internal volume of the reservoir.

[0138] The reservoir of the present disclosure may be made of plastic. The plastic may be compressible. The plastic may include one or a combination of various polyolefins, polypropylene, polyethylene, etc. The reservoir may include low-density polyethylene (e.g., Nalgene TM ). The reservoir may comprise a compressible bottle reservoir. The bottle may be made of a material that is sufficiently soft to allow a person to at least partially collapse the sides of the reservoir, thereby increasing the pressure within the reservoir.

[0139] Fig.17A and Fig. 17BA cross-sectional view and an external view of a nozzle assembly according to some embodiments are illustrated, respectively. The nozzle 2000 can translate as a piston within the reservoir interface 5000. In some cases, the nozzle 2000 and the reservoir interface 5000 can include a portion of the nozzle assembly that can be removed from the reservoir to fill the reservoir. In some cases, once the reservoir interface 5000 is attached to the nozzle 2000, it cannot be removed. The reservoir interface 5000 may include one or more holes 5020. In some cases, the exterior of the reservoir interface 5000 may include alignment features 5120 to assist in assembly of the device, such as rotation and / or translation of the reservoir interface 5000 relative to the reservoir 1000.

[0140] Fig.17A Also illustrated is a filter 2800 within the nozzle cap 2500. In some cases, the nozzle cap may include a filter 2800. The filter may include a mesh or screen. The filter may include a polyester mesh. The filter may include a paper mesh. The filter 2800 may be installed within the nozzle cap 2500. The filter may be installed adjacent to the nozzle cap 2500. The filter may include a mesh size of about 25 microns. The filter may include a mesh size of at least about 1 micron, at least about 1 micron, at least about 2 microns, at least about 5 microns, at least about 10 microns, at least about 20 microns, at least about 50 microns, at least about 100 microns, or more. The filter may include a mesh size of at most about 1 mm, at most about 500 microns, at most about 250 microns, at most about 100 microns, at most about 50 microns, at most about 25 microns, or less. The filter may include a mesh size of between about 1 and about 50 microns, between about 10 and about 50 microns, between about 1 and about 30 microns, between about 20 and about 30 microns, and the like.

[0141] Fig.18A and Fig.18B A cross-sectional view and an external view of a nozzle 2000 according to some embodiments are illustrated, respectively. The flow control device may include a nozzle 2000. The nozzle may include at least one outlet 2020. In some embodiments, the nozzle 2000 may include one or more retaining features on the outer surface of the nozzle. The retaining feature 2100 may abut the spring 7000, which in turn may abut the shelf 5020 of the reservoir interface 5000. In some cases, the nozzle may be removable. The nozzle may be removable with the nozzle cap in place. In some cases, the exterior of the nozzle 2000 may include an alignment feature 2180 to assist in assembly of the device, such as rotation and / or translation of the nozzle 2000 relative to the reservoir interface 5000.

[0142] Nozzle 2000 may include an internal volume that may include a preservative removal device. The preservative removal device may include any example of a preservative removal device as disclosed herein, such as a preservative removal agent and a matrix disclosed in the "preservative removal agent" section elsewhere herein. The nozzle may include an internal volume of about 0.5cc. The nozzle may include an internal volume of about 0.1cc. The nozzle may include an internal volume of about 1cc. The nozzle may include at least about 0.05 cubic centimeters (cc), at least about 0.1cc, at least about 0.2cc, at least about 0.3cc, at least about 0.4cc, at least about 0.5cc, at least about 0.6cc, at least about 0.7cc, at least about 0.8cc, at least about 1cc, at least about 1.5cc, at least about 2cc, at least about 5cc or more of the internal volume. The reservoir may include an internal volume between about 0.01 cc and about 5 cc, between about 0.1 cc and about 5 cc, between about 0.5 cc and about 1.5 cc, between about 0.5 cc and about 5 cc, or the like.

[0143] In some cases, the preservative removal device can at least partially fill the internal volume of the nozzle. For example, the preservative removal device can include a polymer matrix. The preservative removal device can fill at least about 1%, at least about 2%, at least about 5%, at least about 10%, at least about 20%, at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95% or more of the internal volume of the reservoir. The preservative removal device can fill about 1% to about 99%, about 10% to about 98%, about 25% to about 50%, about 10% to about 50%, etc. of the internal volume of the reservoir.

[0144] The nozzle 2000 may include an outlet 2020. The outlet may include a diameter of at least about 1 micron, at least about 2 microns, at least about 5 microns, at least about 10 microns, at least about 20 microns, at least about 50 microns, at least about 100 microns, at least about 500 microns, at least about 1 mm, at least about 2 mm, at least about 5 mm, at least about 10 mm, or more. The outlet may include a hole diameter of between about 10 and about 5000 microns, between about 10 and about 2500 microns, between about 10 and about 1000 microns, between about 10 and about 500 microns, and the like.

[0145] Fig.18A8000 is also illustrated in the figure. The filter can include a mesh or screen. The filter can include a polyester mesh. The filter can include a paper mesh. The filter 8000 can be installed in the outlet cap 8500. The filter can be installed adjacent to the outlet cap 8500. The filter can include a mesh size of about 25 microns. The filter can include a mesh size of at least about 1 micron, at least about 1 micron, at least about 2 microns, at least about 5 microns, at least about 10 microns, at least about 20 microns, at least about 50 microns, at least about 100 microns or more. The filter can include a mesh size of at most about 1 mm, at most about 500 microns, at most about 250 microns, at most about 100 microns, at most about 50 microns, at most about 25 microns or less. The filter can include a mesh size of between about 1 and about 50 microns, between about 10 and about 50 microns, between about 1 and about 30 microns, between about 20 and about 30 microns, etc.

[0146] The outlet filter 8000 can be held in place by an outlet cap 8500. In some cases, the outlet cap 250 is rotationally fixed relative to the nozzle 2000. In some cases, the outlet cap is rotationally fixed relative to the nozzle by one or more retaining features. The retaining features may include snap fits, interference fits, press fits, screws, etc. The rotational fixation of the outlet cap may be assisted by glue, welding, heat sealing, etc. In some cases, the outlet cap may be removable. The outlet cap may help keep the preservative removal device within the internal volume of the nozzle. In some cases, the outlet cap 8500 may be insert molded into the nozzle.

[0147] Fig.19A and Fig.19B An exterior view and a cross-sectional view of a reservoir interface 5000 according to some embodiments are shown, respectively. As described herein, the nozzle 2000 can translate as a piston within the reservoir interface 5000. The reservoir interface 5000 can include bead-shaped sealing elements 5080 and 5060. The reservoir interface 5000 can include one or more holes 5020. In some cases, the exterior of the reservoir interface 5000 can include alignment features 5120 to assist in assembly of the device, such as rotation and / or translation of the reservoir interface 5000 relative to the reservoir 1000.

[0148] As described herein, the nozzle assembly can include a bead seal configuration. When the cap 3000 is in place, the nozzle 2000 can slide along the translation axis 4500, compressing the spring element 7000. In some cases, when the cap is fully in place, the bead seal element 2160 on the reservoir interface facing surface of the nozzle contacts the nozzle facing wall of the reservoir interface 5000. In some cases, when the cap is fully in place, the bead seal elements 5060, 5080 on the nozzle facing surface of the reservoir interface contact the reservoir interface facing wall of the nozzle 2000. The bead seal elements 2160 and 5060, 5080 may include a fluid seal. In some cases, the fluid seal may include contact between the bottom surface of the nozzle cap 2500 and the surface 5160 of the reservoir interface 5000. The reservoir interface 5000 may include one or more retaining features 5100 and 5180.

[0149] The reservoir interface may include one or more holes 5020. One or more holes in the reservoir interface may fluidly connect the interior of the reservoir to the exterior of the reservoir. One or more holes may include at least 1 hole, at least 2 holes, at least about 5 holes, at least about 10 holes, at least about 20 holes, at least about 50 holes, at least about 100 holes or more. In some cases, one or more holes include the opening of the filter. One or more holes may include from about 1 to about 100, from about 1 to about 50, from about 1 to about 10, from about 5 to about 100, from about 10 to about 100, from about 2 to about 20. The number of holes.

[0150] One or more holes may include a diameter of at least about 1 micron, at least about 2 microns, at least about 5 microns, at least about 10 microns, at least about 20 microns, at least about 50 microns, at least about 100 microns, at least about 500 microns, at least about 1 mm, at least about 2 mm, at least about 5 mm, at least about 10 mm, or more. One or more holes may include a hole diameter of between about 10 and about 5000 microns, between about 10 and about 2500 microns, between about 10 and about 1000 microns, between about 10 and about 500 microns, etc.

[0151] Fig. 20An isomorphic view of a nozzle interface 6000 according to some embodiments is illustrated. The nozzle interface 6000 may include a retaining ring. The nozzle interface 6000 may secure the nozzle 2000 within the reservoir interface 5000. The nozzle interface 6000 may include a mating surface 6040. The nozzle interface 6000 may be ultrasonically welded, heat sealed, glued, or bonded to the reservoir interface 5000 at the mating surface 6040. In some cases, the nozzle interface 6000 may be removable. In some cases, the nozzle interface 6000 may include threads, snap fits, press fits, etc. In some cases, the exterior of the nozzle interface 6000 may include alignment features 6020 to assist in assembly of the device, such as rotation and / or translation of the nozzle interface 6000 relative to the reservoir 5000.

[0152] Fig.21 An isomorphic view of a nozzle cap 2500 according to some embodiments is illustrated. The nozzle cap 2500 may include one or more holes 2520. The one or more holes in the nozzle cap may be fluidly connected to the exterior of the nozzle 2000, which may be fluidly connected to the outlet 2020 and the interior of the nozzle. The one or more holes in the nozzle cap may be fluidly connected to the reservoir interface facing surface of the nozzle. The one or more holes may include at least 1 hole, at least 2 holes, at least about 5 holes, at least about 10 holes, at least about 20 holes, at least about 50 holes, at least about 100 holes or more. In some cases, the one or more holes include the opening of the filter. The one or more holes may include a number of holes in the range of from about 1 to about 100, from about 1 to about 50, from about 1 to about 10, from about 5 to about 100, from about 10 to about 100, from about 2 to about 20.

[0153] One or more holes may include a diameter of at least about 1 micron, at least about 2 microns, at least about 5 microns, at least about 10 microns, at least about 20 microns, at least about 50 microns, at least about 100 microns, at least about 500 microns, at least about 1 mm, at least about 2 mm, at least about 5 mm, at least about 10 mm, or more. One or more holes may include a hole diameter of between about 10 microns and about 5000 microns, between about 10 microns and about 2500 microns, between about 10 microns and about 1000 microns, between about 10 microns and about 500 microns, etc.

[0154] In some cases, nozzle cap 2500 is rotationally fixed relative to nozzle 2000. In some cases, nozzle cap is rotationally fixed relative to nozzle by one or more retaining features 2540. Retaining features 2540 may include snap fits, interference fits, press fits, screws, etc. Rotational fixation of the nozzle cap may be assisted by glue, welding, heat sealing, etc. In some cases, the nozzle cap may be removable. The nozzle cap may help retain the preservative removal device within the interior volume of the nozzle.

[0155] Fig.22A , Fig. 22B , Fig. 22C , Fig.23A , Fig. 23B and Fig.23C A cap 3000 is shown according to some embodiments. The cap 3000 may include an inner cap 3500. Fig.22A An isomorphic view of a cap 3000 is shown. The outer portion of the cap 3000 is transparent and the inner cap 3500 is solid. The cap 3000 may include a spring element 3540 that may produce an audible and / or tactile click when the cap is in place. Fig. 22B An exterior view of the cap 3000 is shown. The exterior may have an exterior feature 3100 that may aid in removing or applying the cap. In some cases, the cap 3000 includes a closure assembly that resists manipulation by a child. In some cases, the cap 3000 produces an audible or tactile click when moved to a closed state. Fig. 22C A cross-sectional view of the outer portion of the cap 3000 is shown. The cap 3000 may include a retaining element 3020 that may retain the inner cap 3500. The retaining element 3020 may be shaped to allow the cap portions to slide together but may resist removal from each other. The cap 3000 may include a detent element 3080 that may create a stop for the spring element 3540, thereby creating a detent. The cap 3000 may include a sealing cap 3120 that may receive an outlet extension. When the sealing cap 3120 receives the outlet extension, the outlet 2020 may be sealed. The sealing cap 3120 may provide an airtight and / or watertight seal. One or more films or coatings may be deposited inside the sealing cap to aid in sealing quality.

[0156] Fig.23A , Fig. 23B and Fig.23C An interior view of the inner cap 3500 is illustrated according to some embodiments. Fig.23A An isomorphic view of the inner cap 3500 is shown. The inner cap 3500 may include a spring element 3540 and a ridge 3520. The spring element 3540 may create a detent when it traverses the detent element 3080. The ridge 3520 may reinforce the lower wall of the inner cap, which may help prevent the interior and exterior of the cap 3000 from separating. Fig. 23Band Fig.23C An exterior view and a cross-sectional view of the inner cap 3500 are illustrated, respectively. The inner cap 3500 may include threads 3560 that may engage with threads 1060 of the reservoir 1000.

[0157] Fig.24A and Fig. 24B The diagram shows Fig.15A , Fig. 15B , Fig.16A , Fig. 16B , Fig.17A , Fig. 17B , Fig.18A , Fig.18B , Fig.19A , Fig.19B , Fig. 20 , Fig.21 , Fig.22A , Fig. 22B , Fig. 22C , Fig.23A , Fig. 23B and Fig.23C A variation of the nozzle design shown in FIG. Figures 14 to 23C The flow control device shows a bead seal design, Fig.24A and Fig. 24B The device includes an O-ring seal. The reservoir interface 5000' and the nozzle 2000' of the O-ring seal design may be different from the bead seal design, while other elements may remain substantially the same as the bead seal design. The same reference numerals refer to the same elements.

[0158] The nozzle assembly may include an O-ring seal configuration. The nozzle 2000' may slide along the translation axis 4500' within the reservoir interface 5000'. Translation of the nozzle may prevent the ophthalmic preparation from flowing between the interior of the nozzle and the reservoir, thereby stabilizing the concentration of the preservative in the ophthalmic preparation. An O-ring seal may have additional parts; however, an O-ring seal may provide a more reliable seal and / or may address manufacturing tolerance issues. A bead seal may include fewer parts and / or may be easier to manufacture.

[0159] As shown, when the cap 3000 is in place, the nozzle 2000' can slide along the translation axis 4500', compressing the spring element 7000. In some cases, when the cap is fully in place, the O-rings 9020' and 9040' can contact the surface of the nozzle 2000' facing the reservoir interface and contact the wall of the reservoir interface 5000' facing the nozzle. The O-rings 9020' and 9040' may include fluid seals. The O-rings may include natural rubber, synthetic rubber, elastomeric polymers, PTFE, nitrile (Buna), neoprene, EPDM rubber, and fluorocarbon (Viton), etc.

[0160] The translation distance is 4750'. Fig. 24B In some cases, surface 5160' may include a first translation stop. In some cases, the threads of cap 3000 may include a first translation stop. The second translation stop may include an interaction between outlet 2020' and sealing cap 3120 of cap 3000. The second translation stop may include an interaction between retaining feature 2100' on the surface of nozzle 2000' facing the reservoir seal and nozzle interface 6000. Nozzle interface 6000 may include a retaining ring. Nozzle interface 6000 may be ultrasonically welded, heat sealed, glued or bonded to reservoir interface 5000'. In some cases, nozzle interface 6000 may be removable. In some cases, nozzle interface 6000 may include threads, snap fit, press fit, etc. Spring element 7000 may be compressed between retaining feature 2100' and shelf 5200' of reservoir interface.

[0161] Translation of the nozzle relative to the reservoir along the translation axis 4500' can fluidly connect one or more apertures 5020' in the reservoir interface 5000' with one or more apertures in the nozzle cap 2520'. Fig. 24B The holes 5020' and 2520' in the figure illustrate that the two holes are fluidly connected to allow fluid to pass between the reservoir 1000 and the nozzle 2000'. Fig.24A 5020 and the nozzle 2000 in FIG. 50 , the nozzle cap 2500 is shown abutting the bottom surface 5160 of the reservoir interface, thereby blocking the passage of fluid between the reservoir 1000 and the nozzle 2000 . Fig. 24B The fluid path 4250' through the device is illustrated.

[0162] Fig. 24B The interaction between the reservoir interface 5000' and the reservoir 1000 is also illustrated. The reservoir interface 5000' may include one or more retaining features 5100'. The mouth of the reservoir may include one or more retaining features 1120, which may receive one or more retaining features 5100' of the reservoir interface 5000'. When the reservoir interface is in place within the mouth of the reservoir, the orientation of the reservoir interface relative to the reservoir may be rotationally fixed. The retaining features 5100' may include snap fits, interference fits, press fits, screws, etc. The rotational fixation of the reservoir interface may be assisted by glue, welding, heat sealing, etc. In some cases, the reservoir interface may be removable. The reservoir interface 5000' may include a cavity in which the nozzle 2000' may translate.

[0163] In another aspect, the present disclosure provides a method of controlling the concentration of a preservative in an ophthalmic formulation. The method may include receiving a bottle according to any aspect or embodiment and rotating a nozzle or a bottle cap relative to a reservoir.

[0164] In another aspect, the present disclosure provides a method of manufacturing a flow control device as described in an aspect or embodiment. The method may include: filling a reservoir with an ophthalmic preparation; placing a reservoir interface on the reservoir; placing a nozzle cap on the nozzle; and placing the nozzle at the mouth of the reservoir. In some embodiments, the method also includes placing a bottle cap on the nozzle. The method also includes providing a preservative removal device within the internal volume of the nozzle. The preservative removal device may be made as a plug that partially fills the nozzle volume. In some cases, the preservative removal device may be filled with a liquid that can solidify within the internal volume. In some cases, the preservative removal device may be a powder that is compressed within the internal volume.

[0165] On the other hand, the present disclosure provides a method for using the flow control device described in any aspect or embodiment disclosed herein. The method of use may include removing the cap, allowing the flow control device to advance to the open position, and applying pressure to the compressible bottle to form an ophthalmic preparation. The ophthalmic preparation may contain a reduced amount of preservative. The method of use may also include forming subsequent drops of the ophthalmic preparation, wherein the concentration of the preservative in the reservoir is substantially unchanged. The concentration of the preservative may be substantially unchanged to within about 50%, within about 10%, within about 5%, within about 1% or less. The method of use may include providing a flow control device of any aspect or embodiment to a subject, wherein the concentration of the preservative in the reservoir is configured to be substantially unchanged in multiple instillations. The concentration of the preservative may be substantially unchanged to within about 50%, within about 10%, within about 5%, within about 1% or less. In some cases, according to the methods, apparatuses and devices disclosed herein, the concentration of the preservative in the reservoir may remain substantially unchanged to within about 50%, within about 40%, within about 30%, within about 20%, within about 15%, within about 10%, within about 9%, within about 8%, within about 7%, within about 6%, within about 5%, within about 4%, within about 3%, within about 2%, within about 1% or less compared to the initial concentration after at least 5, at least 10, at least 15, at least 20, at least 30, at least 40, or at least 50 instillations.

[0166] In another aspect, a kit includes the flow control device of any aspect or embodiment, and packaging is provided. In some embodiments, the kit further includes a label, wherein the label includes an indication of the contents of the ophthalmic formulation disposed within the reservoir.

[0167] Preservative remover

[0168] The present disclosure provides a preservative remover (also referred to herein as a preservative removal device (e.g., a matrix)). The preservative remover can quickly and selectively remove the preservative of the present disclosure from a solution, emulsion, or suspension containing an ophthalmic agent. The preservative remover can quickly and selectively extract the preservative, allowing the eye drop formulation to flow through the plug with minimal pressure drop, while still having enough time to remove the preservative and having enough surface area and chemical reaction to adsorb the preservative. The matrix can contain a material that has a high affinity for preservatives such as benzalkonium chloride (BAK), while at the same time having a low affinity for drugs or other ophthalmic agents, particularly when the drug is also in a complex with a capping agent. The preservative remover can have sufficient selectivity so that at least 50% of the preservative is removed and at least 50% of the drug is retained by the solution. BAK (benzalkonium chloride) also has many synonyms: alkylbenzyldimethylammonium chloride, alkyldimethylbenzyl ammonium chloride, benzyl ammonium chloride, and the like. It is also represented by chemical formulas such as: C6H5CH2N(CH3)2RCl(R=C8H 17 to C 18 H 37 ), CAS number: 63449-41-2. For most uses in ophthalmic applications and formulations, use pharmaceutical grade, EP, USP, JP, manufactured under appropriate GMP controls for pharmaceutical or biopharmaceutical production.

[0169] Non-limiting examples of preservative removers may include solid, gel and / or particulate matrices. Preservative removers may act as a physical barrier or filter. Additionally or alternatively, preservative removers may chemically remove preservatives, such as by adsorbing the preservatives onto a matrix. Preservative removers may be placed at the outlet of a container, which may contain a solution, an emulsion, or a suspension.

[0170] In some embodiments, the matrix arranged in the nozzle can be a porous polymer matrix. The porous polymer matrix can include a variety of materials. Such materials can be safe and biocompatible. Such materials can include, but are not limited to, for example, poly (2-hydroxyethyl methacrylate) (pHEMA), poly (hydroxyethyl methacrylate-to-methacrylic acid), cross-linked polyacrylamide, dimethylacrylamide, methyl methacrylate, silicone and / or any combination of the foregoing substances.

[0171] In some embodiments, the matrix can be highly porous. The pores in the matrix can be small enough so that molecules that may initially be away from the surface of the polymer in the matrix can diffuse toward the polymer and adsorb. The matrix can have large interconnected pores that can allow the solution to flow and adsorb the preservative into the pores. The matrix can be formed into a porous gel, a packed bed, and / or a structure formed by 3D printing soft lithography, electrospinning, or any other suitable method. In some embodiments, the matrix can include a microporous gel. In some embodiments, the matrix is ​​a hydrogel. In some embodiments, the matrix can include a packed bed of pHEMA or cross-linked polyacrylamide or other polymer particles. The particles can be macroporous. The particles can be spherical or non-spherical. In some embodiments, the polymer matrix can include nano- or micron-sized polymer particles (e.g., nanogels or microgels). In some embodiments, the polymer matrix can include crystal colloids. In some embodiments, the polymer matrix can be referred to as a hydrogel, which is hydrophilic and easily absorbs water. In some embodiments, the particles themselves can directly impart an antiseptic effect, for example, colloidal silver nanoparticles.

[0172] In some embodiments, the average diameter of the particles of the formulations described herein is from about 1 nm to about 10 μm, from about 1 nm to about 10 μm, from about 1 nm to about 5 μm, from about 1 nm to about 2 μm, from about 1 nm to about 1 μm, from about 1 nm to about 900 nm, from about 1 nm to about 800 nm, from about 1 nm to about 700 nm, from about 1 nm to about 600 nm, from about 1 nm to about 500 nm, from about 1 nm to about 400 nm, from about 1 nm to about 300 nm, from about 1 nm to about 200 nm, or even from about 1 nm to about 100 nm. In some embodiments, the average diameter is the average maximum diameter or the average equivalent diameter.

[0173] In some embodiments, more than 80% of the particles in the formulation, for example, more than 90% or more than 95% of the particles have an average maximum particle size of about 1 nm to about 1000 μm, about 1 nm to about 10 μm, about 1 nm to about 5 μm, about 1 nm to about 2 μm, about 1 nm to about 1 μm, about 1 nm to about 900 nm, about 1 nm to about 800 nm, about 1 nm to about 700 nm, about 1 nm to about 600 nm, about 1 nm to about 500 nm, about 1 nm to about 400 nm, about 1 nm to about 300 nm, about 1 nm to about 200 nm, or even about 1 nm to about 100 nm. In some embodiments, the average diameter is the average maximum diameter or the average equivalent diameter.

[0174] In some embodiments, the average diameter of the particles of the porous polymer matrix described herein is about 100 nm to about 10 μm, about 100 nm to about 10 μm, about 100 nm to about 5 μm, about 100 nm to about 2 μm, about 100 nm to about 1 μm, about 100 nm to about 900 nm, about 100 nm to about 800 nm, about 100 nm to about 700 nm, about 100 nm to about 600 nm, about 200 nm to about 500 nm, about 250 nm to about 600 nm, about 300 nm to about 600 nm, about 350 nm to about 700 nm, about 450 nm to about 550 nm, about 475 nm to about 525 nm, or about 400 nm to about 700 nm. In some embodiments, the average diameter is the average maximum diameter or the average equivalent diameter.

[0175] In some embodiments, more than 80% of the particles of the porous polymer matrix, more than 90% of the particles of the porous polymer matrix, or more than 95% of the particles of the porous polymer matrix have an average diameter of about 100 nm to about 10 μm, about 100 nm to about 10 μm, about 100 nm to about 5 μm, about 100 nm to about 2 μm, about 100 nm to about 1 μm, about 100 nm to about 900 nm, about 100 nm to about 800 nm, about 100 nm to about 700 nm, about 100 nm to about 600 nm, about 200 nm to about 500 nm, about 250 nm to about 600 nm, about 300 nm to about 600 nm, about 350 nm to about 700 nm, about 450 nm to about 550 nm, about 475 nm to about 525 nm, or about 400 nm to about 700 nm. In some embodiments, the average diameter is the average maximum diameter or the average equivalent diameter.

[0176] In some embodiments, more than 80% of the particles of the porous polymer matrix, more than 90% of the particles of the porous polymer matrix, or more than 95% of the particles in the formulation have an average diameter of about 10 μm to about 100 μm, about 50 μm to about 200 μm, about 90 μm to about 180 μm, about 150 μm to about 250 μm, about 200 μm to about 350 μm, about 250 μm to about 500 μm, about 350 μm to about 800 μm, about 500 μm to about 1000 μm. In some embodiments, the average diameter is the average maximum diameter or the average equivalent diameter. The particles can be irregular, regular, spherical, oval, or generally have any shape, and the size can be defined as passing through a separation sieve of a certain size.

[0177] The matrix can include tortuosity so that the flow path of a solution, emulsion, or suspension through a nozzle can be significantly increased. In embodiments where the matrix is ​​a packed bed of macroporous particles, the packed bed of macroporous particles can have three levels of porosity: the spaces between the particles, the macropores in the particles, and the inherent porosity of the polymer. In such embodiments, all three levels of porosity can contribute to the tortuosity of the matrix.

[0178] In some embodiments, the matrix arranged in the nozzle can be a porous polymer matrix. Applying pressure behind the nozzle can cause fluid to flow through the nozzle through a flow path, and the preservative can be removed by adsorbing the preservative onto the matrix along the flow path. The combination of polymer material, hydraulic permeability, partition coefficient, adsorption rate and pores can help absorb all or most of the preservative from the solution, thereby helping the patient's eye drops. The solution with reduced preservatives can be directly delivered to the eyes subsequently. The porous polymer matrix can quickly and selectively extract the preservative, so that the eye drop preparation flows through the plug with a minimum pressure drop, and still has enough time to remove the preservative and has enough surface area to adsorb the preservative. The matrix can include a high affinity for preservatives such as benzalkonium chloride (BAK), and a material with low affinity for medicine or other ophthalmic agents. The porous polymer matrix can include a high affinity for preservatives so that at least 50% of the preservatives can be removed and at least 50% of the medicine can be retained by the solution. In some cases, the methods and devices disclosed herein are configured to remove at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% or more of the preservative during instillation or delivery of an eye drop formulation, while also retaining at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%, or more of the drug.

[0179] The porous polymer matrix can include a variety of materials. Such materials can be safe and biocompatible. The polymers of the present disclosure may include various monomers, for example, poly(2-hydroxyethyl methacrylate) (pHEMA) and / or acrylamide (AM), dimethylacrylamide (DMA) and / or methyl methacrylate (MMA) and / or N-vinylpyrrolidone (NVP) and / or 2-acrylamido-2-methylpropanesulfonic acid (AMPS) and / or polyvinyl alcohol (PVA) and / or polymethylpropanesulfonic acid (PAMPS) and / or 2-sulfoethyl methacrylate (SEM) and / or acrylic acid (AA) and / or vinylphosphonic acid (VP) and / or tert-butyl methacrylate (TBM) and / or methacryloxypropyl tris(trimethylsiloxy)silane (TRIS) and / or tert-amyl methacrylate and / or n-octyl methacrylate and / or isodecyl methacrylate and / or n-decyl methacrylate and / or n-dodecyl acrylate and / or n-hexyl acrylate and / or n-dodecyl acrylate and / or octadecyl acrylamide and / or silicone and / or any combination of the foregoing materials. The polymer matrix may also include a cross-linking agent. The cross-linking agent may include N,N'-methylenebis(acrylamide) (MBAM) and / or trisacrylamide triazine (TATZ) and / or SR 351 and / or SR9035 and / or any combination of the foregoing materials.

[0180] In some embodiments, the matrix material is a copolymer. The copolymer may include more than one monomer. The copolymer may be branched. The copolymer may be linear. The copolymer may include a crosslinker. The copolymer may be a block copolymer, may be an alternating copolymer, may be a periodic copolymer, may be a gradient copolymer, may be a statistical copolymer, may be a stereoblock copolymer. The copolymer may exhibit phases of different hydrophobicity or hydrophilicity. The hydrophobicity and / or hydrophilicity of one or more monomers or crosslinkers may control the binding of the therapeutic agent or preservative to the embolic material.

[0181] In some embodiments, the polymer matrix is ​​a cross-linked polyvinyl alcohol cross-linked with citric acid or other suitable cross-linking agents to make it a hydrophilic hydrogel. In some embodiments, the polymer matrix is ​​a cross-linked copolymer of cross-linked polyvinyl pyrrolidone, cross-linked polyethylene oxide, cross-linked polyacrylamide, methacrylic acid, polyacrylic acid, and a copolymer such as poly(acrylic acid-co-acrylamide) or poly(methacrylic acid-co-acrylamide).

[0182] The polymers of the present disclosure may generally follow the A / B / C formula, wherein A and B are monomers, C is one or more cross-linking agents, and A and B are not the same monomers. In some embodiments, A may be an anionic hydrophilic monomer. In the A / B / C formula, the A-type monomer may include AM or NVP. In some examples, B may be an ionic hydrophilic monomer. In the A / B / C formula, the B-type monomer may include MAA, AMPS, SEM, AA, or VP. In some embodiments, C may be a cross-linking agent. In the A / B / C formula, the C-type monomer may include one or more of MBAM, TATZ, or SR 351. The polymers of the present disclosure may generally follow the A / C formula, wherein A is the above-mentioned monomer and C is one or more cross-linking agents as described above. The polymers of the present disclosure may generally follow the B / C formula, wherein B is the above-mentioned monomer and C is one or more cross-linking agents as described above.

[0183] The polymers of the present disclosure may also include graft copolymers, such that components such as monomer A and a crosslinker C are first copolymerized to form a crosslinked copolymer that can be isolated as small beads or other shaped particles. These beads or particles can then be re-swollen in water, and the B-type monomer can be added and then polymerized into or onto the beads or particles by using free radical "grafting" polymerization. In this embodiment, the particles are composed of A / C copolymers with a "grafted" B polymer as part of the copolymer structure.

[0184] The following is a non-exhaustive list of examples of polymers of the present disclosure. Included below are polymer components and percentage compositions, each separated by a slash, and identifiers corresponding to the example polymers in the following list. The polymers of the present disclosure may include: AMPS / MBAM / TATZ 7.5 / 82.5 / 10 (D-322-018-AW), AMPS / MBAM / TATZ 7.5 / 77.5 / 15 (D-322-020-AW), AMPS / MBAM 7.5 / 92.5 (D-322-022-AW), BioRad Beads / AMPS1g / 0.5 (D-322-028-C-AW), AMPS / MBAM 7.5 / 92.5 (D-322-002-AG-W), AMPS / MBAM / TATZ 7.5 / 87.5 / 5.0 (D-322-006-AW), SEM / MBAM 7.5 / 92.5 (D-322-010-AW), AM / 2-sulfoethyl MA (SEM) / MBAM 30 / 10 / 60(D-298-132-A),AMPS / MBAM 7.5 / 92.5(D-298-190-AW); 7.5 / 92.5(D-298-178-AW),PVA / PAMPS / CA 4.8 / 1.2 / 2.4IPN(D-298-182-A),AMPS / MBAM 7.5 / 92.5ISP(D-298-184-AW),NVP / AMPS / MBAM / TATZ 30 / 10 / 30 / 30(D-298-186-A),AMPS / MBAM 7.5 / 92.5 (D-298-152-AW), N-vinylpyrrolidone / AMPS / MBAM 30 / 10 / 60 (D-298-120-AW), AA / SR351 40 / 60 (D-298-146-A), AA / MBAM / SR351 60 / 30 / 10 (D-298-148-A), AM / 2-sulfoethyl MA (SEM) / MBAM 15 / 25 / 60 (D-298-134-A), AA / MBAM 40 / 60 (D-298-140-A), AA / MBAM 50 / 50 (D-298-142-A), and VP / AA / MBAM 10 / 45 / 45 (D-298-144-A).

[0185] Any matrix material and any drug associated with the complex can be used such that the partition coefficient of the drug / complex in the matrix can be at least one order of magnitude or two orders of magnitude lower than the affinity of the matrix for the preservative. For example, pHEMA, or SO3- or PO3H- or COO- groups on a polymer (or matrix) can bind to BAK with a partition coefficient of about 100-500, or in some embodiments 1000, depending on the BAK concentration and the structure of the matrix and the % concentration of these groups. In some embodiments, the partition coefficient of the matrix to the preservative from the solution, emulsion or suspension can be, for example, at least 10, at least 50, at least 100, at least 200, at least 300, at least 400, at least 500, at least 600, at least 700, at least 800, at least 900, at least 1000, at least 2000, at least 3000, at least 4000, at least 5000, at least 6000, at least 7000, at least 8000, at least 9000, at least 10,000 or in the range defined by any two of the aforementioned values. Additionally or alternatively, the adsorption rate constant can be high enough so that the time that the drug molecule is adsorbed on the polymer can be less than the time of forming a droplet. The time of forming a droplet can include the time in the range of 0.1 second to 10 seconds.

[0186] The matrix can show high hydraulic permeability, so that the distribution fluid can need relatively small pressure.Hydraulic permeability can depend on the design of the filter.For a given pressure drop, larger holes in the matrix can allow higher flow.In some embodiments, hydraulic permeability can be greater than about 0.01 Darcy.Nozzle can have a permeability of about 0.1 Darcy.Hydraulic permeability of 1 Darcy to 10 Darcy can allow fluid to be retained in the filter when pressure may decrease after forming droplets.Larger hydraulic permeability can allow the same plug to be applicable to a wide range of preparations, including for example high viscosity preparations, such as rewetting eye drops.In some embodiments, porous polymer matrix has hydraulic permeability of for example 0.01Da, 0.1Da, 1Da, 10Da, 100Da, 1000Da or hydraulic permeability in the range limited by any two of the aforementioned values.

[0187] In some embodiments, the matrix can be highly porous. The pores in the matrix can be small enough so that molecules that may initially be away from the surface of the polymer in the matrix can diffuse toward the polymer and adsorb. The matrix can have large interconnected pores that can allow the solution to flow and adsorb the preservative into the pores. The matrix can be formed into a porous gel, a packed bed and / or a structure formed by 3D printing soft lithography, electrostatic spinning of fibers, or any other suitable method. In some embodiments, the matrix can include a microporous gel. In some embodiments, the matrix can include pHEMA, or a packed bed of cross-linked polyacrylamide with anionic moieties or acting as a part of a polymer, or other polymer particles. The particles can be macroporous. The particles can be spherical or non-spherical. In some embodiments, the polymer matrix can include polymer particles (e.g., nanogels or microgels) of nanometer or micron size or 10s microns or 100s microns. In some embodiments, the polymer matrix can include crystal colloids. In some embodiments, the particles themselves can directly impart an antiseptic effect, such as colloidal silver nanoparticles.

[0188] In some embodiments, it may be necessary to stably maintain the particles in the nozzle and prevent them from eluting from the nozzle. The particles can be attached to the container wall by long polymer chains and / or by placing a filter at the outlet of the device. Additionally or alternatively, the wall or other surface of the container can include an antiseptic attached thereto and / or incorporated therein. In such embodiments, the antiseptic source comprises a pHEMA film, and 1-10% by volume of the film is balanced with BAK. In some embodiments, the matrix comprises pre-loaded BAK, and its concentration can inhibit the growth of microorganisms over time.

[0189] In some embodiments, the porous matrix material can have tortuosity so that the flow path of solution, emulsion or suspension through nozzle increases. In some embodiments where the matrix comprises a packed bed of macroporous particles, the packed bed of macroporous particles can have three levels of porosity: the space between particles, the macropores in the particles and the intrinsic porosity of the polymer. In such embodiments, all three levels of porosity can contribute to the tortuosity of the matrix. The tortuosity of the porous material combined with the geometric shape flow divider itself can increase the flow path according to the multiplier of the first flow path length corresponding to the flow limited by the nozzle geometry and the second flow path length corresponding to the tortuosity of the porous material.

[0190] The pressure required to generate droplets may exceed the Young-Laplace pressure during droplet generation, which may be approximately 2σ / R d , where σ is the surface tension, R d is the radius of the droplet. R is estimated based on a droplet volume of 30 microliters (μL). dis about 0.5 mm, and using the surface tension of water a Young-Laplace pressure of about 100 Pa can be derived. The pressure at which the droplets are formed can also exceed the pressure required to expel a volume of 30 μL. Typical drop volumes can include volumes in the range of 1 μL to 100 μL. Based on ideal gas estimates using a 3 mL bottle at atmospheric pressure, the minimum pressure to form droplets can be about 0.01 Atm (1000 Pa), but may be lower for larger bottles at different pressures. The maximum pressure at which droplets are formed can be limited by the patient's strength. The pressure at which droplets are formed can be in the range of 0.01 Atm to 0.5 Atm.

[0191] The liquid flow rate through the plug can depend on the applied pressure and the design parameters of the substrate, including but not limited to length, area, porosity, hydraulic permeability, flow path length, etc. These design parameters can be considered alone or in combination to remove the preservative without excessive squeezing pressure. The liquid flow rate can affect the time to form a droplet.

[0192] Solution, emulsion or suspension

[0193] Provided herein are ophthalmic preparations comprising ophthalmic agents, complexing agents and preservatives. In some embodiments, provided herein are ophthalmic preparations that are solutions, emulsions and / or suspensions of ophthalmic agents, complexing agents and preservatives. In some embodiments, provided herein are compositions of any ophthalmic therapeutic compounds or salts of any of the preservatives, ophthalmic agents and / or complexing agents of the present disclosure comprising a therapeutically effective amount. In some embodiments, solutions, emulsions or suspensions can be used in any of the methods described herein. Solutions, emulsions or suspensions can also include one or more pharmaceutically acceptable excipients.

[0194] In some embodiments, the composition of the complexing agent, therapeutic agent and / or preservative can be used to treat therapeutic conditions, such as dry eye, bacterial infection, glaucoma, hypertension, inflammation, allergic conjunctivitis, eyelash hypotrichosis, fungal infection, etc. Additionally or alternatively, the composition of the preservative, therapeutic agent and / or complexing agent can be used during preventive, diagnostic or therapeutic ophthalmic procedures (e.g., local anesthesia, pupil dilation, etc.). The solution, emulsion or suspension applied to the eye can be topically applied, for example, with eye drops. In some embodiments, the compound of the present disclosure or its salt having low water solubility can be formulated as an aqueous suspension.

[0195] Ophthalmic reagents

[0196] Embodiments of the present disclosure can provide ophthalmic agents for delivery to the eye. Ophthalmic agents can be therapeutic agents. The therapeutic agent can include one or more ophthalmic agents. In some embodiments, the present disclosure provides solutions, emulsions or suspensions of preservatives, complexing agents and ophthalmic agents. In some embodiments, solutions, emulsions or suspensions can include preservative removers (e.g., in these embodiments, preservative removers can include a part of solutions, emulsions or suspensions containing ophthalmic agents and preservatives). In other embodiments, preservative removers can be separated from solutions, emulsions or suspensions containing ophthalmic agents, complexing agents and preservatives (e.g., in these embodiments, preservative removers can be located in the neck of the bottle). Ophthalmic agents can include compounds and salts for the treatment of ophthalmic diseases. Optionally, in any embodiment, solutions, emulsions or suspensions can also include one or more pharmaceutically acceptable excipients. Disclosed compounds and salts can be used, for example, to treat or prevent visual disorders, and / or used during ophthalmic processes for the prevention and / or treatment of ophthalmic conditions. The following examples are not intended to be limiting.

[0197] Ophthalmic agents can be integrated into the fluid, and the fluid can flow into the eye from the container through the outlet of the compressible bottle. In some embodiments, the fluid can include a solution, an emulsion or a suspension containing an ophthalmic agent. The solution, emulsion or suspension can include an ophthalmic agent. Example ophthalmic agents that can be used in conjunction with the compressible bottle include but are not limited to: timolol, dorzolamide, dexamethasone phosphate, dexamethasone, Betimol, olopatadine, brimonidine, tetrahydrozoline, latanoprost nitrate, latanoprost, bimatoprost, travoprost and any combination of two or more thereof. Ophthalmic agents can include branded drugs and preparations, including but not limited to Timoptic, Xalatan, Combigan, Lumigan, Pataday, Pazeo, Trusopt, Cosopt, Alphagan, Visine, Vyzulta, Vesneo and other agents such as described herein in the following table. Ophthalmic agents can be dissolved in an aqueous solution. The solution can be sterilized and buffered to a suitable pH. In some embodiments, the solution may include inactive ingredients such as sodium chloride, sodium citrate, hydroxyethylcellulose, sodium phosphate, citric acid, sodium dihydrogen phosphate, polyethylene glycol 40 hydrogenated castor oil, tromethamine, boric acid, mannitol, edetic acid disodium glyceryl, sodium hydroxide and / or hydrochloric acid. In some embodiments, the fluid includes a preservative in addition to the ophthalmic agent. Exemplary preservatives include, but are not limited to, benzalkonium chloride (BAK), alcohols, parabens, methyl parabens, polyparabens, EDTA, chlorhexidine, quaternary ammonium compounds, Stabilized oxychlorine complexes, Sorbic acid, sodium perborate, polyquaternium-1, chlorobutanol, cetrimonium chloride, disodium edetate, etc.

[0198] In some embodiments, the ophthalmic agent is latanoprost. In some embodiments, the ophthalmic agent is bimatoprost. In some embodiments, the ophthalmic agent is travoprost. In some embodiments, the ophthalmic agent is latanoprost and the preservative is benzalkonium chloride (BAK). In some embodiments, the ophthalmic agent is bimatoprost and the preservative is benzalkonium chloride (BAK). In some embodiments, the ophthalmic agent is travoprost and the preservative is benzalkonium chloride (BAK).

[0199] The ophthalmic agents for treating, for example, xerophthalmia, bacterial infection, glaucoma, hypertension, inflammation, allergic conjunctivitis, eyelash hypotrichosis, fungal infection, etc. and the ophthalmic agents for local anesthesia, pupil dilation, etc. can be applied to the patient as a solution, emulsion or suspension that is locally delivered to the eye by a compressible bottle, a dropper or similar delivery mechanism. The solution, emulsion or suspension may be subject to contamination such as microorganisms, fungi or particulates, which may be unfavorable to the patient's health. In order to prevent this contamination, preservatives can be added to the solution, emulsion or suspension. However, patients being exposed to preservatives may have an adverse effect on eye health. It may be advantageous to limit patients being exposed to preservatives by providing a preservative removal device that can remove preservatives from a solution, emulsion or suspension.

[0200] In some embodiments, the ophthalmic agent to be dispensed comprises an active ingredient selected from cyclosporine and rifalast. In such embodiments, the ophthalmic agent may be an active ingredient for treating dry eye.

[0201] In some embodiments, the ophthalmic agent to be distributed comprises an active ingredient selected from sodium sulfacetyl sulfate, ofloxacin, gatifloxacin, ciprofloxacin, moxifloxacin, tobramycin, levofloxacin, prednisolone acetate, polymyxin B sulfate and trimethoprim. In some embodiments, the ophthalmic preparation to be distributed comprises the active ingredients sodium sulfacetyl sulfate and prednisolone acetate. In some embodiments, the ophthalmic preparation to be distributed comprises the active ingredients polymyxin B sulfate and trimethoprim. In such embodiments, the ophthalmic agent can be an active ingredient for treating bacterial infection.

[0202] In some embodiments, the ophthalmic agent to be distributed comprises an active ingredient selected from brimonidine tartrate, bimatoprost, levobunolol hydrochloride, brinzolamide, betaxolol hydrochloride, pilocarpine hydrochloride, apraclonidine, travoprost, timolol maleate, latanoprost, dorzolamide hydrochloride, timolol maleate and tafluprost. In some embodiments, the ophthalmic preparation to be distributed comprises the active ingredients brimonidine tartrate and timolol maleate. In some embodiments, the ophthalmic preparation to be distributed comprises the active ingredients brimonidine tartrate and timolol maleate. In some embodiments, the ophthalmic preparation to be distributed comprises the active ingredients brimonidine tartrate and brimonidine tartrate. In such embodiments, the ophthalmic agent can be an active ingredient for treating glaucoma or hypertension.

[0203] In some embodiments, the ophthalmic agent to be distributed comprises an active ingredient selected from ketorolac tromethamine, fluorometholone, prednisolone acetate, diflupregnant butyl, fluorometholone acetate, nepafenac, dexamethasone, diclofenac sodium, bromfenac, gentamicin, tobramycin, neomycin and polymyxin B sulfate. In some embodiments, the ophthalmic preparation to be distributed comprises the active ingredients gentamicin and prednisolone acetate. In some embodiments, the ophthalmic preparation to be distributed comprises the active ingredients tobramycin and dexamethasone. In some embodiments, the ophthalmic preparation to be distributed comprises the active ingredients neomycin, polymyxin B sulfate and dexamethasone. In such embodiments, the ophthalmic agent can be an active ingredient for treating inflammation.

[0204] In some embodiments, the ophthalmic agent to be dispensed comprises an active ingredient selected from nedocromil sodium, epinastine hydrochloride, alcaftadine, lodoxamide tromethamine, emedastine difumarate, and olopatadine hydrochloride. In such embodiments, the ophthalmic agent may be an active ingredient for treating allergic conjunctivitis.

[0205] In some embodiments, the ophthalmic agent to be dispensed comprises an active ingredient selected from proparacaine hydrochloride and tetracaine hydrochloride. In such embodiments, the ophthalmic agent may be a local anesthetic.

[0206] In some embodiments, the ophthalmic agent to be dispensed comprises an active ingredient selected from cyclopentolate hydrochloride, atropine sulfate, and tropicamide. In some embodiments, the ophthalmic preparation to be dispensed comprises the active ingredients cyclopentolate hydrochloride and phenylephrine hydrochloride. In such embodiments, the ophthalmic agent can dilate the pupil.

[0207] In some embodiments, the ophthalmic agent to be dispensed comprises the active ingredient natamycin. In such embodiments, the ophthalmic agent may be an active ingredient for treating fungal infections.

[0208] In some embodiments, the ophthalmic agent to be distributed comprises an active ingredient selected from lipoic acid cholinester chloride, rebamipide, pilocarpine, ketorolac, acetocridin, tropicamide, sodium hyaluronate, diclofenac sodium, pilocarpine hydrochloride and ketorolac. In some embodiments, the ophthalmic preparation to be distributed comprises the active ingredients acetocridin and tropicamide. In some embodiments, the ophthalmic preparation to be distributed comprises the active ingredients sodium hyaluronate and diclofenac sodium and pilocarpine hydrochloride. In some embodiments, the ophthalmic preparation to be distributed comprises the active ingredients pilocarpine and ketorolac. In such embodiments, the ophthalmic agent can be an active ingredient for treating presbyopia.

[0209] In some embodiments, the solutions, emulsions, or suspensions of the present disclosure comprise a compound or salt of any ophthalmic agent of the present disclosure, wherein the compound or salt of the ophthalmic agent is substantially free of impurities, e.g., at least about 80% by weight (wt %), at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9% pure.

[0210] In some embodiments, a solution, emulsion, or suspension of the present disclosure comprises a compound or salt of any ophthalmic agent of the present disclosure, wherein the ophthalmic agent is about 70% to about 99.99%, about 80% to about 99.9%, about 85% to about 99%, about 90% to about 99%, about 95% to about 99%, about 97% to about 99%, about 98% to about 99%, about 98% to about 99.9%, about 99% to about 99.99%, about 99.5% to about 99.99%, about 99.6% to about 99.99%, about 99.8 to about 99.99%, or about 99.9% to about 99.99% free of impurities.

[0211] The amount of the compound or salt of the ophthalmic agent in the solution, emulsion or suspension of the present disclosure can be measured as a percentage of mass per volume. In some embodiments, the solution, emulsion or suspension (such as, aqueous solution) of the present disclosure comprises about 0.05 wt % to about 10 wt % of any ophthalmic agent disclosed herein. In some embodiments, a solution, emulsion, or suspension (such as an aqueous solution) of the present disclosure comprises about 0.01 wt%, about 0.02 wt%, about 0.03 wt%, about 0.04 wt%, about 0.05 wt%, about 0.06 wt%, about 0.07 wt%, about 0.08 wt%, about 0.09 wt%, about 0.1 wt%, about 0.2 wt%, about 0.3 wt%, about 0.4 wt%, about 0.5 wt%, about 0.6 wt%, about 0.7 wt%, about 0.8 wt%, about 0.9 wt%, about 1 wt%, about 1.1 wt%, about 1.2 wt%, about 1.3 wt%, about 1.4 wt%, about 1.5 wt%, about 1.6 wt%, about 1.7 wt%, about 1.8 wt%, about 1.9 wt%. %, about 9 wt %, about 2 wt %, about 2.1 wt %, about 2.2 wt %, about 2.3 wt %, about 2.4 wt %, about 2.5 wt %, about 2.6 wt %, about 2.7 wt %, about 2.8 wt %, about 2.9 wt %, about 3 wt %, about 3.1 wt %, about 3.2 wt %, about 3.3 wt %, about 3.4 wt %, about 3.5 wt %, about 3.6 wt %, about 3.7 wt %, about 3.8 wt %, about 3.9 wt %, about 4 wt %, about 4.1 wt %, about 4.2 wt %, about 4.3 wt %, about 4.4 wt %, about 4.5 wt %, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %, or about 10 wt % of a compound or salt of an ophthalmic agent described herein.

[0212] The compound or salt of the ophthalmic agent described herein can be, for example, about 500 nanomolar (nM), about 600 nM, about 700 nM, about 800 nM, about 900 nM, about 1 micromolar (μM), about 2 μM, about 3 μM, about 4 μM, about 5 μM, about 6 μM, about 7 μM, about 8 μM, about 9 μM, about 10 μM, about 20 μM, about 30 μM, about 40 μM, about 50 μM, about 60 μM, about 70 μM, about 80 μM, about 90 μM, about 100 μM, about 150 μM, about 200 μM, about 250 μM, about 300 μM, about 350 μM, about 400 μM, about 450 μM In some embodiments, the present invention may be present in a solution, emulsion or suspension of the present disclosure at a concentration of about 100 μM, about 500 μM, about 550 μM, about 600 μM, about 650 μM, about 700 μM, about 750 μM, about 800 μM, about 850 μM, about 900 μM, about 1 millimolar (mM), about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM or about 100 mM. The compound of the ophthalmic agent described herein can be present in a solution, emulsion or suspension with a concentration in a certain range, and the range is defined by the upper and lower limits selected from any of the aforementioned concentrations. For example, the compound or salt of the ophthalmic agent of the present disclosure can be present in a solution, emulsion or suspension at a concentration of about 1 nM to about 100 mM, about 10 nM to about 10 mM, about 100 nM to about 1 mM, about 500 nM to about 1 mM, about 1 mM to about 50 mM, about 10 mM to about 40 mM, about 20 mM to about 35 mM or about 20 mM to about 30 mM.

[0213] preservative

[0214] The present disclosure provides preparations comprising one or more preservatives, which are used for solutions, emulsions or suspensions of ophthalmic agents of the present disclosure. Preservatives can include compounds and salts, and are used as preservatives for solutions, emulsions or suspensions of ophthalmic agents. One or more preservatives can, for example, prevent microorganisms and / or fungal growth. One or more preservatives can, for example, prevent physical or chemical degradation of ophthalmic agents.

[0215] Non-limiting examples of preservatives include benzalkonium chloride, ethylenediaminetetraacetic acid (EDTA), chlorobutanol, phenylmercuric acetate, phenylmercuric nitrate, chlorhexidine acetate, thimerosal, benzethonium chloride, sorbic acid, alcohols, parabens (e.g., methylparaben, polyparaben), chlorhexidine, quaternary ammonium compounds, cetrimide, cetamide, cetyltrimethylammonium bromide, hexadecyltrimethylammonium bromide, polyquaternium-1 Stabilized oxychlorine complex Solution of borate, sorbitol, propylene glycol, and zinc Sodium Perborate Cetrimonium chloride, edetate disodium, etc. In some embodiments, the formulations of the present disclosure include a quaternary ammonium compound preservative. In some embodiments, the preservative is benzalkonium chloride (BAK).

[0216] In some embodiments, the microparticle plug may further include a compound that removes a preservative or a compound that inactivates a preservative. The compound that removes a preservative or a compound that inactivates a preservative can reduce the toxicity of the preparation to be delivered by typical separation methods, including but not limited to adsorption, ion exchange, chemical deposition or solvent extraction. The compound that removes a preservative or a compound that inactivates a preservative may include but is not limited to activated carbon, an antioxidant, ethylenediaminetetraacetic acid (EDTA), an anionic hydrogel, a cationic compound, a neutralizer or a combination thereof.

[0217] The preservative system includes stabilized oxychlorine complexes (SOC), a combination of chlorine dioxide, chlorite, and chlorate. When exposed to light, SOC decomposes into water, oxygen, sodium, and chlorine free radicals, which lead to the oxidation of intracellular lipids and glutathione, interfering with the cellular function and maintenance of important enzymes. For preservatives that generate chlorine free radicals (such as ), the microparticle plugs of the present disclosure may include materials with a high affinity for free radicals, such as activated carbon or antioxidants, such as vitamin E.

[0218] Travatan Z (Alcon Laboratories, Fort Worth, TX) The system contains borate, sorbitol, propylene glycol and zinc. Without being bound by theory, it is believed that the preservative effect comes from the combination of borate and zinc. For preservatives including borate and zinc (such as ), the microparticle plug of the present disclosure may include a metal chelator (such as EDTA), an anionic hydrogel that can extract zinc cations through electrostatic interactions, a cationic hydrogel or resin that can extract borate anions through electrostatic interactions, or a neutralizing agent that can neutralize boric acid.

[0219] In some embodiments, the solutions, emulsions, or suspensions of the present disclosure comprise a compound or salt of any preservative of the present disclosure, wherein the compound or salt of the preservative is substantially free of impurities, e.g., at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9% pure.

[0220] In some embodiments, solutions, emulsions, or suspensions of the present disclosure comprise a compound or salt of any preservative of the present disclosure, wherein the preservative is about 70% to about 99.99%, about 80% to about 99.9%, about 85% to about 99%, about 90% to about 99%, about 95% to about 99%, about 97% to about 99%, about 98% to about 99%, about 98% to about 99.9%, about 99% to about 99.99%, about 99.5% to about 99.99%, about 99.6% to about 99.99%, about 99.8 to about 99.99%, or about 99.9% to about 99.99% free of impurities.

[0221] The amount of the compound or salt of the preservative in the solution, emulsion or suspension of the present disclosure can be measured as a percentage of mass per volume. In some embodiments, the solution, emulsion or suspension (such as an aqueous solution) of the present disclosure comprises about 0.05 wt % to about 10 wt % of any preservative compound or salt disclosed herein. In some embodiments, a solution, emulsion, or suspension of the disclosure, such as an aqueous solution, comprises about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3. %, about 9 wt %, about 2 wt %, about 2.1 wt %, about 2.2 wt %, about 2.3 wt %, about 2.4 wt %, about 2.5 wt %, about 2.6 wt %, about 2.7 wt %, about 2.8 wt %, about 2.9 wt %, about 3 wt %, about 3.1 wt %, about 3.2 wt %, about 3.3 wt %, about 3.4 wt %, about 3.5 wt %, about 3.6 wt %, about 3.7 wt %, about 3.8 wt %, about 3.9 wt %, about 4 wt %, about 4.1 wt %, about 4.2 wt %, about 4.3 wt %, about 4.4 wt %, about 4.5 wt %, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %, or about 10 wt % of a compound or salt of a preservative described herein.

[0222] The compounds or salts of the preservatives described herein can be, for example, about 500 nM, about 600 nM, about 700 nM, about 800 nM, about 900 nM, about 1 μM, about 2 μM, about 3 μM, about 4 μM, about 5 μM, about 6 μM, about 7 μM, about 8 μM, about 9 μM, about 10 μM, about 20 μM, about 30 μM, about 40 μM, about 50 μM, about 60 μM, about 70 μM, about 80 μM, about 90 μM, about 100 μM, about 150 μM, about 200 μM, about 250 μM, about 300 μM, about 350 μM, about 400 μM, about 450 μM, about 500 μM, about 550 μM, about 600 μM, about 650 μM, about 700 μM, about 750 μM, about 800 μM, about 850 μM, about 900 μM, about 1 mM, about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM or about 100 mM concentration is present in the solution, emulsion or suspension of the present disclosure. The compound of the preservative described herein can be present in a solution, emulsion or suspension in a range of concentrations, the range being defined by the upper and lower limits selected from any of the foregoing concentrations. For example, the compound or salt of the preservative of the present disclosure can be present in a solution, emulsion or suspension at a concentration of about 1 nM to about 100 mM, about 10 nM to about 10 mM, about 100 nM to about 1 mM, about 500 nM to about 1 mM, about 1 mM to about 50 mM, about 10 mM to about 40 mM, about 20 mM to about 35 mM, or about 20 mM to about 30 mM.

[0223] Complexing agent

[0224] In some embodiments, the solution, emulsion or suspension of the present disclosure also comprises a complexing agent. In some embodiments, the compound or salt of the ophthalmic agent of the present disclosure shows high affinity to the host material, and the addition of a complexing agent reduces the affinity of the ophthalmic agent to the host material. In some embodiments, the solution, emulsion or suspension comprises cyclodextrin, linoleic acid, lipid mixture, oleic acid, cholesterol, arachidonic acid, cod liver oil, fatty acid, etc. In some embodiments, the solution, emulsion or suspension is an aqueous solution comprising a complexing agent. In some embodiments, the solution, emulsion or suspension for topical application to the eye comprises a complexing agent.

[0225] In some embodiments, ophthalmic agent is hydrophobic. In some embodiments, polymer matrix material is designed to absorb the preservative of all benzalkonium chloride (BAK), and can also absorb hydrophobic ophthalmic agent. Complexing agent can reduce the affinity of ophthalmic agent to matrix material. Matrix material can selectively remove preservative from solution, emulsion or suspension. Complexing agent can be used for regulating the interaction between ophthalmic agent and matrix. Utilizing complexing agent (such as cyclodextrin) can change the relative hydrophobicity (hydrophilicity) of ophthalmic agent relative to polymer matrix material, thereby reduce the affinity of ophthalmic agent to matrix. Utilizing complexing agent can make ophthalmic agent remain soluble in water phase, make it not be absorbed on or in polymer matrix material.

[0226] As a secondary effect, capping agents (also referred to as complexing agents) can increase the solubility of ophthalmic agents. Since the concentrations of ophthalmic agents used herein are relatively low, solubility is generally not a problem even without the use of complexing agents. As an additional secondary effect, capping agents can increase the stability of solutions containing ophthalmic agents and preservatives. As an additional secondary effect, capping agents can improve the delivery of ophthalmic agents to certain areas of the body.

[0227] In some embodiments, the complexing agent (or capping agent) forms a host-guest complex with the ophthalmic agent. The complexing agent can have a hydrophobic interior and a hydrophilic exterior. In some embodiments, the complexing agent is a cyclodextrin. In some embodiments, the complexing agent is a crown ether. In some embodiments, the complexing agent is a zeolite.

[0228] In some embodiments, the complexing agent is a cyclodextrin. The cyclodextrin may contain pyranose glucose subunits. The cyclodextrin may contain 6, 7, 8 or more pyranose glucose units. A cyclodextrin containing 6 pyranose glucose units may be an alpha-cyclodextrin. A cyclodextrin containing 7 pyranose glucose units may be a beta-cyclodextrin. A cyclodextrin containing 8 pyranose glucose units may be a gamma-cyclodextrin. The cyclodextrin may be annular, wherein the C2-hydroxyl and C3-hydroxyl form a larger opening, and the C6-hydroxyl forms a smaller opening. The interior of the ring may be hydrophobic. The size of the hydrophobic cavity within the cyclodextrin may be a function of the number of pyranose glucose units.

[0229] Typical cyclodextrins are composed of 6-8 pyranose glucoside units. These subunits are connected by 1,4 glycosidic bonds. Cyclodextrins have a toroidal shape, in which the larger and smaller openings of the ring are exposed to the solvent secondary hydroxyl groups and primary hydroxyl groups, respectively. Due to this arrangement, the hydrophobicity of the inside of the ring is not high but is much lower than the hydrophilicity of the aqueous environment, so it can accommodate other hydrophobic molecules. In contrast, the outside is sufficiently hydrophilic to give cyclodextrin (or its complex) water solubility. In some embodiments, cyclodextrins can be modified by chemically replacing the hydroxyl groups of the pyranose glucoside units. Each pyranose glucoside unit has 3 hydroxyl groups that can react and be substituted. In some embodiments, a plurality of these hydroxyl groups can react, which is called the degree of substitution. The degree of substitution (DS) describes the number of hydroxyl groups that have reacted (on average). Hydroxypropyl oxidation is an example of such a substitution reaction, which generates so-called hydroxypropyl cyclodextrins of different DS depending on the number of hydroxyl groups that react. In some embodiments, the cyclodextrin can be (2-hydroxypropyl)-β-cyclodextrin. The cyclodextrin can be (2-hydroxypropyl)-α-cyclodextrin, (2-hydroxypropyl)-γ-cyclodextrin, α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, methyl-α-cyclodextrin, methyl-β-cyclodextrin or methyl-γ-cyclodextrin or another substituted cyclic glucose polymer. In other embodiments, the cyclodextrin is selected from dimethyl-β-cyclodextrin, highly sulfated β-cyclodextrin, 6-monodeoxy-6-N-mono(3-hydroxy)propylamino-β-cyclodextrin. In other embodiments, the hydroxyl groups of the cyclodextrin are randomly or selectively substituted by any chemical substance and to any desired degree of α, β or γ or any ring size of cyclodextrin. In other embodiments, other types and degrees of substitution on the cyclodextrin ring are also known and possible. These substances can all be used as complexing agents. In some embodiments, commercial products, such as W7HP PHARMA, which is a pharmaceutical grade hydroxypropyl-β-cyclodextrin from Wacker Chemie AG. W7HP PHARMA is a highly soluble beta-cyclodextrin derivative. Hydroxypropyl Betadex is another example of this same commercial type of cyclodextrin.

[0230] In some embodiments, the solution, emulsion, or suspension may contain cyclodextrin in a 5000% molar excess over the ophthalmic agent (e.g., a 50 to 1 ratio of cyclodextrin to the ophthalmic agent). The solution, emulsion, or suspension may contain cyclodextrin at a concentration greater than the ophthalmic agent. The solution, emulsion, or suspension may contain a molar excess of greater than 100%, greater than 500%, greater than 1000%, greater than 2000%, greater than 5000%, greater than 10000%, or more of cyclodextrin. The concentration of cyclodextrin may be greater than 10 times, 20 times, or more than the ophthalmic agent.

[0231] In the solution, emulsion or suspension of the present disclosure, the molar ratio of the complexing agent of the present disclosure to the ophthalmic agent can be about 200: about 1, about 175: about 1, about 150: about 1, about 125: about 1, about 100: about 1, about 75: about 1, about 65: about 1, about 60: about 1, about 55: about 1, about 50: about 1, about 45: about 1, about 40: about 1, about 30: about 1, about 25: about 1, about 10: about 1, about 9.5: about 1, about 9.0: about 1, about 8.5: about 1, about 8.0: about 1, about 7.5: about 1, about 7.0: about 1, about 6.5: about 1, about 6.0: about 1, about 5.5: about 1, about 5.0: about 1, about 4.5: about 1, about 4.0: about 1, about 3.5: about 1, about 3.0: about 1, about 2.5: about 1, about 2.0: about 1, about 1.9: about 1, about 1.8: about 1, about 1.7: about 1, about 1.6: about 1, about 1.5: about 1, about 1.4: about 1, about 1.3: about 1, about 1.2: about 1, about 1.19: about 1, about 1.18: about 1, about 1.17: about 1, about 1.16: about 1, about 1.15: about 1, about 1.14: about 1, about 1.13: about 1, about 1.12: about 1, about 1.11: about 1. In the solutions, emulsions or suspensions of the present disclosure, the ratio of complexing agent to ophthalmic agent may range from about 100:about 1 to about 10:about 1, about 80:about 1 to about 10:about 1, about 100:about 1 to about 20:about 1.

[0232] In some embodiments, the solution, emulsion or suspension may include a cyclodextrin at a concentration of 127 μM (micromolar). In some embodiments, the solution, emulsion or suspension may include a cyclodextrin at a concentration greater than 1 μM, 2 μM, 5 μM, 10 μM, 20 μM, 50 μM, 100 μM or greater. In some embodiments, the solution, emulsion or suspension may include a cyclodextrin at a concentration less than 500 μM, or the concentration of the cyclodextrin may be 1 mM (millimolar), 2 mM, 5 mM, 10 mM, 20 mM, 50 mM, 100 mM or less.

[0233] In some embodiments, the complexing agent may comprise a cyclodextrin mixture comprising one or more cyclodextrins disclosed elsewhere herein.

[0234] In some embodiments, the complexing agent may comprise a micelle forming compound. In some embodiments, the complexing agent may comprise a surfactant. The complexing agent may generally comprise an amphiphilic compound. The micelle forming compound may comprise a hydrophilic head group and a hydrophobic tail. The hydrophilic head group may form the outer surface of the micelle, while the hydrophobic tail forms the inner surface of the micelle. The hydrophobic drug may be located inside the micelle.

[0235] The complexing agent may include one or more of linoleic acid, lipid mixtures, oleic acid, cholesterol, arachidonic acid, cod liver oil, fatty acids, etc. In some embodiments, the fatty acids may include caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid or hexacosanoic acid, myristoleic acid, palmitoleic acid, cis-6-hexadecenoic acid, oleic acid, elaidic acid, vaccenic acid, linoleic acid, trans-linoleic acid, alpha-linolenic acid, arachidonic acid, eicosapentaenoic acid, erucic acid, docosahexaenoic acid, etc.

[0236] In some embodiments, the preservative of the present disclosure may be a surfactant. For example, a preservative comprising a quaternary ammonium compound may be a surfactant. Purite may be a surfactant. Cetrimide may be a surfactant. In some embodiments, benzalkonium chloride may be a cationic surfactant. Benzalkonium chloride may form micelles. Adding benzalkonium chloride may stabilize and / or increase the solubility of hydrophobic ophthalmic agents (e.g., latanoprost, bimatoprost, travoprost, etc.) in solution. Therefore, hydrophobic ophthalmic agents may be fully dissolved and / or stabilized in preparations comprising benzalkonium chloride. Preparations of hydrophobic ophthalmic agents comprising cyclodextrin may comprise a ratio of about 1:1 (agent to cyclodextrin) or may not comprise cyclodextrin at all, because hydrophobic ophthalmic agents may be fully dissolved without cyclodextrin. For example, commercially available ophthalmic preparations of latanoprost may not comprise cyclodextrin as a solubilizing agent.

[0237] Without being limited by theory, removing benzalkonium chloride by a preservative removal device can reduce the solubility of a hydrophobic ophthalmic agent in a formulation. In this case, the amount of hydrophobic agent that can pass through the preservative removal device may be reduced, which may reduce the concentration of a dose of the ophthalmic agent. Adding a cyclodextrin of the present disclosure can reduce the interaction between the hydrophobic agent and the matrix material of the present disclosure. Adding a cyclodextrin of the present disclosure can maintain the solubility of the hydrophobic agent in the formulation when the hydrophobic agent passes through the matrix material of the present disclosure.

[0238] In some embodiments, the solutions, emulsions, or suspensions of the present disclosure comprise a compound or salt of any complexing agent of the present disclosure, wherein the compound or salt of the complexing agent is substantially free of impurities, e.g., at least about 80% by weight, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, at least about 99.1%, at least about 99.2%, at least about 99.3%, at least about 99.4%, at least about 99.5%, at least about 99.6%, at least about 99.7%, at least about 99.8%, or at least about 99.9% pure.

[0239] In some embodiments, solutions, emulsions, or suspensions of the present disclosure comprise a compound or salt of any complexing agent of the present disclosure, wherein the complexing agent is about 70% to about 99.99%, about 80% to about 99.9%, about 85% to about 99%, about 90% to about 99%, about 95% to about 99%, about 97% to about 99%, about 98% to about 99%, about 98% to about 99.9%, about 99% to about 99.99%, about 99.5% to about 99.99%, about 99.6% to about 99.99%, about 99.8 to about 99.99%, or about 99.9% to about 99.99% free of impurities.

[0240] The amount of the compound or salt of the complexing agent in the solution, emulsion or suspension of the present disclosure can be measured as a percentage of mass per volume. In some embodiments, the solution, emulsion or suspension (such as an aqueous solution) of the present disclosure comprises about 0.05 wt % to about 10 wt % of any compound or salt of the complexing agent disclosed herein. In some embodiments, a solution, emulsion, or suspension (such as an aqueous solution) of the disclosure comprises about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about 2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3. %. .9 wt %, about 2 wt %, about 2.1 wt %, about 2.2 wt %, about 2.3 wt %, about 2.4 wt %, about 2.5 wt %, about 2.6 wt %, about 2.7 wt %, about 2.8 wt %, about 2.9 wt %, about 3 wt %, about 3.1 wt %, about 3.2 wt %, about 3.3 wt %, about 3.4 wt %, about 3.5 wt %, about 3.6 wt %, about 3.7 wt %, about 3.8 wt %, about 3.9 wt %, about 4 wt %, about 4.1 wt %, about 4.2 wt %, about 4.3 wt %, about 4.4 wt %, about 4.5 wt %, about 5 wt %, about 6 wt %, about 7 wt %, about 8 wt %, about 9 wt %, or about 10 wt % of a compound or salt of a complexing agent described herein.

[0241] The compounds or salts of the complexing agents described herein can be present in an amount of, for example, about 500 nM, about 600 nM, about 700 nM, about 800 nM, about 900 nM, about 1 μM, about 2 μM, about 3 μM, about 4 μM, about 5 μM, about 6 μM, about 7 μM, about 8 μM, about 9 μM, about 10 μM, about 20 μM, about 30 μM, about 40 μM, about 50 μM, about 60 μM, about 70 μM, about 80 μM, about 90 μM, about 100 μM, about 150 μM, about 200 μM, about 250 μM, about 300 μM, about 350 μM, about 400 μM, about 450 μM, About 500 μM, about 550 μM, about 600 μM, about 650 μM, about 700 μM, about 750 μM, about 800 μM, about 850 μM, about 900 μM, about 1 mM, about 5 mM, about 10 mM, about 15 mM, about 20 mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM, about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM, about 95 mM or about 100 mM concentration is present in the solution, emulsion or suspension of the present disclosure. The compound of the complexing agent described herein can be present in the solution, emulsion or suspension with a certain range of concentrations, and the range is defined by the upper and lower limits selected from any of the aforementioned concentrations. For example, the compound or salt of the complexing agent of the present disclosure can be present in a solution, emulsion or suspension at a concentration of about 1 nM to about 100 mM, about 10 nM to about 10 mM, about 100 nM to about 1 mM, about 500 nM to about 1 mM, about 1 mM to about 50 mM, about 10 mM to about 40 mM, about 20 mM to about 35 mM, or about 20 mM to about 30 mM.

[0242] excipient

[0243] The devices and methods of the present disclosure may include formulating solutions, emulsions or suspensions with one or more inert, pharmaceutically acceptable excipients. Liquid compositions include, for example, solutions in which the compound is dissolved, emulsions containing the compound, or solutions containing liposomes or micelles containing ophthalmic formulations as disclosed herein. These compositions may also contain small amounts of non-toxic auxiliary substances, such as wetting agents or emulsifiers, pH buffers, tonicity agents and other pharmaceutically acceptable additives.

[0244] In some embodiments, the solutions, emulsions or suspensions of the present disclosure further comprise one or more physiologically acceptable carriers, including excipients and adjuvants, which facilitate processing of the pharmaceutical agent into pharmaceutically acceptable preparations. Appropriate formulation depends on the route of administration chosen.

[0245] Pharmaceutically acceptable carriers include, for example, aqueous solutions (such as water or physiologically buffered saline) or other solvents or vehicles (such as ethylene glycol, glycerol), oils (such as olive oil) or organic esters. Excipients can be selected, for example, to achieve delayed release of the agent or to selectively target one or more cells, tissues or organs. The composition can also be present in a solution suitable for topical administration, such as eye drops.

[0246] Some examples of materials that can be used as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, Methocel, methylcellulose, ethylcellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, , safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; and (21) other non-toxic compatible substances used in pharmaceutical preparations.

[0247] In some embodiments, the solution, emulsion or suspension of the present disclosure may include one or more additional excipients. The amount of excipient in the pharmaceutical preparation of the present disclosure may be about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 71%, about 72 %, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 60%, about 70%, about 80%, about 90%, about 100%, about 200%, about 300%, about 400%, about 500%, about 600%, about 700%, about 800%, about 900% or about 1000%. The amount of excipient in the solution, emulsion or suspension of the present disclosure can be 0.01% to 1000%, 0.02% to 500%, 0.1% to 100%, 1% to 50%, 0.01% to 1%, 1% to 10%, 10% to 100%, 50% to 150%, 100% to 500%, or 500% to 1000% by mass of the compound in the solution, emulsion or suspension.

[0248] The amount of excipient in the solution, emulsion or suspension of the present disclosure can be about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 10%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39%, about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74%, about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about %, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 99%, or about 100%. The amount of excipient in the solution, emulsion or suspension can be 0.01% to 1000%, 0.02% to 500%, 0.1% to 100%, 1% to 50%, 0.01% to 1%, 1% to 10%, 10% to 100%, 50% to 150%, 100% to 500%, or 500% to 1000% by mass or by volume of the unit dosage form.

[0249] The ratio of the compound of the ophthalmic preparation of the present disclosure to the excipient in the pharmaceutical preparation of the present disclosure can be about 100: about 1, about 95: about 1, about 90: about 1, about 85: about 1, about 80: about 1, about 75: about 1, about 70: about 1, about 65: about 1, about 60: about 1, about 55: about 1, about 50: about 1, about 45: about 1, about 40: about 1, about 35: about 1, about 30: about 1. In the solutions, emulsions or suspensions of the present disclosure, the ratio of the compound to the excipient of the ophthalmic formulation can be in the range of about 100: about 1 to about 1: about 10, about 10: about 1 to about 1: about 1, about 5: about 1 to about 2: about 1, about 5: about 1 to about 2: about 1, about 25: about 1, about 20: about 1, about 15: about 1, about 10: about 1, about 9: about 1, about 8: about 1, about 7: about 1, about 6: about 1, about 5: about 1, about 4: about 1, about 3: about 1, about 2: about 1, about 1: about 1, about 1: about 2, about 1: about 3, about 1: about 4, about 1: about 5, about 1: about 6, about 1: about 7, about 1: about 8, about 1: about 9, or about 1: about 10. In the solutions, emulsions or suspensions of the present disclosure, the ratio of the compound to the excipient of the ophthalmic formulation can be in the range of about 100: about 1 to about 1: about 10, about 10: about 1 to about 1: about 1, about 5: about 1 to about 2: about 1.

[0250] In some embodiments, the solution, emulsion or suspension of the present disclosure includes a reagent for adjusting the pH of the preparation. In some embodiments, the reagent for adjusting the pH can be an acid (e.g., hydrochloric acid or boric acid) or a base (e.g., sodium hydroxide or potassium hydroxide). In some embodiments, the reagent for adjusting the pH is an acid, such as boric acid. The preparation can include about 0.05% by weight to about 5% by weight, about 0.1% to about 4%, about 0.1% to about 3% by weight, about 0.1% by weight to about 2% by weight, or about 0.1% by weight to about 1% by weight of the reagent for adjusting the pH.

[0251] The solutions, emulsions, or suspensions of the present disclosure can be formulated to be at any suitable pH. In some embodiments, the pH of the solution, emulsion, or suspension is about 4, about 4.05, about 4.1, about 4.15, about 4.2, about 4.25, about 4.3, about 4.35, about 4.4, about 4.45, about 4.5, about 4.55, about 4.6, about 4.65, about 4.7, about 4.75, about 4.8, about 4.85, about 4.9, about 4.95, about 5, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about about 7.4, about 7.5, about 7.6, about 7.7, about 7.8, about 7.9, about 8, about 8.1, about 8.2, about 8.3, about 8.4, about 8.5, about 8.6, about 8.7, about 8.8, about 8.9, or about 9 pH units. In some embodiments, the pH of the solution, emulsion or suspension is about 4 to about 10, about 4.75 to about 7.40, about 5 to about 9, about 6 to about 8, about 6.5 to about 8, about 7 to about 8, about 7.2 to about 8, about 7.2 to about 7.8, about 7.3 to about 7.5, or about 7.35 to about 7.45. In some embodiments, the pH of the solution, emulsion or suspension is about 7.4.

[0252] In some embodiments, the addition of an excipient to a pharmaceutical formulation of the present disclosure may increase or decrease the viscosity of the composition by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%. In some embodiments, the addition of an excipient to a pharmaceutical formulation of the present disclosure may increase or decrease the viscosity of the composition by no more than 5%, no more than 10%, no more than 15%, no more than 20%, no more than 25%, no more than 30%, no more than 35%, no more than 40%, no more than 45%, no more than 50%, no more than 55%, no more than 60%, no more than 65%, no more than 70%, no more than 75%, no more than 80%, no more than 85%, no more than 90%, no more than 95%, or no more than 99%. Examples of ranges within which viscosity changes can be generated by combining any two of the aforementioned percentages. For example, adding an excipient can increase or decrease the viscosity of the composition by 5% to 99%, 10% to 95%, 20% to 70%, or 35% to 55%.

[0253] In some embodiments, excipients that increase viscosity may include polyvinyl alcohol, poloxamer, hyaluronic acid, carbomer, and polysaccharides (i.e., cellulose derivatives, hydroxymethylcellulose, hydroxypropylmethylcellulose, Methacel, gellan gum, and xanthan gum). In some embodiments, excipients that increase mucoadhesion properties may be added. Excipients that increase mucoadhesion may include polyacrylic acid, hyaluronic acid, sodium carboxymethylcellulose, lectins, and chitosan.

[0254] In some embodiments, the solutions, emulsions or suspensions of the present disclosure further comprise an agent for adjusting the molar osmotic pressure concentration of the solution, emulsion or suspension, such as mannitol, sodium chloride, sodium sulfate, dextrose, potassium chloride, glycerol, propylene glycol, calcium chloride and magnesium chloride. In some embodiments, the solution, emulsion or suspension comprises about 0.1% to about 10% by weight, about 0.5% to about 8% by weight, about 1% to about 5% by weight, about 1% to about 4% by weight or about 1% to about 3% by weight of an agent for adjusting the molar osmotic pressure concentration of the solution, emulsion or suspension. In some embodiments, the solutions, emulsions, or suspensions of the present disclosure have an osmotic pressure concentration of about 10 milliOsomols (mOsm) to about 1000 mOsm, about 100 mOsm to about 700 mOsm, about 200 mOsm to about 400 mOsm, about 250 mOsm to about 350 mOsm, or about 290 mOsm to about 310 mOsm.

[0255] In some embodiments, the solutions, emulsions or suspensions of the present disclosure further comprise a buffer such as tromethamine, potassium phosphate, sodium phosphate, saline sodium citrate buffer (SSC), acetate, saline, physiological saline, phosphate buffer saline (PBS), 4-2-hydroxyethyl-1-piperazineethanesulfonic acid buffer (HEPES), 3-(N-morpholino)propanesulfonic acid buffer (MOPS) and piperazine-N,N'-bis(2-ethanesulfonic acid) buffer (PIPES), sodium acetate-boric acid stock solution, boric acid-sodium carbonate and sodium chloride solution, boric acid-sodium borate buffer, sodium phosphate and potassium phosphate buffer, boric acid-sodium carbonate and potassium chloride solution or a combination thereof. In some embodiments, the solution, emulsion or suspension comprises about 0.05% to about 5% by weight, about 0.1% to about 4% by weight, about 0.1% to about 3% by weight, about 0.1% to about 2% by weight, or about 0.1% to about 1% by weight of an agent for buffering the solution, emulsion or suspension.

[0256] In some embodiments, provided herein are solutions, emulsions or suspensions comprising alcohols as excipients. Non-limiting examples of alcohols include ethanol, propylene glycol, glycerol, polyethylene glycol, chlorobutanol, isopropanol, xylitol, sorbitol, maltitol, erythritol, threitol, arabitol, ribitol, mannitol, galactitol, fucitol, lactitol and combinations thereof.

[0257] Salt

[0258] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids. Inorganic acids that can produce salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids that can produce salts include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases that can produce salts include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, etc. Organic bases that can produce salts include, for example, primary amines, secondary amines and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, etc., specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium salt, potassium salt, sodium salt, calcium salt, and magnesium salt.

[0259] The compounds can be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials. Synthetic chemical transformations and methodologies useful for synthesizing the compounds described herein are known in the art.

[0260] The present disclosure provides salts of any one or both of ophthalmic preparations and preservatives. Pharmaceutically acceptable salts include, for example, acid addition salts and base addition salts. The acid added to the compound to form the acid addition salt can be an organic acid or an inorganic acid. The base added to the compound to form the base addition salt can be an organic base or an inorganic base. In some embodiments, the pharmaceutically acceptable salt is a metal salt.

[0261] Metal salts can be produced by adding an inorganic base to a compound of the present disclosure. The inorganic base consists of a metal cation paired with an alkaline counterion, such as hydroxide, carbonate, bicarbonate, or phosphate. The metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal. In some embodiments, the metal is lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, or zinc.

[0262] In some embodiments, the metal salt is an ammonium salt, lithium salt, sodium salt, potassium salt, cesium salt, cerium salt, magnesium salt, manganese salt, iron salt, calcium salt, strontium salt, cobalt salt, titanium salt, aluminum salt, copper salt, cadmium salt, or zinc salt.

[0263] Ammonium salts can be produced by adding ammonia or an organic amine to the compounds of the present disclosure. In some embodiments, the organic amine is triethylamine, diisopropylamine, ethanolamine, diethanolamine, triethanolamine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzylamine, piperazine, pyridine, pyrazole, piperazole (pipyrrazole), imidazole, pyrazine or piperazole (pipyrazine).

[0264] In some embodiments, the ammonium salt is a triethylamine salt, a diisopropylamine salt, a ethanolamine salt, a diethanolamine salt, a triethanolamine salt, a morpholine salt, an N-methylmorpholine salt, a piperidine salt, an N-methylpiperidine salt, an N-ethylpiperidine salt, a dibenzylamine salt, a piperazine salt, a pyridine salt, a pyrazole salt, an imidazolium salt, or a pyrazine salt.

[0265] Acid addition salts can be produced by adding an acid to a compound of the present disclosure. In some embodiments, the acid is organic. In some embodiments, the acid is inorganic. In some embodiments, the acid is hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, phosphoric acid, isonicotinic acid, lactic acid, salicylic acid, tartaric acid, ascorbic acid, gentisic acid, gluconic acid, glucuronic acid, sugar acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, oxalic acid or maleic acid.

[0266] In some embodiments, the salt is hydrochloride, hydrobromide, hydroiodide, nitrate, nitrite, sulfate, sulfite, phosphate, isonicotinate, lactate, salicylate, tartrate, ascorbate, genetisinate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, pantothenate, acetate, propionate, butyrate, fumarate, succinate, methanesulfonate (methylsulfonate), ethanesulfonate, benzenesulfonate, p-toluenesulfonate, citrate, oxalate, or maleate.

[0267] The methods and formulations described herein include the use of amorphous forms as well as crystalline forms (also referred to as polymorphs). Active metabolites of compounds or salts of any of the compounds of the disclosure having the same type of activity are included within the scope of the disclosure. In addition, the compounds described herein may exist in unsolvated form as well as in solvated form with pharmaceutically acceptable solvents (such as water, ethanol, etc.). Solvated forms of the compounds and salts presented herein are also considered to be disclosed herein.

[0268] In some embodiments, the aqueous solutions, emulsions, or suspensions of the present disclosure comprise at least 90% by weight water, e.g., at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or even at least 99% by weight water.

[0269] dose

[0270] The dosage and frequency (single or multiple doses) of administration to a mammal may vary depending on a variety of factors, such as whether the mammal suffers from another disease and the route of administration; the size, age, sex, health, weight, body mass index, and diet of the recipient; the nature and extent of the symptoms of the disease being treated, the type of concurrent treatment, complications of the disease being treated, or other health-related problems. Other treatment regimens or agents may be used in conjunction with the methods and compounds of the present disclosure. Adjusting and manipulating the determined dosage (e.g., frequency and duration) is well within the capabilities of those skilled in the art.

[0271] The dosage can vary depending on the needs of the patient and the compound used. In the context of the present disclosure, the dosage administered to the patient should be sufficient to induce a beneficial therapeutic response in the patient over time. The size of the dosage can also be determined by the presence, nature and extent of any adverse side effects. It is within the skill of the practitioner to determine the appropriate dosage for a particular situation. Typically, treatment is started with a smaller dose that is less than the optimal dose of the compound. Thereafter, the dosage is increased in small increments until the optimal effect is achieved in a given situation. The dosage and interval can be adjusted individually to provide a level of administered compound that is effective for the specific clinical indication being treated. This can provide a treatment regimen commensurate with the severity of the individual disease state.

[0272] Although preferred embodiments of the present invention have been shown and described herein, it is readily understood to those skilled in the art that such embodiments are provided only by way of example. Without departing from the present invention, those skilled in the art will now expect many variations, changes and replacements. It should be understood that the various alternatives of the embodiments of the present invention described herein may be used to implement the present invention. It is intended to limit the scope of the present invention by the appended claims, and thus encompass methods and structures within these claims and their equivalents.

Claims

1. A flow control device for delivering an ophthalmic preparation, the device comprising: a reservoir, the reservoir comprising an ophthalmic preparation disposed therein, the ophthalmic preparation comprising an ophthalmic agent and a preservative; A nozzle, the nozzle comprising: exit, an internal volume, the internal volume including a preservative removal device, and one or more nozzle orifices fluidly connecting the interior volume with an exterior of the nozzle; a reservoir interface disposed between the reservoir and the nozzle, the reservoir interface comprising one or more reservoir apertures, wherein the one or more nozzle apertures are fluidly connected with the one or more reservoir apertures when the nozzle is rotated or translated relative to the reservoir interface; a vial cap, wherein the one or more nozzle apertures are aligned with the one or more reservoir apertures when the vial cap is removed, and wherein the one or more nozzle apertures are not aligned with the one or more reservoir apertures when the vial cap is coupled to the nozzle; and A spring is disposed between the nozzle and the reservoir interface, wherein a restoring force of the spring translates the nozzle to an aligned translational position when the bottle cap is removed.

2. The flow control device of claim 1, wherein the preservative removal device comprises a polymer matrix comprising absorbing molecules of the preservative from the ophthalmic formulation.

3. The flow control device of claim 2, wherein upon translation of the nozzle, the one or more nozzle apertures are fluidly connected or disconnected from the one or more reservoir apertures, thereby allowing or preventing flow of the ophthalmic formulation between the interior volume of the nozzle and the reservoir and stabilizing the concentration of the preservative in the ophthalmic formulation within the reservoir.

4. The flow control device of claim 1, wherein rotation of the bottle cap relative to the reservoir causes the nozzle to translate relative to the reservoir.

5. The flow control device of claim 4, wherein the bottle cap produces an audible or tactile click when moved to the closed state.

6. A flow control device according to claim 4 or 5, wherein the bottle cap includes a closure assembly which resists manipulation by a child.

7. The flow control device of claim 1, wherein the nozzle includes an outlet filter adjacent the outlet.

8. The flow control device of claim 7, wherein the outlet filter comprises a mesh or screen.

9. The flow control device of claim 1, wherein the nozzle includes an inlet filter adjacent the one or more nozzle orifices.

10. The flow control device of claim 9, wherein the inlet filter comprises a mesh or screen.

11. The flow control device of claim 1 , wherein the nozzle is in an aligned position when the bottle cap is removed.

12. The flow control device of claim 11, wherein rotation of the vial cap relative to the reservoir about an axis of rotation causes the nozzle to translate relative to the reservoir.

13. The flow control device of claim 1, wherein the reservoir includes threads on a surface facing the bottle cap, the threads being receivable by the bottle cap.

14. The flow control device of claim 13, wherein the vial cap includes threads on an inner surface of the vial cap, the threads on the vial cap-facing surface of the reservoir being received within the threads on the inner surface of the vial cap.

15. The flow control device of claim 1, wherein when the bottle cap is in a closed state, the nozzle is not in the aligned translational position.

16. The flow control device of claim 15, wherein the spring is at least partially compressed when the bottle cap is in a closed state.

17. The flow control device of claim 15, further comprising a translation stop.

18. The flow control device of claim 17, wherein the translation stop comprises a plug configured to seal the one or more nozzle orifices.

19. The flow control device of claim 17, wherein the translation stop comprises a rotation stop for the bottle cap.

20. The flow control device of claim 1, wherein the nozzle comprises a housing configured to house the preservative removal device, wherein the housing translates relative to an outer surface of the reservoir interface.

21. The flow control device of claim 2, wherein the polymer matrix comprises at least one monomer selected from hydroxyethyl methacrylate (HEMA), methacrylic acid (MAA), N-vinyl pyrrolidone (NVP), dimethylacrylamide (DMA), tert-butyl methacrylate (TBM), 2-sulfoethyl methacrylate (SEM), acrylamide (AM), and methacryloxypropyl tris(trimethylsiloxane) silane (TRIS).

22. The flow control device of claim 1, wherein the ophthalmic agent comprises at least one of timolol maleate, levofloxacin, dorzolamide, brimonidine tartrate, bimatoprost, tetrahydrozoline hydrochloride, or olopatadine.

23. The flow control device of claim 1, wherein the preservative comprises at least one of benzalkonium chloride, borates, sorbitol, propylene glycol, cetrimonium chloride, cetrimonium bromide, or a stabilized oxychloride complex.

24. A method for controlling the concentration of a preservative in an ophthalmic preparation, comprising: A receiving bottle, the bottle comprising: a reservoir, the reservoir comprising an ophthalmic preparation disposed therein, the ophthalmic preparation comprising an ophthalmic agent and a preservative; a nozzle comprising an outlet, an interior volume including a preservative removal device, and one or more nozzle orifices fluidly connecting the interior volume with an exterior of the nozzle; a reservoir interface disposed between the reservoir and the nozzle, the reservoir interface comprising one or more reservoir apertures, wherein the one or more nozzle apertures are fluidly connected with the one or more reservoir apertures when the nozzle translates relative to the reservoir interface; a vial cap, wherein the one or more nozzle apertures are aligned with the one or more reservoir apertures when the vial cap is removed, and wherein the one or more nozzle apertures are not aligned with the one or more reservoir apertures when the vial cap is coupled to the nozzle; and a spring disposed between the reservoir interface and the nozzle; and The vial cap is removed and the restoring force of the spring translates the nozzle relative to the reservoir interface to an aligned translational position such that the one or more nozzle apertures are fluidly connected with the one or more reservoir apertures.

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