Compositions and methods for delivery of ophthalmic actives

Abstract

Compositions, methods, and dispensers for topical delivery of ophthalmologically active pharmaceutical ingredients (APIs) are provided. In one embodiment, a composition is provided comprising an active pharmaceutical ingredient soluble in MCT, a medium chain triglyceride (MCT), and a semi-fluorinated alkane compound wherein the API is not atropine or a salt thereof. In another embodiment, there is provided a nanoemulsion comprising an active pharmaceutical ingredient soluble in MCT, a medium chain triglyceride (MCT), and a semi-fluorinated alkane compound wherein the nanoemulsion has a droplet particle size D90 of less than about 100 nm. Dispensers containing the compositions are also provided, and the dispensers include glass and polyethylene terephthalate dispensers or containers. Methods of using the compositions are also provided, and include methods for treating an ocular condition in a subject comprising administering the composition or nanoemulsion to an eye of the subject. The present application also provides compositions and methods for treating ophthalmic conditions such as hyperopia and glaucoma. The composition may comprise a muscarinic-like cholinergic receptor agonist and a semi-fluorinated alkane compound; or may comprise a muscarinic-like cholinergic receptor agonist, a semi-fluorinated alkane compound, and an organic co-solvent. The compositions may confer chemical stability to muscarinic-like cholinergic receptor agonists.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 667,874 filed on July 5, 2024, U.S. Provisional Patent Application No. 63 / 658,306 filed on June 10, 2024, U.S. Provisional Patent Application No. 63 / 632,214 filed on April 10, 2024, U.S. Provisional Patent Application No. 63 / 631,841 filed on April 9, 2024, U.S. Provisional Patent Application No. 63 / 596,913 filed on November 7, 2023, and U.S. Provisional Patent Application No. 63 / 530,919 filed on August 4, 2023, the contents of each of which are hereby incorporated by reference in their entirety. Technical Field

[0003] The present disclosure relates to compositions for the topical delivery of ophthalmic active pharmaceutical ingredients (APIs), and methods of making and using the same.

[0004] The present disclosure also relates to pharmaceutical compositions comprising a muscarinic cholinergic receptor agonist and a semifluorinated alkane compound. The present disclosure also relates to methods of using the compositions to treat ophthalmic diseases such as hyperopia.

[0005] background

[0006] Various attempts have been made to formulate active pharmaceutical ingredient compounds (APIs) for ocular delivery, for example, for the treatment and prevention of ocular disorders or to improve their symptoms. However, the challenges of delivery formulations can limit the availability of APIs, their activity and shelf life, and can cause systemic side effects in some cases. In common practice, APIs for ophthalmology are often formulated with aqueous formulations, but many APIs can degrade in aqueous formulations. Sometimes pH regulation can slow down the degradation of APIs in aqueous formulations, but such pH regulation can cause eye irritation and discomfort to users. There is still a need for improved compositions for ophthalmic delivery of APIs.

[0007] Hyperopia is an eye condition in which adults have difficulty seeing close objects clearly. The condition develops with age and is most common in adults aged 45 years or older. It is thought that over time, a decrease in the flexibility of the eye's lens disrupts the proper focusing of light rays on the retina, causing blurriness. Current treatments include glasses or contact lenses, lens implant surgery, or refractive surgery. Certain compounds are being studied as potential drug treatments for hyperopia.

[0008] Overview

[0009] The present disclosure relates to compositions for topical delivery of ophthalmic active pharmaceutical ingredients (APIs) comprising medium chain triglycerides (MCTs), semifluorinated alkanes (SFAs), and active pharmaceutical ingredients (APIs), and methods of making and using the compositions, such as methods for treating an ocular disorder in a subject or slowing its progression or alleviating one or more symptoms thereof. A dispenser or container comprising the compositions is also provided herein.

[0010] In some cases, the composition may be non-aqueous.

[0011] Applicants have surprisingly discovered that a composition comprising a medium chain triglyceride (MCT) and a semifluorinated alkane (SFA) can serve as an advantageous delivery system for an ophthalmic API that is soluble in MCT, resulting in an ophthalmically tolerable formulation with increased stability and prolonged shelf life of the API in the formulation, as well as improved tissue distribution and residence time of the API.

[0012] Applicants have further surprisingly discovered that compositions comprising MCT, SFA and API can be formulated into nanoemulsions having a droplet size D90 of less than 100 nm, less than 50 nm, less than 20 nm, less than 15 nm, less than 10 nm and even less than 5 nm.

[0013] Applicants have further surprisingly discovered that compositions comprising MCTs, SFAs, and APIs may, in certain circumstances, exhibit incompatibility or less compatibility with certain materials used for storage and delivery containers, or may improve the shelf life and stability of the API when stored or delivered in certain materials compared to certain other materials.

[0014] The present disclosure is based at least in part on a surprising recognition that any API soluble in MCT can be effectively delivered to eye tissue using the compositions described herein, and further, in certain embodiments, the compositions can result in improved stability and shelf life of the API. Without being bound by theory, it is believed that MCT provides the increased solubility of the API delivered in a formulation comprising SFA. Without being bound by theory, it is further believed that SFA helps maintain a non-irritating and non-aqueous formulation for delivering API in certain embodiments. The present disclosure is also based on a surprising recognition that, in certain cases described herein, it is possible to prepare a nanoemulsion of a composition having a droplet size D90 less than 100nm, less than 10nm, and even less than 5nm. Without being bound by theory, it is believed that the nanoemulsion comprising MCT and SFA (e.g., small droplet size) results in improved long-term stability of the API in the formulation compared to aqueous formulations, as well as the availability of the API increased, improved tissue penetration and distribution of the API, and improved residence time in eye tissue. The present disclosure is further based on the surprising recognition that in certain cases of the compositions described herein, when stored in containers of certain materials, the compositions may be incompatible with the materials or have lower shelf life and API stability.

[0015] The present disclosure provides compositions comprising medium chain triglycerides (MCT), semifluorinated alkanes (SFA) and active pharmaceutical ingredients (API) soluble in MCT, and methods for preparing and using the compositions. The compositions described herein can provide improved delivery formulations for eye or ophthalmic APIs, including compositions with improved eye tolerance, improved API stability, improved storage life of compositions and APIs, improved ocular tissue distribution and residence time, while limiting the systemic distribution of such APIs and thus limiting systemic effects.

[0016] In one aspect, described herein is a composition comprising:

[0017] about 0.001% to about 20% (w / w) of an active pharmaceutical ingredient (API), wherein the API has a solubility in MCT of at least about 0.01% to about 10% (w / w), and wherein the API is not atropine or a salt thereof;

[0018] about 1% to about 50% (w / w) medium chain triglycerides (MCTs); and

[0019] From about 50% to about 99% (w / w) of the semifluorinated alkane compound.

[0020] In this and other embodiments, the composition may optionally have the following features. The composition may be non-aqueous. The semifluorinated alkane compound may be selected from perfluorobutylheptane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8) and perfluorohexyldecane (F6H10). The MCT may be present in a concentration of about 10% to about 50% (w / w), and the semifluorinated alkane compound may be present in a concentration of about 50% to about 90% (w / w). The MCT may be present in a concentration of about 10% to about 30% (w / w), and the semifluorinated alkane compound may be present in a concentration of about 70% to about 90% (w / w). The API may be present in a concentration of about 0.01% to 1% (w / w). The API may be present in free base form. The MCT may be a triglyceride of a fatty acid and the fatty acid may include caproic acid, caprylic acid, capric acid, dodecanoic acid, or a combination of two or more thereof. The MCT may be present at a concentration of about 5% (w / w), and the semifluorinated alkane compound may be present at a concentration of about 95% (w / w), the MCT may be present at a concentration of about 10% (w / w), and the semifluorinated alkane compound may be present at a concentration of about 90% (w / w), the MCT may be present at a concentration of about 15% (w / w), and the semifluorinated alkane compound may be present at a concentration of about 85% (w / w), or the MCT may be present at a concentration of about 20% (w / w), and the semifluorinated alkane compound may be present at a concentration of about 80% (w / w). The semifluorinated alkane may be perfluorohexyl octane (F6H8). The MCT can be a triglyceride of a fatty acid and the fatty acid can be essentially composed of caproic acid, caprylic acid, capric acid, dodecanoic acid or a combination thereof. The topical ophthalmic composition can be an emulsion. The API in the topical ophthalmic composition can be chemically stable for at least 6 months, at least 1 year, at least 18 months, at least 2 years or longer. The API can be selected from alpha agonists, antibiotics, corticosteroids, antinicotinic agents, antiglaucoma agents, antihistamines, antivirals, ciliary muscle paralytics / mydriatics, mast cell stabilizers, miotics, ophthalmic NSAIDs, cyclosporins, riboflavin 5'-phosphate (riboflavin 5'-phosphate) ophthalmic compounds, and VEGF inhibitors and VEGF receptor inhibitors.

[0021] In certain embodiments, the API is not a muscarinic receptor antagonist.

[0022] In another aspect, described herein is a composition consisting essentially of:

[0023] about 0.001% to about 5% (w / w) of an active pharmaceutical ingredient (API), wherein the API has a solubility in MCT of at least about 0.01% to about 10% (w / w), and wherein the API is not atropine or a salt thereof;

[0024] about 1% to about 50% (w / w) medium chain triglycerides (MCTs); and

[0025] From about 50% to about 99% (w / w) of the semifluorinated alkane compound.

[0026] In this and other embodiments, the composition may have the following optional features: The semifluorinated alkane compound may be selected from perfluorobutylheptane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8) and perfluorohexyldecane (F6H10). The MCT may be present at a concentration of about 5% (w / w) and the semifluorinated alkane compound may be present at a concentration of about 95% (w / w), wherein the MCT may be present at a concentration of about 10% (w / w) and the semifluorinated alkane compound may be present at a concentration of about 90% (w / w), wherein the MCT may be present at a concentration of about 15% (w / w) and the semifluorinated alkane compound may be present at a concentration of about 85% (w / w), or wherein the MCT may be present at a concentration of about 20% (w / w) and the semifluorinated alkane compound may be present at a concentration of about 80% (w / w).

[0027] In another aspect, described herein is a composition comprising:

[0028] about 0.01% to about 1% (w / w) of an active pharmaceutical ingredient (API), wherein the API has a solubility in MCT of at least about 0.01% to about 10% (w / w), and wherein the API is not atropine or a salt thereof;

[0029] about 10% to about 30% (w / w) medium chain triglycerides (MCTs); and

[0030] About 70% to about 90% (w / w) of a semifluorinated alkane compound selected from the group consisting of perfluorobutylheptane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8) and perfluorohexyldecane (F6H10).

[0031] In another aspect, described herein is a topical ophthalmic nanoemulsion comprising:

[0032] about 0.001% to about 5% (w / w) of an active pharmaceutical ingredient (API), wherein the API has a solubility in MCT of at least about 0.01% to about 10% (w / w);

[0033] about 1% to about 50% (w / w) medium chain triglycerides (MCTs); and

[0034] from about 50% to about 99% (w / w) of a semifluorinated alkane compound,

[0035] The nanoemulsion has a droplet size D90 of less than about 100 nm.

[0036] In these and other embodiments, the composition may optionally have the following features. The nanoemulsion may have a droplet diameter D90 of less than about 50 nm, less than about 20 nm, less than about 10 nm, or less than about 5 nm, or a droplet diameter D90 of about 2 to about 3 nm. The nanoemulsion may have a peak droplet diameter of less than about 10 nm or may have a peak droplet diameter of about 1 nm to about 5 nm. The composition may be non-aqueous. The semifluorinated alkane compound may be selected from perfluorobutylheptane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10). The MCT may be present in a concentration of about 10% to about 50% (w / w), and the semifluorinated alkane compound may be present in a concentration of about 50% to about 90% (w / w). The MCT may be present in a concentration of about 10% to about 30% (w / w), and the semifluorinated alkane compound may be present in a concentration of about 70% to about 90% (w / w). The API may be present in a concentration of about 0.01% to 1% (w / w). The API may be present in free base form. The MCT may be a triglyceride of a fatty acid and the fatty acid may comprise caproic acid, caprylic acid, capric acid, dodecanoic acid, or a combination of two or more thereof. The MCT may be present at a concentration of about 5% (w / w), and the semifluorinated alkane compound may be present at a concentration of about 95% (w / w), the MCT may be present at a concentration of about 10% (w / w), and the semifluorinated alkane compound may be present at a concentration of about 90% (w / w), the MCT may be present at a concentration of about 15% (w / w), and the semifluorinated alkane compound may be present at a concentration of about 85% (w / w), or the MCT may be present at a concentration of about 20% (w / w), and the semifluorinated alkane compound may be present at a concentration of about 80% (w / w). The semifluorinated alkane may be perfluorohexyl octane (F6H8). The MCT may be a triglyceride of a fatty acid and the fatty acid may consist essentially of caproic acid, caprylic acid, capric acid, dodecanoic acid, or a combination thereof. The topical ophthalmic composition may be an emulsion. The API in the topical ophthalmic composition can be chemically stable for at least 6 months, at least 1 year, at least 18 months, at least 2 years or longer. The API can be selected from alpha agonists, antibiotics, corticosteroids, anticholinergics, antiglaucoma agents, antihistamines, antivirals, cycloplegics / mydriatics, mast cell stabilizers, miotics, ophthalmic NSAIDs, cyclosporins, riboflavin 5'-phosphate ophthalmic compounds, and VEGF inhibitors and VEGF receptor inhibitors. The API can be a muscarinic receptor antagonist. The API can be atropine, atropine mimetic or analog or its free base or salt form. The API can be atropine free base.The API may be atropine, an atropine mimetic or analog, or a free base or salt form thereof and is present in a concentration of about 0.001% to about 1% (w / w).

[0037] In some cases, the API is optionally not a muscarinic receptor antagonist. In some cases, the API is optionally not atropine, an atropine mimetic or analog, or a free base or salt form thereof.

[0038] In another aspect, described herein is a topical ophthalmic nanoemulsion consisting essentially of:

[0039] about 0.001% to about 5% (w / w) of an active pharmaceutical ingredient (API), wherein the API has a solubility in MCT of at least about 0.01% to about 10% (w / w);

[0040] about 1% to about 50% (w / w) medium chain triglycerides (MCTs); and

[0041] from about 50% to about 99% (w / w) of a semifluorinated alkane compound,

[0042] wherein the nanoemulsion has a droplet size D90 of less than about 100 nm, less than about 50 nm, less than about 20 nm, less than about 10 nm, less than about 5 nm, or about 2 to about 3 nm.

[0043] In these and other embodiments, the topical ophthalmic nanoemulsion may have the following optional features: The semifluorinated alkane compound may be selected from perfluorobutylheptane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10). The MCT may be present at a concentration of about 5% (w / w) and the semifluorinated alkane compound may be present at a concentration of about 95% (w / w), wherein the MCT may be present at a concentration of about 10% (w / w) and the semifluorinated alkane compound may be present at a concentration of about 90% (w / w), wherein the MCT may be present at a concentration of about 15% (w / w) and the semifluorinated alkane compound may be present at a concentration of about 85% (w / w), or wherein the MCT may be present at a concentration of about 20% (w / w) and the semifluorinated alkane compound may be present at a concentration of about 80% (w / w). The API may be a muscarinic receptor antagonist. The API may be atropine, an atropine mimetic or analog, or a free base or salt form thereof. The API may be atropine free base. The API may be atropine, an atropine mimetic or analog, or a free base or salt form thereof and is present in a concentration of about 0.001% to about 1% (w / w).

[0044] In some cases, the API is optionally not a muscarinic receptor antagonist. In some cases, the API is optionally not atropine, an atropine mimetic or analog, or a free base or salt form thereof.

[0045] In another aspect, described herein is a topical ophthalmic nanoemulsion comprising:

[0046] about 0.001% to about 1% (w / w) of an active pharmaceutical ingredient (API), wherein the API has a solubility in MCT of at least about 0.01% to about 10% (w / w);

[0047] about 10% to about 30% (w / w) medium chain triglycerides (MCTs); and

[0048] about 70% to about 90% (w / w) of a semifluorinated alkane compound selected from the group consisting of perfluorobutylheptane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8) and perfluorohexyldecane (F6H10),

[0049] The nanoemulsion has a droplet size D90 of less than about 100 nm, less than about 20 nm, less than about 10 nm, less than about 5 nm, or about 2 to about 3 nm.

[0050] In these and other embodiments, the topical ophthalmic nanoemulsion may have the following optional features. The API may be a muscarinic receptor antagonist. The API may be atropine, an atropine mimetic or analog, or a free base or salt form thereof. The API may be atropine free base. The API may be atropine, an atropine mimetic or analog, or a free base or salt form thereof and is present at a concentration of about 0.001% to about 1% (w / w).

[0051] In some cases, the API is optionally not a muscarinic receptor antagonist. In some cases, the API is optionally not atropine, an atropine mimetic or analog, or a free base or salt form thereof.

[0052] In another aspect, described herein is a dispenser comprising:

[0053] a container portion comprising an interior wall defining an interior volume and adapted to contact and store a liquid within at least a portion of the interior volume;

[0054] a dispensing portion adapted to dispense one or more drops of liquid out of the container portion; and

[0055] Contained in the internal volume

[0056] Any of the composition of claims 1-19 or the nanoemulsion of claims 20-45 or a composition comprising the following components:

[0057] About 0.001% to about 5% (w / w) of an active pharmaceutical ingredient (API), wherein the API has a solubility in MCT of at least about 0.01% to about 10% (w / w)

[0058] about 1% to about 50% (w / w) medium chain triglycerides (MCTs); and

[0059] From about 50% to about 99% (w / w) of the semifluorinated alkane compound.

[0060] In these and other embodiments, the dispenser may have the following optional features. The inner wall may contain less than about 10% of one or more of low-density polyethylene (LDPE) or polypropylene (PP). The inner wall may optionally not contain low-density polyethylene (LDPE) or polypropylene (PP). The inner wall may contain glass or polyethylene terephthalate. The inner wall may consist essentially of glass or polyethylene terephthalate (PET). The concentration of the API may remain above 90% of the initial API concentration after a period of at least 6 months of storage in the dispenser, or the concentration of the API may remain above 90% of the initial API concentration after a period of at least 12 months of storage in the dispenser, or the concentration of the API may remain above 90% of the initial API concentration after a period of at least 24 months of storage in the dispenser. The container portion and the dispensing portion may each independently consist essentially of glass or polyethylene terephthalate (PET). The volume of the one or more drops may each independently be about 5 μl to about 40 μl. The composition in the dispenser may include:

[0061] about 0.001% to about 1% (w / w) of atropine, an atropine mimetic or analog, or a free base or salt form thereof;

[0062] about 5% to about 30% (w / w) medium chain triglycerides (MCTs); and

[0063] About 70% to about 95% (w / w) of a semifluorinated alkane compound selected from the group consisting of perfluorobutylheptane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8) and perfluorohexyldecane (F6H10).

[0064] In another aspect, described herein is a method for treating, slowing the progression of, or alleviating one or more symptoms of an ocular disorder in a subject, comprising administering to an eye of the subject a topical ophthalmic composition or topical ophthalmic nanoemulsion described herein. In these and other embodiments, the ocular disorder can optionally be selected from neurotrophic keratitis, glaucoma, elevated intraocular pressure, ocular hypertension, hyperopia, myopia, ocular rosacea, dry eye disease, meibomian gland dysfunction, blepharitis, allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, pterygium, palpebral fissure, corneal transplant rejection, graft-versus-host disease, ocular allergy, uveitis, anterior uveitis, Behcet's disease, Sjögren's syndrome, Stevens-Johnson syndrome, ocular cicatricial pemphigoid, chronic ocular surface inflammation caused by viral infection, herpes simplex keratitis, atopic conjunctivitis, Lyell's syndrome, syndrome, neovascularization induced by viral, bacterial, fungal, or parasitic infection, contact lens-induced neovascularization, ulceration, alkali burns, stem cell deficiency, neovascular glaucoma, Steven Johnson syndrome, ocular tumors, aphakia, pseudophakia, astigmatism, blepharospasm, cataract, conjunctival diseases, corneal diseases, corneal ulcers, eyelid diseases, lacrimal apparatus diseases, pupillary disorders, refractive disorders, strabismus.

[0065] In another aspect, described herein is a method for delivering an API to an eye of a subject, the method comprising administering to the eye of the subject any of the topical ophthalmic compositions or topical ophthalmic nanoemulsions described herein. In these and other embodiments, the API can be optionally selected from alpha agonists, antibiotics, corticosteroids, anticholinergics, antiglaucoma agents, antihistamines, antivirals, cycloplegics / mydriatics, mast cell stabilizers, miotics, ophthalmic NSAIDs, cyclosporins, riboflavin 5'-phosphate ophthalmic compounds, and VEGF inhibitors and VEGF receptor inhibitors.

[0066] In another aspect, described herein is a method for slowing the progression of myopia in a subject or for alleviating the symptoms of vitreous floaters in a subject, the method comprising administering to the eye of the subject any one of the nanoemulsions described herein, wherein the API is a muscarinic receptor antagonist. In these and other embodiments, the API can be optionally selected from atropine, an atropine mimetic or analog, or a free base or salt form thereof.

[0067] In certain cases of the above methods for treating an ocular disorder, slowing its progression, or alleviating one or more symptoms thereof, methods for delivering an API to an eye of a subject, and methods for slowing the progression of myopia in a subject or for alleviating the symptoms of vitreous floaters in a subject, the topical ophthalmic composition or the nanoemulsion is absorbed in the eye through the cornea. In some cases, the topical ophthalmic composition or the nanoemulsion is selectively absorbed in the eye through the cornea as compared to the periorbital region. In some cases, the topical ophthalmic composition is non-aqueous. In some cases, the topical ophthalmic composition is an emulsion. In some cases, the topical ophthalmic composition is non-aqueous, and wherein the applied dose of the topical ophthalmic composition or the nanoemulsion is 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70%, or 50-70% less than a dose of an aqueous topical ophthalmic composition comprising an API (e.g., for treating an ocular disorder, slowing its progression, or alleviating one or more symptoms thereof, for delivering an API to an eye of a subject, for slowing the progression of myopia in a subject, or for alleviating symptoms of vitreous floaters in a subject). In some cases, the topical ophthalmic composition or the nanoemulsion is administered to the subject every about 6 to about 8 hours or 3 times a day. In some cases, the topical ophthalmic composition or the nanoemulsion is administered to the subject once a day. In some cases, the topical ophthalmic composition or the nanoemulsion is administered to the subject twice a day. In some cases, the API is in free base form.

[0068] In another aspect, described herein is a method for treating an ocular disorder in a subject, slowing its progression, or alleviating one or more symptoms thereof, comprising administering a topical ophthalmic composition to the subject's eye, wherein the topical ophthalmic composition comprises: about 0.001% to about 5% (w / w) API; about 1% to about 50% (w / w) MCT; and about 50% to about 99% (w / w) of a semifluorinated alkane compound, wherein the API has a solubility in MCT of at least about 0.01% to about 10% (w / w), and wherein the API is atropine. In some cases, the topical ophthalmic composition comprises about 0.02% (w / w) API. In some cases, the topical ophthalmic composition comprises about 0.04% (w / w) API. In some cases, the topical ophthalmic composition comprises about 0.05% (w / w) API. In some cases, the topical ophthalmic composition comprises about 1% (w / w) API. In some cases, the topical ophthalmic composition comprises about 5% to about 20% (w / w) MCT. In some cases, the topical ophthalmic composition is applied to the subject's eye every about 6 to about 8 hours or 3 times a day. In some cases, the topical ophthalmic composition is applied to the subject once a day. In some cases, the topical ophthalmic composition is applied to the subject twice a day. In some cases, the topical ophthalmic composition is non-aqueous. In some cases, the topical ophthalmic composition is non-aqueous and the dosage of the topical ophthalmic composition applied is 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70%, or 50-70% less than the dosage of an aqueous topical ophthalmic composition comprising the API for treating an ocular disorder, slowing its progression, or alleviating one or more symptoms thereof. In some cases, the API is in free base form.In some cases, the ocular disorder is selected from neurotrophic keratitis, glaucoma, elevated intraocular pressure, ocular hypertension, hyperopia, myopia, ocular rosacea, dry eye disease, meibomian gland dysfunction, blepharitis, allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, pterygium, palpebral fissure, corneal transplant rejection, graft-versus-host disease, ocular allergy, uveitis, anterior uveitis, Behcet's disease, Sjögren's syndrome, Stevens-Johnson syndrome, ocular cicatricial pemphigoid, chronic ocular surface inflammation caused by viral infection, herpes simplex keratitis, atopic conjunctivitis, Lyell syndrome, neovascularization induced by viral, bacterial, fungal or parasitic infection, contact lens-induced neovascularization, ulceration, alkali burns, stem cell deficiency, neovascular glaucoma, Stevens-Johnson syndrome, Johnson syndrome, ocular tumors, aphakia, pseudophakia, astigmatism, blepharospasm, cataracts, conjunctival diseases, corneal diseases, corneal ulcers, eyelid diseases, tear apparatus diseases, pupillary disorders, refractive disorders, strabismus. In some cases, the topical ophthalmic composition is absorbed into the eye through the cornea. In some cases, the topical ophthalmic composition is selectively absorbed into the eye through the cornea as compared to the periorbital region.

[0069] In another aspect, described herein is a method of delivering an API to an eye of a subject, the method comprising applying a topical ophthalmic composition to the eye of the subject, wherein the topical ophthalmic composition comprises: about 0.001% to about 5% (w / w) API; about 1% to about 50% (w / w) MCT; and about 50% to about 99% (w / w) of a semifluorinated alkane compound, wherein the API has a solubility in MCT of at least about 0.01% to about 10% (w / w), and wherein the API is atropine. In some cases, the topical ophthalmic composition comprises about 0.02% (w / w) API. In some cases, the topical ophthalmic composition comprises about 0.04% (w / w) API. In some cases, the topical ophthalmic composition comprises about 0.05% (w / w) API. In some cases, the topical ophthalmic composition comprises about 1% (w / w) API. In some cases, the topical ophthalmic composition comprises about 5% to about 20% (w / w) MCT. In some cases, the topical ophthalmic composition is applied to the subject's eye every about 6 to about 8 hours or 3 times a day. In some cases, the topical ophthalmic composition is applied to the subject once a day. In some cases, the topical ophthalmic composition is applied to the subject twice a day. In some cases, the topical ophthalmic composition is non-aqueous, and the dosage of the topical ophthalmic composition applied is 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70% or 50-70% less than the dosage of the aqueous topical ophthalmic composition containing the API for treating an ocular condition, slowing its progression, or alleviating one or more symptoms thereof. In some cases, the topical ophthalmic composition is non-aqueous. In some cases, the API is in free base form. In some cases, the topical ophthalmic composition is absorbed in the eye through the cornea. In certain instances, the topical ophthalmic composition is selectively absorbed in the eye through the cornea as compared to the periorbital region.

[0070] In another aspect, described herein is a method for slowing the progression of myopia in a subject or for alleviating the symptoms of vitreous floaters in a subject, the method comprising applying a topical ophthalmic composition to the eye of the subject, wherein the topical ophthalmic composition comprises: about 0.001% to about 5% (w / w) API; about 1% to about 50% (w / w) MCT; and about 50% to about 99% (w / w) of a semifluorinated alkane compound, wherein the API has a solubility in MCT of at least about 0.01% to about 10% (w / w), and wherein the API is selected from atropine or an atropine mimetic. In some cases, the topical ophthalmic composition comprises about 0.02% (w / w) API. In some cases, the topical ophthalmic composition comprises about 0.04% (w / w) API. In some cases, the topical ophthalmic composition comprises about 0.05% (w / w) API. In some cases, the topical ophthalmic composition comprises about 1% (w / w) API. In some cases, the topical ophthalmic composition comprises about 5% to about 20% (w / w) MCT. In some cases, the topical ophthalmic composition is applied to the subject's eye every about 6 to about 8 hours or 3 times a day. In some cases, the topical ophthalmic composition is applied to the subject once a day. In some cases, the topical ophthalmic composition is applied to the subject twice a day. In some cases, the topical ophthalmic composition is non-aqueous, and wherein the dosage of the topical ophthalmic composition applied is 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70% or 50-70% less than the dosage of an aqueous topical ophthalmic composition comprising the API for slowing the progression of myopia in a subject or for alleviating the symptoms of vitreous floaters in a subject. In some cases, the topical ophthalmic composition is non-aqueous. In some cases, the API is in free base form. In certain instances, the topical ophthalmic composition is absorbed in the eye through the cornea. In certain instances, the topical ophthalmic composition is selectively absorbed in the eye through the cornea as compared to the periorbital region.

[0071] In another aspect, described herein is a method for preparing the topical ophthalmic nanoemulsion described herein, the method comprising the steps of:

[0072] (a) combining an ocular API with MCT to form an MCT solution;

[0073] (b) combining the MCT solution with a semifluorinated alkane compound to form a mixture, wherein the mixture comprises from about 1% to about 50% of the MCT solution and from about 50% to about 99% of the semifluorinated alkane compound; and

[0074] (c) emulsifying the mixture and reducing the droplet size D90 in the mixture to less than 100 nm by physical agitation, wherein the physical agitation is selected from high speed stirring, vortexing, sonication, heating and stirring or homogenizing the mixture until the droplet size reaches a droplet size D90 of less than 100 nm.

[0075] In these and other embodiments, the method may have the following optional features. The method may further include measuring the droplet size of the mixture during or after the physical stirring process. Reducing the droplet size D90 in the mixture to less than 100 nm may include reducing the droplet size D90 in the mixture to less than 50 nm, less than 20 nm, less than 10 nm, less than 5 nm, or about 2 to about 3 nm.

[0076] In certain cases of the compositions, nanoemulsions and methods herein, the API may be lifitegrast or a derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer thereof. In these and other cases, the compositions, nanoemulsions and methods may have the following optional features. The MCT may be present in an amount of about 1% to about 50% (w / w), optionally about 1% to about 30% (w / w), about 5% to about 20% (w / w), optionally selected from about 5%, about 10%, about 15% or about 20% (w / w). The semifluorinated alkane compound may be present in an amount of about 70% to about 99% (w / w), optionally about 80% to about 95% (w / w), optionally selected from about 80%, 85%, 90% or 95% (w / w). The semifluorinated alkane compound may be selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8). The MCT may be selected from glyceryl tricaprylate / tricaprate and glyceryl tricaprylate / tricaprylin. The lifilast or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer may be present in the composition in an amount of about 0.01 to about 10 mg / ml, optionally about 0.01 to about 5 mg / ml, optionally about 0.01 to about 1 mg / ml. The lifirastat or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer may be present in the composition in an amount of about 0.05% to about 20% (w / w), optionally about 0.05% to about 10% (w / w), optionally about 0.05% to about 5% (w / w), optionally selected from about 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4% or 5% (w / w).

[0077] In certain cases of the compositions, nanoemulsions, and methods herein, the API may be aceclidine or a derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof. In certain cases of the methods described herein, the eye condition may be hyperopia or myopia. In certain cases, a method for treating myopia or hyperopia in a subject, slowing its progression, improving one or more symptoms thereof, is provided, the method comprising administering a topical ophthalmic composition to the subject's eye, wherein the topical ophthalmic composition comprises:

[0078] about 0.001% to about 10% (w / w) API, wherein the API is selected from aceclidine or a derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof;

[0079] about 1% to about 50% (w / w) MCTs; and

[0080] From about 50% to about 99% (w / w) of the semifluorinated alkane compound.

[0081] In these and other cases, the method may have the following optional features. The topical ophthalmic composition may be applied to the eye of the subject every about 6 to about 8 hours or 3 times a day. The topical ophthalmic composition may be non-aqueous. The dosage of the topical ophthalmic composition may be 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70% or 50-70% less than the dosage of the aqueous topical ophthalmic composition containing the API for treating myopia or hyperopia in the subject, slowing its progression, improving one or more symptoms thereof. The topical ophthalmic composition can be non-aqueous. The API can be in free base form. The topical ophthalmic composition can be absorbed through the cornea in the eye. The topical ophthalmic composition can be selectively absorbed through the cornea in the eye compared to the periorbital region. In these and other cases, the composition, nanoemulsion and method can have the following optional features. The MCT can be present in an amount of about 1% to about 30% (w / w), optionally about 5% to about 20% (w / w), optionally selected from about 5%, about 10%, about 15% or about 20% (w / w). The semifluorinated alkane compound can be present in an amount of about 70% to about 99% (w / w), optionally about 80% to about 95% (w / w), optionally selected from about 80%, 85%, 90% or 95% (w / w). The semifluorinated alkane compound can be selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8). The MCT may be selected from glyceryl tricaprylate / tricaprate and glyceryl tricaprylate / tricaprylin. The aceclidin or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer may be present in the composition in an amount of about 1 to about 30 mg / ml, optionally about 5 to about 20 mg / ml, optionally about 10 to about 15 mg / ml. The aceclidin or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer may be present in the composition in an amount of about 0.1% to about 10% (w / w), optionally about 1% to about 3% (w / w), optionally about 1.75% (w / w).

[0082] In certain cases of the compositions, nanoemulsions and methods herein, the API may be atropine, atropine mimetics or analogs, or free base or salt forms thereof. In these and other cases, the compositions, nanoemulsions and methods may have the following optional features. The MCT may be present in an amount of about 1% to about 30% (w / w), optionally about 5% to about 20% (w / w), optionally selected from about 5%, about 10%, about 15% or about 20% (w / w). The semifluorinated alkane compound may be present in an amount of about 70% to about 99% (w / w), optionally about 80% to about 95% (w / w), optionally selected from about 80%, 85%, 90% or 95% (w / w). The semifluorinated alkane compound may be selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8). The MCT may be selected from glyceryl tricaprylate / tricaprate and glyceryl tricaprylate / tricaprylin. The atropine, atropine mimetic or analog, or its free base or salt form can be present in the composition in an amount of about 0.005 to about 1 mg / ml, optionally about 0.01 to about 0.75 mg / ml, optionally about 0.01 to about 0.1 mg / ml, optionally about 0.05 to about 0.75 mg / ml, optionally about 0.01 to about 0.03 mg / ml, optionally about 0.1 to about 0.5 mg / ml. The atropine, atropine mimetic or analog, or its free base or salt form, may be present in the composition in an amount of about 0.0005% to about 2% (w / w), optionally about 0.001% to about 0.005%, 0.001% to about 0.01%, optionally about 0.005% to about 0.5%, optionally about 0.005% to about 0.1% (w / w), optionally about 0.008% to about 0.02%, optionally about 0.01% (w / w).

[0083] In certain instances of the compositions, nanoemulsions, and methods herein, the API may be AR-15512 ((1R, 2S, 5R)-N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide) or a derivative, analog, racemic mixture, or diastereomer or enantiomer thereof. In these and other instances, the compositions, nanoemulsions, and methods may have the following optional features. The MCT may be present in an amount of about 0.1% to about 50% (w / w), optionally about 0.1% to about 10% (w / w), about 1% to about 30% (w / w), about 5% to about 20% (w / w), optionally selected from about 5%, about 10%, about 15%, or about 20% (w / w). The semifluorinated alkane compound may be present in an amount of about 70% to about 99% (w / w), optionally about 80% to about 95% (w / w), optionally selected from about 80%, 85%, 90% or 95% (w / w). The semifluorinated alkane compound may be selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8). The MCT may be selected from coconut oil alcohol caprylate / caprate, propylene glycol dicaprylocaprate, glyceryl tricaprylate / tricaprate and glyceryl tricaprylate / tricaprylin. The AR-15512 ((1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide) or its derivative, analog, racemic mixture or diastereomer or enantiomer can be present in the composition in an amount of about 0.001 mg / ml to 1 mg / ml, optionally 0.01 mg / ml to 1 mg / ml, 0.01 mg / ml to 0.1 mg / ml, optionally about 0.01 mg / ml, about 0.02 mg / ml, 0.03 mg / ml, about 0.04 mg / ml, about 0.05 mg / ml, about 0.06 mg / ml, about 0.07 mg / ml, about 0.08 mg / ml, about 0.09 mg / ml or about 0.1 mg / ml. The AR-15512 ((1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide) or its derivative, analog, racemic mixture or diastereomer or enantiomer may be present in the composition in an amount of about 0.0001% to 0.1% (w / w), optionally about 0.001% to about 0.1% (w / w), optionally about 0.001% to about 0.01% (w / w), optionally selected from about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009% or about 0.01% (w / w).

[0084] In certain instances of the compositions, nanoemulsions, and methods herein, the API may be AR-15512 ((1R, 2S, 5R)-N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide) or a derivative, analog, racemic mixture, or diastereomer or enantiomer thereof. In certain instances of the methods described herein, the ocular condition may be hyperopia or myopia. In certain instances, a method for treating myopia or hyperopia in a subject, slowing its progression, ameliorating one or more symptoms thereof, is provided, the method comprising administering a topical ophthalmic composition to an eye of the subject, wherein the topical ophthalmic composition comprises:

[0085] about 0.0001% to about 0.1% (w / w) API, wherein the API is selected from AR-15512 ((1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide) or a derivative, analog, racemic mixture, or diastereomer or enantiomer thereof;

[0086] about 0.1% to about 50% (w / w) MCT; and

[0087] From about 50% to about 99% (w / w) of the semifluorinated alkane compound.

[0088] In these and other cases, the method may have the following optional features. The topical ophthalmic composition may be applied to the eye of the subject every about 6 to about 8 hours or 3 times a day. The topical ophthalmic composition may be non-aqueous. The dosage of the topical ophthalmic composition may be 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70% or 50-70% less than the dosage of the aqueous topical ophthalmic composition containing the API for treating myopia or hyperopia in the subject, slowing its progression, improving one or more symptoms thereof. The topical ophthalmic composition can be non-aqueous. The API can be in free base form. The topical ophthalmic composition can be absorbed through the cornea in the eye. The topical ophthalmic composition can be selectively absorbed through the cornea in the eye compared to the periorbital region. In these and other cases, the composition, nanoemulsion and method can have the following optional features. The MCT can be present in an amount of about 0.1% to about 50% (w / w), optionally about 0.1% to about 10% (w / w), optionally about 1% to about 30% (w / w), optionally about 5% to about 20% (w / w), optionally selected from about 5%, about 10%, about 15% or about 20% (w / w). The semifluorinated alkane compound can be present in an amount of about 70% to about 99% (w / w), optionally about 80% to about 95% (w / w), optionally selected from about 80%, 85%, 90% or 95% (w / w). The semifluorinated alkane compound may be selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8). The MCT may be selected from coconut caprylate / caprate, propylene glycol dicaprylate caprate, glyceryl tricaprylate / tricaprate and glyceryl tricaprylate / tricaprylin. The AR-15512 ((1R, 2S, 5R)-N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl) cyclohexanecarboxamide) or its derivatives, analogs, racemic mixtures or diastereomers or enantiomers may be present in the composition in an amount of about 1 to about 30 mg / ml, optionally about 5 to about 20 mg / ml, optionally about 10 to about 15 mg / ml.The AR-15512 ((1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide) or its derivative, analog, racemic mixture or diastereomer or enantiomer may be present in the composition in an amount of about 0.0001% to 0.1% (w / w), optionally about 0.001% to about 0.1% (w / w), optionally about 0.001% to about 0.01% (w / w), optionally selected from about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009% or about 0.01% (w / w).

[0089] In certain instances of the compositions, nanoemulsions, and methods herein, the API may be AR-15512 ((1R, 2S, 5R)-N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide), an AR-15512 mimetic, or an analog. In these and other instances, the compositions, nanoemulsions, and methods may have the following optional features. The MCT may be present in an amount of about 0.1% to about 50% (w / w), optionally about 0.1% to about 10% (w / w), optionally about 1% to about 30% (w / w), optionally about 5% to about 20% (w / w), optionally selected from about 5%, about 10%, about 15%, or about 20% (w / w). The semifluorinated alkane compound may be present in an amount of about 70% to about 99% (w / w), optionally about 80% to about 95% (w / w), optionally selected from about 80%, 85%, 90% or 95% (w / w). The semifluorinated alkane compound may be selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8). The MCT may be selected from coconut oil alcohol caprylate / caprate, propylene glycol dicaprylate caprate, glyceryl tricaprylate / tricaprate and glyceryl tricaprylate / tricaprylin. The AR-15512, AR-15512 mimetic or analog may be present in the composition in an amount of about 0.005 to about 1 mg / ml, optionally about 0.01 to about 0.75 mg / ml, optionally about 0.01 to about 0.1 mg / ml, optionally about 0.05 to about 0.75 mg / ml, optionally about 0.01 to about 0.03 mg / ml, optionally about 0.1 to about 0.5 mg / ml. The AR-15512, AR-15512 mimetic or analog may be present in the composition in an amount of about 0.0001% to 0.1% (w / w), optionally about 0.001% to about 0.1% (w / w), optionally about 0.001% to about 0.01% (w / w), optionally selected from about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009% or about 0.01% (w / w).

[0090] In certain embodiments, the compositions and methods provided herein can provide several advantages. First, in some cases, the compositions provided herein can provide the solubility of the API increased. In some cases, the compositions provided herein can provide the solubility of the API increased in non-aqueous formulations, such as the solubility of the API increased in SFA.

[0091] In certain cases of the compositions, nanoemulsions and methods herein, the API may be lotiranab or a derivative, analog, racemic mixture or diastereomer or enantiomer thereof. In these and other cases, the compositions, nanoemulsions and methods may have the following optional features. The MCT may be present in an amount of about 0.1% to about 50% (w / w), optionally about 0.1% to about 10% (w / w), about 1% to about 30% (w / w), about 5% to about 20% (w / w), optionally selected from about 5%, about 10%, about 15% or about 20% (w / w). The semifluorinated alkane compound may be present in an amount of about 70% to about 99% (w / w), optionally about 80% to about 95% (w / w), optionally selected from about 80%, 85%, 90% or 95% (w / w). The semifluorinated alkane compound may be selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8). The MCT may be selected from coconut oil alcohol caprylate / caprate, propylene glycol dicaprylate caprate, glyceryl tricaprylate / tricaprate and glyceryl tricaprylate / tricaprylin. The lotiranab or its derivative, analog, racemic mixture or diastereomer or enantiomer may be about 0.001 mg / ml to 10 mg / ml, optionally 0.01 mg / ml to 5 mg / ml, 0.01 mg / ml to 4 mg / ml, optionally 0.1 mg / ml to 5 mg / ml, optionally 1 mg / ml to 5 mg / ml, optionally about 0.01 mg / ml, about 0.02 mg / ml, 0.03 mg / ml, about 0.04 In some embodiments, the present invention relates to an amount of about 1 mg / ml, about 0.05 mg / ml, about 0.06 mg / ml, about 0.07 mg / ml, about 0.08 mg / ml, about 0.09 mg / ml, about 0.1 mg / ml, about 1 mg / ml, about 1.5 mg / ml, about 2 mg / ml, about 2.5 mg / ml, about 3 mg / ml, about 3.2 mg / ml, about 3.5 mg / ml, about 4 mg / ml, about 4.5 mg / ml or about 5 mg / ml.The lotiranab or its derivative, analog, racemic mixture or diastereomer or enantiomer may be present in an amount of about 0.0001% to 1% (w / w), optionally about 0.001% to about 1% (w / w), optionally about 0.0001% to 0.9%, optionally about 0.0001% to 0.9%, optionally about 0.0001% to 0.8%, optionally about 0.0001% to 0.7%, optionally about 0.0001% to 0.6%, optionally about 0.0001% to 0.5%, optionally about 0.0001% to 0.4%, optionally about 0.0001% to 0.3%, optionally about 0.001% to 0.9%, optionally about 0.001% to 0.9%, optionally about 0.001% to 0.8%, optionally about 0.001% to 0.7%, optionally about 0.001% to 0.6%, optionally about 0.001% to 0.5%, optionally about 0.001% to 0.4%, optionally about 0.001% to 0.3%, optionally selected from about 0.01%, about 0.05%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9% or about 0.1% (w / w) is present in the composition. In some cases, the lotiranab or its derivative, analog, racemic mixture or diastereomer or enantiomer may be present in the composition in an amount of about 0.25% (w / w).

[0092] In certain instances of the compositions, nanoemulsions, and methods herein, the API may be lotiranab or a derivative, analog, racemic mixture, or diastereomer or enantiomer thereof. In some cases, a method is provided for aiding in the eradication or reduction of parasitic infestations of the eye, ocular tissue, skin, eyelashes or other body hair; for treating or alleviating or relieving symptoms of certain diseases or conditions, such as ocular diseases, skin diseases, vector-borne diseases or other diseases caused by parasites; for treating or alleviating or relieving symptoms of certain ocular diseases or conditions, such as blepharitis, meibomian gland dysfunction or rosacea caused by parasites such as Demodex; for treating or alleviating or relieving symptoms of redness of the eyelid margin caused by Demodex, or improving the health of eyelashes in a subject; for eradicating, reducing the number of, treating or alleviating or relieving symptoms of lice, scabies or bed bugs and related skin, hair, scalp or hair follicle disorders; for treating, slowing the progression of, or ameliorating one or more symptoms of myopia or hyperopia in a subject, the method comprising administering to a subject in need thereof a topical ophthalmic composition, wherein the topical ophthalmic composition comprises:

[0093] about 0.0001% to about 1% (w / w) API, wherein the API is selected from lotiranab or a derivative, analog, racemic mixture or diastereomer or enantiomer thereof;

[0094] about 0.1% to about 50% (w / w) MCT; and

[0095] From about 50% to about 99% (w / w) of the semifluorinated alkane compound.

[0096] In these and other cases, the method may have the following optional features. The topical ophthalmic composition may be applied to the eye of the subject every about 6 to about 8 hours or 3 times a day. The topical ophthalmic composition may be non-aqueous. The dosage of the topical ophthalmic composition may be 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70% or 50-70% less than the dosage of the aqueous topical ophthalmic composition containing the API for treating myopia or hyperopia in the subject, slowing its progression, improving one or more symptoms thereof. The topical ophthalmic composition can be non-aqueous. The API can be in free base form. The topical ophthalmic composition can be absorbed through the cornea in the eye. The topical ophthalmic composition can be selectively absorbed through the cornea in the eye compared to the periorbital region. In these and other cases, the composition, nanoemulsion and method can have the following optional features. The MCT can be present in an amount of about 0.1% to about 50% (w / w), optionally about 0.1% to about 10% (w / w), optionally about 1% to about 30% (w / w), optionally about 5% to about 20% (w / w), optionally selected from about 5%, about 10%, about 15% or about 20% (w / w). The semifluorinated alkane compound can be present in an amount of about 70% to about 99% (w / w), optionally about 80% to about 95% (w / w), optionally selected from about 80%, 85%, 90% or 95% (w / w). The semifluorinated alkane compound may be selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8). The MCT may be selected from coconut caprylate / caprate, propylene glycol dicaprylate caprate, glyceryl tricaprylate / tricaprate and glyceryl tricaprylate / tricaprylin. The lotiranab or its derivative, analog, racemic mixture or diastereomer or enantiomer may be present in the composition in an amount of about 1 to about 30 mg / ml, optionally about 5 to about 20 mg / ml, optionally about 10 to about 15 mg / ml.In some cases, the lotirana or its derivative, analog, racemic mixture or diastereomer or enantiomer can be 0.001 mg / ml to 10 mg / ml, optionally 0.01 mg / ml to 5 mg / ml, 0.01 mg / ml to 4 mg / ml, optionally 0.1 mg / ml to 5 mg / ml, optionally 1 mg / ml to 5 mg / ml, optionally about 0.01 mg / ml, about 0.02 mg / ml, 0.03 mg / ml, about 0.04 mg / ml, about 0.06 mg / ml, about 0.08 mg / ml, about 0.10 mg / ml, about 0.09 mg / ml, about 0.11 mg / ml, about 0.12 mg / ml, about 0.13 mg / ml, about 0.14 mg / ml, about 0.15 mg / ml, about 0.16 mg / ml, about 0.17 mg / ml, about 0.18 mg / ml, about 0.19 mg / ml, about 0.20 mg / ml, about 0.21 mg / ml, about 0.22 mg / ml, about 0.23 mg / ml In some cases, the lotirana or its derivative, analog, racemic mixture or diastereomer or enantiomer may be present in the composition in an amount of about 3.2 mg / ml. The lotiranab or its derivative, analog, racemic mixture or diastereomer or enantiomer may be present in an amount of about 0.0001% to 1% (w / w), optionally about 0.001% to about 1% (w / w), optionally about 0.0001% to 0.9%, optionally about 0.0001% to 0.9%, optionally about 0.0001% to 0.8%, optionally about 0.0001% to 0.7%, optionally about 0.0001% to 0.6%, optionally about 0.0001% to 0.5%, optionally about 0.0001% to 0.4%, optionally about 0.0001% to 0.3%, optionally about 0.001% to 0.9%, optionally about 0.001% to 0.9%, optionally about 0.001% to 0.8%, optionally about 0.001% to 0.7%, optionally about 0.001% to 0.6%, optionally about 0.001% to 0.5%, optionally about 0.001% to 0.4%, optionally about 0.001% to 0.3%, optionally selected from about 0.01%, about 0.05%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9% or about 0.1% (w / w) is present in the composition. In some cases, the lotiranab or its derivative, analog, racemic mixture or diastereomer or enantiomer may be present in the composition in an amount of about 0.25% (w / w).

[0097] In certain cases of the compositions, nanoemulsions and methods herein, the API may be lotirana, lotirana mimetics or the like. In these and other cases, the compositions, nanoemulsions and methods may have the following optional features. The MCT may be present in an amount of about 0.1% to about 50% (w / w), optionally about 0.1% to about 10% (w / w), optionally about 1% to about 30% (w / w), optionally about 5% to about 20% (w / w), optionally selected from about 5%, about 10%, about 15% or about 20% (w / w). The semifluorinated alkane compound may be present in an amount of about 70% to about 99% (w / w), optionally about 80% to about 95% (w / w), optionally selected from about 80%, 85%, 90% or 95% (w / w). The semifluorinated alkane compound may be selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8). The MCT may be selected from coconut oil caprylate / caprate, propylene glycol dicaprylate caprate, glyceryl tricaprylate / tricaprate and glyceryl tricaprylate / tricaprylin. The lotirana, lotirana mimetic or analog may be present in an amount of 0.001 mg / ml to 10 mg / ml, optionally 0.01 mg / ml to 5 mg / ml, 0.01 mg / ml to 4 mg / ml, optionally 0.1 mg / ml to 5 mg / ml, optionally 1 mg / ml to 5 mg / ml, optionally about 0.01 mg / ml, about 0.02 mg / ml, 0.03 mg / ml, about 0.04 mg / ml, about 0. In some cases, the lotirana or its derivative, analog, racemic mixture or diastereomer or enantiomer may be present in the composition in an amount of about 3.2 mg / ml.The lotiranab or its derivative, analog, racemic mixture or diastereomer or enantiomer may be present in an amount of about 0.0001% to 1% (w / w), optionally about 0.001% to about 1% (w / w), optionally about 0.0001% to 0.9%, optionally about 0.0001% to 0.9%, optionally about 0.0001% to 0.8%, optionally about 0.0001% to 0.7%, optionally about 0.0001% to 0.6%, optionally about 0.0001% to 0.5%, optionally about 0.0001% to 0.4%, optionally about 0.0001% to 0.3%, optionally about 0.001% to 0.9%, optionally about 0.001% to 0.9%, optionally about 0.001% to 0.8%, optionally about 0.001% to 0.7%, optionally about 0.001% to 0.6%, optionally about 0.001% to 0.5%, optionally about 0.001% to 0.4%, optionally about 0.001% to 0.3%, optionally selected from about 0.01%, about 0.05%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.4%, about 0.45%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9% or about 0.1% (w / w) is present in the composition. In some cases, the lotiranab or its derivative, analog, racemic mixture or diastereomer or enantiomer may be present in the composition in an amount of about 0.25% (w / w).

[0098] In certain cases of the compositions, nanoemulsions and methods herein, the API may be cyclosporin or a derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer thereof. In these and other cases, the compositions, nanoemulsions and methods may have the following optional features. The MCT may be present in an amount of about 0.1% to about 50% (w / w), optionally about 0.1% to about 10% (w / w), about 1% to about 30% (w / w), about 5% to about 20% (w / w), optionally selected from about 5%, about 10%, about 15% or about 20% (w / w). The semifluorinated alkane compound may be present in an amount of about 70% to about 99% (w / w), optionally about 80% to about 95% (w / w), optionally selected from about 80%, 85%, 90% or 95% (w / w). The semifluorinated alkane compound may be selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8). The MCT may be selected from coconut oil alcohol caprylate / caprate, propylene glycol dicaprylate caprate, glyceryl tricaprylate / tricaprate and glyceryl tricaprylate / tricaprylin. The cyclosporin or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer may be about 0.001mg / ml to 10mg / ml, optionally 0.01mg / ml to 10mg / ml, 0.01mg / ml to 5mg / ml, 0.01mg / ml to 1mg / ml, 0.1mg / ml to 1mg / ml, optionally about 0.01mg / ml, about 0.02mg / ml, 0.03mg / ml, about 0.04mg In some cases, the cyclosporine or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer can be present in the composition in an amount of about 0.65 mg / ml.The cyclosporine or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer may be present in an amount of about 0.0001% to 10% (w / w), optionally about 0.01% to about 5%, optionally about 0.01% to about 1%, optionally about 0.001% to about 0.1% (w / w), optionally about 0.001% to about 0.01% (w / w), optionally selected from about 0.001%, ... In some cases, the cyclosporin or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer may be present in the composition in an amount of about 0.05% (w / w).

[0099] In certain cases of the compositions, nanoemulsions and methods herein, the API may be cyclosporine or a derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer thereof. In certain cases of the methods described herein, the ocular condition may be hyperopia or myopia. In certain cases, a method for treating dry eye syndrome or keratoconjunctivitis sicca, dry eye disease, inflammatory dry eye, redness, meibomian gland dysfunction, myopia or hyperopia in a subject, slowing its progression, improving one or more symptoms thereof, the method comprising applying a topical ophthalmic composition to the subject's eye, wherein the topical ophthalmic composition comprises:

[0100] about 0.0001% to about 10% (w / w) API, wherein the API is selected from cyclosporine or a derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof;

[0101] about 0.1% to about 50% (w / w) MCT; and

[0102] From about 50% to about 99% (w / w) of the semifluorinated alkane compound.

[0103] In these and other cases, the method may have the following optional features. The topical ophthalmic composition may be applied to the eye of the subject every about 6 to about 8 hours or 3 times a day. The topical ophthalmic composition may be non-aqueous. The dosage of the topical ophthalmic composition may be 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70% or 50-70% less than the dosage of the aqueous topical ophthalmic composition containing the API for treating myopia or hyperopia in the subject, slowing its progression, improving one or more symptoms thereof. The topical ophthalmic composition can be non-aqueous. The API can be in free base form. The topical ophthalmic composition can be absorbed through the cornea in the eye. The topical ophthalmic composition can be selectively absorbed through the cornea in the eye compared to the periorbital region. In these and other cases, the composition, nanoemulsion and method can have the following optional features. The MCT can be present in an amount of about 0.1% to about 50% (w / w), optionally about 0.1% to about 10% (w / w), optionally about 1% to about 30% (w / w), optionally about 5% to about 20% (w / w), optionally selected from about 5%, about 10%, about 15% or about 20% (w / w). The semifluorinated alkane compound can be present in an amount of about 70% to about 99% (w / w), optionally about 80% to about 95% (w / w), optionally selected from about 80%, 85%, 90% or 95% (w / w). The semifluorinated alkane compound may be selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8). The MCT may be selected from coconut caprylate / caprate, propylene glycol dicaprylate caprate, glyceryl tricaprylate / tricaprate and glyceryl tricaprylate / tricaprylin. The cyclosporin or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer may be present in the composition in an amount of about 1 to about 30 mg / ml, optionally about 5 to about 20 mg / ml, optionally about 10 to about 15 mg / ml.The cyclosporine or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer may be present in the composition in an amount of about 0.0001% to 0.1% (w / w), optionally about 0.001% to about 0.1% (w / w), optionally about 0.001% to about 0.01% (w / w), optionally selected from about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009% or about 0.01% (w / w). In some cases, the cyclosporine or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer can be administered at about 0.001 mg / ml to 10 mg / ml, optionally 0.01 mg / ml to 10 mg / ml, 0.01 mg / ml to 5 mg / ml, 0.01 mg / ml to 1 mg / ml, 0.1 mg / ml to 1 mg / ml, optionally about 0.01 mg / ml, about 0.02 mg / ml, 0.03 mg / ml, about 0.0 In some cases, the cyclosporin or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer may be present in the composition in an amount of about 0.65 mg / ml.In some cases, the cyclosporine or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer can be present in an amount of about 0.0001% to 10% (w / w), optionally about 0.01% to about 5%, optionally about 0.01% to about 1%, optionally about 0.001% to about 0.1% (w / w), optionally about 0.001% to about 0.01% (w / w), optionally selected from about 0.001%, About 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.065%, about 0.07%, about 0.08%, about 0.08%, about 0.09% or about 0.1% (w / w) is present in the composition. In some cases, the cyclosporin or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer can be present in the composition in an amount of about 0.05% (w / w).

[0104] In some cases of the compositions, nanoemulsions and methods herein, the API may be cyclosporin, cyclosporin mimetics or analogs. In these and other cases, the compositions, nanoemulsions and methods may have the following optional features. The MCT may be present in an amount of about 0.1% to about 50% (w / w), optionally about 0.1% to about 10% (w / w), optionally about 1% to about 30% (w / w), optionally about 5% to about 20% (w / w), optionally selected from about 5%, about 10%, about 15% or about 20% (w / w). The semifluorinated alkane compound may be present in an amount of about 70% to about 99% (w / w), optionally about 80% to about 95% (w / w), optionally selected from about 80%, 85%, 90% or 95% (w / w). The semifluorinated alkane compound may be selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8). The MCT may be selected from the group consisting of coco caprylate / caprate, propylene glycol dicaprylate caprate, glyceryl tricaprylate / tricaprate, and glyceryl tricaprylate / tricaprylin. The cyclosporin, cyclosporin mimetic, or analog may be present in the composition in an amount of about 0.005 to about 1 mg / ml, optionally about 0.01 to about 0.75 mg / ml, optionally about 0.01 to about 0.1 mg / ml, optionally about 0.05 to about 0.75 mg / ml, optionally about 0.01 to about 0.03 mg / ml, optionally about 0.1 to about 0.5 mg / ml. The cyclosporin, cyclosporin mimetic or analog may be present in the composition in an amount of about 0.0001% to 0.1% (w / w), optionally about 0.001% to about 0.1% (w / w), optionally about 0.001% to about 0.01% (w / w), optionally selected from about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009% or about 0.01% (w / w).In some cases, the cyclosporine or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer can be administered at about 0.001 mg / ml to 10 mg / ml, optionally 0.01 mg / ml to 10 mg / ml, 0.01 mg / ml to 5 mg / ml, 0.01 mg / ml to 1 mg / ml, 0.1 mg / ml to 1 mg / ml, optionally about 0.01 mg / ml, about 0.02 mg / ml, 0.03 mg / ml, about 0.0 In some cases, the cyclosporin or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer may be present in the composition in an amount of about 0.65 mg / ml. In some cases, the cyclosporine or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer can be present in an amount of about 0.0001% to 10% (w / w), optionally about 0.01% to about 5%, optionally about 0.01% to about 1%, optionally about 0.001% to about 0.1% (w / w), optionally about 0.001% to about 0.01% (w / w), optionally selected from about 0.001%, About 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about 0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.065%, about 0.07%, about 0.08%, about 0.08%, about 0.09% or about 0.1% (w / w) is present in the composition. In some cases, the cyclosporin or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer can be present in the composition in an amount of about 0.05% (w / w).

[0105] In certain cases of the compositions, nanoemulsions and methods herein, the API may be ivermectin or a derivative, analog, racemic mixture or diastereomer or enantiomer thereof, optionally wherein the ivermectin is a mixture of ivermectin B1a and ivermectin B1b. In these and other cases, the compositions, nanoemulsions and methods may have the following optional features. The MCT may be present in an amount of about 0.1% to about 50% (w / w), optionally about 0.1% to about 10% (w / w), about 1% to about 30% (w / w), about 5% to about 20% (w / w), optionally selected from about 5%, about 10%, about 15% or about 20% (w / w). The semifluorinated alkane compound may be present in an amount of about 70% to about 99% (w / w), optionally about 80% to about 95% (w / w), optionally selected from about 80%, 85%, 90% or 95% (w / w). The semifluorinated alkane compound may be selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8). The MCT may be selected from coconut caprylate / caprate, propylene glycol dicaprylate caprate, glyceryl tricaprylate / tricaprate and glyceryl tricaprylate / tricaprylin. The ivermectin or its derivative, analog, racemic mixture or diastereomer or enantiomer may be present in the composition in an amount of about 0.001 mg / ml to 1 mg / ml, optionally 0.01 mg / ml to 1 mg / ml, 0.01 mg / ml to 0.1 mg / ml, optionally about 0.01 mg / ml, about 0.02 mg / ml, 0.03 mg / ml, about 0.04 mg / ml, about 0.05 mg / ml, about 0.06 mg / ml, about 0.07 mg / ml, about 0.08 mg / ml, about 0.09 mg / ml or about 0.1 mg / ml. In some cases, the ivermectin or its derivative, analog, racemic mixture or diastereomer or enantiomer is present in the composition in an amount of 0.1 mg / ml to 50 mg / ml, optionally 0.1 mg / ml to 40 mg / ml, 0.1 mg / ml to 30 mg / ml, 0.1 mg / ml to 20 mg / ml, 0.1 mg / ml to 10 mg / ml, 1 mg / ml to 50 mg / ml, 10 mg / ml to 50 mg / ml, 20 mg / ml to 50 mg / ml, 30 mg / ml to 50 mg / ml, about 1 mg / ml, about 5 mg / ml, about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25 mg / ml, about 30 mg / ml, about 35 mg / ml, about 40 mg / ml, about 45 mg / ml or about 50 mg / ml.The ivermectin or its derivative, analog, racemic mixture or diastereomer or enantiomer may be present in the composition in an amount of about 0.0001% to 0.1% (w / w), optionally about 0.001% to about 0.1% (w / w), optionally about 0.001% to about 0.01% (w / w), optionally selected from about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009% or about 0.01% (w / w). In some cases, the ivermectin or its derivative, analog, racemic mixture or diastereomer or enantiomer is present in the composition in an amount of 0.01% to 5%, optionally 0.01% to 4%, 0.01% to 3%, 0.01% to 2%, 0.01% to 1%, 0.1% to 5%, 1% to 5%, 2% to 5%, 3% to 5%, about 0.1%, about 0.5%, about 0.1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5% or about 5%. In some cases, the ivermectin is a mixture of ivermectin B1a and ivermectin B1b.

[0106] In certain instances of the compositions, nanoemulsions and methods herein, the API may be ivermectin or a derivative, analog, racemic mixture or diastereomer or enantiomer thereof, optionally wherein the ivermectin is a mixture of ivermectin B1a and ivermectin B1b. In certain instances of the methods described herein, the ocular condition may be hyperopia or myopia. In some cases, a method is provided for treating, slowing the progression of, ameliorating one or more symptoms of Demodex blepharitis, for aiding in the eradication or reduction of parasite infestations of the eye, ocular tissue, skin, eyelashes or other body hair; for treating or alleviating or relieving symptoms of certain diseases or conditions, such as ocular diseases, skin diseases, vector-borne diseases or other diseases caused by parasites; for treating or alleviating or relieving symptoms of certain ocular diseases or conditions, such as blepharitis, meibomian gland dysfunction or rosacea caused by parasites such as Demodex; for treating or alleviating or relieving symptoms of redness of the eyelid margin caused by Demodex, or improving the health of eyelashes in a subject; for eradicating, reducing the number of, treating or alleviating or relieving symptoms of lice, scabies or bed bugs and related skin, hair, scalp or hair follicle disorders; for treating, slowing the progression of, ameliorating one or more symptoms of myopia or hyperopia in a subject, the method comprising applying a topical ophthalmic composition to the eye of the subject, wherein the topical ophthalmic composition comprises:

[0107] about 0.01% to about 5% (w / w) API, wherein the API is selected from ivermectin or a derivative, analog, racemic mixture or diastereomer or enantiomer thereof, optionally wherein the ivermectin is a mixture of ivermectin B1a and ivermectin B1b;

[0108] about 0.1% to about 50% (w / w) MCT; and

[0109] From about 50% to about 99% (w / w) of the semifluorinated alkane compound.

[0110] In these and other cases, the method may have the following optional features. The topical ophthalmic composition may be applied to the eye of the subject every about 6 to about 8 hours or 3 times a day. The topical ophthalmic composition may be non-aqueous. The dosage of the topical ophthalmic composition may be 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70% or 50-70% less than the dosage of the aqueous topical ophthalmic composition containing the API for treating myopia or hyperopia in the subject, slowing its progression, improving one or more symptoms thereof. The topical ophthalmic composition can be non-aqueous. The API can be in free base form. The topical ophthalmic composition can be absorbed through the cornea in the eye. The topical ophthalmic composition can be selectively absorbed through the cornea in the eye compared to the periorbital region. In these and other cases, the composition, nanoemulsion and method can have the following optional features. The MCT can be present in an amount of about 0.1% to about 50% (w / w), optionally about 0.1% to about 10% (w / w), optionally about 1% to about 30% (w / w), optionally about 5% to about 20% (w / w), optionally selected from about 5%, about 10%, about 15% or about 20% (w / w). The semifluorinated alkane compound can be present in an amount of about 70% to about 99% (w / w), optionally about 80% to about 95% (w / w), optionally selected from about 80%, 85%, 90% or 95% (w / w). The semifluorinated alkane compound may be selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8). The MCT may be selected from coconut caprylate / caprate, propylene glycol dicaprylate caprate, glyceryl tricaprylate / tricaprate and glyceryl tricaprylate / tricaprylin. The axitinib, axitinib mimetic or analog, or a free base or salt form thereof may be present in the composition in an amount of about 1 to about 30 mg / ml, optionally about 5 to about 20 mg / ml, optionally about 10 to about 15 mg / ml. The ivermectin or its derivative, analog, racemic mixture or diastereomer or enantiomer may be present in the composition in an amount of about 0.0001% to 0.1% (w / w), optionally about 0.001% to about 0.1% (w / w), optionally about 0.001% to about 0.01% (w / w), optionally selected from about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009% or about 0.01% (w / w).In some cases, the ivermectin or its derivative, analog, racemic mixture or diastereomer or enantiomer is present in the composition in an amount of 0.1 mg / ml to 50 mg / ml, optionally 0.1 mg / ml to 40 mg / ml, 0.1 mg / ml to 30 mg / ml, 0.1 mg / ml to 20 mg / ml, 0.1 mg / ml to 10 mg / ml, 1 mg / ml to 50 mg / ml, 10 mg / ml to 50 mg / ml, 20 mg / ml to 50 mg / ml, 30 mg / ml to 50 mg / ml, about 1 mg / ml, about 5 mg / ml, about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25 mg / ml, about 30 mg / ml, about 35 mg / ml, about 40 mg / ml, about 45 mg / ml or about 50 mg / ml. In some cases, the ivermectin or its derivative, analog, racemic mixture or diastereomer or enantiomer is present in the composition in an amount of 0.01% to 5%, optionally 0.01% to 4%, 0.01% to 3%, 0.01% to 2%, 0.01% to 1%, 0.1% to 5%, 1% to 5%, 2% to 5%, 3% to 5%, about 0.1%, about 0.5%, about 0.1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5% or about 5%. In some cases, the ivermectin is a mixture of ivermectin B1a and ivermectin B1b.

[0111] In some cases of the compositions, nanoemulsions and methods herein, the API may be ivermectin, ivermectin mimetics or analogs. In these and other cases, the compositions, nanoemulsions and methods may have the following optional features. The MCT may be present in an amount of about 0.1% to about 50% (w / w), optionally about 0.1% to about 10% (w / w), optionally about 1% to about 30% (w / w), optionally about 5% to about 20% (w / w), optionally selected from about 5%, about 10%, about 15% or about 20% (w / w). The semifluorinated alkane compound may be present in an amount of about 70% to about 99% (w / w), optionally about 80% to about 95% (w / w), optionally selected from about 80%, 85%, 90% or 95% (w / w). The semifluorinated alkane compound may be selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8). The MCT may be selected from coconut oil alcohol caprylate / caprate, propylene glycol dicaprylate caprate, glyceryl tricaprylate / tricaprate and glyceryl tricaprylate / tricaprylin. The ivermectin, ivermectin mimetic or analog may be present in the composition in an amount of about 0.005 to about 1 mg / ml, optionally about 0.01 to about 0.75 mg / ml, optionally about 0.01 to about 0.1 mg / ml, optionally about 0.05 to about 0.75 mg / ml, optionally about 0.01 to about 0.03 mg / ml, optionally about 0.1 to about 0.5 mg / ml. The ivermectin, ivermectin mimetic or analog may be present in the composition in an amount of about 0.0001% to 0.1% (w / w), optionally about 0.001% to about 0.1% (w / w), optionally about 0.001% to about 0.01% (w / w), optionally selected from about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009% or about 0.01% (w / w). In some cases, the ivermectin or its derivative, analog, racemic mixture or diastereomer or enantiomer is present in the composition in an amount of 0.1 mg / ml to 50 mg / ml, optionally 0.1 mg / ml to 40 mg / ml, 0.1 mg / ml to 30 mg / ml, 0.1 mg / ml to 20 mg / ml, 0.1 mg / ml to 10 mg / ml, 1 mg / ml to 50 mg / ml, 10 mg / ml to 50 mg / ml, 20 mg / ml to 50 mg / ml, 30 mg / ml to 50 mg / ml, about 1 mg / ml, about 5 mg / ml, about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25 mg / ml, about 30 mg / ml, about 35 mg / ml, about 40 mg / ml, about 45 mg / ml or about 50 mg / ml.In some cases, the ivermectin or its derivative, analog, racemic mixture or diastereomer or enantiomer is present in the composition in an amount of 0.01% to 5%, optionally 0.01% to 4%, 0.01% to 3%, 0.01% to 2%, 0.01% to 1%, 0.1% to 5%, 1% to 5%, 2% to 5%, 3% to 5%, about 0.1%, about 0.5%, about 0.1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5% or about 5%.

[0112] In certain cases of the compositions, nanoemulsions and methods herein, the API may be axitinib, axitinib mimetics or analogs, or a free base or salt form thereof. In these and other cases, the compositions, nanoemulsions and methods may have the following optional features. The MCT may be present in an amount of about 0.1% to about 50% (w / w), optionally about 0.1% to about 10% (w / w), about 1% to about 30% (w / w), about 5% to about 20% (w / w), optionally selected from about 5%, about 10%, about 15% or about 20% (w / w). The semifluorinated alkane compound may be present in an amount of about 70% to about 99% (w / w), optionally about 80% to about 95% (w / w), optionally selected from about 80%, 85%, 90% or 95% (w / w). The semifluorinated alkane compound may be selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8). The MCT may be selected from coconut oil caprylate / caprate, propylene glycol dicaprylate caprate, glyceryl tricaprylate / tricaprate and glyceryl tricaprylate / tricaprylin. The axitinib, axitinib mimetic or analog, or a free base or salt form thereof may be present in the composition in an amount of about 0.001 mg / ml to 1 mg / ml, optionally 0.01 mg / ml to 1 mg / ml, 0.01 mg / ml to 0.1 mg / ml, optionally about 0.01 mg / ml, about 0.02 mg / ml, 0.03 mg / ml, about 0.04 mg / ml, about 0.05 mg / ml, about 0.06 mg / ml, about 0.07 mg / ml, about 0.08 mg / ml, about 0.09 mg / ml or about 0.1 mg / ml. The axitinib, axitinib mimetic or analog, or a free base or salt form thereof may be present in the composition in an amount of about 0.0001% to 0.1% (w / w), optionally about 0.001% to about 0.1% (w / w), optionally about 0.001% to about 0.01% (w / w), optionally selected from about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009% or about 0.01% (w / w).

[0113] In certain instances of the compositions, nanoemulsions, and methods herein, the API can be axitinib, an axitinib mimetic or analog, or a free base or salt form thereof. In certain instances of the methods described herein, the ocular condition can be hyperopia or myopia. In some cases, a method is provided for treating, slowing the progression of, or ameliorating one or more symptoms of chalazion, pterygium, angiogenesis-related eye condition (e.g., hyperemia, neovascularization, pterygium, chalazion, glaucoma filtration surgery and minimally invasive glaucoma surgery (MIGS), corneal transplant surgery with graft rejection, graft-versus-host disease, dry eye disease, atopic conjunctivitis, rosacea, ocular pemphigoid, Lyell syndrome, Steven Johnson syndrome, viral infection (e.g., HSV-1), bacterial infection, fungal infection, parasitic infection, contact lens-induced neovascularization, ulceration, alkali burns, and stem cell deficiency), myopia or hyperopia in a subject, the method comprising administering to the subject's eye a topical ophthalmic composition, wherein the topical ophthalmic composition comprises:

[0114] about 0.0001% to about 0.1% (w / w) API, wherein the API is selected from axitinib, an axitinib mimetic or analog, or a free base or salt form thereof;

[0115] about 0.1% to about 50% (w / w) MCT; and

[0116] From about 50% to about 99% (w / w) of the semifluorinated alkane compound.

[0117] In these and other cases, the method may have the following optional features. The topical ophthalmic composition may be applied to the eye of the subject every about 6 to about 8 hours or 3 times a day. The topical ophthalmic composition may be non-aqueous. The dosage of the topical ophthalmic composition may be 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70% or 50-70% less than the dosage of the aqueous topical ophthalmic composition containing the API for treating myopia or hyperopia in the subject, slowing its progression, improving one or more symptoms thereof. The topical ophthalmic composition can be non-aqueous. The API can be in free base form. The topical ophthalmic composition can be absorbed through the cornea in the eye. The topical ophthalmic composition can be selectively absorbed through the cornea in the eye compared to the periorbital region. In these and other cases, the composition, nanoemulsion and method can have the following optional features. The MCT can be present in an amount of about 0.1% to about 50% (w / w), optionally about 0.1% to about 10% (w / w), optionally about 1% to about 30% (w / w), optionally about 5% to about 20% (w / w), optionally selected from about 5%, about 10%, about 15% or about 20% (w / w). The semifluorinated alkane compound can be present in an amount of about 70% to about 99% (w / w), optionally about 80% to about 95% (w / w), optionally selected from about 80%, 85%, 90% or 95% (w / w). The semifluorinated alkane compound may be selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8). The MCT may be selected from coconut oil alcohol caprylate / caprate, propylene glycol dicaprylate caprate, glyceryl tricaprylate / tricaprate and glyceryl tricaprylate / tricaprylin. The axitinib, axitinib mimetic or analog, or its free base or salt form may be present in the composition in an amount of about 1 to about 30 mg / ml, optionally about 5 to about 20 mg / ml, optionally about 10 to about 15 mg / ml. In some cases, the axitinib, axitinib mimetic or analog, or its free base or salt form may be present in the composition in an amount of about 0.5 to about 1 mg / ml.The axitinib, axitinib mimetic or analog, or its free base or salt form may be present in the composition in an amount of about 0.0001% to 0.1% (w / w), optionally about 0.001% to about 0.1% (w / w), optionally about 0.001% to about 0.01% (w / w), optionally selected from about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009% or about 0.01% (w / w). In some cases, the axitinib, axitinib mimetic or analog, or its free base or salt form may be present in the composition in an amount of about 0.05 to about 0.1% (w / w).

[0118] In some cases of the compositions, nanoemulsions and methods herein, the API may be axitinib, axitinib mimetics or the like. In these and other cases, the compositions, nanoemulsions and methods may have the following optional features. The MCT may be present in an amount of about 0.1% to about 50% (w / w), optionally about 0.1% to about 10% (w / w), optionally about 1% to about 30% (w / w), optionally about 5% to about 20% (w / w), optionally selected from about 5%, about 10%, about 15% or about 20% (w / w). The semifluorinated alkane compound may be present in an amount of about 70% to about 99% (w / w), optionally about 80% to about 95% (w / w), optionally selected from about 80%, 85%, 90% or 95% (w / w). The semifluorinated alkane compound may be selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8). The MCT may be selected from coconut oil alcohol caprylate / caprate, propylene glycol dicaprylate caprate, glyceryl tricaprylate / tricaprylate and glyceryl tricaprylate / tricaprylin. The axitinib, axitinib mimetic or analog may be present in the composition in an amount of about 0.005 to about 1 mg / ml, optionally about 0.01 to about 0.75 mg / ml, optionally about 0.01 to about 0.1 mg / ml, optionally about 0.05 to about 0.75 mg / ml, optionally about 0.01 to about 0.03 mg / ml, optionally about 0.1 to about 0.5 mg / ml. In some cases, the axitinib, axitinib mimetic or analog may be present in the composition in an amount of about 0.5 to about 1 mg / ml. The axitinib, axitinib mimetic or analog may be present in the composition in an amount of about 0.0001% to 0.1% (w / w), optionally about 0.001% to about 0.1% (w / w), optionally about 0.001% to about 0.01% (w / w), optionally selected from about 0.001%, about 0.002%, about 0.003%, about 0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009% or about 0.01% (w / w). In some cases, the axitinib, axitinib mimetic or analog may be present in the composition in an amount of about 0.05% to 0.1% (w / w).

[0119] Second, in some cases of the compositions and methods provided herein, the compositions can provide better stability of the API, for example, compared to aqueous or other standard ocular formulations of the API. This provides several additional advantages, including the possibility of using certain APIs that were previously difficult to formulate for ocular use, or preventing the formation of API-based impurities, or improving shelf life and storage time compared to other standard ocular or aqueous formulations of the API.

[0120] Third, in some cases, the compositions described herein can be formulated as nanoemulsions with droplet sizes below 100 nm, 50 nm, 15 nm, 10 nm, and even 5 nm. Without being bound by theory, it is believed that smaller droplet sizes can lead to improved longer term stability of the API in the formulation, as well as increased availability of the API, improved tissue penetration and distribution of the API, and improved residence time in ocular tissues compared to aqueous formulations.

[0121] Fourth, in some cases, the dispensers provided herein can provide increased compatibility with the compositions described herein, such as compositions comprising MCT and / or SFA. The increased compatibility of the dispenser can result in better stability of the composition and the API in the composition, longer shelf life of the composition, and improved delivery of the prescribed amount or desired amount of API to the eye or ocular tissue of a patient or subject.

[0122] Fifth, in some cases, the compositions described herein (e.g., topical ophthalmic compositions or topical ophthalmic nanoemulsions) can provide improved delivery of the API to the cornea, for example, by absorption through the cornea, compared to an aqueous composition comprising the API or an aqueous composition comprising a salt of the API. In some cases, the compositions described herein are selectively absorbed through the cornea (e.g., compared to periorbital absorption). Improved delivery of the API to the cornea can allow lower doses and / or more frequent lower doses to be administered to the subject. Therefore, improved delivery of the API to the cornea reduces one or more adverse side effects of the API, and can be used to treat eye conditions in subjects who are highly sensitive to the API.

[0123] Thus, in some cases, a method of administering a topical ophthalmic composition to a subject for selective transcorneal absorption is also described herein, comprising administering a composition (e.g., a topical ophthalmic composition or a topical ophthalmic nanoemulsion described herein) to the subject's eye. In some cases, the topical ophthalmic composition is non-aqueous. In some cases, the API is in free base form. In some cases, the API is atropine.

[0124] In some cases, a method of treating an ocular condition in a subject is also described herein, comprising: (a) (i) selecting a subject in need of corneal absorption of an API; or (ii) selecting a subject with an ocular condition, wherein the ocular condition requires corneal absorption of an API; and (b) administering a composition described herein (e.g., a topical ophthalmic composition or a topical ophthalmic nanoemulsion) to the eye of the subject. In some cases, the topical ophthalmic composition is non-aqueous. In some cases, the API is in free base form. In some cases, the API is atropine.

[0125] Subjects in need of transcorneal absorption of the API include subjects with high sensitivity to the API, subjects in need of a lower dose of the API, subjects with one or more adverse effects of aqueous solutions of the API (e.g., adverse effects attributed to the API rather than to another component or characteristic of the composition comprising the API (e.g., pH or preservatives)), subjects in need of treatment with an API having target receptors in one or more of the cornea, aqueous humor, or iris, and subjects in need of treatment with an API associated with one or more adverse events in one or more of the conjunctiva, sclera, and ciliary body.

[0126] In some cases, a method of selectively delivering an API to the cornea of ​​a subject is also described herein, comprising administering a composition described herein (e.g., a topical ophthalmic composition or a topical ophthalmic nanoemulsion) to the subject's eye. In some cases, the topical ophthalmic composition is non-aqueous. In some cases, the API is in free alkali form. In some cases, the API is atropine. In some cases, the composition is administered to the subject's eye every about 6 to about 8 hours or 3 times a day. In some cases, the composition is administered to the subject once a day. In some cases, the composition is administered to the subject 2 times a day. In certain instances, the composition is administered at a dose that is 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70%, or 50-70% less than the dose of an aqueous topical ophthalmic composition comprising the API for treating an ocular disorder or a symptom thereof.

[0127] In some cases, a method of treating an ocular condition in a subject is also described herein, the method comprising administering to the subject a composition comprising an API described herein (e.g., a topical ophthalmic composition or a topical ophthalmic nanoemulsion), wherein the composition is non-aqueous; and wherein the subject does not respond to treatment with an aqueous composition comprising the API, wherein the subject has had adverse side effects from the API (or its salt) after receiving an aqueous composition comprising the API (or its salt), and / or wherein the subject is highly sensitive to an aqueous composition comprising the API. In some cases, the subject has had adverse side effects from a salt of the API. In some cases, the subject has had adverse side effects from an API in its free base form. In some cases, the API is in free base form. In some cases, the API is atropine. In some cases, the composition is administered to the subject's eye every about 6 to about 8 hours or 3 times a day. In some cases, the composition or the nanoemulsion is administered to the subject once a day. In some cases, the composition or the nanoemulsion is administered to the subject 2 times a day. In certain instances, the dosage of the topical ophthalmic composition or the topical ophthalmic nanoemulsion administered is 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70%, or 50-70% less than the dosage of an aqueous topical ophthalmic composition comprising the API for treating an ocular condition.

[0128] In some cases, the present invention also describes a method for preparing a topical ophthalmic composition for transcorneal absorption, the method comprising: (a) identifying an aqueous topical ophthalmic composition comprising an active pharmaceutical ingredient (API) for selective transcorneal absorption; (b) combining the API with a medium chain triglyceride (MCT) and a semifluorinated alkane compound to form a mixture; and (d) emulsifying the mixture; optionally wherein the topical ophthalmic composition for transcorneal absorption comprises about 0.001% to about 5% (w / w) API, about 1% to about 50% (w / w) MCT and about 50% to about 99% (w / w) semifluorinated alkane compound, and optionally wherein the API has a solubility in medium chain triglycerides (MCT) of at least about 0.01% to about 10% (w / w). In some cases, the topical ophthalmic composition comprises about 0.02% (w / w) API. In some cases, the topical ophthalmic composition comprises about 0.04% (w / w) API. In some cases, the topical ophthalmic composition comprises about 0.05% (w / w) API. In some cases, the topical ophthalmic composition comprises about 1% (w / w) API. In some cases, the topical ophthalmic composition comprises about 5% to about 20% (w / w) MCT. In some cases, the API is not atropine or a salt thereof. In some cases, the API is atropine. In some cases, the API is in free base form. In some cases, the method further comprises, prior to step (a), identifying an aqueous topical ophthalmic composition comprising an API for selective transcorneal absorption. In some cases, the topical ophthalmic composition is non-aqueous.

[0129] The present disclosure also relates to compositions and methods for treating ophthalmic conditions such as hyperopia. The composition may include a muscarinic cholinergic receptor agonist and a semifluorinated alkane compound. In some cases, the composition may further include an organic co-solvent.

[0130] The present disclosure is also based, at least in part, on the recognition that certain compositions comprising semifluorinated alkane compounds can provide improved stability of muscarinic cholinergic receptor agonists for use in ophthalmic formulations. The formulations disclosed herein can maintain potency and stability and can be used with minimal or no irritation to the subject's eye.

[0131] Various compounds such as aceclidine, muscarinic cholinergic receptor agonists, have been studied for treating hyperopia, but these compounds may have stability issues in traditional aqueous ophthalmic formulations. For example, aceclidine can decompose rapidly in traditional aqueous formulations. Because of the compounds used to stabilize active pharmaceutical ingredients, many attempts to improve the stability of these compounds in pharmaceutical formulations can result in eye irritation. There remains a need for improved treatments for hyperopia, including compositions that maintain stability and efficacy while also providing minimal or no irritation to the eye.

[0132] The present disclosure also provides compositions comprising a muscarinic cholinergic receptor agonist and a semifluorinated alkane compound, and methods of treating hyperopia using the compositions disclosed herein. The compositions described herein provide improved stability of the muscarinic cholinergic receptor agonist without negative effects on efficacy or eye irritation. In some cases, the formulations also provide the ability to use higher concentrations of the muscarinic cholinergic receptor agonist in the composition.

[0133] In one aspect, described herein is a topical ophthalmic composition comprising: a therapeutically effective amount of a muscarinic cholinergic receptor agonist as an active pharmaceutical ingredient; and a semifluorinated alkane compound.

[0134] The composition may optionally include one or more of the following features. The semifluorinated alkane compound may be present as a liquid vehicle. The muscarinic cholinergic receptor agonist may be selected from aceclidin, pilocarpine, bethanechol, cevimeline, methacholine, xanomeline and aprolidin. The semifluorinated alkane may be a compound of formula RFRH or RFRHRF, wherein RF is a perfluorinated hydrocarbon having 15 or less carbon atoms, and wherein RH is a non-fluorinated hydrocarbon having 15 or less carbon atoms. The semifluorinated alkane may be selected from perfluorobutylheptane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8) and perfluorohexyldecane (F6H10). The semifluorinated alkane may be F6H8 (perfluorohexyloctane). The semifluorinated alkane may be perfluorobutylheptane (F4H5).

[0135] The composition may optionally further comprise one or more organic co-solvents. The organic co-solvent may be selected from medium chain triglycerides (MCT), liquid paraffin, vitamin E acetate, D-α-tocopherol, oleic acid, ethyl oleate and combinations thereof. The organic co-solvent may be a medium chain triglyceride (MCT) or a medium chain triglyceride (MCT) with two or three fatty acids, each of which independently has an aliphatic tail of 6-12 carbon atoms.

[0136] In these and other embodiments, the composition may include the following optional features. The concentration of the organic co-solvent in the composition may be less than or equal to about 50% (w / w). The concentration of the organic co-solvent in the composition may be about 1% to 15% (w / w). The organic co-solvent may be present in a concentration of about 1% (w / w) to about 50% (w / w), and the semifluorinated alkane compound may be present in a concentration of about 50% to about 99%. The muscarinic cholinergic receptor agonist may be present in a concentration of about 0.1% to about 2.0% (w / w), 0.5% to about 2.0% (w / w), or 0.5% to about 1.5% (w / w). The muscarinic cholinergic receptor agonist may be aceclidin. The aceclidin may be in free base form or in salt form. The aceclidin may be in free base form and the concentration of the aceclidin may be about 0.1% to about 2.0% (w / w), about 0.5% to about 2.0% (w / w), or about 0.5% to about 1.5% (w / w). The muscarinic cholinergic receptor agonist may be pilocarpine. The pilocarpine may be in free base form or in salt form. The pilocarpine may be in free base form and the concentration of the pilocarpine may be about 0.1% to about 2.0% (w / w), about 0.5% to about 2.0% (w / w), or about 0.5% to about 1.5% (w / w). The topical ophthalmic composition may be a non-aqueous solution, suspension, or emulsion. The muscarinic cholinergic receptor agonist in the topical ophthalmic composition may be chemically stable at room temperature for at least 0.5 years, at least 1 year, or at least 2 years. The topical ophthalmic composition may cause minimal or no irritation in the mammalian eye.

[0137] In another aspect, provided herein are eye drops comprising any of the topical ophthalmic compositions described herein.

[0138] In another aspect, provided herein is a method for treating hyperopia in a subject in need thereof, the method comprising administering any of the topical ophthalmic compositions described herein. In such a method, the topical ophthalmic composition may optionally cause minimal or no irritation in the subject's eye.

[0139] In another aspect, provided herein is a topical ophthalmic composition comprising: a therapeutically effective amount of aceclidin; and a semifluorinated alkane compound as a liquid vehicle. The composition may optionally include one or more of the following features. The composition may further comprise a medium chain triglyceride (MCT) having two or three fatty acids, each of which independently has an aliphatic tail of 6-12 carbon atoms. The aceclidin may be in free base form and may be present in a concentration of about 0.1% to about 2.0% (w / w), about 0.5% to about 2.0% (w / w), or about 0.5% to about 1.5% (w / w).

[0140] In another aspect, provided herein is a topical ophthalmic composition comprising: a therapeutically effective amount of pilocarpine; and a semifluorinated alkane compound as a liquid vehicle. The composition may optionally include one or more of the following features. The composition may further comprise a medium chain triglyceride (MCT) having two or three fatty acids, each independently having an aliphatic tail of 6-12 carbon atoms. The pilocarpine may be in free base form and may be present at a concentration of about 0.1% to about 2.0% (w / w), about 0.5% to about 2.0% (w / w), or about 0.5% to about 1.5% (w / w).

[0141] In another aspect, provided herein is a method for treating glaucoma in a subject in need thereof, the method comprising administering any of the topical ophthalmic compositions described herein. In such a method, the topical ophthalmic composition may optionally cause minimal or no irritation in the subject's eye.

[0142] In another aspect, provided herein is a method of improving a subject's ability to focus on nearby objects, the method comprising administering any of the topical ophthalmic compositions described herein. In such a method, the topical ophthalmic composition may optionally cause minimal or no irritation in the subject's eye.

[0143] In another aspect, provided herein is a method for reducing intraocular pressure in an eye of a subject in need thereof, the method comprising administering any of the topical ophthalmic compositions described herein. In such a method, the topical ophthalmic composition may optionally cause minimal or no irritation in the eye of the subject.

[0144] In certain embodiments, the compositions and methods provided herein can provide several advantages. The present disclosure is based on the following discovery: muscarinic cholinergic receptor agonists (such as, for example, aceclidin) can be dissolved in semifluorinated alkane compounds at sufficient concentrations or form stable emulsions in semifluorinated alkane compounds to have biological efficacy. The preparations of muscarinic cholinergic receptor agonists (such as aceclidin) in semifluorinated alkane compounds (such as F6H8) can be stable for a long time at room temperature. Such preparations can be made into useful products with sufficient shelf life for medical use and regulatory approval. When the concentration of administration is higher than the concentration required for certain indications, these preparations can be non-irritating in the eye.

[0145] In certain embodiments, the compositions described herein can exhibit greater stability of the muscarinic cholinergic receptor agonist than, for example, aqueous compositions of the same compound. In certain embodiments, such improved stability can allow the use of compositions that do not contain preservatives or additional excipients or other irritants used in aqueous formulations to impart stability, thereby reducing the likelihood of irritation (such as eye irritation) or allergic reactions associated with the inclusion of such additives.

[0146] In certain embodiments, the compositions described herein may exhibit improved pharmacokinetic profiles to modulate certain target tissues, such as, for example, pupillary tissue, thereby more effectively treating certain conditions, such as, for example, hyperopia.

[0147] Other features and advantages of the present application will be apparent from the following detailed description and drawings, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0149] Figure 1 The graph shows the efficacy of an exemplary embodiment of a nanoemulsion according to Example 4.

[0150] Figure 2 The graph shows changes in pupil diameter of rabbits after administration of an exemplary embodiment of a nanoemulsion according to Example 4.

[0151] Figure 3 The graph shows the pupil diameter of a human after administration of an exemplary embodiment of a nanoemulsion according to Example 4.

[0152] Figure 4 is an exploded schematic cross-sectional view of an exemplary embodiment of a dispenser as described herein.

[0153] Figure 5 The series of graphs depict drug concentrations in ocular tissue at various times following topical ocular administration of atropine-10% MCT-F6H8 to both eyes of rabbits (n=2).

[0154] Figure 6 Series of graphs depicting drug residues in ocular tissues at different times following topical ocular administration of atropine-10% MCT-F6H8 to both eyes of rabbits (n=4 eyes). Top (A): Bar graphs at each time point, from left to right: cornea, conjunctiva, sclera, aqueous humor, iris-ciliary body, retina-choroid, and vitreous humor. Middle (B): Bar graphs at each time point, from left to right: cornea and conjunctiva. Bottom (C): Bar graphs at each time point, from left to right: sclera, aqueous humor, iris-ciliary body, retina-choroid, and vitreous humor.

[0155] Figure 7is a GC chromatogram of an exemplary formulation according to Example 17.

[0156] Fig. 8A The graphs show the effect of an exemplary formulation on pupil diameter according to Example 21. *P<0.05 or **P<0.01 compared to baseline using T-TEST.

[0157] Figure 8B The graphs show the change in pupil diameter for an exemplary formulation according to Example 21. *P<0.05 or **P<0.01 compared to baseline using T-TEST.

[0158] Fig.9A The graph shows the effects of three exemplary formulations according to Example 22 on pupil diameter.

[0159] Fig. 9B The graph shows the effects of three exemplary formulations according to Example 22 on pupil diameter.

[0160] Detailed Description

[0161] Provided herein are compositions for topical delivery of ophthalmic active pharmaceutical ingredients (APIs), comprising medium chain triglycerides (MCTs), semifluorinated alkanes (SFAs), and active pharmaceutical ingredients (APIs), as well as methods of preparing and using the compositions, such as methods for treating or slowing the progression of an ocular disorder in a subject or alleviating one or more symptoms thereof. Also provided herein are dispensers or containers comprising the compositions.

[0162] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which this application belongs. Methods and materials for use in this application are described herein; other suitable methods and materials known in the art may also be used. The materials, methods, and embodiments are merely exemplary and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In the event of a conflict, the present specification (including definitions) shall prevail.

[0163] As used herein, the term "about" means "approximately" (eg, ± about 10% of the indicated value).

[0164] As used herein, the term "contacting" means bringing the specified moieties together in an in vitro system or an in vivo system. For example, "contacting" an ocular tissue with a compound of the invention includes administering the compound of the invention to an individual or patient, such as a human, having an ocular tissue in need of treatment, as well as, for example, introducing the compound of the invention into a sample containing cells or purified preparations of ocular tissue.

[0165] As used herein, the terms "individual," "patient," or "subject" are used interchangeably to refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and most preferably humans. In certain embodiments, a human subject can be of any age, e.g., from 0 to 100 years old. As used herein, "pediatric subject" and "child" are used interchangeably and refer to a subject between 0 and 18 years old, e.g., 1, 2, 5, 10, 12, or 14 years old.

[0166] As used herein, the phrases "effective amount" or "therapeutically effective amount" means that amount of an active compound or pharmaceutical agent that elicits the biological or medical response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

[0167] As used herein, the term "treat" means: 1) inhibiting a disease; e.g., inhibiting a disease, condition or disorder in an individual who is experiencing or exhibiting symptoms or signs of the disease, condition or disorder (i.e., arresting further development of the condition and / or symptoms), or 2) ameliorating a disease; e.g., ameliorating a disease, condition or disorder in an individual who is experiencing or exhibiting symptoms or signs of the disease, condition or disorder (i.e., reversing the condition and / or symptoms).

[0168] In certain instances, provided herein are compositions comprising an active pharmaceutical ingredient (API), a medium chain triglyceride (MCT), and a semifluorinated alkane compound, wherein the API is soluble in the MCT.

[0169] In certain instances of the compositions described herein, the composition is non-aqueous. In certain instances of the compositions described herein, the composition is an oil-in-oil emulsion.

[0170] The compositions described herein can include active pharmaceutical ingredient (API) compounds. API, its analogs, its salts and their free base forms (where applicable) are included within the scope of the present invention. Such solvates include, for example, hydrates, alcoholates (e.g., ethanol solvates), etc. API can exist in different polymorphic forms. Such forms are intended to be included within the scope of the present disclosure.

[0171] Exemplary, non-limiting APIs that can be used in the compositions and nanoemulsions described herein can include alpha agonists, antibiotics, antiparasitics, pressure regulators, local transient receptor potential melastatin 8 (TRPM8) agonists, inhibitors of inflammatory cell binding, corticosteroids, anticholinergics (e.g., antimuscarinics and antinicotinic drugs), antiglaucoma agents (e.g., alpha agonists, beta blockers, carbonic anhydrase inhibitors, miotics, prostaglandin agonists, etc.), antihistamines, antivirals, cycloplegics / mydriatics, mast cell stabilizers, miotics (e.g., cholinesterase inhibitors, direct-acting miotics, etc.), ophthalmic nonsteroidal anti-inflammatory drugs (NSAIDs), cyclosporine, riboflavin 5'-phosphate ophthalmic compounds, and vascular endothelial growth factor (VEGF) and VEGF receptor inhibitors.

[0172] Exemplary, non-limiting antibiotics can include moxifloxacin, levofloxacin, ofloxacin, besifloxacin, gatifloxacin, azithromycin, tobramycin, erythromycin, bacitracin, neomycin-polymyxin B-gramicidin, neomycin-polymyxin B-bacitracin, bacitracin-polymyxin B, and sulfacetamide.

[0173] Exemplary, non-limiting antiparasitics may include formamidine parasiticides or isoxazoline parasiticides, such as, but not limited to, flurellan, sarolanab, lotiranab, afoxolanab, and / or fluoxetine.

[0174] An additional exemplary, non-limiting antiparasitic is ivermectin (e.g., ivermectin B1a, ivermectin B1b, or a combination thereof). In some cases, the antiparasitic is ivermectin (e.g., ivermectin B1a, ivermectin B1b, or a combination thereof), or a derivative, analog, and L- and D-isomers (including, but not limited to, enantiomers), a composition comprising a racemic mixture, and an enantiomerically pure composition thereof. In some cases, the antiparasitic comprises a mixture of ivermectin B1 homologues (e.g., a mixture of ivermectin B1a and ivermectin B1b). In some cases, the antiparasitic comprises a mixture of ivermectin B1a and ivermectin B1b. Ivermectin B1a has the structure of compound (I):

[0175]

[0176] Ivermectin B1b has the structure of compound (II):

[0177]

[0178] In some cases, the antiparasitic drug comprises a mixture of ivermectin B1a and ivermectin B1b, wherein the ratio of ivermectin B1a: ivermectin B1b is about 1000:1, about 500:1, about 400:1, about 300:1, about 200:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 10:1, about 5:1, about 4:1, about 2:1 or about 1:1. In some cases, the antiparasitic drug comprises a mixture of ivermectin B1a and ivermectin B1b, wherein the amount of ivermectin B1a in the antiparasitic drug is about 1-, about 1.25-, about 1.5-, about 2-, about 3-, about 4-, about 5-, about 6-, about 7-, about 10-, about 11-, about 12-, about 13-, about 14-, about 15-, about 20-, about 25-, about 30-, about 35-, about 40-, about 45-, about 50-, about 55-, about 60-, about 70-, about 80-, about 90-, about 100-, about 200-, about 300-, about 400-, about 500-, about 750- or about 1000-fold the amount of ivermectin B1b in the antiparasitic drug.

[0179] Exemplary, non-limiting steroids and NSAIDs can include fluorometholone, loteprednol, rimexolone, prednisolone, and difluprednate.

[0180] Exemplary, non-limiting antimicrobial agents can include Natamycin, Ganciclovir, Trifluiridine, and Cysteamine.

[0181] Exemplary, non-limiting pressure-regulating agents can include Brimonidine, Apraclonidine Iopidine, Dorzolamide, Brinzolamide, Azopt, Timolol, Timoptic / Istalol / Betimol, Betaxolol, Betoptic, Levobunolol, Betagan, Metipranolol, Optipranolol, Latanoprost, Xalatan Green, Bimatoprost, Lumigan, Tafluprost, Zioptan, Latanoprostene, Vyzulta Turquoise, Pilocarpine, Carbachol, Isopto Carbachol, Netarsudil, and Rhopressa.

[0182] Exemplary, non-limiting dilators and cycloplegics include atropine, Isopto Atropine, Atropisol, Scopolamine, Isopto Hyoscine Red, Cyclopentolate, Cyclogyl, AK Pentolate, Tropicamide, Mydriacyl, Tropicacyl, and Phenylephrine.

[0183] In some cases, the API can be a muscarinic receptor agonist. Exemplary non-restrictive muscarinic receptor agonists can include acetylcholine, arecoline, oxotremorine, muscarine, carbachol, neliraracetam, bethanechol, pilocarpine and demethylclozapine or a pharmaceutically acceptable salt thereof. Suitable examples of muscarinic receptor antagonists include atropine, hyoscyamine, scopolamine, diphenhydramine, dimenhydrinate, dicyclomine, tolterodine, oxybutynin, ipratropium, pirenzepine, telenzepine, tripitramine, galarium iodide, methotriamine, darifenacin, tiotropium bromide, chlorpromazine and haloperidol, free alkali form or a pharmaceutically acceptable salt thereof.

[0184] In some cases, the API can be a muscarinic receptor antagonist. Exemplary non-limiting muscarinic receptor antagonists can include atropine, hyoscyamine, scopolamine, diphenhydramine, dimenhydrinate, dicyclomine, tolterodine, oxybutynin, ipratropium, pirenzepine, telenzepine, tripitramine, galarium iodide, methotriamine, darifenacin, tiotropium bromide, chlorpromazine and haloperidol, free base form or a pharmaceutically acceptable salt thereof.

[0185] In some cases, the API is not a muscarinic receptor antagonist. In some cases, the API is not atropine or a salt thereof.

[0186] In certain instances, the API is in free base form.

[0187] In certain instances, the API is in the free acid form.

[0188] In some cases, the API may be present in an amount of about 0.001% to about 5% (w / w), about 0.01% to about 5% (w / w), about 0.1% to about 5% (w / w), about 0.2% to about 5% (w / w), about 0.5% to about 5% (w / w), about 1% to about 5% (w / w), about 2% to about 5% (w / w), about 3% to about 5% (w / w), about 4% to about 5% (w / w), about 0.001% to about 2% (w / w), about 0.001% to about 1% (w / w), about 0.001% to about 1% (w / w), about 0.001% to about 5 ...). 0.01% to about 0.9% (w / w), about 0.001% to about 0.8% (w / w), about 0.001% to about 0.7% (w / w), about 0.001% to about 0.6% (w / w), about 0.001% to about 0.5% (w / w), about 0.001% to about 0.4% (w / w), about 0.001% to about 0.3% (w / w), about 0.001% to about 0.2% (w / w), about 0.001% to about 0.1% (w / w), about 0.01% to about 2% (w / w), about 0.01% to about 1% (w / w), about 0.01% to about 0.9% (w / w), about 0.01% to about 0.8% (w / w), about 0.01% to about 0.7% (w / w), about 0.01% to about 0.6% (w / w), about 0.01% to about 0.5% (w / w), about 0.01% to about 0.4% (w / w), about 0.01% to about 0.3% (w / w), about 0.01% to about 0.2% (w / w), about 0.01% to about 0.1% (w / w), about 0.00 1% to about 2% (w / w), about 0.001% to about 1% (w / w), about 0.1% to about 0.9% (w / w), about 0.1% to about 0.8% (w / w), about 0.1% to about 0.7% (w / w), about 0.1% to about 0.6% (w / w), about 0.1% to about 0.5% (w / w), about 0.1% to about 0.4% (w / w), about 0.1% to about 0.3% (w / w) and about 0.1% to about 0.2% (w / w) are present in the composition described herein or nanoemulsion. In some cases, the API can be present in the composition described herein or nanoemulsion in an amount of about 0.02% (w / w). In some cases, the API can be present in the composition described herein or nanoemulsion in an amount of about 0.04% (w / w). In some cases, the API may be present in an amount of about 0.05% (w / w) in a composition or nanoemulsion described herein. In some cases, the API may be present in an amount of about 1% (w / w) in a composition or nanoemulsion described herein.

[0189] In certain instances of the compositions or nanoemulsions described herein, the API in the topical ophthalmic composition is chemically stable for at least 6 months, at least 1 year, at least 18 months, or at least 2 years.

[0190] In some cases, provided herein are compositions comprising a therapeutically effective amount of an antiparasitic compound as an active pharmaceutical ingredient; a semifluorinated alkyl alcohol; and a semifluorinated alkane compound. The composition may be a topical ophthalmic composition in some cases.

[0191] Antiparasitic compounds can assist in eradicating or reducing parasite infestations of the eye, eye tissue, skin, eyelashes or other body hair in some cases. In some cases, this can temporarily or permanently treat or alleviate or relieve symptoms of certain diseases or conditions (such as eye diseases, skin diseases, vector-borne diseases or other diseases caused by parasites). In some cases, antiparasitic compounds can temporarily or permanently treat or alleviate or relieve symptoms of certain eye diseases or conditions (such as blepharitis, meibomian gland dysfunction or rosacea caused by parasites such as Demodex). In some cases, antiparasitic compounds can temporarily or permanently treat or alleviate or relieve symptoms of redness of the eyelid margins caused by Demodex, or improve eyelash health of the subject. In some cases, antiparasitic compounds can temporarily or permanently eradicate lice, scabies or bed bugs and related skin, hair, scalp or hair follicle disorders, reduce their number, treat or alleviate or relieve their symptoms. In some cases, the antiparasitic compound may be an isoxazoline parasiticide or a carboxamidine parasiticide. In some cases, the antiparasitic compound may be an isoxazoline parasiticide selected from flurellana, sarolana, lotirana, afolan and / or fluoxazolamide, including derivatives, analogs and L- and D-isomers (including, but not limited to enantiomers) thereof, compositions comprising racemic mixtures and enantiomerically pure compositions. In some cases, the antiparasitic compound may be ivermectin (e.g., ivermectin B1a, ivermectin B1b or a combination thereof) or derivatives, analogs, isomers (including, but not limited to enantiomers), compositions comprising racemic mixtures and enantiomerically pure compositions. In some cases, the antiparasitic compound comprises a mixture of ivermectin B1 homologues (e.g., a mixture of ivermectin B1a and ivermectin B1b). In certain cases, the antiparasitic compound may be in free base form.

[0192] In some cases, the antiparasitic compound can be present in an amount of about 0.1% to about 5% (w / w), about 0.1% to about 2.5% (w / w), about 0.1% to about 2% (w / w), about 0.1% to about 1.5% (w / w), about 0.1% to about 1% (w / w), about 0.1% to about 0.5% (w / w), about 0.1% to about 0.45% (w / w), about 0.1% to about 0.4% (w / w), about 0.1% to about 0.35% (w / w), about 0.1% to about 0.3% (w / w), about 0.1% to about 0.25% (w / w), about 0.1% to about 0.2% (w / w), or about 0.1% to about 0.45% (w / w). , about 0.15% to about 0.5% (w / w), about 0.15% to about 0.45% (w / w), about 0.15% to about 0.4% (w / w), about 0.15% to about 0.35% (w / w), about 0.15% to about 0.3% (w / w), about 0.15% to about 0.25% (w / w), about 0.15% to about 0.2% (w / w), about 0.1% to about 1.7% (w / w), about 0.1% to about 1.3% (w / w), about 0.1% to about 0.7% (w / w), about 0.1% to about 2% (w / w), about 0.3% to about 2% (w / w), about 0.5% to about 2 % (w / w), about 0.7% to about 2% (w / w), about 1% to about 2% (w / w), about 1.3% to about 2% (w / w), about 1.5% to about 2% (w / w), about 1.7% to about 2% (w / w), about 0.3% to about 1% (w / w), about 0.3% to about 1.3% (w / w), about 0.3% to about 1% (w / w), about 0.5% to about 1% (w / w), about 0.5% to about 0.7% (w / w), about 0.5% to about 1% (w / w), about 0.5 to about 1.5% (w / w), about 0.5% to about 2% (w / w), about 0.5% to about 0.7% (w / w). w), about 0.7% to about 1% (w / w), about 1% to about 1.3% (w / w), about 1.3% to about 1.5% (w / w), about 1.5% to about 2% (w / w), about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.3% (w / w), about 1.5% (w / w), about 1.7% (w / w) or about 2% (w / w).

[0193] In some cases, the antiparasitic compound may be lotirana or TP-03. In some cases, the lotirana or TP-03 may be in a form including derivatives, analogs, and L- and D-isomers thereof (including, but not limited to, enantiomers), compositions comprising racemic mixtures, and enantiomerically pure compositions. In some cases, the lotirana or TP-03 may be in free base form.In some cases, the lotirana or TP-03 may be present in an amount of about 0.1% to about 5% (w / w), about 0.1% to about 2.5% (w / w), about 0.1% to about 2% (w / w), about 0.1% to about 1.5% (w / w), about 0.1% to about 1% (w / w), about 0.1% to about 0.5% (w / w), about 0.1% to about 0.45% (w / w), about 0.1% to about 0.4% (w / w), about 0.1% to about 0.35% (w / w), about 0.1% to about 0.3% (w / w), about 0.1% to about 0.25% (w / w), about 0.1% to about 0.2% (w / w). %, about 0.1% to about 1.7% (w / w), about 0.1% to about 1.3% (w / w), about 0.1% to about 0.7% (w / w), about 0.1% to about 2% (w / w), about 0.3% to about 2% (w / w), about 0.5% to about 1.5% (w / w), about 0.6% to about 1.6% (w / w), about 0.7% to about 1.9% (w / w), about 0.8% to about 1.1% (w / w), about 0.9% to about 2.0% (w / w), about 0.1% to about 0.2% (w / w), about 0.1% to about 1.7% (w / w), about 0.1% to about 1.3% (w / w), about 0.1% to about 0.7% (w / w), about 0.1% to about 2% (w / w), about 0.3% to about 2% (w / w), about 0.5% to about 1.5% (w / w), about 0.6% to about 1.6% (w / w), about 0.7% to about 1.5% (w / w), about 0.8% to about 1.9% (w / w), about 0.9% to about 2.0% (w / w), about 0.1 about 2% (w / w), about 0.7% to about 2% (w / w), about 1% to about 2% (w / w), about 1.3% to about 2% (w / w), about 1.5% to about 2% (w / w), about 1.7% to about 2% (w / w), about 0.3% to about 1% (w / w), about 0.3% to about 1.3% (w / w), about 0.3% to about 1% (w / w), about 0.5% to about 1% (w / w), about 0.5% to about 0.7% (w / w), about 0.5% to about 1% (w / w), about 0.5 to about 2% (w / w), about 0.5% to about 0.7% (w / w), about 0.5% to about 1.5% (w / w), about 0.5% to about 2% (w / w), about 0.5% to about 0.7% (w / w). % (w / w), about 0.7% to about 1% (w / w), about 1% to about 1.3% (w / w), about 1.3% to about 1.5% (w / w), about 1.5% to about 2% (w / w), about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.3% (w / w), about 1.5% (w / w), about 1.7% (w / w) or about 2% (w / w). In some cases, the lotiranab or its derivative, analog, racemic mixture or diastereomer or enantiomer may be present in the composition in an amount of about 0.25% (w / w).

[0194] In some cases, the antiparasitic compound may be ivermectin (e.g., ivermectin B1a, ivermectin B1b, or a combination thereof). In some cases, the ivermectin may be in a form including derivatives, analogs, and L- and D-isomers thereof (including, but not limited to, enantiomers), compositions comprising racemic mixtures, and enantiomerically pure compositions. In some cases, the ivermectin may be a mixture of ivermectin B1a and ivermectin B1b.In some cases, the ivermectin (e.g., a mixture of ivermectin B1a and ivermectin B1b) can be present in an amount of about 0.1% to about 5% (w / w), about 0.1% to about 2.5% (w / w), about 0.1% to about 2% (w / w), about 0.1% to about 1.5% (w / w), about 0.1% to about 1% (w / w), about 0.1% to about 0.5% (w / w), about 0.1% to about 0.45% (w / w), about 0.1% to about 0.4% (w / w), about 0.1% to about 0.35% (w / w), about 0.1% to about 0.3% (w / w), about 0.1% to about 0.25% (w / w), about 0.1% to about 0.5% (w / w), about 0.1% to about 0.65% (w / w), about 0.1% to about 0.75% (w / w), about 0.1% to about 0.85% (w / w), about 0.1% to about 0.95% (w / w), about 0.2% to about 0.86% (w / w), about 0.1% to about 0.97% (w / w), about 0.2% to about 0.88% (w / w), about 0.1% to about 0.99% (w / w), about 0.2% to about 0.89% (w / w), about 0.1% to about 0.91% (w / w), about 0.1% to about 0. about 0.1% to about 0.2% (w / w), about 0.15% to about 0.5% (w / w), about 0.15% to about 0.45% (w / w), about 0.15% to about 0.4% (w / w), about 0.15% to about 0.35% (w / w), about 0.15% to about 0.3% (w / w), about 0.15% to about 0.25% (w / w), about 0.15% to about 0.2% (w / w), about 0.1% to about 1.7% (w / w), about 0.1% to about 1.3% (w / w), about 0.1% to about 0.7% (w / w), about 0.1% to about 2% (w / w), about 0.3% to about 2% (w / w). w), about 0.5% to about 2% (w / w), about 0.7% to about 2% (w / w), about 1% to about 2% (w / w), about 1.3% to about 2% (w / w), about 1.5% to about 2% (w / w), about 1.7% to about 2% (w / w), about 0.3% to about 1% (w / w), about 0.3% to about 1.3% (w / w), about 0.3% to about 1% (w / w), about 0.5% to about 1% (w / w), about 0.5% to about 0.7% (w / w), about 0.5% to about 1% (w / w), about 0.5 to about 2% (w / w), about 0.5 to about 0.7% (w / w), about 0.5% to about 1.5% (w / w), about 0.5% to about 2% (w / w), about 0.5% to about 0.0 The invention relates to an amount of at least about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.3% (w / w), about 1.5% (w / w), about 1.7% (w / w) or about 2% (w / w).In some cases, the antiparasitic compound can be ivermectin (e.g., ivermectin B1a, ivermectin B1b, or a combination thereof), or a derivative, analog, and L- and D-isomers (including, but not limited to, enantiomers), a composition comprising a racemic mixture, and an enantiomerically pure composition. In some cases, the antiparasitic compound comprises a mixture of ivermectin B1 homologues (e.g., a mixture of ivermectin B1a and ivermectin B1b). In some cases, the antiparasitic compound comprises a mixture of ivermectin B1a and ivermectin B1b. In some cases, the antiparasitic drug comprises a mixture of ivermectin B1a and ivermectin B1b, wherein the ratio of ivermectin B1a: ivermectin B1b is about 1000:1, about 500:1, about 400:1, about 300:1, about 200:1, about 100:1, about 90:1, about 80:1, about 70:1, about 60:1, about 50:1, about 40:1, about 30:1, about 20:1, about 10:1, about 5:1, about 4:1, about 2:1 or about 1:1. In some cases, the antiparasitic drug comprises a mixture of ivermectin B1a and ivermectin B1b, wherein the amount of ivermectin B1a in the antiparasitic drug is about 1-, about 1.25-, about 1.5-, about 2-, about 3-, about 4-, about 5-, about 6-, about 7-, about 10-, about 11-, about 12-, about 13-, about 14-, about 15-, about 20-, about 25-, about 30-, about 35-, about 40-, about 45-, about 50-, about 55-, about 60-, about 70-, about 80-, about 90-, about 100-, about 200-, about 300-, about 400-, about 500-, about 750- or about 1000-fold the amount of ivermectin B1b in the antiparasitic drug. In some cases, the ivermectin or its derivative, analog, racemic mixture or diastereomer or enantiomer is present in the composition in an amount of 0.1 mg / ml to 50 mg / ml, optionally 0.1 mg / ml to 40 mg / ml, 0.1 mg / ml to 30 mg / ml, 0.1 mg / ml to 20 mg / ml, 0.1 mg / ml to 10 mg / ml, 1 mg / ml to 50 mg / ml, 10 mg / ml to 50 mg / ml, 20 mg / ml to 50 mg / ml, 30 mg / ml to 50 mg / ml, about 1 mg / ml, about 5 mg / ml, about 10 mg / ml, about 15 mg / ml, about 20 mg / ml, about 25 mg / ml, about 30 mg / ml, about 35 mg / ml, about 40 mg / ml, about 45 mg / ml or about 50 mg / ml.In some cases, the ivermectin or its derivative, analog, racemic mixture or diastereomer or enantiomer is present in the composition in an amount of 0.01% to 5%, optionally 0.01% to 4%, 0.01% to 3%, 0.01% to 2%, 0.01% to 1%, 0.1% to 5%, 1% to 5%, 2% to 5%, 3% to 5%, about 0.1%, about 0.5%, about 0.1%, about 1.5%, about 2%, about 2.5%, about 3%, about 3.5%, about 4%, about 4.5% or about 5%.

[0195] In some cases, provided herein is a composition comprising a therapeutically effective amount of lifilast or its derivatives, analogs, pharmaceutically acceptable salts, free base forms, racemic mixtures or diastereomers or enantiomers as active pharmaceutical ingredients; semifluorinated alkyl alcohols; and semifluorinated alkane compounds. The composition may be a topical ophthalmic composition in some cases.

[0196] Lifelast is an N-acyl-L-α-amino acid obtained by condensing the carboxyl group of N-[2-(1-benzofuran-6-carbonyl)]-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carboxylic acid with the amino group of 3-(methylsulfonyl)-L-phenylalanine. Lifelast can inhibit the binding of inflammatory cells by inhibiting the binding of integrin, lymphocyte function-associated antigen 1 (LFA-1) and intercellular adhesion molecule 1 (ICAM-1), thereby reducing inflammation.

[0197] In some cases, lifirastat, or its derivatives, analogs, pharmaceutically acceptable salts, free base forms, racemic mixtures or diastereomers or enantiomers can be used as adjuncts to treat dry eye syndrome or keratoconjunctivitis sicca. In some cases, lifirastat or its derivatives, analogs, pharmaceutically acceptable salts, free base forms, racemic mixtures or diastereomers or enantiomers can treat certain eye diseases or conditions (such as dry eye syndrome or keratoconjunctivitis sicca, dry eye, inflammatory dry eye, redness or meibomian gland dysfunction), slow down its progression, or alleviate or relieve its symptoms.

[0198] In some cases, the lifirastat or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer can be present in an amount of about 0.1% to about 10% (w / w), about 0.1% to about 9% (w / w), about 0.1% to about 8% (w / w), about 0.1% to about 7% (w / w), about 0.1% to about 6% (w / w), about 0.1% to about 5% (w / w), about 0.2% to about 10% (w / w), about 0.3% to about 10% (w / w), about 0.4% to about 10% (w / w), about 0.5% to about 10% (w / w), about 0.6% to about 10% (w / w), about 0.7% to about 10% (w / w), about 0. 8% to about 10% (w / w), about 0.9% to about 10% (w / w), about 1% to about 10% (w / w), about 1.5% to about 10% (w / w), about 2% to about 10% (w / w), about 2.5% to about 10% (w / w), about 3% to about 10% (w / w), about 3.5% to about 10% (w / w), about 4% to about 10% (w / w), about 4.5% to about 10% (w / w), about 5% to about 10% (w / w), about 5.5% to about 10% (w / w), about 6% to about 10% (w / w), about 6.5% to about 10% (w / w), about 7% to about 10% (w / w), about 7.5% to about 10% (w / w), about 8% to about 10% (w / w), about 10% to about 10% (w / w), about 15% to about 10% (w / w), about 16% to about 10% (w / w), about 17% to about 10% (w / w), about 18% to about 10% (w / w), about 19% to about 10% (w / w), about 20% to about 10% (w / w), about 21% to about 10% (w / w), about 24% to about 10% (w / w), about 25% to about 10% (w / w), about 26% to about 10% (w / w), about 27% to about 10% (w / w), about 28% to about 10% (w / w), about 29% to about 10% (w / w), about 30% to about 10% (w / w), about w), about 8.5% to about 10% (w / w), about 9% to about 10% (w / w), about 9.5% to about 10% (w / w), about 1% to about 5% (w / w), about 2% to about 8% (w / w), about 3% to about 9% (w / w), about 4% to about 9% (w / w), about 0.1% to about 2.5% (w / w), about 0.1% to about 2% (w / w), about 0.1% to about 1.5% (w / w), about 0.1% to about 1% (w / w), about 0.1% to about 0.5% (w / w), about 0.1% to about 0.45% (w / w), about 0.1% to about 0.4% (w / w), about 0.1% to about 0.35% (w / w), about 0.1% to about 0.3% (w / w), ), about 0.1% to about 0.25% (w / w), about 0.1% to about 0.2% (w / w), about 0.15% to about 0.5% (w / w), about 0.15% to about 0.45% (w / w), about 0.15% to about 0.4% (w / w), about 0.15% to about 0.35% (w / w), about 0.15% to about 0.3% (w / w), about 0.15% to about 0.25% (w / w), about 0.15% to about 0.2% (w / w), about 0.1% to about 1.7% (w / w), about 0.1% to about 1.3% (w / w), about 0.1% to about 0.7% (w / w), about 0.1% to about 2% (w / w), about 0.3% to about 2% (w / w), about 0.5% to about 2% (w / w), about 0.7% to about 2% (w / w), about 1% to about 2% (w / w), about 1.3% to about 2% (w / w), about 1.5% to about 2% (w / w), about 1.7% to about 2% (w / w), about 0.3% to about 1% (w / w), about 0.3% to about 1.3% (w / w), about 0.3% to about 1% (w / w), about 0.5% to about 1% (w / w), about 0.5% to about 0.7% (w / w), about 0.5% to about 1% (w / w), about 0.5 to about 1.5% (w / w), about 0.5% to about 2% (w / w), about 0.5% to about 0.7% (w / w), about 0.7% to about 1% (w / w), about 1% to about 1.3% (w / w), The invention relates to an amount of about 1.3% to about 1.5% (w / w), about 1.5% to about 2% (w / w), about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.3% (w / w), about 1.5% (w / w), about 1.7% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w), about 3.5% (w / w), about 4% (w / w), about 4.5% (w / w), about 5% (w / w) or about 5.5% (w / w). In some cases, the lifirastat or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer may be present in an amount of about 0.1% to about 10% (w / w).

[0199] In some cases, provided herein are compositions comprising a therapeutically effective amount of AR-15512 ((1R, 2S, 5R) -N- (4-methoxyphenyl) -5-methyl-2- (1-methylethyl) cyclohexanecarboxamide) or a derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer as an active pharmaceutical ingredient; semifluorinated alkyl alcohol; and semifluorinated alkane compound. The composition may be a topical ophthalmic composition in some cases.

[0200] AR-15512 can act as a potent and selective agonist of the TRPM8 (transient receptor potential melastatin 8) cold temperature receptor. TRPM8 is a calcium-permeable ion channel that acts as a cold detector in humans and is involved in the regulation of blink rate and tear production. Stimulation of this receptor can lead to restoration of tear film volume and reduction of ocular discomfort in patients with dry eye symptoms or dry eye syndrome.

[0201] In some cases, AR-15512, or its derivatives, analogs, pharmaceutically acceptable salts, free base forms, racemic mixtures, or diastereomers or enantiomers can be used as adjuncts to treat dry eye syndrome or keratoconjunctivitis sicca. In some cases, AR-15512 or its derivatives, analogs, pharmaceutically acceptable salts, free base forms, racemic mixtures, or diastereomers or enantiomers can treat certain ocular diseases or conditions (such as dry eye syndrome or keratoconjunctivitis sicca, dry eye, inflammatory dry eye, redness, or meibomian gland dysfunction), slow down its progression, or alleviate or relieve its symptoms.

[0202] In some cases, the AR-15512 or its derivative, analog, racemic mixture or diastereomer or enantiomer can be present in an amount of about 0.0001% to about 5% (w / w), about 0.0001% to about 0.1% (w / w), about 0.1% to about 2.5% (w / w), about 0.1% to about 2% (w / w), about 0.1% to about 1.5% (w / w), about 0.1% to about 1% (w / w), about 0.001% to about 0.01% (w / w), about 0.001% to about 0.009% (w / w), about 0.001% to about 0.008% (w / w), about 0.001% to about 0.007% (w / w), about 0.001% to about 0.006% (w / w). (w / w), about 0.001% to about 0.005% (w / w), about 0.001% to about 0.004% (w / w), about 0.001% to about 0.003% (w / w), about 0.001% to about 0.002% (w / w), about 0.0001% to about 0.001% (w / w), about 0.0001% to about 0.0009% (w / w), about 0.0001% to about 0.0008% (w / w), about 0.0001% to about 0.0007% (w / w), about 0.0001% to about 0.0006% (w / w), about 0.0001% to about 0.0005% (w / w), about 0.0001% to about 0.0004% (w / w) , about 0.0001% to about 0.0003% (w / w), about 0.0001% to about 0.0002% (w / w), about 0.15% to about 0.5% (w / w), about 0.15% to about 0.45% (w / w), about 0.15% to about 0.4% (w / w), about 0.15% to about 0.35% (w / w), about 0.15% to about 0.3% (w / w), about 0.15% to about 0.25% (w / w), about 0.15% to about 0.2% (w / w), about 0.1% to about 1.7% (w / w), about 0.1% to about 1.3% (w / w), about 0.1% to about 0.5% (w / w), about 0.1% to about 0.45% (w / w), about 0.1 % to about 0.4% (w / w), about 0.1% to about 0.35% (w / w), about 0.1% to about 0.3% (w / w), about 0.1% to about 0.25% (w / w), about 0.1% to about 0.2% (w / w), about 0.15% to about 0.5% (w / w), about 0.15% to about 0.45% (w / w), about 0.15% to about 0.4% (w / w), about 0.15% to about 0.35% (w / w), about 0.15% to about 0.3% (w / w), about 0.15% to about 0.25% (w / w), about 0.15% to about 0.2% (w / w), about 0.1% to about 1.7% (w / w), about 0.1% to about 1.3% (w / w), about 0.1% to about 0.7% (w / w), about 0.1% to about 2% (w / w), about 0.3% to about 2% (w / w), about 0.5% to about 2% (w / w), about 0.7% to about 2% (w / w), about 1% to about 2% (w / w), about 1.3% to about 2% (w / w), about 1.5% to about 2% (w / w), about 1.7% to about 2% (w / w), about 0.3% to about 1% (w / w), about 0.3% to about 1.3% (w / w), about 0.3% to about 1% (w / w), about 0.5% to about 1% (w / w), about 0.5% to about 0.7% (w / w), about 0.5% to about 1% (w / w), about 0.5 to about 1.5% (w / w), about 0.5% to about 2% (w / w), about 0.5% to about 0.7% (w / w), about 0.7% to about 1% (w / w), about 1% to about 1.3% (w / w), about 1.3% to about 1.5% (w / w), about 1.5% to about 2% (w / w), about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.3% (w / w), about 1.5% (w / w), about 1.7% (w / w), about 2% (w / w), about 2.5% (w / w). w), about 3% (w / w), about 3.5% (w / w), about 4% (w / w), about 4.5% (w / w), about 5% (w / w), about 5.5% (w / w), about 0.001% (w / w), about 0.002% (w / w), about 0.003% (w / w), about 0.004% (w / w), about 0.005% (w / w), about 0.0011% (w / w), about 0.0012% (w / w), about 0.0013% (w / w), about 0.0014% (w / w), about 0.0015% (w / w), about 0.0016% (w / w), about 0.0017% (w / w), about 0.0018% (w / w), about 0.0019% (w / w), about 0.011% (w / w), about 0.012% (w / w), about 0.013% (w / w), about 0.014% (w / w), about 0.015% (w / w), about 0.016% (w / w), about 0.017% (w / w), about 0.018% (w / w), about 0.019 %(w / w), about 0.002%(w / w), about 0.0021%(w / w), about 0.0022%(w / w), about 0.0023%(w / w), about 0.0024%(w / w), about 0.0025%(w / w), about 0.0026%(w / w), about 0.0027%(w / w), about 0.0028%(w / w), about 0.0029%(w / w), about 0.0030%(w / w), about 0.0031%(w / w), about 0.0032%(w / w), about 0.0033%(w / w), about 0.0034%(w / w), about 0.0035%(w / w), about 0.0036%(w / w), about 0.0.0037% (w / w), about 0.0038% (w / w), about 0.0039% (w / w), about 0.0001% (w / w), about 0.0002% (w / w), about 0.0003% (w / w), about 0.0004% (w / w), about 0.0005% (w / w), about 0.0006% (w / w), about 0.0007% (w / w), about 0.0008% (w / w), or about 0.0009% (w / w).

[0203] In some cases, provided herein is a composition comprising a therapeutically effective amount of lotirana or its derivatives, analogs, racemic mixtures or diastereomers or enantiomers as active pharmaceutical ingredients; a semifluorinated alkyl alcohol; and a semifluorinated alkane compound. The composition may be a topical ophthalmic composition in some cases.

[0204] In some cases, the lotirana or its derivative, analog, racemic mixture or diastereomer or enantiomer can be present in an amount of about 0.0001% to about 5% (w / w), about 0.1% to about 2.5% (w / w), about 0.1% to about 2% (w / w), about 0.1% to about 1.5% (w / w), about 0.1% to about 1% (w / w), about 0.001% to about 0.01% (w / w), about 0.001% to about 0.009% (w / w), about 0.001% to about 0.008% (w / w), about 0.001% to about 0.007% (w / w), about 0.001% to about 0.006% (w / w), about 0.001% to about 0.005% (w / w). w / w), about 0.001% to about 0.004% (w / w), about 0.001% to about 0.003% (w / w), about 0.001% to about 0.002% (w / w), about 0.0001% to about 0.001% (w / w), about 0.0001% to about 0.0009% (w / w), about 0.0001% to about 0.0008% (w / w), about 0.0001% to about 0.0007% (w / w), about 0.0001% to about 0.0006% (w / w), about 0.0001% to about 0.0005% (w / w), about 0.0001% to about 0.0004% (w / w), about 0.0001% to about 0.0003% (w / w), %, about 0.1% to about 0.5% (w / w), about 0.15% to about 0.45% (w / w), about 0.15% to about 0.4% (w / w), about 0.15% to about 0.35% (w / w), about 0.15% to about 0.3% (w / w), about 0.15% to about 0.25% (w / w), about 0.15% to about 0.2% (w / w), about 0.1% to about 1.7% (w / w), about 0.1% to about 1.3% (w / w), about 0.1% to about 0.5% (w / w), about 0.1% to about 0.45% (w / w), about 0.1% to about 0.4% (w / w), about 0.1% to about 0. to about 0.35% (w / w), about 0.1% to about 0.3% (w / w), about 0.1% to about 0.25% (w / w), about 0.1% to about 0.2% (w / w), about 0.15% to about 0.5% (w / w), about 0.15% to about 0.45% (w / w), about 0.15% to about 0.4% (w / w), about 0.15% to about 0.35% (w / w), about 0.15% to about 0.3% (w / w), about 0.15% to about 0.25% (w / w), about 0.15% to about 0.2% (w / w), about 0.1% to about 1.7% (w / w), about 0.1% to about 1.3% (w / w), about 0.1% to about 0.7% (w / w), about 0.1% to about 2% (w / w), about 0.3% to about 2% (w / w), about 0.5% to about 2% (w / w), about 0.7% to about 2% (w / w), about 1% to about 2% (w / w), about 1.3% to about 2% (w / w), about 1.5% to about 2% (w / w), about 1.7% to about 2% (w / w), about 0.3% to about 1% (w / w), about 0.3% to about 1.3% (w / w), about 0.3% to about 1% (w / w), about 0.5% to about 1% (w / w), about 0.5% to about 0.7% (w / w), about 0.5% to about 1% (w / w), about 0.5 to about 1.5% (w / w), about 0.5% to about 2% (w / w), about 0.5% to about 0. 7% (w / w), about 0.7% to about 1% (w / w), about 1% to about 1.3% (w / w), about 1.3% to about 1.5% (w / w), about 1.5% to about 2% (w / w), about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.3% (w / w), about 1.5% (w / w), about 1.7% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w), about 3.5% (w / w) , about 4% (w / w), about 4.5% (w / w), about 5% (w / w), about 5.5% (w / w), about 0.001% (w / w), about 0.002% (w / w), about 0.003% (w / w), about 0.004% (w / w), about 0.005% (w / w), about 0.0011% (w / w), about 0.0012% (w / w), about 0.0013% (w / w), about 0.0014% (w / w), about 0.0015% (w / w), about 0.0016% (w / w), about 0.0017% (w / w), about 0.0018% (w / w), about 0.0019% (w / w), about 0.002% (w / w), about 0.00 21% (w / w), about 0.0022% (w / w), about 0.0023% (w / w), about 0.0024% (w / w), about 0.0025% (w / w), about 0.0026% (w / w), about 0.0027% (w / w), about 0.0028% (w / w), about 0.0029% (w / w), about 0.0030% (w / w), about 0.0031% (w / w), about 0.0032% (w / w), about 0.0033% (w / w), about 0.0034% (w / w), about 0.0035% (w / w), about 0.0036% (w / w), about 0.0037% (w / w), about 0.0038% (w / w), about 0.0.0039% (w / w), about 0.0001% (w / w), about 0.0002% (w / w), about 0.0003% (w / w), about 0.0004% (w / w), about 0.0005% (w / w), about 0.0006% (w / w), about 0.0007% (w / w), about 0.0008% (w / w) or about 0.0009% (w / w). In some cases, the lotirana or its derivative, analog, racemic mixture or diastereomer or enantiomer may be present in the composition in an amount of about 0.25% (w / w). .

[0205] In some cases, provided herein are compositions comprising a therapeutically effective amount of cyclosporin or its derivatives, analogs, pharmaceutically acceptable salts, free base forms, racemic mixtures, or diastereomers or enantiomers as active pharmaceutical ingredients; semifluorinated alkyl alcohols; and semifluorinated alkane compounds. The compositions may be topical ophthalmic compositions in some cases.

[0206] In some cases, cyclosporine or its derivatives, analogs, pharmaceutically acceptable salts, free base forms, racemic mixtures or diastereomers or enantiomers can assist in the treatment of dry eye syndrome or keratoconjunctivitis sicca. In some cases, cyclosporine or its derivatives, analogs, pharmaceutically acceptable salts, free base forms, racemic mixtures or diastereomers or enantiomers can treat certain eye diseases or conditions (such as dry eye syndrome or keratoconjunctivitis sicca, dry eye, inflammatory dry eye, redness or meibomian gland dysfunction), slow its progression, or alleviate or relieve its symptoms.

[0207] In some cases, the cyclosporine or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer can be present in an amount of about 0.0001% to about 5% (w / w), about 0.1% to about 2.5% (w / w), about 0.1% to about 2% (w / w), about 0.1% to about 1.5% (w / w), about 0.1% to about 1% (w / w), about 0.001% to about 0.01% (w / w), about 0.001% to about 0.009% (w / w), about 0.001% to about 0.008% (w / w), about 0.001% to about 0.007% (w / w), about 0.001% to about 0.006% (w / w), about 0.001% to about 0.008% (w / w), about 0.001% to about 0.009% (w / w), about 0.001% to about 0.010% (w / w), about 0.001% to about 0.011% (w / w), about 0.001% to about 0.008% (w / w), about 0.001% to about 0.009% (w / w), about 0.001% to about 0.011% (w / w), about 0.001% to about 0.012% (w / w), about 0.001% to about 0.013% (w / w), about 0.001% to about 0.014% (w / w), about 0.001% to about 0.015% (w / w), about 0.001% to about 0.016% (w / w), about 0.001 0.001% to about 0.005% (w / w), about 0.001% to about 0.004% (w / w), about 0.001% to about 0.003% (w / w), about 0.001% to about 0.002% (w / w), about 0.0001% to about 0.001% (w / w), about 0.0001% to about 0.0009% (w / w), about 0.0001% to about 0.0008% (w / w), about 0.0001% to about 0.0007% (w / w), about 0.0001% to about 0.0006% (w / w), about 0.0001% to about 0.0005% (w / w), about 0.0001% to about 0.0004 ...7% (w / w), about 0.0001% to about 0.0006% (w / w), about 0.0001% to about 0.0005% (w / w), about 0.0001% to about 0.0004% (w / w), about 0.0001% to about 0.0006% (w / w), about 0.0001% to about 0.0006% (w / w), about 0.0001% to about 0.000 1% to about 0.0003% (w / w), about 0.0001% to about 0.0002% (w / w), about 0.15% to about 0.5% (w / w), about 0.15% to about 0.45% (w / w), about 0.15% to about 0.4% (w / w), about 0.15% to about 0.35% (w / w), about 0.15% to about 0.3% (w / w), about 0.15% to about 0.25% (w / w), about 0.15% to about 0.2% (w / w), about 0.1% to about 1.7% (w / w), about 0.1% to about 1.3% (w / w), about 0.1% to about 0.5% (w / w), about 0.1% to about 0.45% (w / w), about 0.1% to about 0.4 % (w / w), about 0.1% to about 0.35% (w / w), about 0.1% to about 0.3% (w / w), about 0.1% to about 0.25% (w / w), about 0.1% to about 0.2% (w / w), about 0.15% to about 0.5% (w / w), about 0.15% to about 0.45% (w / w), about 0.15% to about 0.4% (w / w), about 0.15% to about 0.35% (w / w), about 0.15% to about 0.3% (w / w), about 0.15% to about 0.25% (w / w), about 0.15% to about 0.2% (w / w), about 0.1% to about 1.7% (w / w), about 0.1% to about 1.3% (w / w), about 0.1% to about 0.7% (w / w), about 0.1% to about 2% (w / w), about 0.3% to about 2% (w / w), about 0.5% to about 2% (w / w), about 0.7% to about 2% (w / w), about 1% to about 2% (w / w), about 1.3% to about 2% (w / w), about 1.5% to about 2% (w / w), about 1.7% to about 2% (w / w), about 0.3% to about 1% (w / w), about 0.3% to about 1.3% (w / w), about 0.3% to about 1% (w / w), about 0.5% to about 1% (w / w), about 0.5% to about 0.7% (w / w), about 0.5% to about 1% (w / w), about 0.5 to about 1.5% (w / w), about 0.5% to about 2% (w / w) ), about 0.5% to about 0.7% (w / w), about 0.7% to about 1% (w / w), about 1% to about 1.3% (w / w), about 1.3% to about 1.5% (w / w), about 1.5% to about 2% (w / w), about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.3% (w / w), about 1.5% (w / w), about 1.7% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w). ), about 3.5% (w / w), about 4% (w / w), about 4.5% (w / w), about 5% (w / w), about 5.5% (w / w), about 0.001% (w / w), about 0.002% (w / w), about 0.003% (w / w), about 0.004% (w / w), about 0.005% (w / w), about 0.0011% (w / w), about 0.0012% (w / w), about 0.0013% (w / w), about 0.0014% (w / w), about 0.0015% (w / w), about 0.0016% (w / w), about 0.0017% (w / w), about 0.0018% (w / w), about 0.0019% (w / w), about 0.00 2% (w / w), about 0.0021% (w / w), about 0.0022% (w / w), about 0.0023% (w / w), about 0.0024% (w / w), about 0.0025% (w / w), about 0.0026% (w / w), about 0.0027% (w / w), about 0.0028% (w / w), about 0.0029% (w / w), about 0.0030% (w / w), about 0.0031% (w / w), about 0.0032% (w / w), about 0.0033% (w / w), about 0.0034% (w / w), about 0.0035% (w / w), about 0.0036% (w / w), about 0.0037% (w / w), about 0.0.0038% (w / w), about 0.0039% (w / w), about 0.0001% (w / w), about 0.0002% (w / w), about 0.0003% (w / w), about 0.0004% (w / w), about 0.0005% (w / w), about 0.0006% (w / w), about 0.0007% (w / w), about 0.0008% (w / w) or about 0.0009% (w / w). In some cases, the cyclosporin or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer may be present in the composition in an amount of about 0.05% (w / w). .

[0208] In some cases, provided herein are compositions comprising a therapeutically effective amount of a pressure regulator as an active pharmaceutical ingredient, such as brimonidine, Apraclonidine Iopidine, Dorzolamide, Brinzolamide, Azopt, Timolol, Timoptic / Istalol / Betimol, Betaxolol, Betoptic, Levobunolol, Betagan, Metipranolol, Optipranolol, Latanoprost, Xalatan Green, Bimatoprost, Lumigan, Tafluprost, Zioptan, Latanoprostene, Vyzulta Turquoise, Pilocarpine, Carbachol, Isopto Carbachol, Netarsudil and Rhopressa, or a derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer thereof; semifluorinated alkyl alcohol; and semifluorinated alkane compounds. The composition may be a topical ophthalmic composition in some cases.

[0209] In some cases, pressure regulators can assist in the treatment of glaucoma. In some cases, pressure regulators can treat certain eye diseases or conditions (such as glaucoma, ocular hypertension, or high fluid pressure in the subject's eye), slow their progression, or alleviate or relieve their symptoms. In some cases, pressure regulators can reduce fluid pressure in the subject's eye.

[0210] In some cases, the pressure regulating agent such as brimonidine or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer can be present in an amount of about 0.0001% to about 5% (w / w), about 0.1% to about 2.5% (w / w), about 0.1% to about 2% (w / w), about 0.1% to about 1.5% (w / w), about 0.002% to about 0.3% (w / w), about 0.0025% to about 0.25% (w / w), about 0.1% to about 1% (w / w), about 0.001% to about 0.01% (w / w), about 0.001% to about 0.009% (w / w), about 0.001% to about 0.008% (w / w). , about 0.001% to about 0.007% (w / w), about 0.001% to about 0.006% (w / w), about 0.001% to about 0.005% (w / w), about 0.001% to about 0.004% (w / w), about 0.001% to about 0.003% (w / w), about 0.001% to about 0.002% (w / w), about 0.0001% to about 0.001% (w / w), about 0.0001% to about 0.0009% (w / w), about 0.0001% to about 0.0008% (w / w), about 0.0001% to about 0.0007% (w / w), about 0.0001% to about 0.0006% (w / w), about 0.0001% to about 0.0008% (w / w), about 0.0001% to about 0.0007% (w / w), about 0.0001% to about 0.0006% (w / w), about 0.0001% to about about 0.0005% (w / w), about 0.0001% to about 0.0004% (w / w), about 0.0001% to about 0.0003% (w / w), about 0.0001% to about 0.0002% (w / w), about 0.15% to about 0.5% (w / w), about 0.15% to about 0.45% (w / w), about 0.15% to about 0.4% (w / w), about 0.15% to about 0.35% (w / w), about 0.15% to about 0.3% (w / w), about 0.15% to about 0.25% (w / w), about 0.15% to about 0.2% (w / w), about 0.1% to about 1.7% (w / w), about 0.1% to about 1.3% (w / w), about 0.1 % to about 0.5% (w / w), about 0.1% to about 0.45% (w / w), about 0.1% to about 0.4% (w / w), about 0.1% to about 0.35% (w / w), about 0.1% to about 0.3% (w / w), about 0.1% to about 0.25% (w / w), about 0.1% to about 0.2% (w / w), about 0.15% to about 0.5% (w / w), about 0.15% to about 0.45% (w / w), about 0.15% to about 0.4% (w / w), about 0.15% to about 0.35% (w / w), about 0.15% to about 0.3% (w / w), about 0.15% to about 0.25% (w / w), about 0.15% to about 0.2% (w / w), about 0.1% to about 1.7% (w / w), about 0.1% to about 1.3% (w / w), about 0.1% to about 0.7% (w / w), about 0.1% to about 2% (w / w), about 0.3% to about 2% (w / w), about 0.5% to about 2% (w / w), about 0.7% to about 2% (w / w), about 1% to about 2% (w / w), about 1.3% to about 2% (w / w), about 1.5% to about 2% (w / w), about 1.7% to about 2% (w / w), about 0.3% to about 1% (w / w), about 0.3% to about 1.3% (w / w), about 0.3% to about 1% (w / w), about 0.5% to about 1% (w / w), about 0.5% to about 0.7% (w / w), about 0. 5% to about 1% (w / w), about 0.5 to about 1.5% (w / w), about 0.5% to about 2% (w / w), about 0.5% to about 0.7% (w / w), about 0.7% to about 1% (w / w), about 1% to about 1.3% (w / w), about 1.3% to about 1.5% (w / w), about 1.5% to about 2% (w / w), about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.3% (w / w), about 1.5% (w / w), about w), about 1.7% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w), about 3.5% (w / w), about 4% (w / w), about 4.5% (w / w), about 5% (w / w), about 5.5% (w / w), about 0.001% (w / w), about 0.002% (w / w), about 0.003% (w / w), about 0.004% (w / w), about 0.005% (w / w), about 0.0011% (w / w), about 0.0012% (w / w), about 0.0013% (w / w), about 0.0014% (w / w), about 0.0015% (w / w), about 0.0016% (w / w), about 0.00 17% (w / w), about 0.0018% (w / w), about 0.0019% (w / w), about 0.002% (w / w), about 0.0021% (w / w), about 0.0022% (w / w), about 0.0023% (w / w), about 0.0024% (w / w), about 0.0025% (w / w), about 0.0026% (w / w), about 0.0027% (w / w), about 0.0028% (w / w), about 0.0029% (w / w), about 0.0030% (w / w), about 0.0031% (w / w), about 0.0032% (w / w), about 0.0033% (w / w), about 0.0034% (w / w), about 0.0.0035% (w / w), about 0.0036% (w / w), about 0.0037% (w / w), about 0.0038% (w / w), about 0.0039% (w / w), about 0.0001% (w / w), about 0.0002% (w / w), about 0.0003% (w / w), about 0.0004% (w / w), about 0.0005% (w / w), about 0.0006% (w / w), about 0.0007% (w / w), about 0.0008% (w / w), or about 0.0009% (w / w).

[0211] In certain instances, the brimonidine or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer may be present in an amount of about 0.0025% to about 0.25% (w / w).

[0212] In some cases, provided herein are compositions comprising a therapeutically effective amount of a muscarinic cholinergic receptor agonist as an active pharmaceutical ingredient; a semifluorinated alkyl alcohol; and a semifluorinated alkane compound. The composition may be a topical ophthalmic composition in some cases.

[0213] In some cases, muscarinic cholinergic receptor agonists can cause pupillary constriction to change the focusing depth of the eye. In some cases, this can temporarily relieve the symptoms of certain eye diseases or disorders such as hyperopia. In some cases, through muscarinic cholinergic receptors, the agonist can reduce intraocular pressure (IOP). This mechanism can be used to treat glaucoma in some cases. In some cases, the muscarinic cholinergic receptor agonist can be selected from aceclidin, pilocarpine, bethanechol, cevimeline, methacholine, xanomeline and aprolidin or a combination thereof. In some cases, the muscarinic cholinergic receptor agonist can be in salt form. In some cases, the muscarinic cholinergic receptor agonist can be in free base form.

[0214] In some cases, the muscarinic cholinergic receptor agonist can be present in an amount of about 0.1% to about 5% (w / w), about 0.1% to about 2.5% (w / w), about 0.1% to about 2% (w / w), about 0.1% to about 1.5% (w / w), about 0.1% to about 1% (w / w), about 0.1% to about 0.5% (w / w), about 0.1% to about 1.7% (w / w), about 0.1% to about 1.3% (w / w), about 0.1% to about 0.7% (w / w), about 0.1% to about 2% (w / w), about 0.3% to about 2% (w / w), about 0.5% to about 2% (w / w), about 0.7% to about 2% (w / w), about 1% to about 2% (w / w), about 1.3% to about 2% (w / w), about 1.5% to about 2% (w / w), about 1.7% to about 2% (w / w), about 0.3% to about 1% (w / w), about 0.3% to about 1.3% (w / w), about 0. .3% to about 1% (w / w), about 0.5% to about 1% (w / w), about 0.5% to about 0.7% (w / w), about 0.5% to about 1% (w / w), about 0.5% to about 1.5% (w / w), about 0.5% to about 2% (w / w), about 0.5% to about 0.7% (w / w), about 0.7% to about 1% (w / w), about 1% to about 1.3% (w / w), about 1.3% to about 1.5% (w / w), about 1.5% to about 2% (w / w), about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.3% (w / w), about 1.5% (w / w), about 1.7% (w / w) or about 2% (w / w).

[0215] In some cases, the muscarinic cholinergic receptor agonist can be aceclidine. In some cases, the aceclidine can be in salt form, such as, for example, aceclidine sulfate. In some cases, the aceclidine can be in salt form, such as, for example, aceclidine hydrochloride. In some cases, the aceclidine can be in free base form. In some cases, the aceclidinium may be present in an amount of about 0.01% to about 10% (w / w), about 0.01% to about 9% (w / w), about 0.01% to about 8% (w / w), about 0.01% to about 7% (w / w), about 0.01% to about 6% (w / w), about 0.01% to about 5% (w / w), about 0.01% to about 4% (w / w), about 0.01% to about 3% (w / w), about 0.01% to about 2% (w / w), about 0.01% to about 1% (w / w), about 0.01% to about 0.9% (w / w), about 0.01% to about 0.8% (w / w), about 0.01% to about about 0.7% (w / w), about 0.01% to about 0.6% (w / w), about 0.01% to about 0.5% (w / w), about 0.01% to about 0.4% (w / w), about 0.01% to about 0.3% (w / w), about 0.01% to about 0.2% (w / w), about 0.01% to about 0.1% (w / w), about 1% to about 10% (w / w), about 1% to about 9% (w / w), about 1% to about 8% (w / w), about 1% to about 7% (w / w), about 1% to about 6% (w / w), about 1% to about 5% (w / w), about 1% to about 4% (w / w), about 1% to about 3% (w / w). %, about 0.01% to about 0.95% (w / w), 0.01% to about 9% (w / w), 0.01% to about 0.85% (w / w), 0.01% to about 0.8% (w / w), 0.01% to about 0.75% (w / w), 0.01% to about 0.7% (w / w), 0.01% to about 0.65% (w / w), 0.01% to about 0.6% (w / w), 0.01% to about 0.55% (w / w), 0.01% to about 0.5% (w / w), 0.01% to about 0.45% (w / w), 0.01% to about 0.6% (w / w), 0.01% to about 0.75 ... .01% to about 0.4% (w / w), 0.01% to about 0.35% (w / w), 0.01% to about 0.3% (w / w), 0.01% to about 0.25% (w / w), 0.01% to about 0.2% (w / w), 0.01% to about 0.15% (w / w), 0.01% to about 0.1% (w / w), 0.01% to about 0.09% (w / w), 0.01% to about 0.08% (w / w), 0.01% to about 0.07% (w / w), 0.01% to about 0.06% (w / w), 0.01% to about 0.05% (w / w), 0.01% to about 0.04% (w / w), 0.01% to about 0.03% (w / w), 0.01% to about 0.02% (w / w), about 0.1% to about 5% (w / w), about 0.1% to about 2.5% (w / w), about 0.1% to about 2% (w / w), about 0.1% to about 1.5% (w / w), about 0.1% to about 1% (w / w), about 0.1% to about 0.5% (w / w), about 0.1% to about 1.7% (w / w), about 0.1% to about 1. 3% (w / w), about 0.1% to about 0.7% (w / w), about 0.1% to about 2% (w / w), about 0.3% to about 2% (w / w), about 0.5% to about 2% (w / w), about 0.7% to about 2% (w / w), about 1% to about 2% (w / w), about 1.3% to about 2% (w / w), about 1.5% to about 2% (w / w), about 1.7% to about 2% (w / w), about 0.3% to about 1% (w / w), about 0.3% to about 1. 3% (w / w), about 0.3% to about 1% (w / w), about 0.5% to about 1% (w / w), about 0.5% to about 0.7% (w / w), about 0.5% to about 1% (w / w), about 0.5% to about 1% (w / w), about 0.5% to about 1.5% (w / w), about 0.5% to about 2% (w / w), about 0.5% to about 0.7% (w / w), about 0.7% to about 1% (w / w), about 1% to about 1.3% (w / w), about 1.3% to about 1.5% (w / w), about 1 .5% to about 2% (w / w), about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.3% (w / w), about 1.5% (w / w), about 1.7% (w / w), or about 2% (w / w). In some cases, the aceclidinium may be present in an amount of about 0.01% to about 10% (w / w). .

[0216] In some cases, the muscarinic cholinergic receptor agonist can be pilocarpine. In some cases, the pilocarpine can be in the form of a salt, such as, for example, pilocarpine hydrochloride. In some cases, the pilocarpine can be in the form of a salt, such as, for example, pilocarpine nitrate. In some cases, the pilocarpine can be in the form of a free base. In some cases, the pilocarpine can be in the form of about 0.1% to about 2% (w / w), about 0.1% to about 1.5% (w / w), about 0.1% to about 1% (w / w), about 0.1% to about 0.5% (w / w), about 0.1% to about 1.7% (w / w), about 0.1% to about 1.3% (w / w), about 0.1% to about 0.7% (w / w), about 0.1% to about 2% (w / w), about 0.3% to about 2% (w / w), about 0.5% to about 2% (w / w), about 0.7% to about 2% (w / w), about 1% to about 2% (w / w), about 1.3% to about 2% (w / w), about 1.5% to about 2% (w / w), about 1.7% to about 2% (w / w), about 0.3% to about 1% (w / w), about 0.3% to about 1.3% (w / w), about 0.3% to about 1% (w / w), about 0.5% to about 1% (w / w), about 0.5% to about 0.7% (w / w), about 0.5% to about 1% (w / w), about 0.5% to about 1.5% (w / w), about 0.5% to about 2% (w / w), about 0.5% to about 0.7% (w / w), about 0.7% to about 1% (w / w), about 1% to about 1.3% (w / w), about 1.3% to about 1.5% (w / w), about 1.5% to about 2% (w / w), about 0. The invention relates to an aqueous solution of at least about 1% (w / w), about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.3% (w / w), about 1.5% (w / w), about 1.7% (w / w) or about 2% (w / w).

[0217] In some cases, the API can be a tyrosine kinase inhibitor. In some cases, the tyrosine kinase inhibitor can be a multikinase inhibitor (MKI) that inhibits one or more selected from vascular endothelial growth factor receptor (VEGFR) 1, 2 and 3 and platelet-derived growth factor receptor (PDGFR), α, β and Lyn.

[0218] In some cases, the API can be a multikinase inhibitor selected from afatinib, amvatinib, axitinib, cabozantinib, cannutinib, cediranib, ceritinib, crenolanib, crizotinib, dabrafenib, dacomitinib, dasatinib, erlotinib, fretinib, gefitinib, govatinib, ibrutinib, icotinib, idelalisib, imatinib, lapatinib, lenvatinib, neratinib, nilotinib, nintedanib, palbociclib, pazopanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sorafenib, sunitinib, tandutinib, tivantinib, tivozanib, trametinib, fentanib, varanib, vemurafenib or a combination thereof. In some cases, the multikinase inhibitor can be selected from axitinib, nintedanib and pazopanib. In some cases, the multi-kinase inhibitor may be axitinib, and may optionally be present in an amount of about 0.0001% to about 5% (w / w), about 0.0005% to about 2% (w / w), or about 0.001% to about 1% (w / w) in the compositions described herein. In some cases, the multi-kinase inhibitor may be axitinib, and may optionally be present in an amount of about 0.001% to about 1% (w / w) in the compositions described herein. In some cases, the multi-kinase inhibitor may be nintedanib, and may optionally be present in an amount of about 0.0001% to about 5% (w / w), about 0.0005% to about 2% (w / w), about 0.001% to about 1% (w / w), or about 0.01% to about 1% (w / w) in the compositions described herein. In some cases, the multi-kinase inhibitor may be nintedanib, and may optionally be present in an amount of about 0.01% to about 1% (w / w) in the compositions described herein. In some cases, the multi-kinase inhibitor can be pazopanib, and optionally can be present in the compositions described herein in an amount of about 0.0001% to about 5% (w / w), about 0.0005% to about 2% (w / w), or about 0.001% to about 1% (w / w).

[0219] In some cases, the API may be present in an amount of about 0.0001% to about 5% (w / w), about 0.1% to about 2.5% (w / w), about 0.1% to about 2% (w / w), about 0.1% to about 1.5% (w / w), about 0.1% to about 1% (w / w), about 0.001% to about 0.01% (w / w), about 0.001% to about 0.009% (w / w), about 0.001% to about 0.008% (w / w), about 0.001% to about 0.007% (w / w), about 0.001% to about 0.006% (w / w), about 0.001% to about 0.005% (w / w), about 0.001% to about 0.004% (w / w), about 0.0 0.01% to about 0.003% (w / w), about 0.001% to about 0.002% (w / w), about 0.0001% to about 0.001% (w / w), about 0.0001% to about 0.0009% (w / w), about 0.0001% to about 0.0008% (w / w), about 0.0001% to about 0.0007% (w / w), about 0.0001% to about 0.0006% (w / w), about 0.0001% to about 0.0005% (w / w), about 0.0001% to about 0.0004% (w / w), about 0.0001% to about 0.0003% (w / w), about 0.0001% to about 0.0002% (w / w), about 0.0001% to about 0.0003% (w / w), about 0.0001% to about 0.0002% (w / w), about 0.0001% to about 0.0003% (w / w), about 0.0001% to about 0.0004% (w / w), about 0.0001% to about 0.0005% (w / w), about 0.0001% to about 0.0006% (w / w), about 0.0001% to about 0.0007% (w / w), about 0.0001% to about 0.0006% (w / w), 15% to about 0.5% (w / w), about 0.15% to about 0.45% (w / w), about 0.15% to about 0.4% (w / w), about 0.15% to about 0.35% (w / w), about 0.15% to about 0.3% (w / w), about 0.15% to about 0.25% (w / w), about 0.15% to about 0.2% (w / w), about 0.1% to about 1.7% (w / w), about 0.1% to about 1.3% (w / w), about 0.1% to about 0.5% (w / w), about 0.1% to about 0.45% (w / w), about 0.1% to about 0.4% (w / w), about 0.1% to about 0.35% (w / w), about 0.1% to about 0.3% (w / w), From about 0.1% to about 0.25% (w / w), from about 0.1% to about 0.2% (w / w), from about 0.15% to about 0.5% (w / w), from about 0.15% to about 0.45% (w / w), from about 0.15% to about 0.4% (w / w), from about 0.15% to about 0.35% (w / w), from about 0.15% to about 0.3% (w / w), from about 0.15% to about 0.25% (w / w), from about 0.15% to about 0.2% (w / w), from about 0.1% to about 1.7% (w / w), from about 0.1% to about 1.3% (w / w), from about 0.1% to about 0.7% (w / w), from about 0.1% to about 2% (w / w), from about 0.3% to about 2% (w / w), from about 0.5% to about 2% (w / w), about 0.7% to about 2% (w / w), about 1% to about 2% (w / w), about 1.3% to about 2% (w / w), about 1.5% to about 2% (w / w), about 1.7% to about 2% (w / w), about 0.3% to about 1% (w / w), about 0.3% to about 1.3% (w / w), about 0.3% to about 1% (w / w), about 0.5% to about 1% (w / w), about 0.5% to about 0.7% (w / w), about 0.5% to about 1% (w / w), about 0.5% to about 2% (w / w), about 0.5% to about 0.7% (w / w), about 0.7% to about 1% (w / w), about 1% to about 1.5% (w / w), about 0.5% to about 2% (w / w), about 0.5% to about 0.7% (w / w), about 0.7% to about 1% (w / w), about 1% to about 1. 3% (w / w), about 1.3% to about 1.5% (w / w), about 1.5% to about 2% (w / w), about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.3% (w / w), about 1.5% (w / w), about 1.7% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w), about 3.5% (w / w), about 4% (w / w), about 4.5% (w / w), about 5% (w / w) , about 5.5% (w / w), about 0.001% (w / w), about 0.002% (w / w), about 0.003% (w / w), about 0.004% (w / w), about 0.005% (w / w), about 0.0011% (w / w), about 0.0012% (w / w), about 0.0013% (w / w), about 0.0014% (w / w), about 0.0015% (w / w), about 0.0016% (w / w), about 0.0017% (w / w), about 0.0018% (w / w), about 0.0019% (w / w), about 0.002% (w / w), about 0.0021% (w / w), about 0.0022% (w / w), about 0.00 23% (w / w), about 0.0024% (w / w), about 0.0025% (w / w), about 0.0026% (w / w), about 0.0027% (w / w), about 0.0028% (w / w), about 0.0029% (w / w), about 0.0030% (w / w), about 0.0031% (w / w), about 0.0032% (w / w), about 0.0033% (w / w), about 0.0034% (w / w), about 0.0035% (w / w), about 0.0036% (w / w), about 0.0037% (w / w), about 0.0038% (w / w), about 0.0039% (w / w), about 0.0001% (w / w), about 0.0.0002% (w / w), about 0.0003% (w / w), about 0.0004% (w / w), about 0.0005% (w / w), about 0.0006% (w / w), about 0.0007% (w / w), about 0.0008% (w / w), or about 0.0009% (w / w).

[0220] The compositions described herein may include semifluorinated alkanes (SFA). Semifluorinated alkanes are amphiphilic liquids having two covalently bonded mutually immiscible portions (a hydrocarbon segment and a perfluorinated segment). In some cases, the semifluorinated alkane may be a compound having the formula CF3(CF2): m (CH2) n In some cases, m is an integer from 1 to 10, and n is an integer from 1 to 10. For example, m can be 1, 2, 3, 4, 5 or 6. In another embodiment, n can be 1, 2, 3, 4, 5 or 6. Suitable examples of semifluorinated alkane compounds include perfluorobutylheptane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8) and perfluorohexyldecane (F6H10). In some cases, the SFA is perfluorohexyloctane (F6H8).

[0221] The structure of F6H8 is shown below:

[0222]

[0223] In some cases, the SFA may be present in an amount of about 50% to about 99% (w / w), about 60% to about 99% (w / w), about 65% to about 99% (w / w), about 70% to about 99% (w / w), about 75% to about 99% (w / w), about 80% to about 99% (w / w), about 85% to about 99% (w / w), about 90% to about 99% (w / w), about 95% to about 99% (w / w), about 50% to about 90% (w / w), about 60% to about 90% (w / w), about 70% to about 90% (w / w), about 99% (w / w), about 98% (w / w). ), about 97% (w / w), about 96% (w / w), about 95% (w / w), about 94% (w / w), about 93% (w / w), about 92% (w / w), about 91% (w / w), about 90% (w / w), about 89% (w / w), about 88% (w / w), about 87% (w / w), about 86% (w / w), about 85% (w / w), about 80% (w / w), about 75% (w / w), about 70% (w / w), about 65% (w / w), about 60% (w / w), about 55% (w / w) or about 50% (w / w) (w / w).

[0224] Compositions described herein can include medium chain triglycerides (MCT). Medium chain triglycerides (MCT) are triglycerides of fatty acids. The fatty acids have an aliphatic chain of 6-12 carbon atoms, and can be, for example, caproic acid, caprylic acid, capric acid, and dodecanoic acid. The MCT can be a single triglyceride or a mixture of triglycerides. The representative chemical structure of MCT is shown below.

[0225]

[0226] In some cases, the fatty acids in the MCT may include caproic acid, caprylic acid, capric acid, dodecanoic acid, or a combination of two or more thereof. In some cases, the fatty acids in the MCT consist essentially of caproic acid, caprylic acid, capric acid, dodecanoic acid, or a combination thereof.

[0227] In certain embodiments, the MCT may be present in an amount of about 0.1% to about 50% (w / w), about 0.1% to about 10% (w / w), about 1% to about 30% (w / w), about 1% to about 25% (w / w), about 1% to about 20% (w / w), about 1% to about 15% (w / w), about 1% to about 10% (w / w), about 5% to about 20% (w / w), about 5% to about 15% (w / w), about 10 ...20% (w / w). About 20% (w / w), about 10% to about 30% (w / w), about 30% (w / w), about 25% (w / w), about 20% (w / w), about 15% (w / w), about 10% (w / w), about 9% (w / w), about 8% (w / w), about 7% (w / w), about 6% (w / w), about 5% (w / w), about 4% (w / w), about 3% (w / w), about 2% (w / w) or about 1% (w / w) is present in the composition. In certain embodiments, the MCT may be present in the composition in an amount of about 5% to about 20% (w / w) MCT. In certain embodiments, the MCT may be present in the composition in an amount of about 0.1% to about 10% (w / w) MCT. Applicants have found that these amounts of MCT provide a balance of ocular tolerance (such as non-irritation) and the desired solubility of the API in some cases. In certain instances of the nanoemulsion compositions provided herein, Applicants have discovered that these amounts of MCT also balance the desired droplet size and ocular tolerability of the composition.

[0228] In some cases, the compositions disclosed herein may also contain one or more additional therapeutic agents, excipients or diluents, including, but not limited to, absorbents, anti-irritants, preservatives, antioxidants, colorants / pigments, emollients (wetting agents), emulsifiers, film forming / preserving agents, prescription drugs, surfactants / detergents, cleaning agents, penetration enhancers, viscosity enhancers and thickeners.

[0229] The composition of the present application can include compositions suitable for any acceptable route of administration. Suitable examples of acceptable routes of administration include eye, topical eye, eye injection, etc. In certain embodiments, the topical composition is an ophthalmic composition, for example, for intraocular administration. Suitable examples of ophthalmic compositions include eye drops, emulsions, nanoemulsions, and oils. Any of these ophthalmic compositions can be directly applied to the cornea or ocular surface, for example, using plastic or latex applicators (for example, disposable applicators), eye droppers, glass pipettes, or rubber balls.

[0230] In some cases, the composition has a pH of about 6 to about 8.

[0231] In some cases, the composition of the present application (e.g., topical ophthalmic composition or topical ophthalmic nanoemulsion) is absorbed through the cornea or selectively absorbed through the cornea. The phrases "absorbed through the corneal route", "absorbed through the corneal path" and "absorbed through the cornea" are used interchangeably and are related to absorption through the cornea. In percorneal absorption, the drug usually penetrates the eye through the cornea to the aqueous humor and then to the iris. In periorbital absorption, the drug usually penetrates the eye through the conjunctiva to the sclera and then to the ciliary body. In some cases, the composition described herein is absorbed through the cornea (e.g., at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60% or at least 70% of the composition is absorbed through the cornea, for example, as determined by a determination known in the art or described in the working examples herein). In some cases, the compositions described herein are selectively absorbed through the cornea (e.g., at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, or at least 70% more of the composition is absorbed through the cornea than the amount absorbed in the periorbital region, e.g., as determined by an assay known in the art or described in the working Examples herein, or at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 10 times, or at least 20 times more of the composition is absorbed through the cornea than the amount absorbed in the periorbital region, e.g., as determined by an assay known in the art or described in the working Examples herein). In some cases, the amount of the composition absorbed through the cornea is at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, or at least 70% greater than the amount absorbed in the periorbital region.

[0232] In some cases, the API of the composition of the present application is absorbed by the cornea or selectively absorbed by the cornea. In some cases, the API described herein is absorbed by the cornea (e.g., at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, or at least 70% of the API is absorbed by the cornea, for example, as determined by an assay known in the art or described in the working examples herein). In some cases, the API described herein is selectively absorbed by the cornea (e.g., at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, or at least 70% of the API is absorbed by the cornea compared to the amount absorbed by the periorbital, for example, as determined by an assay known in the art or described in the working examples herein, or at least 1.5 times, at least 2 times, at least 3 times, at least 4 times, at least 5 times, at least 10 times, or at least 20 times of the API is absorbed by the cornea compared to the amount absorbed by the periorbital, for example, as determined by an assay known in the art or described in the working examples herein). In certain instances, the amount of API absorbed via the cornea is at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, or at least 70% greater than the amount absorbed periosteally.

[0233] In some cases, the composition is prepared by uniformly and intimately combining an API disclosed herein with MCTs and SFAs disclosed herein.

[0234] In some cases, the composition may be in the form of an organic composition that does not contain an aqueous component.

[0235] The disclosure also provides nanoemulsions as described herein and methods for preparing the nanoemulsions. Applicants have surprisingly found that nanoemulsions of compositions described herein may be formed, such as compositions comprising API, MCT and SFA. In some cases, the nanoemulsion may be an oil-in-oil emulsion. In some cases, the nanoemulsion may have a droplet size D90 less than 100 nm.

[0236] The "droplet size" of an emulsion refers to the peak droplet size or the average droplet size of the dispersed phase. The "droplet size D90" refers to the situation where 90% of the particles have a size smaller than a specified size. The droplet size can be measured by methods known in the art, for example, by light scattering after dilution in water using a high performance particle sizer.

[0237] In some cases, the nanoemulsion can have a droplet size D90 of less than about 50 nm, less than about 50 nm, less than about 50 nm, less than about 50 nm, less than about 50 nm, less than about 50 nm, less than about 50 nm, or less than about 50 nm, or about 1 to 20 nm, about 1 to 10 nm, about 1 to 5 nm, or about 2 to 3 nm. Without being bound by theory, it is believed that smaller oil droplet size can increase the surface area and residence time of the API in the eye tissue, thereby increasing the concentration of the API in the eye tissue, and increasing the efficacy to the target tissue and reducing systemic exposure to the API.

[0238] In some cases, the method for preparing a nanoemulsion can include combining an ocular API with MCT to form an MCT solution; combining the MCT solution with a semifluorinated alkane compound to form a mixture, wherein the mixture comprises about 1% to about 50% (w / w) of the MCT solution and about 50% to about 99% (w / w) of the semifluorinated alkane compound; and emulsifying the mixture and reducing the droplet size D90 within the mixture to less than 100 nm by physical agitation selected from high speed stirring, vortexing, sonication, heating and stirring or homogenizing the mixture until the droplet size reaches less than 100 nm, less than about 50 nm, less than about 50 nm, less than about 50 nm, less than about 50 nm, less than about 50 nm, less than about 50 nm, less than about 50 nm, less than about 50 nm, or less than about 50 nm, or a droplet size D90 of about 1 to 20 nm, about 1 to 10 nm, about 1 to 5 nm, or about 2 to 3 nm. In some cases, the method for preparing a nanoemulsion may comprise uniformly and intimately combining an API disclosed herein with MCT and SFA disclosed herein, and emulsifying the mixture by physical agitation as described herein and reducing the droplet size D90 within the mixture to less than 100 nm.

[0239] In some cases, the method may further comprise measuring the droplet size of the mixture during or after the physical stirring.

[0240] Also provided herein are dispensers comprising the compositions or nanoemulsions described herein. Figure 4 In one example, the example dispenser 10 contains a liquid 14 of a composition or nanoemulsion. Applicants surprisingly found that the stability of the compositions and nanoemulsions described herein in low density polyethylene (LDPE) and in polypropylene (PP) is lower than the stability in other materials such as glass or polyethylene terephthalate (PET). Without being bound by theory, it is believed that the LDPE and PET materials absorb one or more components of the compositions or nanoemulsions described herein, thereby reducing the content of the active pharmaceutical ingredient (API) over time.

[0241] The dispenser 10 includes a container portion 18 having an inner wall 22 defining an interior volume 26 and adapted to contact a liquid 14 and store it within at least a portion of the interior volume 26; a dispensing portion 30 adapted to dispense one or more drops of the liquid 14 from the container portion 18; and a liquid 14 contained within the interior volume 26 comprising a composition or nanoemulsion as described herein, or a composition comprising about 0.001% to about 5% (w / w) API, about 1% to about 50% (w / w) medium chain triglycerides (MCTs), and about 50% to about 99% (w / w) semifluorinated alkane compounds, wherein the API has a solubility in MCT of at least about 0.01% to about 10% (w / w).

[0242] In some cases, the inner wall 22 of the dispenser 10 comprises one or more of low density polyethylene (LDPE) or polypropylene (PP) less than about 10%, less than about 5%, or less than about 1%. In some cases, the inner wall 22 does not comprise low density polyethylene (LDPE) or polypropylene (PP). In some cases, the inner wall 22 comprises glass or polyethylene terephthalate. In some cases, the inner wall 22 consists essentially of glass or polyethylene terephthalate (PET).

[0243] In some cases, the concentration of the API in the composition of liquid 14 or nanoemulsion remains greater than 90% of the initial API concentration after a period of 6 months of storage in the dispenser 10. In some cases, the concentration of the API in the composition of liquid 14 or nanoemulsion remains greater than 90% of the initial API concentration after a period of 12 months of storage in the dispenser 10.

[0244] In some cases, the container portion 18 and the dispensing portion 30 may each independently comprise or consist of the same material or different materials. In some cases, the container portion 18 and the dispensing portion 30 may each independently consist essentially of glass or polyethylene terephthalate (PET). In some cases, the dispensing portion 30 may comprise low-density polyethylene (LDPE) or polypropylene (PP), particularly in the following cases: the composition of liquid 14 or nanoemulsion is not generally in contact with the dispensing portion 30 during normal storage of the composition of liquid 14 or nanoemulsion, but briefly contacts the dispensing portion 30 during dispensing, such as during administration to the eye of a subject, when a drop passes through the dispensing portion 30 from the container portion 18. Without being bound by theory, it is believed that such limited contact of the composition of liquid 14 or nanoemulsion with LDPE or PET will have little or no effect on the composition of liquid 14 or nanoemulsion.

[0245] In some cases, the dispenser 10 is adapted to dispense droplets each independently having a volume of about 5 μl to about 40 μl.

[0246] The compositions and nanoemulsions described herein can be conveniently presented in unit dosage form or in multiple dosage forms (e.g., dispenser 10). In certain embodiments, the compositions and formulations described herein can be conveniently presented in dosage forms (unit or multiple) that can be used with or in an automated drug delivery device or regimen.

[0247] In some cases, the dispenser 10 may optionally have a cap 34 that is removable from the container portion 18. For example, the cap 34 may cover the dispensing portion 30 during storage.

[0248] The present disclosure also includes pharmaceutical kits that can be used, for example, to treat the disorders, diseases and conditions mentioned herein, comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure. If desired, such a kit may further include one or more of various conventional pharmaceutical kit components, such as, for example, a container containing one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions (as inserts or as labels) indicating the amounts of the components to be administered, instructions for administration, and / or instructions for mixing the components may also be included in the kit. The kit may optionally include additional therapeutic agents as described herein.

[0249] In certain embodiments, a kit may comprise a dispensing device prefilled with a composition described herein.

[0250] Also provided herein are methods for treating ocular diseases or conditions using compositions, dispensers, and methods described herein. In some cases, the ocular diseases or conditions may be associated with the cornea or corneal tissue. In some cases, the ocular diseases or conditions are preferably treated with compositions that are absorbed (e.g., selectively absorbed) through the cornea.

[0251] Exemplary, non-limiting ocular diseases that can be treated with the compositions, dispensers, and methods described herein include chemical burns or a disease selected from the group consisting of keratoconus, thin cornea, keratitis, infectious keratitis (including bacterial or fungal keratitis), corneal ulcers, bullous keratopathy and other forms of corneal edema, keratolysis, autoimmune diseases, scarring diseases (such as ocular cicatricial pemphigoid), Stevens disease, Johnson syndrome, lupus erythematosus, rheumatoid arthritis, corneal ectasia (including corneal ectasia following laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK)), postrefractive ectasia, corneal degeneration, fragile corneal syndrome, Ehlers-Danlos syndrome type VI, corneal neovascularization, corneal melt (including corneal melt in Boston I keratoprosthesis), hyperopia, hyperopic astigmatism, myopia, astigmatism, myopic astigmatism, myopia regression, keratopathy, corneal astigmatism, unstable cornea, or pellucid marginal degeneration (PMD).

[0252] In some cases, the disease or condition can be an anterior eye disease or condition. Exemplary, non-limiting anterior eye diseases or conditions that can be treated with the compositions, dispensers, and methods described herein include neurotrophic keratitis, glaucoma, elevated intraocular pressure, ocular hypertension, hyperopia, myopia, ocular rosacea, dry eye disease, meibomian gland dysfunction, blepharitis, allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, pterygium, palpebral fissures, corneal transplant rejection, graft-versus-host disease, ocular allergies, uveitis, anterior uveitis, Behcet's disease, Sjögren's syndrome, Stevens-Johnson syndrome, ocular cicatricial pemphigoid, chronic ocular surface inflammation caused by viral infection, herpes simplex keratitis, atopic conjunctivitis, Lyell syndrome, neovascularization induced by viral, bacterial, fungal or parasitic infection, contact lens-induced neovascularization, ulceration, alkali burns, stem cell deficiency, neovascular glaucoma, Stevens-Johnson syndrome, Johnson syndrome, ocular tumors, aphakia, pseudophakia, astigmatism, blepharospasm, cataracts, conjunctival diseases, corneal diseases, corneal ulcers, eyelid diseases, lacrimal apparatus diseases, pupil disorders, refractive disorders, strabismus.

[0253] In certain instances, the disease or disorder may be a posterior ocular disease or disorder.

[0254] In some cases, the method may include a method for treating an ocular disorder in a subject, slowing its progression, or alleviating one or more symptoms thereof, comprising administering a topical ophthalmic composition or nanoemulsion composition described herein to the subject's eye. In some cases, the method may include a method for delivering an API to the subject's eye, comprising administering a topical ophthalmic composition or nanoemulsion composition described herein. In some cases, administration may include contacting the eye with the composition.

[0255] In some cases, the method may include a method for slowing the progression of myopia in a subject or for alleviating the symptoms of vitreous floaters in a subject, the method comprising administering to the subject a topical ophthalmic composition or nanoemulsion composition described herein, wherein the API is a muscarinic receptor antagonist, such as, for example, atropine, an atropine mimetic or analog, or a free base or salt form thereof.

[0256] In some cases, the method further comprises (a) (i) selecting a subject in need of transcorneal absorption of the API; or (ii) selecting a subject having an ocular condition, wherein the ocular condition requires transcorneal absorption of the API.

[0257] In some instances of the methods, the API is selectively delivered to the cornea of ​​the subject.

[0258] In certain instances of the method, the subject has not responded to treatment with an aqueous composition comprising the API of the composition or a salt thereof. Failure to respond to treatment includes disease progression and failure to achieve clinically significant symptom relief following treatment.

[0259] In some cases of the method, after receiving the aqueous composition comprising the API, the subject has had an adverse side effect from the API. In some cases of the method, after receiving the aqueous composition comprising a salt of the API, the subject has had an adverse side effect from the API. Adverse side effects from the API include adverse side effects attributed to the API rather than to other components or characteristics of the composition comprising the API (e.g., preservatives or pH). Adverse side effects include headaches and eye irritation.

[0260] In certain instances of the methods, the subject is highly sensitive to an aqueous composition comprising the API or a salt thereof.

[0261] In some cases, the API may be present in an effective amount (e.g., a therapeutically effective amount). The effective dose may vary with the disease being treated, the severity of the disease, the route of administration, the sex, age and general health of the subject, excipient use, the possibility of co-use with other therapeutic treatments (such as the use of other agents), and the judgment of the treating physician. For example, in certain embodiments, where the compositions described herein can be used to treat a disease in the eye of a patient, such as myopia, the treating physician can adjust the dose and dosage regimen based on the current progression of the disease in the patient, the age of the patient, or other relevant factors.

[0262] In some cases, the API is administered at a dose that is 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70%, or 50-70% less than the API dose when administered as an aqueous topical ophthalmic composition for the same method of use. The reduction in dose is not due to a weight difference between the free base form and the acid form of the API. For example, in certain instances of the method of treating an ocular condition in a subject, the API is administered to the subject at a dose that is at least 30% less than the dose of the API in an aqueous topical ophthalmic composition used to treat the ocular condition.

[0263] In some cases, the API dose can be administered daily (e.g., as a single dose or as two or more divided doses, e.g., once a day, twice a day, three times a day, or four times a day) or non-daily (e.g., every other day, every two days, every three days, once a week, twice a week, once every two weeks, once a month). In some cases, the API dose can be administered once every about 6 to about 8 hours. In some cases, the API dose can be administered three times a day. In some cases, the API dose can be administered once a day.

[0264] Also provided herein is a composition comprising: a therapeutically effective amount of a muscarinic cholinergic receptor agonist as an active pharmaceutical ingredient; and a semifluorinated alkane compound. In certain embodiments, the semifluorinated alkane compound can be a liquid vehicle for the composition. In certain embodiments, the composition can further comprise an organic cosolvent. The composition can provide a stable formulation of a muscarinic cholinergic receptor agonist.

[0265] In some cases, provided herein are compositions comprising a therapeutically effective amount of a muscarinic cholinergic receptor agonist as an active pharmaceutical ingredient; and a semifluorinated alkane compound. The composition may be a topical ophthalmic composition in some cases.

[0266] In some cases, muscarinic cholinergic receptor agonists can cause pupillary constriction to change the focusing depth of the eye. In some cases, this can temporarily relieve the symptoms of certain eye diseases or disorders such as hyperopia. In some cases, through muscarinic cholinergic receptors, the agonist can reduce intraocular pressure (IOP). This mechanism can be used to treat glaucoma in some cases. In some cases, the muscarinic cholinergic receptor agonist can be selected from aceclidin, pilocarpine, bethanechol, cevimeline, methacholine, xanomeline and aprolidin or a combination thereof. In some cases, the muscarinic cholinergic receptor agonist can be in salt form. In some cases, the muscarinic cholinergic receptor agonist can be in free base form.

[0267] In some cases, the muscarinic cholinergic receptor agonist can be present in an amount of 0.1% to about 5% (w / w), about 0.1% to about 2.5% (w / w), about 0.1% to about 2% (w / w), about 0.1% to about 1.5% (w / w), about 0.1% to about 1% (w / w), about 0.1% to about 0.5% (w / w), about 0.1% to about 1.7% (w / w), about 0.1% to about 1.3% (w / w), about 0.1% to about 0. .7% (w / w), about 0.1% to about 2% (w / w), about 0.3% to about 2% (w / w), about 0.5% to about 2% (w / w), about 0.7% to about 2% (w / w), about 1% to about 2% (w / w), about 1.3% to about 2% (w / w), about 1.5% to about 2% (w / w), about 1.7% to about 2% (w / w), about 0.3% to about 1% (w / w), about 0.3% to about 1.3% (w / w), about 0. 3% to about 1% (w / w), about 0.5% to about 1% (w / w), about 0.5% to about 0.7% (w / w), about 0.5% to about 1% (w / w), about 0.5% to about 1.5% (w / w), about 0.5% to about 2% (w / w), about 0.5% to about 0.7% (w / w), about 0.7% to about 1% (w / w), about 1% to about 1.3% (w / w), about 1.3% to about 1.5% (w / w), about 1.5% to about 2% (w / w), about 0.1% (w / w), about 0.2% (w / w), about 0.3% (w / w), about 0.4% (w / w), about 0.5% (w / w), about 0.6% (w / w), about 0.7% (w / w), about 0.8% (w / w), about 0.9% (w / w), about 1% (w / w), about 1.3% (w / w), about 1.5% (w / w), about 1.7% (w / w), about 2% (w / w).

[0268] In some cases, the muscarinic cholinergic receptor agonist can be aceclidine. In some cases, the aceclidine can be in the form of a salt, such as, for example, aceclidine sulfate. In some cases, the aceclidine can be in the form of a salt, such as, for example, aceclidine hydrochloride. In some cases, the aceclidine can be in the form of a free base. In some cases, the aceclidine can be in the form of 0.1% to about 5% (w / w), about 0.1% to about 2.5% (w / w), about 0.1% to about 2% (w / w), about 0.1% to about 1.5% (w / w), about 0.1% to about 1% (w / w), about 0.1% to about 0.5% (w / w), about 0.1% to about 1.7% (w / w), about 0.1% to about 1.3% (w / w), about 0.1% to about 0.7% (w / w). w), about 0.1% to about 2% (w / w), about 0.3% to about 2% (w / w), about 0.5% to about 2% (w / w), about 0.7% to about 2% (w / w), about 1% to about 2% (w / w), about 1.3% to about 2% (w / w), about 1.5% to about 2% (w / w), about 1.7% to about 2% (w / w), about 0.3% to about 1% (w / w), about 0.3% to about 1.3% (w / w), about 0.3% to about 1% (w / w), about 0.5% to about 1% (w / w), about 0.5% to about 0.7% (w / w), about 0.5% to about 1% (w / w), about 0.5% to about 1.5% (w / w), about 0.5% to about 2% (w / w), about 0.5% to about 0.7% (w / w), about 0.7% to about 1% (w / w), about 1% to about 1.3% (w / w), about 1.3% to about 1.5% (w / w), about 1.5% to about 2% The invention relates to an amount of at least one molecule of the present invention to at least one molecule of the present invention. The invention relates to an amount of at least one molecule of the present invention to ...

[0269] In some cases, the muscarinic cholinergic receptor agonist can be pilocarpine. In some cases, the pilocarpine can be in the form of a salt, such as, for example, pilocarpine hydrochloride. In some cases, the pilocarpine can be in the form of a salt, such as, for example, pilocarpine nitrate. In some cases, the pilocarpine can be in the form of a free base. In some cases, the pilocarpine can be in the form of about 0.1% to about 2% (w / w), about 0.1% to about 1.5% (w / w), about 0.1% to about 1% (w / w), about 0.1% to about 0.5% (w / w), about 0.1% to about 1.7% (w / w), about 0.1% to about 1.3% (w / w), about 0.1% to about 0.7% (w / w), about 0.1% to about 2% (w / w), about 0.3% to about 2% (w / w), about 0.5% to about 2% (w / w), about 0.7% to about 2% (w / w), about 1% to about 2% (w / w), about 1.3% to about 2% (w / w), about 1.5% to about 2% (w / w), about 1.7% to about 2% (w / w), about 0.3% to about 1% (w / w), about 0.3% to about 1.3% (w / w), about 0.3% to about 1% (w / w), about 0.5% to about 1% (w / w), about 0.5% to about 0.7% (w / w), about 0.5% to about 1% (w / w), about 0.5% to about 1.5% (w / w), about 0.5% to about 2% (w / w), about 0.5% to about 0.7% (w / w), about 0.7% to about 1% (w / w), about 1% to about 1.3% (w / w), about 1.3% to about 1.5% (w / w), about 1.5% to about 2% (w / w), about 0. The composition comprises a semifluorinated alkane compound. In some cases, the semifluorinated alkane compound can act as a liquid vehicle. The semifluorinated alkane compound is an amphiphilic liquid having two mutually immiscible parts (a hydrocarbon segment and a perfluorinated segment) covalently bonded. In certain cases, the semifluorinated alkane compound may have the formula of RFRH or the formula of RFRHRF; RF is a perfluorinated hydrocarbon having 1 to 15 carbon atoms, and wherein RH is a non-fluorinated hydrocarbon having 1 to 15 carbon atoms.

[0270] Examples of semifluorinated alkanes that can be used in the compositions described herein include perfluorobutylpentane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10); preferably perfluorobutylpentane (F4H5), perfluorohexylhexane (F6H6), and perfluorohexyloctane (F6H8).

[0271] The structure of F6H8 is shown below.

[0272]

[0273] F6H8(CF3(CF2)5(CH2)7CH3)

[0274] In some cases, the semifluorinated alkane can be present in an amount of about 0% to about 99.9% (w / w), about 0.1% to about 99.9% (w / w), about 0.1% to about 30% (w / w), about 1% to about 25% (w / w), about 1% to about 20% (w / w), about 5% to about 20% (w / w), about 5% to about 15% (w / w), about 10% to about 99.9% (w / w), about 20% to about 99.9% (w / w), about 30% to about 99.9% (w / w), about 40% to about 99.9% (w / w), about 50% to about 99.9% (w / w), about 60% to about 99.9% (w / w), about 65% to about 99.9% (w / w), about 70% to about 99.9% (w / w), about 75% to about 99.9% (w / w), about 80% to about 99.9% (w / w), about 85% to about 99.9% (w / w), about 90% to about 99.9% (w / w), about 95% to about 99.9% (w / w), about 98% to about 99.9% (w / w), about 20% to about 80% (w / w), about 20% to about 70% (w / w), about 20% to about 60% (w / w), about 20% to about 50% (w / w), about 20% to about 40% (w / w), about 20% to about 30% (w / w), about 30% to about 80% (w / w), about 40% to about 80% (w / w), about 50% to about 80% (w / w), about 60% to about 80% (w / w), about 70% to about 80% (w / w), about 99.9% (w / w), about 99% (w / w), about 98% (w / w), about 97% (w / w), about 96% (w / w), about 95% (w / w), about 94% (w / w), about 93% (w / w), about 92% (w / w), about 91% (w / w), about 90% (w / w), about 85% (w / w), about 80% (w / w), about 75% (w / w), about 70% (w / w), The invention also provides an amount of about 65% (w / w), about 60% (w / w), about 55% (w / w), about 50% (w / w), about 45% (w / w), about 40% (w / w), about 35% (w / w), about 30% (w / w), about 25% (w / w), about 20% (w / w), about 15% (w / w), about 10% (w / w), about 9% (w / w), about 8% (w / w), about 7% (w / w), about 6% (w / w), about 5% (w / w), about 4% (w / w), about 3% (w / w), about 2% (w / w), about 1% (w / w), about 0.5% (w / w) or about 0.1% (w / w).

[0275] In some cases, the semifluorinated alkane is F6H8 (perfluorohexyl octane). In some cases, the semifluorinated alkane is perfluorobutylheptane (F4H5).

[0276] In some cases, the composition may further comprise one or more organic co-solvents. In some cases, the co-solvent may act to further increase the solubility of the muscarinic cholinergic receptor agonist. In some cases, the organic co-solvent may be selected from medium chain triglycerides (MCT), liquid paraffin, vitamin E acetate, D-α-tocopherol, oleic acid, ethyl oleate, and combinations thereof.

[0277] In some cases, the organic co-solvent may be present in an amount of about 1% to about 50% (w / w), about 1% to about 50% (w / w), about 5% to about 50% (w / w), about 10% to about 50% (w / w), about 15% to about 50% (w / w), about 20% to about 50% (w / w), about 25% to about 50% (w / w), about 30% to about 50% (w / w), about 30% to about 50% (w / w), about 35 ...10% to about 50% (w / w). about 50% (w / w), about 40% to about 50% (w / w), about 45% to about 50% (w / w), about 1% to about 50% (w / w), about 1% to about 45% (w / w), about 1% to about 40% (w / w), about 1% to about 35% (w / w), about 1% to about 30% (w / w), about 1% to about 25% (w / w), about 1% to about 20% (w / w), about 1% to about 15% (w / w), about 1% to about 10% (w / w), about 1% to about 5% (w / w), about 3% to about 5% (w / w), about 5% to about 7% (w / w), about 7% to about 9% (w / w), about 9% to about 11% (w / w), about 11% to about 13% (w / w), about 13% to about 15% (w / w), about 1% to about 3% (w / w), about 15% to about 20% (w / w), about 20% to about 25% (w / w), about 25% to about The invention relates to an amount of about 30% (w / w), about 15% (w / w), about 14% (w / w), about 13% (w / w), about 12% (w / w), about 11% (w / w), about 10% (w / w), about 9% (w / w), about 8% (w / w), about 7% (w / w), about 6% (w / w), about 5% (w / w), about 4% (w / w), about 3% (w / w), about 2% (w / w), and about 1% (w / w).

[0278] In some cases, the composition may include a combination of one or more organic co-solvents as described herein and one or more SFAs as described herein. In some cases, the co-solvent may be present in an amount of about 1% (w / w) and the SFA may be present in an amount of about 99% (w / w); the co-solvent may be present in an amount of about 2% (w / w) and the SFA may be present in an amount of about 98% (w / w); the co-solvent may be present in an amount of about 5% (w / w) and the SFA may be present in an amount of about 95% (w / w); the co-solvent may be present in an amount of about 7% (w / w) and the SFA may be present in an amount of about 93% (w / w); the co-solvent may be present in an amount of about 10% (w / w) and the SFA may be present in an amount of about 90% (w / w); the co-solvent may be present in an amount of about 10% (w / w) and the SFA may be present in an amount of about 90% (w / w); The cosolvent may be present in an amount of about 13% (w / w) and the SFA may be present in an amount of about 87% (w / w); the cosolvent may be present in an amount of about 15% (w / w) and the SFA may be present in an amount of about 85% (w / w); the cosolvent may be present in an amount of about 17% (w / w) and the SFA may be present in an amount of about 83% (w / w); the cosolvent may be present in an amount of about 20% (w / w) and the SFA may be present in an amount of about 80% (w / w); the cosolvent may be present in an amount of about 23% (w / w) and the SFA may be present in an amount of about 77% (w / w); the cosolvent may be present in an amount of about 25% (w / w); and the SFA may be present in an amount of about 75% (w / w); the cosolvent may be present in an amount of about 27% (w / w) and the SFA may be present in an amount of about 73% (w / w); the cosolvent may be present in an amount of about 30% (w / w) and the SFA may be present in an amount of about 70% (w / w); the cosolvent may be present in an amount of about 33% (w / w) and the SFA may be present in an amount of about 67% (w / w); the cosolvent may be present in an amount of about 35% (w / w) and the SFA may be present in an amount of about 65% (w / w); the cosolvent may be present in an amount of about 37% (w / w) and the SFA may be present in an amount of about 6 3% (w / w); the cosolvent may be present in an amount of about 40% (w / w) and the SFA may be present in an amount of about 60% (w / w); the cosolvent may be present in an amount of about 43% (w / w) and the SFA may be present in an amount of about 57% (w / w); the cosolvent may be present in an amount of about 45% (w / w) and the SFA may be present in an amount of about 55% (w / w); the cosolvent may be present in an amount of about 47% (w / w) and the SFA may be present in an amount of about 53% (w / w); the cosolvent may be present in an amount of about 50% (w / w) and the SFA may be present in an amount of about 50% (w / w);SFA may be the sole vehicle and the SFA may be present in an amount of about 98% (w / w); SFA may be the sole vehicle and the SFA may be present in an amount of about 98.5% (w / w); SFA may be the sole vehicle and the SFA may be present in an amount of about 98.6% (w / w); SFA may be the sole vehicle and the SFA may be present in an amount of about 98.7% (w / w); SFA may be the sole vehicle and the SFA may be present in an amount of about 98.8% (w / w); or SFA may be the sole vehicle and the SFA may be present in an amount of about 98.9% (w / w). ;

[0279] In some cases, the concentration of the organic co-solvent in the composition is less than or equal to about 50% (w / w). In some cases, the concentration of the organic co-solvent in the composition is about 1% to 15% (w / w).

[0280] In some cases, the organic co-solvent may be a medium chain triglyceride (MCT). In some cases, the medium chain triglyceride (MCT) may have two or three fatty acids, each independently having an aliphatic tail of 6-12 carbon atoms.

[0281] In some cases, the MCT may be present in an amount of about 1% to about 50% (w / w), about 1% to about 50% (w / w), about 5% to about 50% (w / w), about 10% to about 50% (w / w), about 15% to about 50% (w / w), about 20% to about 50% (w / w), about 25% to about 50% (w / w), about 30% to about 50% (w / w), about 30% to about 50% (w / w), about 35% to about 50% (w / w), about 50 ... 0% (w / w), about 40% to about 50% (w / w), about 45% to about 50% (w / w), about 1% to about 50% (w / w), about 1% to about 45% (w / w), about 1% to about 40% (w / w), about 1% to about 35% (w / w), about 1% to about 30% (w / w), about 1% to about 25% (w / w), about 1% to about 20% (w / w), about 1% to about 15% (w / w), about 1% to about 10% (w / w), about 1% to about 5% (w / w), about 3% to about 5% (w / w), about 5% to about 7% (w / w), about 7% to about 9% (w / w), about 9% to about 11% (w / w), about 11% to about 13% (w / w), about 13% to about 15% (w / w), about 1% to about 3% (w / w), about 15% to about 20% (w / w), about 20% to about 25% (w / w), about 25% to about 30% (w / w), about 15% (w / w), about 14% (w / w), about 13% (w / w), about 12% (w / w), about 11% (w / w), about 10% (w / w), about 9% (w / w), about 8% (w / w), about 7% (w / w), about 6% (w / w), about 5% (w / w), about 4% (w / w), about 3% (w / w), about 2% (w / w), about 1% (w / w)).

[0282] In some cases, the concentration of MCT in the composition is less than or equal to about 50% (w / w). In some cases, the concentration of MCT in the composition is about 1% to 15% (w / w).

[0283] In some cases, the composition may include a combination of one or more MCTs as described herein and one or more SFAs as described herein. In some cases, the MCT may be present in an amount of about 1% (w / w) and the SFA may be present in an amount of about 99% (w / w); the MCT may be present in an amount of about 2% (w / w) and the SFA may be present in an amount of about 98% (w / w); the MCT may be present in an amount of about 5% (w / w) and the SFA may be present in an amount of about 95% (w / w); the MCT may be present in an amount of about 7% (w / w) and the SFA may be present in an amount of about 93% (w / w); the MCT may be present in an amount of about 10% (w / w) and the SFA may be present in an amount of about 90% (w / w); the MCT may be present in an amount of about 10% (w / w) and the SFA may be present in an amount of about 15 ... The MCT may be present in an amount of about 13% (w / w) and the SFA may be present in an amount of about 87% (w / w); the MCT may be present in an amount of about 15% (w / w) and the SFA may be present in an amount of about 85% (w / w); the MCT may be present in an amount of about 17% (w / w) and the SFA may be present in an amount of about 83% (w / w); the MCT may be present in an amount of about 20% (w / w) and the SFA may be present in an amount of about 80% (w / w); the MCT may be present in an amount of about 23% (w / w) and the SFA may be present in an amount of about 77% (w / w); the MCT may be present in an amount of about 25% (w / w); and the SFA may be present in an amount of about 75% (w / w); the MCT may be present in an amount of about 27% (w / w) and the SFA may be present in an amount of about 73% (w / w); the MCT may be present in an amount of about 30% (w / w) and the SFA may be present in an amount of about 70% (w / w); the MCT may be present in an amount of about 33% (w / w) and the SFA may be present in an amount of about 67% (w / w); the MCT may be present in an amount of about 35% (w / w) and the SFA may be present in an amount of about 65% (w / w); the MCT may be present in an amount of about 37% (w / w) and the SFA may be present in an amount of about 6 The MCT may be present in an amount of about 3% (w / w); the MCT may be present in an amount of about 40% (w / w) and the SFA may be present in an amount of about 60% (w / w); the MCT may be present in an amount of about 43% (w / w) and the SFA may be present in an amount of about 57% (w / w); the MCT may be present in an amount of about 45% (w / w) and the SFA may be present in an amount of about 55% (w / w); the MCT may be present in an amount of about 47% (w / w) and the SFA may be present in an amount of about 53% (w / w); the MCT may be present in an amount of about 50% (w / w) and the SFA may be present in an amount of about 50% (w / w);SFA may be the sole vehicle and the SFA may be present in an amount of about 98% (w / w); SFA may be the sole vehicle and the SFA may be present in an amount of about 98.5% (w / w); SFA may be the sole vehicle and the SFA may be present in an amount of about 98.6% (w / w); SFA may be the sole vehicle and the SFA may be present in an amount of about 98.7% (w / w); SFA may be the sole vehicle and the SFA may be present in an amount of about 98.8% (w / w); or SFA may be the sole vehicle and the SFA may be present in an amount of about 98.9% (w / w). ;

[0284] The pharmaceutical composition may also contain one or more additional therapeutic agents, excipients or diluents, including, but not limited to, absorbents, anti-irritants, preservatives, antioxidants, colorants / pigments, emollients (wetting agents), emulsifiers, film forming / preserving agents, prescription drugs, surfactants / detergents, penetration enhancers, viscosity enhancers and thickeners.

[0285] The pharmaceutical compositions of the present application may include those suitable for any acceptable route of administration. Suitable examples of acceptable routes of administration include topical, ocular, topical ocular, injection, and the like.

[0286] Compositions and preparations described herein can be conveniently presented in unit dosage form or multiple dosage form. In some cases, compositions and preparations described herein can be conveniently presented in dosage form (unit or multiple) that can be used with or in an automatic drug delivery device or regimen.

[0287] In some cases, the topical compositions of the present disclosure can be prepared and used in the form of non-aqueous solutions, suspensions, or emulsions. In some cases, the topical compositions can be in the form of emulsions. In some cases, the topical compositions can be in the form of organic solutions. In some cases, the compositions can be in the form of organic compositions that do not contain an aqueous component.

[0288] In certain cases, the topical composition is an ophthalmic composition, e.g., for intraocular administration. Suitable examples of topical ophthalmic compositions described herein are non-aqueous solutions, suspensions, or emulsions.

[0289] In some cases, the compositions described herein can be stable compositions. The compositions can provide chemical stability of the muscarinic cholinergic receptor agonist in the composition at room temperature for at least 1 month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 7 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 1 year, at least 2 years, or more.

[0290] In some cases, the compositions described herein can be non-irritating. In some cases, the compositions described herein can cause minimal or no irritation in the eye of a mammal.

[0291] Any of these ophthalmic compositions can be administered directly to the eye, for example, using a plastic or latex applicator (eg, a disposable applicator), an eye dropper, a glass pipette, or a rubber bulb.

[0292] The present disclosure also includes pharmaceutical kits that can be used, for example, to treat the disorders, diseases and conditions mentioned herein, comprising one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure. If desired, such a kit may further include one or more of various conventional pharmaceutical kit components, such as, for example, a container containing one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions (as inserts or as labels) indicating the amounts of the components to be administered, instructions for administration, and / or instructions for mixing the components may also be included in the kit. The kit may optionally include additional therapeutic agents as described herein.

[0293] In some cases, the kit may comprise a dispensing device prefilled with a composition described herein.

[0294] Also provided herein are methods of treating an ocular disease or condition using the compositions and methods described herein. In some cases, the ocular disease or condition may be hyperopia.

[0295] In some cases, a method of administering an effective amount of a muscarinic cholinergic receptor agonist to an eye of a subject is provided. In some cases, the compositions described herein may be in the form of eye drops. In some cases, the method may further comprise applying the eye drops to the eye of the subject.

[0296] The present invention will be further described in the following examples, which do not limit the scope of the present invention.

[0297] It should be understood that although the invention has been described in conjunction with its detailed description, the foregoing description is intended to be illustrative only and not to limit the scope of the invention, which is defined by the scope of the following claims. Other aspects, advantages and modifications are within the scope of the following claims. Example

[0298] Example 1: Droplet size in atropine nanoemulsion

[0299] Preparation of Atropine Free Base Nanoemulsion Compositions Table 1 below shows the oil droplet size distribution of the MCT / F6H8 nanoemulsions below 10 nm.

[0300] Table 1: Oil droplet size distribution of CBT-009 nanoemulsion

[0301]

[0302] Example 2: Systemic Exposure of Atropine Nanoemulsion

[0303] The systemic exposure of atropine free base nanoemulsions following ocular administration in rabbits was analyzed. Table 2 below shows that 0.025% CBT-009 in a 10% MCT:90% F6H8 nanoemulsion had lower systemic exposure to atropine compared to 0.03% atropine sulfate in water when both formulations were dosed twice daily in rabbits for 28 days.

[0304] Table 2: Systemic exposure to atropine following twice daily administration of 0.02% atropine free base nanoemulsion and 0.03% atropine sulfate aqueous solution in rabbits for 28 days

[0305]

[0306] Example 3: Ocular tissue distribution of atropine free base nanoemulsion

[0307] Table 3 below shows that the atropine concentration in the ocular tissue of rabbits when administered 12 μL of a 0.02% atropine free base nanoemulsion was significantly higher than that when administered 50 μL of a 1% atropine sulfate aqueous solution.

[0308] Table 3: Atropine concentrations in ocular tissues after administration of one drop of 0.02% atropine free base nanoemulsion and 1% atropine sulfate aqueous solution in rabbits

[0309]

[0310] Conc. = concentration; MCT = medium chain triglycerides; F6H8 = perfluorohexyl octane; AH = aqueous humor; ICB = iris-ciliary body.

[0311] (1) 0.02% atropine free base in 10% MCT:90% F6H8 was administered in a 12 μL drop size per eye.

[0312] (2) A 1% aqueous atropine sulfate solution was administered in a 50 μL drop size per eye. Tissue concentrations were estimated from visual maps (reference article Wang_2019).

[0313] (3) Calculate the concentration / dose based on the administered concentration and the drop size per eye.

[0314] Embodiment 4:

[0315] Figure 1 The effectiveness of atropine in dilating pupil size when atropine free base nanoemulsion and atropine sulfate aqueous solution were administered twice daily for 22 days. The 0.025% atropine free base nanoemulsion showed longer pupil dilation compared to the 0.03% atropine sulfate aqueous solution. Figure 2 It was shown that 0.01% and 0.012% atropine free base nanoemulsions had superior efficacy in pupil dilation compared to 0.01% atropine sulfate aqueous solution after administration of 1 drop to rabbits on day 1. Figure 3 It was shown that in humans, a 0.02% atropine free base nanoemulsion administered at 12 μL had superior efficacy in pupil dilation compared to a 0.03% atropine sulfate aqueous solution administered at 40 μL.

[0316] Embodiment 5:

[0317] Atropine free base nanoemulsions are as safe as aqueous atropine sulfate solutions. As shown in Table 4 below, 0.01, 0.02, and 0.04% atropine free base nanoemulsions have been shown to be safe and well tolerated in rabbits when administered twice daily for 6 months.

[0318] Atropine free base 0.02% nanoemulsion has been shown to be safe and well tolerated in humans when administered once daily for 28 days, as shown in Table 5 below. Treatment-emergent adverse events (TEAEs) such as blurred vision and glare reported in clinical trials are believed to be pharmacologically related to the pupil dilation of atropine.

[0319] Table 4: Summary of ocular TEAEs following one drop administration in humans

[0320]

[0321] Abbreviations: m = number of events; MedDRA = Medical Dictionary for Regulatory Activities; TEAE = treatment-emergent adverse event.

[0322] NOTE: A TEAE was defined as an adverse event that occurred after the first IP administration or, if it started before IP administration, persisted thereafter and worsened in severity.

[0323] If a participant experienced more than one TEAE, that participant is shown only once in the Participant Count (n) column for a given system organ class and preferred term. The number of times the event occurred is shown under the Occurrence Count (m) column.

[0324] Events were coded using MedDRA version 25.0.

[0325] Table 5: Summary of ocular TEAEs following once daily administration of 0.02% atropine free base nanoemulsion for 28 days in humans

[0326]

[0327] Abbreviations: m = number of events; MedDRA = Medical Dictionary for Regulatory Activities; TEAE = treatment-emergent adverse event.

[0328] NOTE: A TEAE was defined as an adverse event that occurred after the first IP administration or, if it started before IP administration, persisted thereafter and worsened in severity.

[0329] If a participant experienced more than one TEAE, that participant is shown only once in the Participant Count (n) column for a given system organ class and preferred term. The number of times the event occurred is shown under the Occurrence Count (m) column.

[0330] Events were coded using MedDRA version 25.0.

[0331] Embodiment 6:

[0332] Atropine free base nanoemulsion is more stable than atropine aqueous solution. The stability of atropine free base nanoemulsion shows that atropine is stable in the emulsion system for more than 1 year, while atropine sulfate aqueous solution tends to have a low pH to maintain stability for more than 6 months. However, low pH aqueous solutions often cause irritation in the eyes (Berton et al. 2020).

[0333] Table 6: Summary of ongoing laboratory development stability of representative atropine free base nanoemulsions (10% MCT:90% F6H8) in PET dropper bottles

[0334]

[0335] nm = nanometer; NT = not tested; %RH = % relative humidity; PET = polyethylene terephthalate; M = month

[0336] Embodiment 7:

[0337] For PET container system, atropine free base nanoemulsion is more stable and compatible, as shown in Table 6 below. For LDPE and PP container system, the stability of atropine free base nanoemulsion is poor and the compatibility is poor. Table 7 below shows the stability of atropine free base nanoemulsion in different types of container systems. Without being bound by theory, it is believed that the atropine free base nanoemulsion extracts the plastic materials of LDPE and PP, thereby absorbing atropine into the surface area of ​​the container system, as shown in the determination of dripping in LDPE and PP containers. LDPE and PP plastic polymer materials were detected in the samples of atropine free base nanoemulsion.

[0338] Table 7: Summary of in-laboratory development stability of representative atropine free base nanoemulsions (10% MCT:90% F6H8) in LDPE and PP dropper bottles

[0339]

[0340] NT = Not Tested; %RH = %Relative Humidity; PP = Polypropylene, LDPE = Low Density Polyethylene; M = Months

[0341] Embodiment 8:

[0342] After LC-MS / MS measurement and calculation results, it can be seen that after topical ocular administration of 0.02% atropine-10% MCT-F6H8 (0.0043 mg per eye, which is equivalent to 40-50 μL of 0.01% atropine sulfate drops per eye), the drug concentration distribution of atropine in ocular tissue at different times is as follows: Figure 5 and Figure 6 and Table 8. The drug concentration of atropine in plasma at different times is shown in Table 9 below. The drug concentrations in different parts of the ocular tissues show that the drug is rapidly absorbed in the eye after administration, reaches a peak concentration after 0.25-0.5h, and then gradually decreases, with only a small amount of drug present in various parts of the ocular tissue after 8h-12h. There is almost no drug in the vitreous humor, and only a small amount of drug in the retina and choroid after drug administration. The drug concentration in plasma reaches a peak concentration 0.25h after administration, and then the drug is rapidly metabolized, reaching the minimum detection limit after 1h.

[0343] Table 8: Drug concentrations in the vitreous humor at different times after topical ocular administration of atropine-10% MCT-F6H8 to both eyes of rabbits (n=2)

[0344] serial number <![CDATA[C 0.25hr(ng / mL) ]]> <![CDATA[C 0.5hr(ng / mL) ]]> <![CDATA[C 1hr(ng / mL) ]]> <![CDATA[C 2hr(ng / mL) ]]> 1-L 2.04 BLQ BLQ BLQ 1-R BLQ BLQ BLQ BLQ 2-L BLQ BLQ BLQ BLQ 2-R BLQ BLQ BLQ BLQ serial number <![CDATA[C 4hr(ng / mL) ]]> <![CDATA[C 8hr(ng / mL) ]]> <![CDATA[C 12hr(ng / mL) ]]> <![CDATA[C 24hr(ng / mL) ]]> 1-L BLQ BLQ BLQ BLQ 1-R 0.476 BLQ BLQ BLQ 2-L BLQ BLQ BLQ BLQ 2-R BLQ BLQ BLQ BLQ

[0345] Abbreviation: BLQ = below limit of quantitation (0.04 ng / mL).

[0346] Table 9: Plasma concentrations and PK parameters at different times after topical ocular administration of atropine-10% MCT-F6H8 to both eyes of rabbits (n=2)

[0347]

[0348]

[0349] Abbreviations: BLQ = below limit of quantitation (0.04 ng / mL); T 1 / 2 and AUC 0-inf It cannot be calculated due to lack of sufficient data.

[0350] Table 10. Pharmacokinetic parameters in ocular tissues following topical ocular administration of atropine-10% MCT-F6H8 to both eyes of rabbits (n=4 eyes)

[0351]

[0352] Note: NR is not reportable (Rsq < 0.85%); pharmacokinetic parameters in vitreous could not be calculated statistically due to lack of data points.

[0353] As in Figure 6 As shown in Table 10, after topical application of 0.02% atropine-10% MCT-F6H8, the ocular tissue reaches the drug peak at 0.25-0.5h, and the atropine concentration in different tissues is cornea>conjunctiva>iris-ciliary body>aqueous humor>sclera>retina>vitreous body. In general, there are two pathways to absorb topically applied drugs, including the corneal pathway and the conjunctival-sclera pathway. The corneal absorption pathway follows the cornea, aqueous humor, iris-ciliary body and vitreous body, and the conjunctival absorption pathway follows the conjunctiva, sclera and choroid-retina. There is almost no drug in the vitreous body, so atropine is difficult to deliver to the retina through the vitreous body through the corneal pathway, and there is a small amount of drug concentration in the retina, which is most likely absorbed by the conjunctiva and then delivered to the retina-choroid through the sclera.

[0354] In contrast to the drug concentration and delivery in ocular tissues after administration of atropine sulfate eye drops described in Wang et al., Acta Ophthalmol, 2019 (97): 238-247 and Ji et al., Pharmaceutical Research, 38 (11): 1931-1946, atropine sulfate eye drops are difficult to absorb and transfer to the posterior segment of the eye through the corneal route, and the drug is mainly absorbed through the conjunctival-scleral route and delivered to the choroid-retina through the sclera. This is due to the fact that atropine sulfate has a pKa of 9.43 after contact with ocular surface tears, which makes it difficult to be absorbed through the cornea. The distribution of drug concentrations in each eye tissue at different times after ocular administration of 0.02% atropine-10% MCT-F6H8 shows that atropine-10% MCT-F6H8 is mainly absorbed through the corneal route. This is because the Log P of atropine free base is 1.83, which has good corneal penetration, coupled with the good surface diffusion and tear film stability of F6H8, the drug concentration in the cornea is higher than that in the conjunctiva within 8 hours after application.

[0355] The mechanism of action of atropine in controlling myopia progression is still unclear, and it is generally believed that there is a complex interaction between atropine and multiple receptors on different tissues of the eye, slowing down the deepening of myopic refractive error and axial progression through multiple pathways. Based on the above drug distribution in ocular tissues at different times after administration and the results of the above efficacy studies, it can be seen that atropine is metabolized most in ocular tissues, and its effect disappears 8 hours after the administration of atropine-10% MCT-F6H8.

[0356] Example 9: Solubility of Acetocline in Exemplary Formulations

[0357] 9.1 Experiments

[0358] An appropriate amount of aceclidin was dissolved in various MCTs (to obtain a mixed solution), and then SFA (F6H8 or F4H5) was added to the solution at a specified ratio and the solution was mixed uniformly with magnetic stirring. The resulting mixture was filtered through a 0.22 μm filter and the filtered solution was analyzed by GC.

[0359] 9.2 Chromatographic conditions

[0360] Instrument: Agilent-8860 (CGC-001)

[0361]

[0362] 9.3 Results

[0363]

[0364] *Captex 355EP / NF / JPE and Captex 300EP / NF are glyceryl tricaprylate / tricaprate, respectively.

[0365] **Captex 8000NF is glyceryl tricaprylate, tricaprylin.

[0366] Example 10: Solubility of Lifelast in an Exemplary Formulation

[0367] 10.1 Experiments

[0368] An appropriate amount of lifilast was dissolved in various MCTs by vortexing, then SFA (F6H8 or F4H5) was added to the mixture at the indicated ratio and the solution was vortexed. The resulting mixture was filtered through a 0.22 μm filter and the filtered solution was analyzed by GC.

[0369] 10.2 Chromatographic conditions

[0370] Chromatographic column: Agilent ZORBAX SB-C18, 4.6*250mm, 5μm

[0371] Mobile phase A: 0.1% phosphoric acid-H2O

[0372] Mobile phase B: acetonitrile

[0373] Flow rate: 1.0mL / min Wavelength: UV / 220nm

[0374] Injection volume: 10 μL Column temperature: 35°C

[0375]

[0376]

[0377] Since the auxiliary peaks of MCM and MC8-2 overlapped with the main peak in the above gradient method, the analysis method of MCM and MC8-2 was adjusted as follows:

[0378] Chromatographic column: Agilent ZORBAX SB-C18, 4.6*250mm, 5μm

[0379] Mobile phase A: 0.1% phosphoric acid-H2O

[0380] Mobile phase B: acetonitrile

[0381] Flow rate: 1.0mL / min Wavelength: UV / 220nm

[0382] Injection volume: 10 μL Column temperature: 35°C

[0383] Time / min Mobile phase A Mobile phase B 0.01 80 20 30.00 40 60 30.01 80 20 40.00 80 20

[0384] 10.3 Results

[0385]

[0386] *Captex 355EP / NF / JPE and Captex 300EP / NF are glyceryl tricaprylate / tricaprate, respectively.

[0387] **Captex 8000NF is glyceryl tricaprylate, tricaprylin.

[0388] Example 11: Solubility of Atropine in Exemplary Formulations

[0389] 11.1 Experiments

[0390] An appropriate amount of atropine was dissolved in various MCTs by vortexing, then SFA (F6H8 or F4H5) was added to the mixture in the indicated ratio and the solution was vortexed. The resulting mixture was filtered through a 0.22 μm filter and the filtered solution was analyzed by GC.

[0391] 11.2 Chromatographic conditions

[0392] Chromatographic column: Shimadzu Shim-pack GIST C18-AQ HP 3μm, 4.6mm(ID)x 100mm(L), 3μm

[0393] Guard column: Shimadzu Shim-pack GIST HP(G)C18 3μm, 2.1mm(ID)x 10mm(L), 3μm

[0394] Mobile phase A: 0.02% TFA / water

[0395] Mobile phase B: 0.02% TFA / acetonitrile

[0396] Flow rate: 0.5mL / min Wavelength: 220nm

[0397] Injection volume: 5 μL Column temperature: 30°C

[0398] Time (min) % Mobile phase A % Mobile phase B

[0399] Time (min) % Mobile phase A % Mobile phase B 0 100 0 10 60 40 20 1 99 21 100 0 30 100 0

[0400] 11.3 Results

[0401]

[0402]

[0403] *Captex 355EP / NF / JPE and Captex 300EP / NF are glyceryl tricaprylate / tricaprate, respectively.

[0404] **Captex 8000NF is glyceryl tricaprylate, tricaprylin.

[0405] Example 12: Solubility of Acoltremon (AR-15512) in an exemplary formulation

[0406] 12.1 Experiments

[0407] An appropriate amount of Acoltremon (AR-15512) was dissolved in various MCTs by vortexing, then SFA (F6H8 or F4H5) was added to the mixture in the indicated ratio and the solution was vortexed. The resulting mixture was filtered through a 0.22 μm filter and the filtered solution was analyzed by GC.

[0408] 12.2 Chromatographic conditions

[0409] Chromatographic column: Shimadau Shim-pack GIST C18 5um, 4.6mm (ID) x 250mm (L), 5μm

[0410] Mobile phase A: 0.05% (v / v) TFA / water

[0411] Mobile phase B: 0.05% (v / v) TFA / acetonitrile

[0412] Flow rate: 1.0 mL / min Wavelength: 214 nm Injection volume: 10 μL Column temperature: 45°C Time (min) % Mobile phase A % Mobile phase B

[0413]

[0414] 12.3 Results

[0415]

[0416]

[0417] Captex 170EP is Coco-Caprylate / Caprate

[0418] Captex 200P is Propylene glycol dicaprylate

[0419] Captex 8000 is glyceryl tricaprylate, tricaprylin

[0420] Captex 355 is glyceryl tricaprylate / tricaprate

[0421] Example 13: Solubility of Lotiranab in an exemplary formulation

[0422] 13.1 Experiments

[0423] An appropriate amount of Lotiranal was dissolved in various MCTs by vortexing, then SFA (F6H8 or F4H5) was added to the mixture in the indicated ratio and the solution was vortexed. The resulting mixture was filtered through a 0.22 μm filter and the filtered solution was analyzed by GC.

[0424] 13.2 Chromatographic conditions

[0425] Chromatographic column: SHIMADAU Shim-pack GIST C18 5um, 4.6mm (ID) x 250mm (L), 5μm

[0426] Mobile phase A: 0.05% (v / v) TFA in water

[0427] Mobile phase B: 0.05% (v / v) TFA in acetonitrile

[0428] Flow rate: 1.0mL / min Wavelength: 214nm

[0429] Injection volume: 10 μL Column temperature: 45°C

[0430] Time (min) % Mobile phase A % Mobile phase B

[0431]

[0432] 13.3 Results

[0433]

[0434] Example 14: Solubility of Brimonidine in an Exemplary Formulation

[0435] 14.1 Experiments

[0436] The appropriate amount of brimonidine was dissolved in various MCTs by vortexing, then SFA (F6H8 or F4H5) was added to the mixture in the indicated ratio and the solution was vortexed. The resulting mixture was filtered through a 0.22 μm filter and the filtered solution was analyzed by GC.

[0437] 14.2 Chromatographic conditions

[0438] Chromatographic column: SHIMADZU Shim-pack GIST C18 5um, 4.6mm x 250mm, 5μm

[0439] Mobile phase A: 0.05% TFA-H2O

[0440] Mobile phase B: 0.05% TFA-acetonitrile

[0441] Flow rate: 1.0mL / min Wavelength: UV / 214nm

[0442] Injection volume: 5 μL Column temperature: 45°C

[0443] Time / min Mobile phase A Mobile phase B 0.01 95 5 10 85 15 15 85 15 15.01 95 5 25 95 5

[0444] 14.3 Results

[0445]

[0446]

[0447] Example 15: Solubility of Cyclosporin in Exemplary Formulations

[0448] 15.1 Experiments

[0449] An appropriate amount of cyclosporin was dissolved in various MCTs by vortexing, then SFA (F6H8 or F4H5) was added to the mixture in the indicated ratio and the solution was vortexed. The resulting mixture was filtered through a 0.22 μm filter and the filtered solution was analyzed by GC.

[0450] 15.2 Chromatographic conditions

[0451] Chromatographic column: SHIMADZU Shim-pack GIST C18 5um, 4.6mm x 250mm, 5μm

[0452] Mobile phase A: 0.05% (v / v) TFA in water

[0453] Mobile phase B: 0.05% (v / v) TFA in acetonitrile

[0454] Flow rate: 1.0mL / min Wavelength: 214nm

[0455] Injection volume: 10 μL Column temperature: 45°C

[0456] Time (min) % Mobile phase A % Mobile phase B 0.01 60 40 25 10 90 25.01 60 40 35 60 40

[0457] 15.3 Results

[0458]

[0459]

[0460] Example 16: Solubility of Ivermectin (CBT-273) in Exemplary Formulations

[0461] 16.1 Experiments

[0462] An appropriate amount of ivermectin (CBT-273) was dissolved in various MCTs by vortexing, then SFA (F6H8 or F4H5) was added to the mixture at the indicated ratio and the solution was vortexed. The resulting mixture was filtered through a 0.22 μm filter and the filtered solution was analyzed by GC.

[0463] 16.2 Chromatographic conditions

[0464] Chromatographic column: SHIMADAU Shim-pack GIST C18 5um, 4.6(ID)mm x250mm(L), 5μm

[0465] Mobile phase: acetonitrile: methanol: water = 55:35:10 (v:v:v)

[0466] Flow rate: 1.0mL / min Wavelength: 214nm

[0467] Injection volume: 10 μL Column temperature: 45°C

[0468] 16.3 Results

[0469]

[0470]

[0471] Example 17: Solubility of Acetocline in F6H8

[0472] Methods: Formulations of aceclidine free base were studied according to the following procedure:

[0473] 1. Determine the solubility of aceclidinium in F6H8

[0474] 5 mg of aceclidin was added to the PP tube, 1 ml of F6H8 was added, and the PP tube was shaken for about 5 minutes to completely dissolve the aceclidin in the solution. Another 18 mg of aceclidin was added, and the shaking was continued until no insoluble matter was found. The PP tube was centrifuged for 3 minutes, and a small amount of yellow-brown oil droplets were observed floating. This phenomenon disappeared after re-shaking.

[0475] 2. Preparation of GC Samples

[0476] The preparations were centrifuged and the supernatant was filtered through a 0.45 micron filter without further dilution. One sample was prepared from each solvent for GC analysis.

[0477] 3. Analyze GC Samples

[0478] The samples were analyzed using an Agilent 8890GC method using an HP-5 30m*0.32mm*0.5um GC column (150mm X 2.1mm FD.). The GC protocol and parameters are listed below:

[0479] parameter:

[0480] Gas flow rate: 2ml / min

[0481] Injection volume: 0.5ul (direct injection)

[0482] Column temperature: 70°C

[0483] Injection temperature: 280℃

[0484] Detector temperature (FID): 300°C

[0485] Gradient: 70℃ (hold for 2 min) → 12℃ / min → 280℃ (hold for 7 min)

[0486] Gas ratio: 30:1

[0487] N2:25ml / min

[0488] H2:30ml / min

[0489] Air: 300ml / min

[0490] like Figure 7 As shown in the chromatogram in FIG, the aceclidinium peak is at a retention time of 6.783 minutes.

[0491] result

[0492] Based on the GC method described above, the solubility of aceclidine in F6H8 was determined to be approximately 1.5% (w / v).

[0493] Example 18: Solubility of Acetidine in MCT

[0494] Sample preparation

[0495] 20 mg of aceclidin was added to a PP tube and 1 ml of MCT was added. The PP tube was shaken for about 5 minutes and the resulting solution became clear. Another 40 mg of aceclidin was added. The PP tube was shaken again. A small amount of transparent oil droplets were found to be insoluble. After centrifugation for 3 minutes, a small amount of yellow-brown oil droplets were observed to float. After shaking again, this phenomenon disappeared. Take a small sample and determine the solubility according to the GC method described in Example 17.

[0496] Based on the GC method described in Example 17, the solubility of aceclidin in MCT was determined to be approximately 5% (w / v).

[0497] Example 19: Solubility of Acetaminophen in a 10% MCT Solution in F6H8

[0498] Sample preparation and analysis were based on the protocols described in Examples 17 and 18. The solubility of aceclidinium in a 10% solution of MCT in F6H8 was determined to be approximately 2% (w / v).

[0499] Example 20: Stability of formulations of aceclidine in F6H8

[0500] method

[0501] Acetidine was dissolved in F6H8 as described in Example 17. The levels of acetidine were measured by GC method at 1, 3, 6, 9 and 12 months at 25° C. Acetidine in the formulation was defined as stable if the levels remained between 90-110% of the original levels.

[0502] result

[0503] Acetocline remained stable during the study period.

[0504] Example 21: In vivo pharmacological efficacy in a rabbit model

[0505] method:

[0506] Acetidine ophthalmic formulation: 2% acetidine in F6H8, MCT as co-solvent (ratio: MCT:F6H8 1:9)

[0507] Animal: Dutch Rabbit

[0508] On day 1, one drop of 2% aceclidin was applied once to each eye of 3 female rabbits. Before the start of administration, pupil diameters of both eyes of all animals were measured. Pupil diameters of both eyes of all animals were measured at baseline, 0.5h, 1h, 2h, 4h, 6h, 8h, 12h and 24h after administration.

[0509] result:

[0510] The baseline pupil diameter was 7.94±0.22 mm. 2% aceclidinium caused significant pupil constriction 0.5 hours after instillation (Table 19, Figure 8). Compared with the pupil diameter at baseline, significant pupil constriction (p≤0.05 or 0.01) was noted at 0.5h, 1h, 2h, 4h, 6h and 8h after treatment with the 2% aceclidinium ophthalmic preparation prepared as above, and the pupil diameter changes were -4.97, -4.24, -3.44, -1.64 and -0.40 mm. The peak effect (Emax) of pupil diameter constriction was -4.97 mm, which occurred 0.5 hours after administration.

[0511] Table 19. Changes in pupil diameter after single instillation administration of 2% aceclidin F8H8 MCT (ratio 9:1) formulation

[0512]

[0513]

[0514] For pupil diameter, *P < 0.05 or **P < 0.01 compared with baseline using T-TEST. No statistical comparison was made for changes in pupil diameter.

[0515] Example 22: In vivo pharmacological efficacy in a rabbit model

[0516] Effect of aceclidine on pupil diameter after a single topical instillation

[0517] method:

[0518] Test substances: 0.5% aceclidin, 1% aceclidin, 2% aceclidin in F6H8 ophthalmic preparations

[0519] Animal: Dutch Rabbit

[0520] One drop of 0.5% aceclidin, 1% aceclidin or 2% aceclidin in F6H8 was applied once to both eyes of 3 female rabbits in each group. Before the start of administration, the pupil diameter of both eyes of all animals was measured as a baseline. The pupil diameter of both eyes of all animals was measured at 0.5h, 1h, 2h, 4h, 6h, 8h, 12h and 24h after administration to evaluate the effect of aceclidin on pupil diameter.

[0521] result:

[0522] At 0.5% aceclidin, 1% aceclidin and 2% aceclidin dose levels, the baseline pupil diameters were 8.17 ± 0.50, 8.11 ± 0.72 and 7.94 ± 0.22 mm, respectively. All three dose levels of aceclidin caused significant pupil constriction at 0.5 hours after instillation and lasted until 2-6 hours (Table 20, Figure 9). Compared with the pupil diameter at baseline, significant pupil constriction (p ≤ 0.01) was observed after 0.5% aceclidin was applied for 0.5h, 1h, and 2h, and the pupil diameter changed to -3.56, -2.54 and -1.43mm. Compared with the pupil diameter at baseline, significant pupil constriction (p ≤ 0.01 or 0.05) was observed after 1% aceclidin was applied for 0.5h, 1h, 2h and 4h, and the pupil diameter changed to -4.57, -3.38, -2.07 and -1.16mm. Significant pupil constriction (p≤0.01 or 0.05) was observed at 0.5h, 1h, 2h, 4h and 6h after 2% aceclidin administration, with pupil diameter changes of -4.97, -4.24, -3.44, -1.64 and -0.40 mm, compared to the pupil diameter at baseline. The peak effect (Emax) of pupil constriction with pupil diameters of -3.56, -4.57 and -4.97 mm occurred at 0.5h after administration at the 0.5%, 1% and 2% aceclidin dose levels, respectively. Dose effects and relationships of pupil constriction were observed at the 0.5-2% aceclidin dose levels.

[0523] Table 20. Effects on pupil diameter following single instillation and administration of aceclidine.

[0524]

[0525] Examples 17, 18 and 19 demonstrate that stable aceclidine formulations can be obtained in F6H8, including the addition of co-solvents in some cases. Example 21 shows that an equivalent dose of aceclidine free base F6H8 organic formulation achieves efficacy similar to that of aceclidine aqueous formulation in a rabbit model. The study suggests that muscarinic cholinergic receptor agonists in formulations with semifluorinated alkane compounds such as F6H8 as liquid vehicles may also be effective.

[0526] Example 23: Solubility of Axitinib in Exemplary Formulations

[0527] 23.1 Experiment

[0528] An appropriate amount of axitinib was dissolved in various MCTs by vortexing, then SFA (F6H8 or F4H5) was added to the mixture at the indicated ratio and the solution was vortexed. The resulting mixture was filtered through a 0.22 μm filter and the filtered solution was analyzed by GC.

[0529] 23.2 Chromatographic conditions

[0530] Column: SHIMADZU Shim-pack GIST C18 5um, 4.6mm x 150mm, 5μm

[0531] Mobile phase A: 0.05% TFA-H2O

[0532] Mobile phase B: 0.05% TFA-acetonitrile

[0533] Flow rate: 1.0mL / min Wavelength: 362nm

[0534] Injection volume: 30 μL Column temperature: 40°C

[0535] Table 21.

[0536] Time / min Mobile phase A Mobile phase B 0.00 80 20 6.00 50 50 6.10 80 20 10.00 80 20

[0537] 23.3 Results

[0538]

[0539]

[0540] Implementation

[0541] 1. A topical ophthalmic composition comprising: about 0.001% to about 5% (w / w) or about 0.0001% to about 20% (w / w) of an active pharmaceutical ingredient (API), about 1% to about 50% (w / w) of MCT, and about 50% to about 99% (w / w) of a semifluorinated alkane compound, wherein the API has a solubility in medium chain triglycerides (MCT) of at least about 0.01% to about 10% (w / w), and wherein the API is not atropine or a salt thereof.

[0542] 2. The topical ophthalmic composition of embodiment 1, wherein the composition is non-aqueous.

[0543] 3. The topical ophthalmic composition of any one of embodiments 1-2, wherein the semifluorinated alkane compound is selected from perfluorobutylheptane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8) and perfluorohexyldecane (F6H10).

[0544] 4. The topical ophthalmic composition of any one of embodiments 1-3, wherein the MCT is present in a concentration of about 10% to about 50% (w / w) and the semifluorinated alkane compound is present in a concentration of about 50% to about 90% (w / w).

[0545] 5. The topical ophthalmic composition of any one of embodiments 1-4, wherein the MCT is present in a concentration of about 10% to about 30% (w / w) and the semifluorinated alkane compound is present in a concentration of about 70% to about 90% (w / w).

[0546] 6. The topical ophthalmic composition of any one of embodiments 1-5, wherein the API is present in a concentration of about 0.01% to 1% (w / w).

[0547] 7. The topical ophthalmic composition of any one of embodiments 1-6, wherein the API is in free base form.

[0548] 8. The topical ophthalmic composition of any one of embodiments 1-7, wherein the MCT is a triglyceride of a fatty acid and the fatty acid comprises caproic acid, caprylic acid, capric acid, dodecanoic acid, or a combination of two or more thereof.

[0549] 9. The topical ophthalmic composition of any one of embodiments 1-8, wherein the MCT is present at a concentration of about 5% (w / w) and the semifluorinated alkane compound is present at a concentration of about 95% (w / w), wherein the MCT is present at a concentration of about 10% (w / w) and the semifluorinated alkane compound is present at a concentration of about 90% (w / w), wherein the MCT is present at a concentration of about 15% (w / w) and the semifluorinated alkane compound is present at a concentration of about 85% (w / w), or wherein the MCT is present at a concentration of about 20% (w / w) and the semifluorinated alkane compound is present at a concentration of about 80% (w / w).

[0550] 10. The topical composition of any one of embodiments 1-9, wherein the semifluorinated alkane is perfluorohexyl octane (F6H8).

[0551] 11. The topical composition of any one of embodiments 1-10, wherein the MCT is a triglyceride of a fatty acid and the fatty acid consists essentially of caproic acid, caprylic acid, capric acid, dodecanoic acid, or a combination thereof.

[0552] 12. The topical ophthalmic composition of any one of embodiments 1-11, wherein the topical ophthalmic composition is an emulsion.

[0553] 13. The topical ophthalmic composition of any one of embodiments 1-12, wherein the API in the topical ophthalmic composition is chemically stable for at least 6 months, at least 1 year, at least 18 months, at least 2 years, or longer.

[0554] 14. The topical ophthalmic composition of any one of embodiments 1-13, wherein the API is not a muscarinic receptor antagonist.

[0555] 15. The topical ophthalmic composition of any one of embodiments 1-14, wherein the API is selected from alpha agonists, antibiotics, corticosteroids, antinicotinic agents, antiglaucoma agents, antihistamines, antivirals, antiparasitics, pressure regulators, topical transient receptor potential melastatin 8 (TRPM8) agonists, inhibitors of inflammatory cell binding, cycloplegics / mydriatics, mast cell stabilizers, miotics, ophthalmic NSAIDs, cyclosporins, riboflavin 5'-phosphate ophthalmic compounds, and VEGF inhibitors and VEGF receptor inhibitors.

[0556] 16. A topical ophthalmic composition consisting essentially of about 0.001% to about 5% (w / w) or about 0.0001% to about 10% (w / w) active pharmaceutical ingredient (API), about 1% to about 50% (w / w) medium chain triglycerides (MCT), and about 50% to about 99% (w / w) semifluorinated alkane compound, wherein the API has a solubility in MCT of at least about 0.01% to about 10% (w / w), and wherein the API is not atropine or a salt thereof.

[0557] 17. The topical ophthalmic composition of embodiment 16, wherein the semifluorinated alkane compound is selected from perfluorobutylheptane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8) and perfluorohexyldecane (F6H10).

[0558] 18. The topical ophthalmic composition of any of embodiments 16 or 17, wherein the MCT is present at a concentration of about 5% (w / w) and the semifluorinated alkane compound is present at a concentration of about 95% (w / w), wherein the MCT is present at a concentration of about 10% (w / w) and the semifluorinated alkane compound is present at a concentration of about 90% (w / w), wherein the MCT is present at a concentration of about 15% (w / w) and the semifluorinated alkane compound is present at a concentration of about 85% (w / w), or wherein the MCT is present at a concentration of about 20% (w / w) and the semifluorinated alkane compound is present at a concentration of about 80% (w / w).

[0559] 19. A topical ophthalmic composition comprising: about 0.01% to about 1% (w / w) or about 0.0001% to about 10% (w / w) of an active pharmaceutical ingredient (API), wherein the API has a solubility in MCT of at least about 0.01% to about 10% (w / w), and wherein the API is not atropine or a salt thereof; about 10% to about 30% (w / w) of a medium chain triglyceride (MCT); and about 70% to about 90% (w / w) of a semifluorinated alkane compound selected from the group consisting of perfluorobutylheptane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyldecane (F6H10).

[0560] 20. A topical ophthalmic nanoemulsion comprising: about 0.001% to about 5% (w / w) or about 0.0001% to about 20% (w / w) of an active pharmaceutical ingredient (API), about 1% to about 50% (w / w) of a medium chain triglyceride (MCT), and about 50% to about 99% (w / w) of a semifluorinated alkane compound, wherein the API has a solubility in MCT of at least about 0.01% to about 10% (w / w); wherein the nanoemulsion has a droplet size D90 of less than about 100 nm.

[0561] 21. The topical ophthalmic nanoemulsion of embodiment 20, wherein the nanoemulsion has a droplet size D90 of less than about 20 nm, less than about 10 nm, or less than about 5 nm, or has a droplet size D90 of about 2 to about 3 nm.

[0562] 22. The topical ophthalmic nanoemulsion of any one of embodiments 20-21, wherein the nanoemulsion has a peak droplet size of less than about 10 nm or has a peak droplet size of about 1 nm to about 5 nm.

[0563] 23. The topical ophthalmic nanoemulsion of any one of embodiments 20-22, wherein the composition is non-aqueous.

[0564] 24. The topical ophthalmic nanoemulsion of any one of embodiments 20-23, wherein the semifluorinated alkane compound is selected from perfluorobutylheptane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8) and perfluorohexyldecane (F6H10).

[0565] 25. The topical ophthalmic nanoemulsion of any one of embodiments 20-24, wherein the MCT is present in a concentration of about 10% to about 50% (w / w) and the semifluorinated alkane compound is present in a concentration of about 50% to about 90% (w / w).

[0566] 26. The topical ophthalmic nanoemulsion of any one of embodiments 20-25, wherein the MCT is present in a concentration of about 10% to about 30% (w / w) and the semifluorinated alkane compound is present in a concentration of about 70% to about 90% (w / w).

[0567] 27. The topical ophthalmic nanoemulsion of any one of embodiments 20-26, wherein the API is present in a concentration of about 0.01% to 1% (w / w) or about 0.0001% to about 10% (w / w).

[0568] 28. The topical ophthalmic nanoemulsion of any one of embodiments 20-27, wherein the API is in free base form.

[0569] 29. The topical ophthalmic nanoemulsion of any one of embodiments 20-28, wherein the MCT is a triglyceride of a fatty acid and the fatty acid comprises caproic acid, caprylic acid, capric acid, dodecanoic acid, or a combination of two or more thereof.

[0570] 30. The topical ophthalmic nanoemulsion of any one of embodiments 20-29, wherein the MCT is present at a concentration of about 5% (w / w) and the semifluorinated alkane compound is present at a concentration of about 95% (w / w), wherein the MCT is present at a concentration of about 10% (w / w) and the semifluorinated alkane compound is present at a concentration of about 90% (w / w), wherein the MCT is present at a concentration of about 15% (w / w) and the semifluorinated alkane compound is present at a concentration of about 85% (w / w), or wherein the MCT is present at a concentration of about 20% (w / w) and the semifluorinated alkane compound is present at a concentration of about 80% (w / w).

[0571] 31. The topical ophthalmic nanoemulsion of any one of embodiments 20-30, wherein the semifluorinated alkane is perfluorohexyl octane (F6H8).

[0572] 32. The topical ophthalmic nanoemulsion of any one of embodiments 20-31, wherein the MCT is a triglyceride of a fatty acid and the fatty acid consists essentially of caproic acid, caprylic acid, capric acid, dodecanoic acid, or a combination thereof.

[0573] 33. The topical ophthalmic nanoemulsion of any one of embodiments 20-32, wherein the topical ophthalmic nanoemulsion is an emulsion.

[0574] 34. The topical ophthalmic nanoemulsion of any one of embodiments 20-33, wherein the API in the topical ophthalmic nanoemulsion is chemically stable for at least 6 months, at least 1 year, at least 18 months, at least 2 years, or longer.

[0575] 35. The topical ophthalmic nanoemulsion of any one of embodiments 20-34, wherein the API is selected from alpha agonists, antibiotics, corticosteroids, anticholinergics, antiglaucoma agents, antihistamines, antivirals, antiparasitics, pressure regulators, local transient receptor potential melastatin 8 (TRPM8) agonists, inhibitors of inflammatory cell binding, cycloplegics / mydriatics, mast cell stabilizers, miotics, ophthalmic NSAIDs, cyclosporins, riboflavin 5'-phosphate ophthalmic compounds, and VEGF inhibitors and VEGF receptor inhibitors.

[0576] 36. A topical ophthalmic nanoemulsion consisting essentially of: about 0.001% to about 5% (w / w) or about 0.0001% to about 10% (w / w) active pharmaceutical ingredient (API), about 1% to about 50% (w / w) medium chain triglycerides (MCT), and about 50% to about 99% (w / w) semifluorinated alkane compound, wherein the API has a solubility in MCT of at least about 0.01% to about 10% (w / w); wherein the nanoemulsion has a droplet size D90 of less than about 100 nm, less than about 20 nm, less than about 10 nm, less than about 5 nm, or about 2 to about 3 nm.

[0577] 37. The topical ophthalmic nanoemulsion of embodiment 36, wherein the semifluorinated alkane compound is selected from perfluorobutylheptane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8) and perfluorohexyldecane (F6H10).

[0578] 38. The topical ophthalmic nanoemulsion of any of embodiments 36 or 37, wherein the MCT is present at a concentration of about 5% (w / w) and the semifluorinated alkane compound is present at a concentration of about 95% (w / w), wherein the MCT is present at a concentration of about 10% (w / w) and the semifluorinated alkane compound is present at a concentration of about 90% (w / w), wherein the MCT is present at a concentration of about 15% (w / w) and the semifluorinated alkane compound is present at a concentration of about 85% (w / w), or wherein the MCT is present at a concentration of about 20% (w / w) and the semifluorinated alkane compound is present at a concentration of about 80% (w / w).

[0579] 39. A topical ophthalmic nanoemulsion comprising: about 0.001% to about 1% (w / w) or about 0.0001% to about 10% (w / w) of an active pharmaceutical ingredient (API), wherein the API has a solubility in MCT of at least about 0.01% to about 10% (w / w); about 10% to about 30% (w / w) of medium chain triglycerides (MCT); and about 70% to about 90% (w / w) of semi-fluoro A fluoroalkylated alkane compound selected from the group consisting of perfluorobutylheptane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8) and perfluorohexyldecane (F6H10), wherein the nanoemulsion has a droplet size D90 of less than about 100 nm, less than about 20 nm, less than about 10 nm, less than about 5 nm, or about 2 to about 3 nm.

[0580] 40. The topical ophthalmic nanoemulsion of any one of embodiments 20-39, wherein the API is a muscarinic receptor antagonist.

[0581] 41. The topical ophthalmic nanoemulsion of any one of embodiments 20-40, wherein the API is atropine, an atropine mimetic or analog, or a free base or salt form thereof.

[0582] 42. The topical ophthalmic nanoemulsion of any one of embodiments 20-41, wherein the API is atropine free base.

[0583] 43. The topical ophthalmic composition of any one of embodiments 20-39, wherein the API is atropine, an atropine mimetic or analog, or a free base or salt form thereof and is present in a concentration of about 0.001% to about 1% (w / w).

[0584] 44. The topical ophthalmic nanoemulsion of any one of embodiments 20-39, wherein the API is not a muscarinic receptor antagonist.

[0585] 45. The topical ophthalmic nanoemulsion of any one of embodiments 20-39, wherein the API is not atropine, an atropine mimetic or analog, or a free base or salt form thereof.

[0586] 46. ​​A dispenser comprising: a container portion comprising an inner wall defining an interior volume and adapted to contact and store a liquid within at least a portion of the interior volume; a dispensing portion adapted to dispense one or more drops of liquid out of the container portion; and a composition of embodiments 1-19, 77, 78, 80-82, 84, 85, 101-106, 112-116, 122-128, 134-155, 160-164, 203, 209-214, or 220-224, or embodiments 20-45, 77, 78, 80-82, 84, 85, 101-106, 112-116, 122-128, 134-155, 160-164, 203, 209-214, or 220-224 contained in the interior volume. 5, 101-106, 112-128 or 134-155, 160-164, 203, 209-214 or 220-224, or any of the compositions comprising: about 0.001% to about 5% (w / w) or about 0.0001% to about 10% (w / w) of an active pharmaceutical ingredient (API), about 1% to about 50% (w / w) of a medium chain triglyceride (MCT), and about 50% to about 99% (w / w) of a semifluorinated alkane compound, wherein the API has a solubility in MCT of at least about 0.01% to about 10% (w / w).

[0587] 47. The dispenser of embodiment 46, wherein the inner wall comprises less than about 10% of one or more of low density polyethylene (LDPE) or polypropylene (PP).

[0588] 48. The dispenser of any of embodiments 46-47, wherein the inner wall does not comprise low-density polyethylene (LDPE) or polypropylene (PP).

[0589] 49. The dispenser of any of embodiments 46-48, wherein the inner wall comprises glass or polyethylene terephthalate.

[0590] 50. The dispenser of any of embodiments 46-49, wherein the inner wall consists essentially of glass or polyethylene terephthalate (PET).

[0591] 51. The dispenser of any one of embodiments 46-50, wherein the concentration of the API remains above 90% of the initial API concentration after a storage period of at least 6 months in the dispenser, or wherein the concentration of the API remains above 90% of the initial API concentration after a storage period of at least 12 months in the dispenser, or wherein the concentration of the API remains above 90% of the initial API concentration after a storage period of at least 24 months in the dispenser.

[0592] 52. The dispenser of any of embodiments 46-51, wherein the container portion and the dispensing portion each independently consist essentially of glass or polyethylene terephthalate (PET).

[0593] 53. The dispenser of any one of embodiments 46-52, wherein the volume of the one or more drops is each independently about 5 μl to about 40 μl.

[0594] 54. The dispenser of any of embodiments 46-53, wherein the composition comprises: about 0.001% to about 1% (w / w) atropine, an atropine mimetic or analog, or a free base or salt form thereof; about 5% to about 30% (w / w) medium chain triglycerides (MCT); and about 70% to about 95% (w / w) semifluorinated alkane compounds selected from perfluorobutylheptane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8) and perfluorohexyldecane (F6H10).

[0595] 55. A method for treating, slowing the progression of, or alleviating one or more symptoms of an ocular disorder in a subject, the method comprising administering to an eye of the subject a topical ophthalmic composition of any one of embodiments 1-19, 77, 78, 80-82, 84, 85, 101-106, 112-116, 122-128, 134-155, 160-164, 203, 209-214, or 220-224, or a nanoemulsion of any one of embodiments 20-45, 77, 78, 80-82, 84, 85, 101-106, 112-128, 134-155, 160-164, 203, 209-214, or 220-224.

[0596] 56. The method of embodiment 55, wherein the ocular condition is selected from the group consisting of neurotrophic keratitis, glaucoma, elevated intraocular pressure, ocular hypertension, hyperopia, myopia, ocular rosacea, dry eye disease, meibomian gland dysfunction, blepharitis, allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, pterygium, palpebral fissure, corneal transplant rejection, graft-versus-host disease, ocular allergy, uveitis, anterior uveitis, Behcet's disease, Sjögren's syndrome, Stevens-Johnson syndrome, ocular cicatricial pemphigoid, chronic ocular surface inflammation caused by viral infection, herpes simplex keratitis, atopic conjunctivitis, Lyell's syndrome, neovascularization induced by viral, bacterial, fungal or parasitic infection, contact lens-induced neovascularization, ulceration, alkali burns, stem cell deficiency, neovascular glaucoma, Stevens-Johnson syndrome, Johnson syndrome, ocular tumors, aphakia, pseudophakia, astigmatism, blepharospasm, cataracts, conjunctival diseases, corneal diseases, corneal ulcers, eyelid diseases, lacrimal apparatus diseases, pupil disorders, refractive disorders, strabismus.

[0597] 57. A method of delivering an API to an eye of a subject, the method comprising administering to the eye of the subject any of the compositions of embodiments 1-19, 77, 78, 80-82, 84, 85, 101-106, 112-116, 122-128, 134-155, or 160-164, 203, 209-214, or 220-224, or the nanoemulsions of embodiments 20-45, 77, 78, 80-82, 84, 85, 101-106, 112-128, 134-155, or 160-164, 203, 209-214, or 220-224.

[0598] 58. The method of any one of embodiments 55-57, wherein the API is selected from alpha agonists, antibiotics, corticosteroids, anticholinergics, antiglaucoma agents, antihistamines, antivirals, antiparasitics, pressure regulators, local transient receptor potential melastatin 8 (TRPM8) agonists, inhibitors of inflammatory cell binding, cycloplegics / mydriatics, mast cell stabilizers, miotics, ophthalmic NSAIDs, cyclosporine, riboflavin 5'-phosphate ophthalmic compounds, and VEGF inhibitors and VEGF receptor inhibitors.

[0599] 59. The method of any one of embodiments 55 to 58, wherein the topical ophthalmic composition or the nanoemulsion is absorbed in the eye through the cornea.

[0600] 60. The method of any one of embodiments 55 to 58, wherein the topical ophthalmic composition or the nanoemulsion is selectively absorbed in the eye through the cornea as compared to the periorbital region.

[0601] 61. The method of any one of embodiments 55 to 60, wherein the topical ophthalmic composition is non-aqueous; optionally wherein the topical ophthalmic composition is an emulsion.

[0602] 62. The method of any one of embodiments 55 to 61, wherein the topical ophthalmic composition is non-aqueous, and wherein the applied dose of the topical ophthalmic composition or the nanoemulsion is 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70%, or 50-70% less than a dose of an aqueous topical ophthalmic composition comprising the API for treating, slowing the progression of, or alleviating one or more symptoms of an ocular disorder.

[0603] 63. The method of any one of embodiments 55 to 62, wherein the topical ophthalmic composition or the nanoemulsion is administered to the subject every about 6 to about 8 hours or three times a day.

[0604] 64. The method of any one of embodiments 55 to 63, wherein the API is in free base form.

[0605] 65. A method for slowing myopia progression in a subject or for alleviating the symptoms of vitreous floaters in a subject, the method comprising administering to an eye of the subject the nanoemulsion of any one of embodiments 20-45, wherein the API is a muscarinic receptor antagonist.

[0606] 66. The method of embodiment 65, wherein the API is selected from atropine, an atropine mimetic or analog, or a free base or salt form thereof.

[0607] 67. The method of embodiment 65 or 66, wherein the API is in free base form.

[0608] 68. The method of any one of embodiments 65 to 67, wherein the nanoemulsion is absorbed in the eye through the cornea.

[0609] 69. The method of any one of embodiments 65 to 67, wherein the nanoemulsion is selectively absorbed in the eye through the cornea compared to the periorbital region.

[0610] 70. The method of any one of embodiments 65 to 69, wherein the dose of the nanoemulsion administered is 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70%, or 50-70% less than the dose of an aqueous topical ophthalmic composition comprising the API for slowing the progression of myopia in a subject or for alleviating the symptoms of vitreous floaters in a subject.

[0611] 71. The method of any one of embodiments 65 to 70, wherein the nanoemulsion is administered to the subject every about 6 to about 8 hours or three times a day.

[0612] 72. A method for preparing a topical ophthalmic nanoemulsion of any one of embodiments 20-45, 77, 78, 80-82, 84, 85, 101-106 or 112-121, the method comprising the steps of: (a) combining an ocular API with MCT to form an MCT solution; (b) combining the MCT solution with a semifluorinated alkane compound to form a mixture, wherein the mixture comprises about 1% to about 50% of the MCT solution and about 50% to about 99% of the semifluorinated alkane compound; and (c) emulsifying the mixture and reducing the droplet size D90 within the mixture to less than 100 nm by physical agitation, wherein the physical agitation is selected from high speed stirring, vortexing, sonication, heating and stirring or homogenizing the mixture until the droplet size reaches a droplet size D90 of less than 100 nm.

[0613] 73. The method of embodiment 72, further comprising measuring the droplet size of the mixture during or after the physical stirring.

[0614] 74. The method of embodiment 72 or 73, wherein reducing the droplet size D90 within the mixture to less than 100 nm comprises reducing the droplet size D90 within the mixture to less than 50 nm, less than 20 nm, less than 10 nm, less than 5 nm, or about 2 to about 3 nm.

[0615] 75. The method of any one of embodiments 72-74, wherein the API is selected from alpha agonists, antibiotics, corticosteroids, anticholinergics, antiglaucoma agents, antihistamines, antivirals, antiparasitics, pressure regulators, local transient receptor potential melastatin 8 (TRPM8) agonists, inhibitors of inflammatory cell binding, cycloplegics / mydriatics, mast cell stabilizers, miotics, ophthalmic NSAIDs, cyclosporine, riboflavin 5'-phosphate ophthalmic compounds, and VEGF inhibitors and VEGF receptor inhibitors.

[0616] 76. A method for treating or reducing one or more symptoms of blepharitis, ocular rosacea, rosacea, or redness of the eyelid margins in a subject, or for improving eyelash health in a subject, or for treating or eradicating Demodex, lice, scabies, or bed bugs in a subject, or for treating or preventing a vector-borne disease in a subject, the method comprising administering to the subject, to the eye of the subject, or to the skin or hair of the subject a composition of embodiments 1-19 or a nanoemulsion of embodiments 20-45, wherein the API is an antiparasitic drug.

[0617] 77. The composition of any one of embodiments 1-19, or the nanoemulsion of embodiments 20-45, or the method of any one of embodiments 55-58 or 76, wherein the API is an isoxazoline parasiticide or a formamidine parasiticide.

[0618] 78. The composition of any one of embodiments 1-19, or the nanoemulsion of embodiments 20-45, or the method of any one of embodiments 55-58 or 76, wherein the API is flurana, sarolana, lotirana, afoxolana and / or fluoxetine, a derivative, an analog, an enantiomer, a racemic mixture, a free base, an enantiomerically pure composition, or one or more of the L- and D-isomers thereof.

[0619] 79. A method for treating, slowing the progression of, or alleviating one or more symptoms of dry eye, meibomian gland dysfunction, or inflammatory dry eye in a subject, the method comprising administering to the subject's eye a composition of any one of embodiments 1-19 or a nanoemulsion of embodiments 20-45, wherein the API is selected from rifemilast, AR-15512 ((1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide), cyclosporine, or one or more of its derivatives, analogs, pharmaceutically acceptable salts, free base forms, racemic mixtures, or diastereomers or enantiomers.

[0620] 80. The composition of any one of embodiments 1-19, or the nanoemulsion of embodiments 20-45, or the method of any one of embodiments 55-58 or 65, wherein the API is rifirastat, or a derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.

[0621] 81. The composition of any one of embodiments 1-19, or the nanoemulsion of embodiments 20-45, or the method of any one of embodiments 55-58 or 76, wherein the API is cyclosporine or a derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.

[0622] 82. The composition of any one of embodiments 1-19, or the nanoemulsion of embodiments 20-45, or the method of any one of embodiments 55-58 or 76, wherein the API is AR-15512 ((1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide) or a derivative, analog, racemic mixture, or diastereomer or enantiomer thereof.

[0623] 83. A method for treating, slowing the progression of, or alleviating one or more symptoms of glaucoma, ocular hypertension or high fluid pressure in an eye of a subject, or a method of reducing fluid pressure in an eye of a subject, the method comprising administering to the eye of the subject a composition of any one of embodiments 1-19 or a nanoemulsion of embodiments 20-45, wherein the API is a pressure modulator.

[0624] 84. The composition of any one of embodiments 1-19, or the nanoemulsion of embodiments 20-45, or the method of any one of embodiments 55-58 or 76, wherein the API is selected from one or more of Brimonidine, Apraclonidine Iopidine, Dorzolamide, Brinzolamide, Azopt, Timolol, Timoptic / Istalol / Betimol, Betaxolol, Betoptic, Levobunolol, Betagan, Metipranolol, Optipranolol, Latanoprost, Xalatan Green, Bimatoprost, Lumigan, Tafluprost, Zioptan, Latanoprostene, Vyzulta Turquoise, Pilocarpine, Carbachol, Isopto Carbachol, Netarsudil and Rhopressa, and pharmaceutically acceptable salts or free base forms thereof.

[0625] 85. The composition of any one of embodiments 1-19, or the nanoemulsion of embodiments 20-45, or the method of any one of embodiments 55-58 or 76, wherein the API is brimonidine.

[0626] 86. A method for treating, slowing the progression of, or alleviating one or more symptoms of an ocular disorder in a subject, the method comprising administering a topical ophthalmic composition to an eye of the subject, wherein the topical ophthalmic composition comprises: about 0.001% to about 5% (w / w) of an active pharmaceutical ingredient (API), about 1% to about 50% (w / w) of MCT, and about 50% to about 99% (w / w) of a semifluorinated alkane compound, wherein the API has a solubility in medium chain triglycerides (MCT) of at least about 0.01% to about 10% (w / w), and wherein the API is atropine; wherein (i) the topical ophthalmic composition is administered to the eye of the subject every about 6 to about 8 hours or three times per day, or (ii) the topical ophthalmic composition is a non-aqueous and wherein the topical ophthalmic composition is administered at a dose that is 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70%, or 50-70% less than a dose of an aqueous topical ophthalmic composition comprising the API for treating an ocular disorder, slowing its progression, or alleviating one or more symptoms thereof; optionally wherein the topical ophthalmic composition is non-aqueous; and optionally wherein the API is in free base form.

[0627] 87. The method of embodiment 86, wherein the ocular condition is selected from the group consisting of neurotrophic keratitis, glaucoma, elevated intraocular pressure, ocular hypertension, hyperopia, myopia, ocular rosacea, dry eye disease, meibomian gland dysfunction, blepharitis, allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, pterygium, palpebral fissure, corneal transplant rejection, graft-versus-host disease, ocular allergy, uveitis, anterior uveitis, Behcet's disease, Sjögren's syndrome, Stevens-Johnson syndrome, ocular cicatricial pemphigoid, chronic ocular surface inflammation caused by viral infection, herpes simplex keratitis, atopic conjunctivitis, Lyell syndrome, neovascularization induced by viral, bacterial, fungal or parasitic infection, contact lens-induced neovascularization, ulceration, alkali burns, stem cell deficiency, neovascular glaucoma, Stevens-Johnson syndrome, Johnson syndrome, ocular tumors, aphakia, pseudophakia, astigmatism, blepharospasm, cataracts, conjunctival diseases, corneal diseases, corneal ulcers, eyelid diseases, lacrimal apparatus diseases, pupil disorders, refractive disorders, strabismus.

[0628] 88. A method of delivering an active pharmaceutical ingredient (API) to an eye of a subject, the method comprising administering to the eye of the subject a topical ophthalmic composition, wherein the topical ophthalmic composition comprises: about 0.001% to about 5% (w / w) API, about 1% to about 50% (w / w) MCT, and about 50% to about 99% (w / w) a semifluorinated alkane compound, wherein the API has a solubility in medium chain triglycerides (MCT) of at least about 0.01% to about 10% (w / w), and wherein the API is atropine; wherein (i) the topical ophthalmic composition is administered to the eye of the subject every about 6 to about 8 hours or three times per day, or (ii) the topical ophthalmic composition is non-aqueous, and wherein the topical ophthalmic composition is administered to the eye of the subject. The dosage of the topical ophthalmic composition administered is 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70%, or 50-70% less than the dosage of an aqueous topical ophthalmic composition comprising the API for treating an ocular disorder, slowing its progression, or alleviating one or more symptoms thereof; optionally wherein the topical ophthalmic composition is non-aqueous; and optionally wherein the API is in free base form.

[0629] 89. A method for slowing the progression of myopia in a subject or for alleviating the symptoms of vitreous floaters in a subject, the method comprising administering a topical ophthalmic composition to an eye of the subject, wherein the topical ophthalmic composition comprises: about 0.001% to about 5% (w / w) API, about 1% to about 50% (w / w) MCT, and about 50% to about 99% (w / w) semifluorinated alkane compound, wherein the API has a solubility in medium chain triglycerides (MCT) of at least about 0.01% to about 10% (w / w), and wherein the API is selected from atropine or an atropine mimetic; wherein (i) the topical ophthalmic composition is administered to the eye of the subject every about 6 to about 8 hours or three times a day, or (ii) the topical ophthalmic composition is non-aqueous, and wherein the dosage of the topical ophthalmic composition administered is 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70% or 50-70% less than a dosage of an aqueous topical ophthalmic composition comprising the API for slowing myopia progression in a subject or for alleviating symptoms of vitreous floaters in a subject; optionally wherein the topical ophthalmic composition is non-aqueous; and optionally wherein the API is in free base form.

[0630] 90. The method of any one of embodiments 86 to 89, wherein the topical ophthalmic composition is absorbed in the eye through the cornea.

[0631] 91. The method of any one of embodiments 86 to 89, wherein the topical ophthalmic composition is selectively absorbed in the eye through the cornea as compared to the periorbital region.

[0632] 92. A method of administering a topical ophthalmic composition to a subject for selective transcorneal absorption, the method comprising administering to an eye of the subject the topical ophthalmic composition of any one of embodiments 1 to 19 or the topical ophthalmic nanoemulsion of any one of embodiments 20 to 45; optionally wherein the topical ophthalmic composition is non-aqueous; and optionally wherein the API is in free base form.

[0633] 93. A method of treating an ocular condition in a subject, the method comprising: (a) (i) selecting a subject in need of transcorneal absorption of an API; or (ii) selecting a subject having an ocular condition, wherein the ocular condition requires transcorneal absorption of an API; and (b) administering to an eye of the subject the topical ophthalmic composition of any one of embodiments 1 to 19 or the topical ophthalmic nanoemulsion of any one of embodiments 20 to 45; optionally wherein the topical ophthalmic composition is non-aqueous; and optionally wherein the API is in free base form.

[0634] 94. A method of treating an ocular condition in a subject, the method comprising: (a) (i) selecting a subject in need of transcorneal absorption of an active pharmaceutical ingredient (API), or (ii) selecting a subject having an ocular condition, wherein the ocular condition requires transcorneal absorption of an API; and (b) administering to an eye of the subject a topical ophthalmic composition, wherein the topical ophthalmic composition comprises:

[0635] From about 0.001% to about 5% (w / w) API, from about 1% to about 50% (w / w) MCT, and from about 50% to about 99% (w / w) semifluorinated alkane compound, wherein the API has a solubility in medium chain triglycerides (MCT) of at least about 0.01% to about 10% (w / w), and wherein the API is atropine; optionally wherein the topical ophthalmic composition is non-aqueous; and optionally wherein the API is in free base form.

[0636] 95. A method of selectively delivering an API to the cornea of ​​a subject, the method comprising administering to an eye of the subject the topical ophthalmic composition of any one of embodiments 1 to 19 or the topical ophthalmic nanoemulsion of any one of embodiments 20 to 45; optionally wherein the topical ophthalmic composition is non-aqueous; and optionally wherein the API is in free base form.

[0637] 96. A method for selectively delivering an active pharmaceutical ingredient (API) to the cornea of ​​a subject, the method comprising administering to the subject's eye a topical ophthalmic composition, wherein the topical ophthalmic composition comprises: about 0.001% to about 5% (w / w) API, about 1% to about 50% (w / w) MCT, and about 50% to about 99% (w / w) semifluorinated alkane compound, wherein the API has a solubility in medium chain triglycerides (MCT) of at least about 0.01% to about 10% (w / w), and wherein the API is atropine; optionally wherein the topical ophthalmic composition is non-aqueous; and optionally wherein the API is in free base form; optionally wherein each about 6 to about 8 The topical ophthalmic composition is applied to the eye of the subject 1 hour or 3 times a day, and / or optionally wherein the topical ophthalmic composition is applied at a dose that is 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70%, or 50-70% less than a dose of an aqueous topical ophthalmic composition comprising the API for treating an ocular disorder or a symptom thereof.

[0638] 97. A method of treating an ocular condition in a subject, the method comprising administering to the subject the topical ophthalmic composition of any one of embodiments 1 to 19 or the topical ophthalmic nanoemulsion of any one of embodiments 20 to 45, wherein the topical ophthalmic composition is non-aqueous; wherein the subject has not responded to treatment with an aqueous composition comprising the API, wherein after receiving an aqueous composition comprising the API, the subject has had adverse side effects from the API, and / or wherein the subject is highly sensitive to aqueous compositions comprising the API; optionally wherein the API is in free base form; optionally wherein the topical ophthalmic composition is administered every about 6 to about 8 hours or three times a day. or the topical ophthalmic nanoemulsion is administered to an eye of the subject, and / or optionally wherein the topical ophthalmic composition or the topical ophthalmic nanoemulsion is administered at a dose that is 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70% or 50-70% less than a dose of an aqueous topical ophthalmic composition comprising the API for treating an ocular condition.

[0639] 98. A method of treating an ocular condition in a subject, the method comprising administering to the subject the topical ophthalmic composition of any one of embodiments 1 to 19 or the topical ophthalmic nanoemulsion of any one of embodiments 20 to 45, wherein the topical ophthalmic composition comprises: about 0.001% to about 5% (w / w) API, about 1% to about 50% (w / w) MCT, and about 50% to about 99% (w / w) semifluorinated alkane compound, wherein the API has a solubility in medium chain triglycerides (MCT) of at least about 0.01% to about 10% (w / w), and wherein the API is atropine; wherein the topical ophthalmic composition is non-aqueous; wherein the subject has not responded to treatment with an aqueous composition comprising the API, wherein after receiving the aqueous composition comprising the API, the subject has had an unresponsiveness from the API wherein the subject is highly sensitive to an aqueous composition comprising the API; optionally wherein the API is in free base form; optionally wherein the topical ophthalmic composition is applied to the subject's eye every about 6 to about 8 hours or 3 times a day, and / or optionally wherein the topical ophthalmic composition is applied at a dose that is 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70% or 50-70% less than a dose of an aqueous topical ophthalmic composition comprising the API for treating an ocular condition.

[0640] 99. A method for formulating a topical ophthalmic composition for transcorneal absorption, the method comprising: (a) combining an active pharmaceutical ingredient (API) with a medium chain triglyceride (MCT) to form an MCT solution; (b) combining the MCT solution with a semifluorinated alkane compound to form a mixture, wherein the mixture comprises about 1% to about 50% of the MCT solution and about 50% to about 99% of the semifluorinated alkane compound; and (c) emulsifying the mixture by physical agitation and reducing the droplet size D90 within the mixture to less than 100 nm, the physical agitation being selected from high speed stirring, vortexing, sonication, The invention relates to a method of treating, heating and stirring or homogenizing the mixture until the droplet size reaches a droplet size D90 of less than 100 nm; wherein the topical ophthalmic composition for transcorneal absorption comprises about 0.001% to about 5% (w / w) API, about 1% to about 50% (w / w) MCT and about 50% to about 99% (w / w) semifluorinated alkane compound, wherein the API has a solubility in medium chain triglycerides (MCT) of at least about 0.01% to about 10% (w / w), and wherein the API is not atropine or a salt thereof; and wherein the topical ophthalmic composition is non-aqueous.

[0641] 100. A method for formulating a topical ophthalmic composition for transcorneal absorption, the method comprising: (a) identifying an aqueous topical ophthalmic composition comprising an active pharmaceutical ingredient (API) for selective transcorneal absorption; (b) combining the API with a medium chain triglyceride (MCT) and a semifluorinated alkane compound to form a mixture; and (d) emulsifying the mixture; optionally wherein the topical ophthalmic composition for transcorneal absorption comprises about 0.001% to about 5% (w / w) API, about 1% to about 50% (w / w) MCT, and about 50% to about 99% (w / w) semifluorinated alkane compound, and optionally wherein the API has a solubility in medium chain triglycerides (MCT) of at least about 0.01% to about 10% (w / w).

[0642] 101. The method of embodiment 79 or the composition, nanoemulsion or method of embodiment 80, wherein: the MCT is present in an amount of about 1% to about 50% (w / w), optionally about 1% to about 30% (w / w), about 5% to about 20% (w / w), optionally selected from about 5%, about 10%, about 15% or about 20% (w / w); and the semifluorinated alkane compound is present in an amount of about 70% to about 99% (w / w), optionally about 80% to about 95% (w / w), optionally selected from about 80%, 85%, 90% or 95% (w / w).

[0643] 102. The method, composition, or nanoemulsion of embodiment 101, wherein the semifluorinated alkane compound is selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8).

[0644] 103. The method, composition, or nanoemulsion of any one of embodiments 101-102, wherein the MCT is selected from glyceryl tricaprylate / tricaprate and glyceryl tricaprylate / tricaprylin.

[0645] 104. The method, composition or nanoemulsion of any one of embodiments 101-103, wherein the rifiralast or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer is present in the composition in an amount of about 0.01 to about 10 mg / ml, optionally about 0.01 to about 5 mg / ml, optionally about 0.01 to about 1 mg / ml.

[0646] 105. The method, composition or nanoemulsion of any one of embodiments 101-103, wherein the lifirastat or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer is present in the composition in an amount of about 0.05% to about 20% (w / w), optionally about 0.05% to about 10% (w / w), optionally about 0.05% to about 5% (w / w), optionally selected from about 0.05%, 0.1%, 0.5%, 1%, 2%, 3%, 4% or 5% (w / w).

[0647] 106. The composition of any one of embodiments 1-19, the nanoemulsion of any one of embodiments 20-40 and 45, or the method of any one of embodiments 65 and 86-100, wherein: the API is aceclidine or a derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.

[0648] 107. The method of embodiment 106, wherein the eye disorder is hyperopia or myopia.

[0649] 108. A method for treating myopia or hyperopia in a subject, slowing its progression, ameliorating one or more symptoms thereof, the method comprising administering a topical ophthalmic composition to the eye of the subject, wherein the topical ophthalmic composition comprises: about 0.001% to about 10% (w / w) API, about 1% to about 50% (w / w) MCT, and about 50% to about 99% (w / w) semifluorinated alkane compound, wherein the API is selected from aceclidine or a derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.

[0650] 109. The method of embodiment 108, wherein (i) the topical ophthalmic composition is applied to the eye of the subject every about 6 to about 8 hours or three times a day, or (ii) the topical ophthalmic composition is non-aqueous, and wherein the dosage of the topical ophthalmic composition applied is 5-10%, 5-15%, 5-20%, 5-25%, 5-60%, 5-70%, 5-80%, 5-90%, 5-100%, 5-150%, 5-200%, 5-250%, 5-300%, 5-300%, 5-400%, 5-500%, 5-600%, 5-700%, 5-800%, 5-900%, 5-1000%, 5-1000%, 5-1500%, 5-2000%, 5-2500%, 5-3000%, 5-4000%, 5-5000%, 5-6000%, 5-7000%, 5-8000%, 5-9000%, 5-10 ... 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70% or 50-70%; optionally wherein the topical ophthalmic composition is non-aqueous; and optionally wherein the API is in free base form.

[0651] 110. The method of any one of embodiments 108-109, wherein the topical ophthalmic composition is absorbed in the eye through the cornea.

[0652] 111. The method of any one of embodiments 108-109, wherein the topical ophthalmic composition is selectively absorbed in the eye through the cornea as compared to the periorbital region.

[0653] 112. The composition or nanoemulsion of embodiment 106, or the method of any one of embodiments 106-111, wherein: the MCT is present in an amount of about 1% to about 30% (w / w), optionally about 5% to about 20% (w / w), optionally selected from about 5%, about 10%, about 15% or about 20% (w / w); and the semifluorinated alkane compound is present in an amount of about 70% to about 99% (w / w), optionally about 80% to about 95% (w / w), optionally selected from about 80%, 85%, 90% or 95% (w / w).

[0654] 113. The composition or nanoemulsion of any of embodiments 106 or 112, or the method of any of embodiments 106-112, wherein the semifluorinated alkane compound is selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8).

[0655] 114. The composition or nanoemulsion of any one of embodiments 106 or 112-113, or the method of any one of embodiments 106-113, wherein the MCT is selected from glyceryl tricaprylate / tricaprate and glyceryl tricaprylate / tricaprylin.

[0656] 115. The composition or nanoemulsion of any one of embodiments 106 or 112-114, or the method of any one of embodiments 106-114, wherein the aceclidine or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer is present in the composition in an amount of about 1 to about 30 mg / ml, optionally about 5 to about 20 mg / ml, optionally about 10 to about 15 mg / ml.

[0657] 116. The composition or nanoemulsion of any one of embodiments 106 or 112-115, or the method of any one of embodiments 106-115, wherein the aceclidine or its derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture or diastereomer or enantiomer is present in the composition in an amount of about 0.1% to about 10% (w / w), optionally about 1% to about 3% (w / w), optionally about 1.75% (w / w).

[0658] 117. The nanoemulsion of embodiment 41 or the method of any one of embodiments 66, 86-89 or 94, wherein: the MCT is present in an amount of about 1% to about 30% (w / w), optionally about 5% to about 20% (w / w), optionally selected from about 5%, about 10%, about 15% or about 20% (w / w); and the semifluorinated alkane compound is present in an amount of about 70% to about 99% (w / w), optionally about 80% to about 95% (w / w), optionally selected from about 80%, 85%, 90% or 95% (w / w).

[0659] 118. The nanoemulsion or method of embodiment 117, wherein the semifluorinated alkane compound is selected from perfluorobutylheptane (F4H5) and perfluorohexyloctane (F6H8).

[0660] 119. The nanoemulsion or ...

Claims

1. A topical ophthalmic composition comprising: about 0.001% to about 5% (w / w) or about 0.0001% to about 20% (w / w) of an active pharmaceutical ingredient (API), wherein the API has a solubility in medium chain triglycerides (MCTs) of at least about 0.01% to about 10% (w / w), and wherein the API is not atropine or a salt thereof; about 1% to about 50% (w / w) MCT, optionally wherein the MCT is a triglyceride of a fatty acid and the fatty acid comprises caproic acid, caprylic acid, capric acid, dodecanoic acid, or a combination of two or more thereof; and about 50% to about 99% (w / w) of a semifluorinated alkane compound, optionally wherein the semifluorinated alkane compound is selected from perfluorobutylheptane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8) and perfluorohexyldecane (F6H10); and Optionally wherein the composition is non-aqueous.

2. A topical ophthalmic composition comprising: a therapeutically effective amount of a muscarinic cholinergic receptor agonist as an active pharmaceutical ingredient, wherein the muscarinic cholinergic receptor agonist is selected from the group consisting of aceclidine, pilocarpine, bethanechol, cevimeline, methacholine, xanomeline, and aprolidinedine; and Semifluorinated alkane compounds; and Optionally further comprises one or more organic co-solvents, optionally wherein the organic co-solvent is selected from medium chain triglycerides (MCT), medium chain triglycerides (MCT) of fatty acids having two or three aliphatic tails each independently having 6-12 carbon atoms, liquid paraffin, vitamin E acetate, D-α-tocopherol, oleic acid, ethyl oleate and combinations thereof.

3. A topical ophthalmic nanoemulsion comprising: about 0.001% to about 5% (w / w) or about 0.0001% to about 20% (w / w) of an active pharmaceutical ingredient (API), wherein the API has a solubility in MCT of at least about 0.01% to about 10% (w / w); about 1% to about 50% (w / w) medium chain triglycerides (MCTs); and from about 50% to about 99% (w / w) of a semifluorinated alkane compound, The nanoemulsion has a droplet size D90 of less than about 100 nm.

4. The topical ophthalmic composition of claim 1 or 2 or the topical ophthalmic nanoemulsion of claim 3, wherein the API: (a) is not a muscarinic receptor antagonist; or (b) selected from alpha agonists, antibiotics, corticosteroids, antinicotinic agents, antiglaucoma agents, antihistamines, antivirals, antiparasitics, pressure regulators, topical transient receptor potential melastatin 8 (TRPM8) agonists, inhibitors of inflammatory cell binding, cycloplegics / mydriatics, mast cell stabilizers, miotics, ophthalmic NSAIDs, cyclosporine, riboflavin 5'-phosphate ophthalmic compounds, and VEGF inhibitors and VEGF receptor inhibitors.

5. The topical ophthalmic composition of claim 1 or 2 or the topical ophthalmic nanoemulsion of claim 3, wherein the API is aceclidine or a derivative, analog, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.

6. The topical ophthalmic composition of claim 1 or 2 or the topical ophthalmic nanoemulsion of claim 2, wherein the API is lotiranab or a derivative, analog, racemic mixture, or diastereomer or enantiomer thereof.

7. The topical ophthalmic composition of claim 1 or 2 or the topical ophthalmic nanoemulsion of claim 3, wherein the API is AR-15512 ((1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide) or a derivative, analog, racemic mixture, or diastereomer or enantiomer thereof.

8. The topical ophthalmic nanoemulsion of claim 3, wherein the API is a muscarinic receptor agonist, optionally wherein the API is atropine, an atropine mimetic or analog, or a free base or salt form thereof.

9. Eye drops comprising the topical ophthalmic composition of claim 2.

10. A method for treating hyperopia in a subject in need thereof, the method comprising administering the topical ophthalmic composition of claim 2 or the eye drops of claim 9 to an eye of the subject.

11. A method for treating glaucoma in a subject in need thereof, for improving a subject's ability to focus on nearby objects, or for reducing intraocular pressure in an eye of a subject in need thereof, the method comprising administering to the eye of the subject the topical ophthalmic composition of claim 2 or the eye drops of claim 9.

12. A method of delivering an API to an eye of a subject, the method comprising administering to the eye of the subject (i) the topical ophthalmic composition of any one of claims 1, 2, and 4-8, (ii) the topical ophthalmic nanoemulsion of any one of claims 3-8, or (iii) a topical ophthalmic composition comprising: about 0.001% to about 5% (w / w) API, about 1% to about 50% (w / w) MCT, and about 50% to about 99% (w / w) semifluorinated alkane compound, wherein the API has a solubility in medium chain triglycerides (MCT) of at least about 0.01% to about 10% (w / w), and wherein the API is atropine; wherein (a) the topical ophthalmic composition of (iii) is applied to the eye of the subject every about 6 to about 8 hours or three times per day, or (b) the topical ophthalmic composition of (iii) is non-aqueous and wherein the dosage of the topical ophthalmic composition of (iii) applied is 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70% or 50-70% less than the dosage of an aqueous topical ophthalmic composition comprising the API used to treat, slow the progression of, or alleviate one or more symptoms of an ocular disorder; Optionally wherein the topical ophthalmic composition of (iii) is non-aqueous; Optionally wherein the API is in free base form; and Optionally wherein the method comprises selectively delivering the API to the cornea of ​​the subject.

13. A method for treating, slowing the progression of, or alleviating one or more symptoms of an ocular disorder in a subject, the method comprising administering to an eye of the subject: (i) the topical ophthalmic composition of any one of claims 1, 2, and 4-8, (ii) the topical ophthalmic nanoemulsion of any one of claims 3-8, or (iii) a topical ophthalmic composition comprising: about 0.001% to about 5% (w / w) API, about 1% to about 50% (w / w) MCT, and about 50% to about 99% (w / w) semifluorinated alkane compound, wherein the API has a solubility in medium chain triglycerides (MCT) of at least about 0.01% to about 10% (w / w), and wherein the API is atropine; Optionally, (a) the topical ophthalmic composition of (iii) is applied to the eye of the subject every about 6 to about 8 hours or 3 times a day, or (b) the topical ophthalmic composition of (iii) is non-aqueous, and the dosage of the topical ophthalmic composition of (iii) applied is 5-10%, 5-10% less than the dosage of an aqueous topical ophthalmic composition comprising the API used to treat an ocular disorder, slow its progression, or alleviate one or more symptoms thereof. 15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70% or 50-70%; Optionally wherein the topical ophthalmic composition is non-aqueous; and Optionally wherein the API is in free base form.

14. A method of administering a topical ophthalmic composition to a subject for selective transcorneal absorption, the method comprising administering to an eye of the subject (i) the topical ophthalmic composition of any one of claims 1, 2, and 4-8 or (ii) the topical ophthalmic nanoemulsion of any one of claims 3-8; optionally wherein the topical ophthalmic composition is non-aqueous; and optionally wherein the API is in free base form.

15. A method for treating or reducing one or more symptoms of blepharitis, ocular rosacea, rosacea, or redness of the eyelid margin in a subject, or for improving eyelash health in a subject, or for treating or eradicating Demodex, lice, scabies, or bed bugs in a subject, or for treating or preventing a vector-borne disease in a subject, the method comprising applying to the eye of the subject or to the skin or hair of the subject (i) the topical ophthalmic composition of claim 1 or 2 or (ii) the topical ophthalmic nanoemulsion of claim 3, wherein the API is an antiparasitic drug.

16. A method for treating, slowing the progression of, or alleviating one or more symptoms of dry eye disease, meibomian gland dysfunction, or inflammatory dry eye in a subject, the method comprising administering to the subject's eye (i) the topical ophthalmic composition of claim 1 or 2 or (ii) the topical ophthalmic nanoemulsion of claim 3, wherein the API is selected from rifelast, AR-15512 ((1R,2S,5R)-N-(4-methoxyphenyl)-5-methyl-2-(1-methylethyl)cyclohexanecarboxamide), cyclosporine, or one or more of their derivatives, analogs, pharmaceutically acceptable salts, free base forms, racemic mixtures, or diastereomers or enantiomers.

17. A method for treating, slowing the progression of, or alleviating one or more symptoms of glaucoma, ocular hypertension or high fluid pressure in an eye of a subject, or a method of reducing fluid pressure in an eye of a subject, the method comprising administering to the eye of the subject (i) the topical ophthalmic composition of claim 1 or 2 or (ii) the topical ophthalmic nanoemulsion of claim 3, wherein the API is a pressure modulator.

18. A method for slowing the progression of myopia in a subject or for alleviating the symptoms of vitreous floaters in a subject, the method comprising administering to an eye of the subject the nanoemulsion of claim 3, wherein the API is a muscarinic receptor antagonist, optionally wherein the API is selected from atropine, an atropine mimetic or analog, or a free base or salt form thereof.

19. A method of treating an ocular disorder in a subject, the method comprising: (a)(i) selecting subjects who require transcorneal absorption of the API; or (ii) selecting a subject having an ocular condition, wherein the ocular condition requires transcorneal absorption of the API; and (b) administering a composition to an eye of the subject, wherein the composition (i) is the topical ophthalmic composition of any one of claims 1, 2, and 4-8 or (ii) is the topical ophthalmic nanoemulsion of any one of claims 3-8; optionally wherein the topical ophthalmic composition is non-aqueous; and optionally wherein the API is in free base form, or (iii) is a topical ophthalmic composition comprising: about 0.001% to about 5% (w / w) API, about 1% to about 50% (w / w) MCT, and about 50% to about 99% (w / w) semifluorinated alkane compound, wherein the API has a solubility in MCT of at least about 0.01% to about 10% (w / w), and wherein the API is atropine; optionally wherein the topical ophthalmic composition is non-aqueous; and optionally wherein the API is in free base form.

20. A method for slowing the progression of myopia in a subject or for alleviating the symptoms of vitreous floaters in a subject, the method comprising administering to an eye of the subject a topical ophthalmic composition, wherein the topical ophthalmic composition comprises: about 0.001% to about 5% (w / w) of an active pharmaceutical ingredient (API), wherein the API has a solubility in medium chain triglycerides (MCTs) of at least about 0.01% to about 10% (w / w), and wherein the API is selected from atropine or an atropine mimetic; about 1% to about 50% (w / w) MCTs; and about 50% to about 99% (w / w) of a semifluorinated alkane compound; wherein (i) the topical ophthalmic composition is applied to the eye of the subject every about 6 to about 8 hours or three times per day, or (ii) the topical ophthalmic composition is non-aqueous and wherein the dosage of the topical ophthalmic composition applied is 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70% or 50-70% less than a dosage of an aqueous topical ophthalmic composition comprising the API for slowing myopia progression in the subject or for alleviating symptoms of vitreous floaters in the subject; Optionally wherein the topical ophthalmic composition is non-aqueous; and Optionally wherein the API is in free base form.

21. A method of selectively delivering an active pharmaceutical ingredient (API) to the cornea of ​​a subject, the method comprising administering to an eye of the subject a topical ophthalmic composition, wherein the topical ophthalmic composition comprises: about 0.001% to about 5% (w / w) API, wherein the API has a solubility in medium chain triglycerides (MCTs) of at least about 0.01% to about 10% (w / w), and wherein the API is atropine; about 1% to about 50% (w / w) MCTs; and about 50% to about 99% (w / w) of a semifluorinated alkane compound; Optionally wherein the topical ophthalmic composition is non-aqueous; and Optionally wherein the API is in free base form; Optionally wherein the topical ophthalmic composition is applied to the eye of the subject every about 6 to about 8 hours or 3 times a day, and / or Optionally wherein the dosage of the topical ophthalmic composition administered is 5-10%, 5-15%, 5-20%, 5-25%, 5-30%, 10-30%, 10-40%, 10-50%, 10-60%, 10-70%, 20-30%, 20-40%, 20-50%, 20-60%, 20-70%, 30-40%, 30-50%, 30-60%, 30-70%, 40-50%, 40-60%, 40-70% or 50-70% less than the dosage of an aqueous topical ophthalmic composition comprising the API for treating an ocular disorder or a symptom thereof.

22. A distributor comprising: a container portion comprising an interior wall defining an interior volume and adapted to contact a liquid and store the liquid within at least a portion of the interior volume; a dispensing portion adapted to dispense one or more drops of liquid out of the container portion; and contained within the interior volume (i) the topical ophthalmic composition of any one of claims 1, 2, and 4-8, (ii) the topical ophthalmic nanoemulsion of any one of claims 3-8, or (iii) a composition comprising: about 0.001% to about 5% (w / w) or about 0.0001% to about 10% (w / w) of an active pharmaceutical ingredient (API), about 1% to about 50% (w / w) of a medium chain triglyceride (MCT), and about 50% to about 99% (w / w) of a semifluorinated alkane compound, wherein the API has a solubility in MCT of at least about 0.01% to about 10% (w / w).

23. A method of preparing a topical ophthalmic composition, the method comprising the steps of: (a) combining an active pharmaceutical ingredient (API) with a medium chain triglyceride (MCT) to form an MCT solution; (b) combining the MCT solution with a semifluorinated alkane compound to form a mixture, wherein the mixture comprises from about 1% to about 50% of the MCT solution and from about 50% to about 99% of the semifluorinated alkane compound; and (c) emulsifying the mixture and reducing the droplet size D90 in the mixture to less than 100 nm by physical agitation, wherein the physical agitation is selected from high speed stirring, vortexing, sonication, heating and stirring or homogenizing the mixture until the droplet size reaches a droplet size D90 of less than 100 nm; Optionally wherein the topical ophthalmic composition is for absorption through the cornea, Optionally wherein the topical ophthalmic composition comprises from about 0.001% to about 5% (w / w) API, from about 1% to about 50% (w / w) MCT, and from about 50% to about 99% (w / w) semifluorinated alkane compound, Optionally wherein the API has a solubility in medium chain triglycerides (MCT) of at least about 0.01% to about 10% (w / w), Optionally wherein the API is not atropine or a salt thereof; and Optionally wherein the topical ophthalmic composition is non-aqueous.

24. A method of formulating a topical ophthalmic composition for transcorneal absorption, the method comprising: (a) identifying aqueous topical ophthalmic compositions comprising an active pharmaceutical ingredient (API) for selective transcorneal absorption; (b) combining the API with a medium chain triglyceride (MCT) and a semifluorinated alkane compound to form a mixture; and (d) emulsifying the mixture; Optionally wherein the topical ophthalmic composition for transcorneal absorption comprises from about 0.001% to about 5% (w / w) API, from about 1% to about 50% (w / w) MCT, and from about 50% to about 99% (w / w) semifluorinated alkane compound, and Optionally wherein the API has a solubility in medium chain triglycerides (MCT) of at least about 0.01% to about 10% (w / w).

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