Compositions and methods for delivery of pharmaceutical actives

Abstract

The present application provides compositions, excipient systems, methods, and dispensers for delivery of active pharmaceutical ingredients (APIs) selected from aceclidine and lifitegrast, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof. In one example, a composition is provided comprising an active pharmaceutical ingredient; an alcohol selected from phenethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, polyethylene glycol, n-butanol, and combinations thereof; and a semifluorinated alkane compound. In another example, an excipient system is provided comprising an alcohol and a semi-fluorinated alkane compound. Dispensers containing the compositions are also provided and include glass and polyethylene terephthalate dispensers or containers. Methods of using the compositions are also provided and include a method for treating a condition in a subject comprising administering the compositions to the subject.

Description

[0001] COMPOSITIONS AND METHODS FOR DELIVERY OF

[0002] PHARMACEUTICAL ACTIVES

[0003] CROSS-REFERENCE TO RELATED APPLICATIONS

[0004] This application claims the benefit of priority to U.S. Application No. 63 / 658,719, filed on June 11, 2024, the contents of which are hereby incorporated by reference.

[0005] TECHNICAL FIELD

[0006] This disclosure relates to compositions for delivery of active pharmaceutical ingredients (APIs), and methods for making and using the compositions.

[0007] BACKGROUND

[0008] Formulation of active pharmaceutical ingredients compounds (APIs) is an important step in delivering useful medicinal compounds to humans and animals in need and in making the compounds biologically available within the body, e.g., for treating and preventing various conditions or improving symptoms thereof. However, challenges with delivery formulations can limit the usability of the APIs, their activity7and shelf life, and can in some instances result in systemic side effects. APIs are often formulated in aqueous formulations, however, many APIs can be insoluble in or degrade in aqueous formulations. Additionally, delivery7needs, such as tissue type and preferences of the patient, among others, may make aqueous formulations less practical in some situations. A class of compounds, semi-fluorinated alkanes, has recently shown promise in formulating some APIs (Tsagogiorgas et al., "Semi fluorinated Alkanes as New Drug Carriers-An Overview of Potential Medical and Clinical Applications,” Pharmaceutics, April 2023, 15(4): 1211 ; Holm et al., “A novel excipient, 1 -perfluorohexyloctane shows limited utility for the oral delivery of poorly water-soluble drugs,” European Journal of Pharmaceutical Sciences, March 201 1, 42(4):416-422), including in nonaqueous formulations. However, many APIs remain challenging to formulate. There remains a need for improved compositions for delivery' of APIs.

[0009] SUMMARY

[0010] This disclosure relates to excipient systems and to compositions for delivery' of active pharmaceutical ingredients (APIs).

[0011] Applicant has surprisingly discovered an excipient system comprising semifluorinated alkanes (SFA) in combination with certain alcohols can act as an ideal composition for formulating certain APIs, including difficult to formulate APIs such as lifitegrast and aceclidine. While semi-fluorinated alkanes (SFA), which are amphiphilic nonaqueous organic liquids, have recently been shown to be useful as an excipient for, e.g., ocular and pulmonary uses, the use of SFAs as an API earner seem to be limited due to the poor solubility of most APIs in SFAs (Holm et al., European Journal of Pharmaceutical Sciences, March 2011, 42(4):416-422). Applicant has surprisingly discovered that certain alcohols can be mixed with semi-fluorinated alkanes to form stable, clear formulations, that allow' solubility and / or suitable formulation of certain APIs such as lifitegrast and aceclidine. Applicant has surprisingly discovered that formulations or lifitegrast or aceclidine in certain alcohols mixed with semi-fluorinated alkanes can, in some instances, have improved solubility' and / or stability over aqueous formulations of lifitegrast or aceclidine, and, in some instances, over other formulations of lifitegrast or aceclidine in semi-fluorinated alkanes, with or without other cosolvents or excipients. Applicant has also surprisingly discovered that the excipient system described herein and compositions described herein can provide improved delivery of the certain APIs to the cornea, e.g., by transcomeal absorption. In some instances, the compositions described herein are selectively transcomeally absorbed (e.g., compared with periorbital absorption). The improved deliver}' of the API to the cornea can allow' for lower doses to be administered to a subject, and / or more frequent lower doses. Thus, the improved delivery’ of the API to the cornea can reduce one or more adverse side effects of an API and can be used to treat ocular conditions in subjects highly sensitive to the API.

[0012] In some instances, provided herein are compositions comprising: an active pharmaceutical ingredient (API) selected from aceclidine and lifitegrast, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof; an alcohol selected from phenethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, polyethylene glycol, n- butanol, and combinations thereof; and a semi-fluorinated alkane compound.

[0013] In these and other instances, the compositions can optionally have the following features. The composition can be non-aqueous. The semi-fluorinated alkane compound can be selected from the group consisting of perfluorobutylpentane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyl decane (F6H10). The alcohol can be selected from phenethyl alcohol, ethanol, and isopropanol. The alcohol can be present in a concentration of from about 0.1% to about 99% (w / w), from about 0.1% to about 80% (w / w), from about 0.1% to about 50% (w / w), from about 0.1% to about 30% (w / w), from about 0.1% to about 20% (w / w), from about 0. 1% to about 15% (w / w), from about 0. 1% to about 10% (w / w), from about 0.1 % to about 5% (w / w), about 20% (w / w), about 15% (w / w), about 10% (w / w), about 5% (w / w), about 3% (w / w), about 1% (w / w), about 0.9% (w / w), about 0.8% (w / w), about 0.7% (w / w), about 0.6% (w / w), about 0.5% (w / w), about 0.4% (w / w), about 0.3% (w / w), about 0.2% (w / w), or about 0.1% (w / w). The semifluorinated alkane compound can be present in a concentration of from about 1 % to about 99.9% (w / w), from about 20% to about 99.9% (w / w), from about 50% to about 99.9% (w / w), from about 70% to about 99.9% (w / w), from about 80% to about 99.9% (w / w), from about 85% to about 99.9% (w / w), from about 90% to about 99.9% (w / w), from about 95% to about 99.9% (w / w), about 80% (w / w), about 85% (w / w), about 90% (w / w), about 95% (w / w), about 97% (w / w), about 99% (w / w), about 99.1% (w / w), about 99.2% (w / w) , about 99.3% (w / w), about 99.4% (w / w), about 99.5% (w / w), about 99.6% (w / w), about 99.7% (w / w), about 99.8% (w / w), or about 99.9% (w / w). The API can be present in a concentration of from about 0.0001% to about 20%, from about 0.001% to 15% (w / w), from about 0.001% to 10% (w / w), from about 0.001% to 5% (w / w), from about 0.01% to 5% (w / w), or from about 0.01% to 4% (w / w). The API can be in a free base or salt form. The alcohol can be ethanol. The alcohol can be phenethyl alcohol. The semi-fluorinated alkane can be perfluorohexyloctane (F6H8). The semi-fluorinated alkane can be perfluorobutylpentane (F4H5) The API in the composition can be chemically stable for at least 6 months, at least 1 year, at least 18 months, at least 2 years or longer.

[0014] In some instances, the composition can comprise: from about 0.0001% to about 20% of the (w / w) active pharmaceutical ingredient (API); from about 0. 1% to about 10% (w / w) of the alcohol, optionally about 0.1% to about 5% (w / w) of the alcohol, about 0.1% to about 3% (w / w) of the alcohol about 0. 1% to about 2.5% (w / w) of the alcohol, about 0. 1% to about 1% (w / w) of the alcohol, or about 0.1% to about 0.5% (w / w) of the alcohol; and from about 90% to about 99.9% (w / w) of the semi-fluorinated alkane compound.

[0015] In these and other instances, the compositions can optionally consist of or consist essentially of: the (w / w) active pharmaceutical ingredient (API); the alcohol; and the semi-fluorinated alkane compound.

[0016] In another instance, a method is provided herein for delivering an API selected from aceclidine, lifitegrast, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof, to a subject comprising dissolving the API in a composition comprising: an alcohol selected from phenethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, and polyethylene glycol; a semi-fluorinated alkane compound, to form an API composition, and administering the API composition to the subject.

[0017] In these and other instances, the method can have the following optional features. The method can comprise dissolving the API in the alcohol to form a first composition; and mixing the first composition with the semi-fluorinated alkane compound, to form the API composition. The API can be lifitegrast or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof. The API can be aceclidine or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof. Administering the API composition to the subject can comprise administering the API composition to skin or mucosal membrane of a subject, to an eye of the subject, or to a lung of the subject.

[0018] In another instance, a method is provided for delivering an API to a target tissue of a subject, wherein the target tissue is selected from skin, mucosal membrane, eye tissue, lung tissue, or a tissue of the oral cavity or esophagus, comprising administering any one of the compositions described herein to said target tissue of the subject. In these and other instances, the methods can optionally have the following features. The API can be lifitegrast or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof. The API can be aceclidine or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.

[0019] In another instance, a method is provided for treating, slowing the progression of, or reducing one or more symptoms of a condition in a subject, or inducing one or more symptoms of miosis in a subject, comprising administering any one of the compositions described herein to the subject.

[0020] In another instance, a method is provided for treating, slowing the progression of, or reducing one or more symptoms of an ocular condition in a subject, or inducing one or more symptoms of miosis in a subject, comprising administering the any one of the compositions provided herein to an eye of the subject. In these and other instances, the methods can optionally have the following features. The ocular condition can be selected from neurotrophic keratitis, glaucoma, elevated intraocular pressure, ocular hypertension, presbyopia, myopia, ocular rosacea, dry eye disease, meibomian gland dysfunction, blepharitis, allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, pterygium, pinguecula, corneal transplant rejection, graft versus host disease, ocular allergy, uveitis, anterior uveitis, Behcet's disease, Sjogren'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 or an associated disease or symptom thereof, contact lens induced neovascularization, ulceration, alkali bums, stem cell deficiency, neovascular glaucoma, Steven Johnson syndrome, tumor in the eye, aphakia, pseudophakia, astigmatism, blepharospasm, cataract, conjunctival diseases, comeal diseases, comeal ulcer, eyelid diseases, lacrimal apparatus diseases, pupil disorders, refractive disorders, and strabismus.

[0021] In another instance, a method is provided for slowing presbyopia progression in a subject, comprising administering the any one of the compositions described herein to an eye of the subject, wherein the API is a muscarinic receptor antagonist. The API can optionally be selected from aceclidine or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.

[0022] In another instance, a method is provided for treating, slowing the progression of, or reducing one or more symptoms of presbyopia or glaucoma in a subject, or for inducing miosis in a subject, comprising administering any one of the compositions described herein to an eye of the subject, wherein the API comprises a muscarinic cholinergic receptor agonist.

[0023] In these and other instances, the methods can optionally have the following features. The subject can be in need of transcomeal absorption of an API. The subject can have failed to respond to treatment with an aqueous composition comprising the API. The subject can have had an adverse side effect from the API after receiving an aqueous composition comprising the API. The subject can be highly sensitive to an aqueous composition comprising the API. The API can be in a free base form. The composition can be administered to the eye of the subject about every about 6 to about 8 hours or three times a day. The composition can be administered at a dose 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-

[0024] 50%, 40-60%, 40-70%, or 50-70% less than a dose of an aqueous topical ophthalmological composition comprising the API used for the same ocular condition or purpose.

[0025] In another instance, a method is provided for administering to a subject a topical ophthalmological composition for selective transcomeal absorption, the method comprising administering to an eye of the subject any one of the compositions described herein. Optionally, the composition can be non-aqueous. Optionally, the API can be in free base form.

[0026] In another instance, a method is provided for treating an ocular condition in a subject, the method comprising:

[0027] (a) (i) selecting a subject in need of transcomeal absorption of an API; or (ii) selecting a subject having an ocular condition, wherein the ocular condition is in need of transcomeal absorption of an API; and

[0028] (b) administering to an eye of the subject any one of the compositions described herein. Optionally, the composition can be non-aqueous. Optionally, the API can be in free base form.

[0029] In another instance, a method is provided for selectively delivering an API to a cornea of an eye of a subject, the method comprising administering to the eye of the subject any one of the compositions described herein. Optionally, the composition can be non-aqueous. Optionally, the API can be in free base form.

[0030] In another instance, a method is provided for making any one of the compositions described herein, comprising dissolving the API in a composition comprising: an alcohol selected from phenethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, polyethylene glycol, n- butanol, and combinations thereof; and a semi-fluorinated alkane compound. In these and other instances, the methods can optionally have the following features.

[0031] The method can comprise dissolving the API in the alcohol to form a first composition; and mixing the first composition with the semi-fluorinated alkane compound.

[0032] In the compositions and methods described herein, the compositions can optionally be in the form of a solution, suspension, emulsion, or implant.

[0033] In another instance, a dispenser is provided comprising: 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; and any one of the compositions described herein contained within the interior volume.

[0034] In these and other instances, the dispenser can optionally have the following features. The interior wall can comprise less than about 10% of one or more of low-density polyethylene (LDPE) or polypropylene (PP). The interior wall can not comprise low density polyethylene (LDPE) or polypropylene (PP). The interior wall can comprise glass or polyethylene terephthalate. The interior wall can consist essentially of glass or polyethylene terephthalate (PET). A concentration of the API can remain more than 90% of an initial API concentration after storage in the dispenser for a period of at least 6 months, or wherein a concentration of the API remains more than 90% of an initial API concentration after storage in the dispenser for a period of at least 12 months or wherein a concentration of the API remains more than 90% of an initial API concentration after storage in the dispenser for at least a period of 24 months. The dispenser can further comprise: a dispensing portion adapted to dispense one or more drops of a liquid out of the container portion. The container portion and the dispensing portion can each, independently, consist essentially of glass or polyethylene terephthalate (PET). The dispenser can further comprise: a dispensing portion adapted to dispense one or more drops of a liquid out of the container portion. The volume of the one or more drops can each independently be from about 5 pl to about 40 pl.

[0035] In another instance, a method is provided for treating, slowing the progression of, or reducing one or more symptoms of dry eye disease, meibomian gland disfunction, or inflammatory dry eye in a subject, comprising administering any one of the compositions described herein to an eye of the subject, wherein the API is lifitegrast, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof. In these and other instances, the methods can optionally have the following features. The composition can be administered to an eye of the subject. The API can be absorbed transcomeally in the eye. The composition can be administered to an eye of the subject. The API can be selectively absorbed transcomeally in the eye as compared to periorbitally. The composition can be non-aqueous. The composition can be an emulsion. The composition can be non-aqueous The composition can be administered at a dose 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 composition comprising the API for treating, slowing the progression of, or reducing one or more symptoms of the ocular condition. The composition can be administered to the subject: (i) every about 6 to about 8 hours or three times a day, (ii) once a day, or (iii) twice a day. The API can be in a free base form.

[0036] In another instance, a method is provided for formulating a topical ophthalmological composition for transcomeal absorption, the method comprising combining an active pharmaceutical ingredient (API) selected from aceclidine and lifitegrast, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof; an alcohol selected from phenethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, polyethylene glycol, n-butanol, and combinations thereof; and a semi-fluorinated alkane compound.

[0037] The disclosed compositions and methods herein can optionally have the following features. The API can be lifitegrast, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof. In these and other instances, the compositions and methods described herein can further optionally have the following features. The alcohol can be present in an amount of from about 0. 1% to about 20% (w / w), optionally from about 0.1% to about 10% (w / w), from about 0.1% to about 5% (w / w), from about 0.1% to about 1% (w / w), optionally selected from about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 4%. about 5%, about 6%, about 7%, about 8%, about 9%. and about 10% (w / w). The semi-fluorinated alkane compound can be present in an amount of from about 50% to about 95% (w / w), optionally selected from about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, and about 95% (w / w). The semi-fluorinated alkane compound can be selected from perfluorobutylpentane (F4H5) and perfluorohexyloctane (F6H8). The alcohol can be ethanol. The lifitegrast or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof can be present in the composition in an amount of from about 0.1 to about 100 mg / ml, optionally from about 0.5 to about 50 mg / ml, optionally from about 1 to about 20 mg / ml. The lifitegrast or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof can be present in the composition in an amount of from about 0.1% to about 20 % (w / w), optionally from about 1% to about 10% (w / w), optionally about 5% (w / w).

[0038] The disclosed compositions and methods herein can optionally have the following features. The API can be aceclidine, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof. In these and other instances, the compositions and methods described herein can further optionally have the following features. The alcohol can be present in an amount of from about 0. 1% to about 20% (w / w), optionally from about 0. 1% to about 10% (w / w), from about 0.1% to about 5% (w / w), from about 0.1% to about 1% (w / w), optionally selected from about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, and about 10% (w / w). The semi-fluorinated alkane compound can be present in an amount of from about 80% to about 99% (w / w), optionally selected from about 80%, about 85%, about 90% and about 95% (w / w). The semi-fluorinated alkane compound can be selected from perfluorobutylpentane (F4H5) and perfluorohexyl octane (F6H8). The alcohol can be ethanol. The aceclidine, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof can be present in the composition in an amount of from about 1 to about 30 mg / ml, optionally from about 5 to about 20 mg / ml, optionally from about 10 to about 15 mg / ml. The API can be present in the composition in an amount of from about 0.1% to about 10 % (w / w), optionally from about 1% to about 3% (w / w), optionally selected from about 1%. about 1.5%, about 1.75% (w / w).

[0039] In some instances, the compositions and methods provided herein can provide several advantages. First, in some instances, the compositions provided herein can provide increased solubility of the API. In some instances, the compositions provided herein can provide increased solubility of the API in non-aqueous formulations, for example increased solubility of the API in an SFA. This is especially beneficial in instances where the API cannot achieve desired solubility in SFA alone.

[0040] Second, in some instances of the compositions and methods provided herein, the compositions can provide better stability' of the API as compared to, e.g., aqueous or other standard formulations of the API. This provides several additional advantages, including, in some instances, the possibility to use certain APIs that were previously difficult to formulate for use, or the prevention of formation of API-based impurities, or improved shelf life and storage time as compared to other standard formulations or aqueous formulations of the API.

[0041] Third, in some instances, the compositions described herein can be made into nanoemulsions having droplet sizes below 500 nm, 100 nm. 50 nm. 15 nm. 10 nm, and even 5 nm, or microemulsion, or an emulsion solution. Without being bound by theory, it is believed the smaller droplet sizes can lead to improved longer term stability of the API in the formulation as compared to aqueous formulations, as well as increased availability of the API, improved tissue penetration and distribution of the API, and improved residence time in ocular tissues.

[0042] Fourth, in some instances, the dispenser provided herein can provide increased compatibility with the compositions described herein, e.g., compositions comprising alcohol and SFA. The increased compatibility of the dispensers can lead to better stability of the compositions and of the API in the compositions, longer shelf life for the compositions, and improved delivery' of the prescribed or desired amount of API to a patient’s or subject’s eye or ocular tissue.

[0043] Fifth, in some instances, where the compositions described herein are emulsions, it is believed, without being bound by theory', that in some instances, the alcohol can provide a dual role of both solubilizing the API, and acting on its own in a manner like a surfactant for stabilizing a micro- or nano-emulsion, emulsion solution, or suspension, thus potentially eliminating the need for an added surfactant and thereby eliminating potential toxic complications from such surfactants. In some instances, this can lead to stability of the compositions and stability of the API in the compositions without added surfactants. In some instances, additional surfactant may be added for desired stability, but the presence of alcohol can. in some instances, allow for decreased amounts of surfactant to achieve desired stability'.

[0044] Sixth, the compatibility of alcohol with SFA can allow for useful compositions (e.g., with desired solubility of API in SFA) without undesirable effects to the compositions or the API.

[0045] Seventh, in some instances, the compositions (e.g., topical ophthalmological compositions) described herein can provide improved delivery' of the API to the cornea, e.g., by7transcomeal absorption, e.g., as compared to an aqueous composition comprising the API or an aqueous composition comprising a salt of the API. In some instances, the compositions described herein are selectively transcomeally absorbed (e.g., compared with periorbital absorption). The improved delivery of the API to the cornea can allow for lower doses to be administered to a subject, and / or more frequent lower doses. Thus, the improved delivery of the API to the cornea reduces one or more adverse side effects of an API and can be used to treat ocular conditions in subjects highly sensitive to the API.

[0046] Thus, in some instances, the disclosure provides a method of administering to a subject a composition (e.g., a topical ophthalmological composition) for selective transcomeal absorption, the method comprising administering to an eye of the subject a composition described herein; optionally wherein the composition is non-aqueous; and optionally wherein the API is in free base form.

[0047] In some instances, the disclosure provides a method of treating an ocular condition in a subject, the method comprising: (a) (i) selecting a subject in need of transcomeal absorption of an API; or (ii) selecting a subject having an ocular condition, wherein the ocular condition is in need of transcomeal absorption of an API; and (b) administering to an eye of the subject the any one of the compositions disclosed herein; optionally wherein the composition is non-aqueous; and optionally wherein the API is in free base form.

[0048] Subjects in need of transcomeal absorption of an API include subjects having high sensitivity to an API, subjects in need of a lower dose of an API. subjects having one or more adverse effects of an aqueous API (e.g., an adverse effect attributed to the API and not attributed to another component or feature of the composition comprising the API, e.g., pH or a preservative), subjects in need of treatment with an API having a target receptor in one or more of the cornea, the aqueous humor, or the iris, and subjects in need of treatment with an API that is associated with one or more adverse events in one or more of conjunctival, scleral, and ciliary body.

[0049] In some instances, the disclosure provides a method of selectively delivering an API to a cornea of an eye of a subject, the method comprising administering to the eye of the subject a composition described herein; optionally wherein the composition is non-aqueous; and optionally wherein the API is in free base form. In some instances, the API is absorbed transcomeally in the eye. In some instances, the API is selectively absorbed transcomeally in the eye as compared to periorbitally.

[0050] In some instances, the composition is non-aqueous. In some instances, the composition is an emulsion.

[0051] In some instances, the composition is non-aqueous, and the composition is administered at a dose 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 composition comprising the API or a salt thereof for the same purpose. For example, in some instances of a method of treating an ocular condition, the composition is administered at a dose 30% less than a dose of an aqueous composition comprising the API or a salt thereof for treating the ocular condition.

[0052] In some instances, the composition is administered to the subject: (i) every about 6 to about 8 hours or three times a day, (ii) once a day, or (iii) twice a day.

[0053] In some instances, the API is in a free base form.

[0054] Other features and advantages of the present application will be apparent from the following detailed description and figures, and from the claims.

[0055] BRIEF DESCRIPTION OF THE DRAWINGS

[0056] FIG. 1 is an exploded, schematic cross-sectional view of an exemplary embodiment of a dispenser as described herein.

[0057] DETAILED DESCRIPTION

[0058] Provided herein are compositions for delivery7of active pharmaceutical ingredients (APIs) selected from aceclidine and lifitegrast, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof, comprising medium chain a semi-fluorinated alkane (SFA), an alcohol selected from phenethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, polyethylene glycol, n-butanol, and combinations thereof, and an active pharmaceutical ingredient (API) selected from aceclidine and lifitegrast, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof, and methods for making and using the compositions, such as methods for treating or slowing the progression of, or reducing one or more symptoms of a condition in a subject, or inducing one or more symptoms of miosis in a subject. Also provided herein are dispensers or containers comprising the compositions.

[0059] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. Methods and materials are described herein for use in the present application; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and 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 case of conflict, the present specification, including definitions, will control.

[0060] As used herein, the tenn ‘‘about” means “approximately” (e.g., plus or minus approximately 10% of the indicated value).

[0061] As used herein, the term “contacting” refers to the bringing together of indicated moi eties in an in vitro system or an in vivo system. For example, “contacting” the eye tissue with a compound of the invention includes the administration of a compound of the present invention to an individual or patient, such as a human, having the eye tissue in need of treatment, as well as, for example, introducing a compound of the invention into a sample containing a cellular or purified preparation containing the ocular tissue. As used herein, the term “individual”, “patient”, or “subject” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. In some embodiment, a human subject may be of any age, for example, from 0 to 100 years old. As used herein, “pediatric subject” and “child” are used interchangeably and refer to subjects from 0 to 18 years old, for example, 1, 2, 5, 10, 12, or 14 years old.

[0062] As used herein, the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

[0063] As used herein the term “treating” or “treatment” refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (z.e. , arresting further development of the pathology and / or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology’ of the disease, condition or disorder (i.e., reversing the pathology and / or symptomatology ).

[0064] The term “alkyl,” as used herein, refers to saturated, monovalent hydrocarbon moieties having linear or branched moieties or combinations thereof and containing the specified (e.g., 1 to 26) carbon atoms.

[0065] The term “cycloalkyl,” as used herein, refers to a monovalent or divalent group of, e.g., 3 to 8 carbon atoms, derived from a saturated cyclic hydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic.

[0066] The formula “H”, as used herein, represents a hydrogen atom.

[0067] The formula “O”, as used herein, represents an oxygen atom.

[0068] The formula “P”, as used herein, represents a phosphorus atom. The term '‘compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted, including racemic mixtures. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified.

[0069] In some instances, provided herein are compositions comprising an active pharmaceutical ingredient (API) selected from aceclidine and lifitegrast, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof, an alcohol selected from phenethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, polyethylene glycol, n- butanol, and combinations thereof, and a semi-fluorinated alkane compound.

[0070] In some instances of the compositions described herein, the composition is non-aqueous. In some instances of the compositions described herein, the composition is an oil-in-oil emulsion. In some instances of the compositions described herein, the composition is an emulsion solution.

[0071] The compositions described herein can include an active pharmaceutical ingredient (API) compound. APIs, their analogs, their 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 solvate), and the like. APIs can exist in different polymorphic forms. Such forms are intended to be included within the scope of the present disclosure.

[0072] Exemplary, non-limiting APIs useful in the compositions described herein can include aceclidine or lifitegrast, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof. In some instances, the API can be a muscarinic cholinergic receptor agonist, such as aceclidine or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof. In some instances, the API can be lifitegrast or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.

[0073] In some instances, the API is in a free base form.

[0074] In some instances, the API is in a free acid form.

[0075] In some instances, provided herein are compositions comprising a therapeutically effective amount of lifitegrast or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof as an active pharmaceutical ingredient; an alcohol selected from phenethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, polyethylene glycol, n-butanol, and combinations thereof; and a semifluorinated alkane compound. The compositions can, in some instances, be topical ophthalmological compositions.

[0076] Lifitegrast is an N-acyl-L-alpha-amino acid obtained by formal condensation of the carboxy group of N-[2-(l-benzofuran-6-carbonyl)]-5.7-dichloro-l, 2,3,4- tetrahydroisoquinoline-6-carboxylic acid with the amino group of 3- (methanesulfonyl)-L-phenylalanine. Lifitegrast can reduce inflammation by inhibiting inflammatory cell binding through inhibition of an integrin, lymphocyte function- associated antigen 1 (LFA-1), from binding to intercellular adhesion molecule 1 (1CAM-1).

[0077] Lifitegrast, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof, can, in some instances, aid in treatment of dry eye syndrome, or keratoconjunctivitis sicca. In some instances, lifitegrast or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof, can slow the progression of, treat, or reduce or relieve symptoms of certain ocular diseases or conditions, such as dry7eye syndrome or keratoconjunctivitis sicca, diy eye disease, inflammatory dry eye, redness, or meibomian gland disfunction.

[0078] In some instances, the lifitegrast or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof, can be present in an amount of from about 0.1 % to about 10% (w / w), from about 0.1% to about 9% (w / w), from about 0.1% to about 8% (w / w), from about 0.1% to about 7% (w / w), from about 0.1% to about 6% (w / w), from about 0.1% to about 5% (w / w), from about 0.2% to about 10% (w / w), from about 0.3% to about 10% (w / w), from about 0.4% to about 10% (w / w), from about 0.5% to about 10% (w / w), from about 0.6% to about 10% (w / w), from about 0.7% to about 10% (w / w), from about 0.8% to about 10% (w / w). from about 0.9% to about 10% (w / w). from about 1% to about 10% (w / w), from about 1.5% to about 10% (w / w), from about 2% to about 10% (w / w), from about 2.5% to about 10% (w / w), from about 3% to about 10% (w / w), from about 3.5% to about 10% (w / w), from about 4% to about 10% (w / w), from about 4.5% to about 10% (w / w), from about 5% to about 10% (w / w), from about 5.5% to about 10% (w / w), from about 6% to about 10% (w / w), from about 6.5% to about 10% (w / w), from about 7% to about 10% (w / w), from about 7.5% to about 10% (w / w), from about 8% to about 10% (w / w), from about 8.5% to about 10% (w / w), from about 9% to about 10% (w / w), from about 9.5% to about 10% (w / w), from about 1% to about 5% (w / w), from about 2% to about 8% (w / w), from about 3% to about 9% (w / w), from about 4% to about 9% (w / w), from about 0.1% to about 2.5% (w / w), from about 0.1% to about 2% (w / w), from about 0.1% to about 1.5% (w / w), from about 0.1% to about 1% (w / w), from about 0.1% to about 0.5% (w / w), from about 0.1% to about 0.45% (w / w), from about 0.1% to about 0.4% (w / w), from about 0.1% to about 0.35% (w / w), from 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), from about 0.7% to about 2% (w / w), from about 1 % to about 2% (w / w), from about 1.3% to about 2% (w / w). from about 1.5% to about 2% (w / w), from about 1.7% to about 2% (w / w), from about 0.3% to about 1% (w / w), from about 0.3% to about 1.3% (w / w), from about 0.3% to about 1% (w / w), from about 0.5% to about 1% (w / w), from about 0.5% to about 0.7% (w / w). from about 0.5% to about 1% (w / w), from about 0.5 to about 1.5% (w / w), from about 0.5% to about 2% (w / w), from about 0.5% to about 0.7% (w / w). from about 0.7% to about 1% (w / w), from about 1% to about 1.3 % (w / w), from about 1.3% to about 1.5% (w / w), from 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).

[0079] In some instances, provided herein are compositions comprising a therapeutically effective amount of a muscarinic cholinergic receptor agonist as an active pharmaceutical ingredient; an alcohol selected from phenethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, polyethylene glycol, n-butanol, and combinations thereof; and a semi-fluorinated alkane compound. The compositions can, in some instances, be topical ophthalmological compositions.

[0080] Muscarinic cholinergic receptor agonists can, in some instances, cause pupil contraction to alter the focusing depth of field of an eye. In some instances, this can temporarily relieve symptoms of certain eye diseases or conditions such as presbyopia. In some instances, through the muscarinic cholinergic receptors, the agonists can lower intraocular pressure (IOP). This mechanism can, in some instances, be used to treat glaucoma. In some instances, the muscarinic cholinergic receptor agonist can be selected from the group consisting of aceclidine, or a derivative, analogue, phanwaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof. In some instances, the muscarinic cholinergic receptor agonist can be in salt form. In some instances, the muscarinic cholinergic receptor agonist can be in free base form.

[0081] In some instances, the muscarinic cholinergic receptor agonist can be present in an amount of from about 0.1% to about 5% (w / w), from about 0. 1% to about 2.5% (w / w), from about 0.1% to about 2% (w / w), from about 0.1% to about 1.5% (w / w), from about 0.1% to about 1% (w / w), from about 0.1% to about 0.5% (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), from about 0.7% to about 2% (w / w), from about 1% to about 2% (w / w), from about 1.3% to about 2% (w / w), from about 1.5% to about 2% (w / w), from about 1.7% to about 2% (w / w), from about 0.3% to about 1% (w / w), from about 0.3% to about 1.3% (w / w), from about 0.3% to about 1% (w / w), from about 0.5% to about 1% (w / w), from about 0.5% to about 0.7% (w / w), from about 0.5% to about 1% (w / w), from about 0.5 to about 1.5% (w / w), from about 0.5% to about 2% (w / w), from about 0.5% to about 0.7% (w / w), from about 0.7% to about 1% (w / w), from about 1% to about 1.3 % (w / w), from about 1.3% to about 1.5% (w / w), from 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).

[0082] In some instances, the muscarinic cholinergic receptor agonist can be aceclidine. In some instances, the aceclidine can be in salt form, such as, for example aceclidine sulfate. In some instances, the aceclidine can be in salt form, such as, for example aceclidine hydrochloride. In some instances, the aceclidine can be in free base form. In some instances, the aceclidine can be present in an amount of from about 0.01% to about 10% (w / w), from about 0.01% to about 9% (w / w), from about 0.01% to about 8% (w / w), from about 0.01% to about 7% (w / w), from about 0.01% to about 6% (w / w), from about 0.01% to about 5% (w / w), from about 0.01 % to about 4% (w / w), from about 0.01% to about 3% (w / w), from about 0.01% to about 2% (w / w), from about 0.01% to about 1% (w / w), from about 0.01% to about 0.9% (w / w), from about 0.01% to about 0.8% (w / w), from about 0.01% to about 0.7% (w / w), from about 0.01% to about 0.6% (w / w), from about 0.01% to about 0.5% (w / w), from about 0.01% to about 0.4% (w / w), from about 0.01% to about 0.3% (w / w), from about 0.01% to about 0.2% (w / w), from about 0.01% to about 0.1% (w / w), from about 1% to about 10% (w / w). from about 1% to about 9% (w / w), from about 1% to about 8% (w / w), from about 1% to about 7% (w / w), from about 1% to about 6% (w / w), from about 1% to about 5% (w / w), from about 1% to about 4% (w / w), from about 1% to about 3% (w / w), from about 1% to about 2% (w / w), from about 0.01% to about 1%, 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 0.4% (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), from about 0.1% to about 5% (w / w), from about 0.1% to about 2.5% (w / w). from about 0.1% to about 2% (w / w), from about 0.1% to about 1.5% (w / w), from about 0.1% to about 1% (w / w), from about 0.1% to about 0.5% (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), from about 0.7% to about 2% (w / w). from about 1% to about 2% (w / w), from about 1.3% to about 2% (w / w), from about 1.5% to about 2% (w / w), from about 1.7% to about 2% (w / w), from about 0.3% to about 1% (w / w), from about 0.3% to about 1.3% (w / w), from about 0.3% to about 1% (w / w), from about 0.5% to about 1 % (w / w), from about 0.5% to about 0.7% (w / w). from about 0.5% to about 1% (w / w), from about 0.5 to about 1.5% (w / w), from about 0.5% to about 2% (w / w), from about 0.5% to about 0.7% (w / w), from about 0.7% to about 1% (w / w), from about 1% to about 1.3 % (w / w), from about 1.3% to about 1.5% (w / w), from 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).

[0083] In some instances, the API can be present in the compositions described herein in an amount of from about 0.0001% to about 5% (w / w), from about 0.1% to about 2.5% (w / w), from about 0.1% to about 2% (w / w), from about 0.1% to about 1.5% (w / w), from about 0.1% to about 1% (w / w), from about 0.001% to about 0.01% (w / w), from about 0.001% to about 0.009% (w / w), from about 0.001% to about 0.008% (w / w), from about 0.001% to about 0.007% (w / w), from about 0.001% to about 0.006% (w / w), from about 0.001% to about 0.005% (w / w), from about 0.001% to about 0.004% (w / w), from about 0.001% to about 0.003% (w / w), from about 0.001% to about 0.002% (w / w), from about 0.0001% to about 0.001% (w / w), from about 0.0001% to about 0.0009% (w / w), from about 0.0001% to about 0.0008% (w / w), from about 0.0001% to about 0.0007% (w / w), from about 0.0001% to about 0.0006% (w / w), from about 0.0001% to about 0.0005% (w / w), from about 0.0001% to about 0.0004% (w / w), from about 0.0001% to about 0.0003% (w / w), from about 0.0001% to about 0.0002% (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 0.5% (w / w), from about 0.1 % to about 0.45% (w / w), from about 0.1 % to about 0.4% (w / w). from about 0.1% to about 0.35% (w / w). from 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). from about 0.7% to about 2% (w / w), from about 1% to about 2% (w / w), from about 1.3% to about 2% (w / w), from about 1.5% to about 2% (w / w), from about 1.7% to about 2% (w / w), from about 0.3% to about 1% (w / w), from about 0.3% to about 1.3% (w / w). from about 0.3% to about 1% (w / w), from about 0.5% to about 1% (w / w), from about 0.5% to about 0.7% (w / w), from about 0.5% to about 1% (w / w), from about 0.5 to about 1.5% (w / w), from about 0.5% to about 2% (w / w), from about 0.5% to about 0.7% (w / w), from about 0.7% to about 1% (w / w), from about 1% to about 1.3 % (w / w), from about 1.3% to about 1.5% (w / w), from 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 0.0023% (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 0.0039% (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 instances, the API can be present in the compositions described herein in an amount of about 0.02% (w / w). In some instances, the API can be present in the compositions described herein in an amount of about 0.04% (w / w). In some instances, the API can be present in the compositions described herein in an amount of about 0.05% (w / w). In some instances, the API can be present in the compositions described herein in an amount of about 1% (w / w).

[0084] In some instances of the compositions described herein, the API in the composition is chemically stable for at least 6 months, at least 1 year, at least 18 months, or at least 2 years.

[0085] The compositions described herein can include a semi-fluorinated alkane (SFA). A semi-fluorinated alkane is an amphiphilic liquid with two mutually immiscible moieties (hydrocarbon segment and perfluorinated segment) bound covalently. In some instances, the semifluorinated alkane can be a partially fluorinated alkane compound having a formula CF3(CF2)m(CH2)nCH3. In some instances, 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 example, n can be 1, 2, 3, 4, 5, or 6. Suitable examples of semifluorinated alkane compounds include perfluorobutylpentane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyl decane (F6H10). In some instances, the SFA is perfluorohexyloctane (F6H8).

[0086] The structure of F6H8 is shown below:

[0087] F6.H8 (CF3(CF2)5(CM2)?CH3)

[0088] In some instances, the SFA can be present in the compositions in an amount of from about 1% to about 99.9% (w / w), from about 1% to about 30% (w / w), from about 1% to about 25% (w / w), from about 1% to about 20% (w / w), from about 5% to about 20% (w / w), from about 5% to about 15% (w / w), from about 10% to about 99.9% (w / w), from about 20% to about 99.9% (w / w), from about 30% to about 99.9% (w / w), from about 40% to about 99.9% (w / w), from about 50% to about 99.9% (w / w). from about 60% to about 99.9% (w / w), from about 65% to about 99.9% (w / w), from about 70% to about 99.9% (w / w), from about 75% to about 99.9% (w / w), from about 80% to about 99.9% (w / w), from about 85% to about 99.9% (w / w), from about 90% to about 99.9% (w / w), from about 95% to about 99.9% (w / w), from about 98% to about 99.9% (w / w), from about 20% to about 80% (w / w), from about 20% to about 70% (w / w), from about 20% to about 60% (w / w), from about 20% to about 50% (w / w), from about 20% to about 40 % (w / w), from about 20% to about 30% (w / w), from about 30% to about 80% (w / w), from about 40% to about 80% (w / w), from about 50% to about 80% (w / w), from about 60% to about 80% (w / w), from about 70% to about 80% (w / w), from about 50% to about 90% (w / w), from about 60% to about 90% (w / w), from about 70% to about 90% (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), 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).

[0089] The compositions described herein can include as a cosolvent an alcohol selected from phenethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, polyethylene glycol, n-butanol, and combinations thereof. Applicant has surprisingly found that the addition of certain alcohols described herein to SFA can result in increased solubility- of the APIs disclosed herein in the composition, e.g.. in SFAs. Applicant has surprisingly found that the inclusion of the SFAOH in the compositions described herein can create a suitable delivery system for APIs such as lifitegrast and aceclidine. The compositions described herein can thus provide suitable delivery compositions for lifitegrast and aceclidine for which there were, prior to the present invention disclosed herein, very limited ways to formulate, or APIs that have low solubility in aqueous formulations. Exemplary non-limiting alcohols can include, for example, phenethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, or polyethylene glycol. The alcohol together with the semifluorinated alkane can, in some instances, increase the solubility of atropine and the stability- of the formulation over an extended period of time, particularly as compared to aqueous formulations of the particular APIs.

[0090] In some instances, the alcohol can be present in the compositions in an amount of from about 0.1% to about 99% (w / w), from about 0.1% to about 80% (w / w), from about 0. 1% to about 50% (w / w), from about 0. 1% to about 30% (w / w), from about 0.1% to about 20% (w / w), from about 0.1% to about 15% (w / w), from about 0.1% to about 10% (w / w), from about 0.1% to about 5% (w / w), about 20% (w / w), about 15% (w / w), about 10% (w / w), about 5% (w / w), about 3% (w / w), or about 1% (w / w), from about 1% to about 30% (w / w), from about 1% to about 25% (w / w), from about 1% to about 20% (w / w), from about 5% to about 20% (w / w), from about 5% to about 15% (w / w), from about 10% to about 99.9% (w / w), from about 20% to about 99.9% (w / w), from about 30% to about 99.9% (w / w), from about 40% to about 99.9% (w / w), from about 50% to about 99.9% (w / w), from about 60% to about 99.9% (w / w), from about 65% to about 99.9% (w / w), from about 70% to about 99.9% (w / w). from about 75% to about 99.9% (w / w), from about 80% to about 99.9% (w / w), from about 85% to about 99.9% (w / w), from about 90% to about 99.9% (w / w), from about 95% to about 99.9% (w / w), from about 98% to about 99.9% (w / w), from about 20% to about 80% (w / w), from about 20% to about 70% (w / w), from about 20% to about 60% (w / w), from about 20% to about 50% (w / w), from about 20% to about 40 % (w / w), from about 20% to about 30% (w / w), from about 30% to about 80% (w / w), from about 40% to about 80% (w / w), from about 50% to about 80% (w / w), from about 60% to about 80% (w / w), from about 70% to about 80% (w / w). from about 50% to about 90% (w / w), from about 60% to about 90% (w / w), from about 70% to about 90% (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), 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), from about 1% to about 30% (w / w), from about 1% to about 25% (w / w), from about 1% to about 20% (w / w), from about 1% to about 15% (w / w), from about 1% to about 10% (w / w), from about 5% to about 20% (w / w), from about 5% to about 15% (w / w), from about 10% to about 15% (w / w), from about 10% to about 20% (w / w), from 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). The compositions disclosed herein may, in some instances, also comprise one or more additional therapeutic agents, excipients, or diluents including, but not limited to, absorbents, anti-irritants, preservatives, antioxidants, coloring agents / pigments, emollients (moisturizers), emulsifiers, film-forming / holding agents, prescription drugs, surfactants / detergent cleansing agents, penetration enhancers, viscosity enhancers, and thickeners. In some instances, the compositions herein can include a surfactant. In some instances, the surfactant can be an ionic surfactant or a non-ionic surfactant.

[0091] The compositions of the present application can include those suitable for any acceptable route of administration. Suitable examples of acceptable routes of administration include ocular, topical ocular, ocular injection, inhalation, dermal, topical dermal, oral, and the like.

[0092] In some instances, the compositions described herein can be prepared and used in the form of an aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, pomade, or solution. In some instances, the composition is in any form commonly employed in the art of cosmetic and skin care formulation. In some instances, the compositions can be in an emulsion or nanoemulsion form. In some instances, the compositions can be in the form of an emulsion solution. In some instances, the compositions can be in the form of an organic composition without aqueous components.

[0093] In some instances, the compositions described herein can be an ophthalmic composition, e.g., for intraocular administration. Suitable examples of ophthalmic compositions include eye drops, suspensions, ointments, emulsions, nanoemulsions, emulsion solutions, oils, gels, hydrogels, and solutions. Any one of these ophthalmic compositions can be administered directly to the cornea or other portion of the eye, using, for example, a plastic or latex applicator (e.g., a single-use applicator), an eye dropper, a glass pipette, syringe, or a rubber bulb. In some instances, the compositions described herein have a pH of about 6 to about 8.

[0094] In some instances, the compositions described herein are absorbed transcomeally or are selectively absorbed transcomeally. The phrases “absorbed via the transcomeal route,” “absorbed via transcomeal pathway,” and “absorbed transcomeally” are used interchangeably and relate to transcomeal absorption. In transcomeal absorption, a drug typically penetrates the eye through cornea to the aqueous humor to the iris. In the periorbital absorption, drug ty pically penetrates the eye through the conjunctival to the scleral to the ciliary body. In some instances, a composition described herein is absorbed transcomeally (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 transcomeally, e.g., as determined by an assay known in the art or described in the working examples herein). In some instances, a composition described herein is selectively absorbed transcomeally (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 transcomeally as compared to the amount absorbed periorbitally, e.g., as determined by an assay known in the art or described in the working examples herein, or at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, or at least 20-fold more of the composition is absorbed transcomeally as compared to the amount absorbed periorbitally, e.g., as determined by an assay known in the art or described in the working examples herein). In some instances, the amount of the composition that is absorbed transcomeally 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 that is absorbed periorbitally.

[0095] In some instances, the API of a composition of the present application is absorbed transcomeally or is selectively absorbed transcomeally. In some instances, an API described herein is absorbed transcomeally (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 transcomeally, e.g., as determined by an assay known in the art or described in the working examples herein). In some instances, an API described herein is selectively absorbed transcomeally (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 API is absorbed transcomeally as compared to the amount absorbed periorbitally, e.g., as determined by an assay known in the art or described in the working examples herein, or at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 10-fold, or at least 20-fold more of the API is absorbed transcomeally as compared to the amount absorbed periorbitally, e.g.. as determined by an assay known in the art or described in the working examples herein). In some instances, the amount of the API that is absorbed transcomeally 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 that is absorbed periorbitally.

[0096] In some instances, the compositions described herein can be a cosmetic composition, e.g., for topical administration to e.g., epidermal tissue, nails, or hair. Suitable examples of cosmetic compositions include suspensions, ointments, emulsions, nanoemulsions, emulsion solutions, oils, gels, creams, mousse, sprays, hydrogels, and solutions. Any one of these cosmetic compositions can be administered directly to the skin, hair, or nails, using, for example, a plastic or latex applicator (e.g., a single-use applicator), a dropper, a cotton or fabric applicators, a sponge, a glass pipette, or a rubber bulb.

[0097] In some instances, the compositions are prepared by uniformly and intimately bringing into association the API as disclosed herein with the SFAOH and SFA as disclosed herein. In some instances, the compositions can be solutions. In some instances, the compositions can be emulsions. In some instances, the emulsions can be micro-emulsions or nano-emulsions. In some instances, the compositions can be in the form of emulsion solutions. In some instances, the methods for making the compositions described herein can comprise combining an API with the alcohol to form a first solution; and combining said first solution with a semi-fluorinated alkane compound to form a mixture. Optionally, the mixture can be further mixed, suspended, or emulsified, and / or droplet particle size D90 reduced within said mixture to less than 100 nm, byphysical agitation selected from high-speed stirring, vortexing, sonicating, heating and stirring, or homogenizing the mixture. In some instances, the methods for making the nano emulsions can comprise uniformly and intimately bringing into association the API as disclosed herein with the alcohol and SFA as disclosed herein, and, optionally, emulsifying said mixture and reducing droplet particle size D90 within said mixture to less than 100 nm by physical agitation as described herein.

[0098] In some instances, the methods can further comprise measuring the droplet particle size of the mixture during or following said physical agitation.

[0099] In some instances, the compositions can be in the form of an organic composition without aqueous components.

[0100] Also provided herein are methods of formulating a topical ophthalmological composition for transcomeal absorption, the method comprising combining an API selected from aceclidine and lifitegrast, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof, an alcohol selected from phenethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, polyethylene glycol, n-butanol, and combinations thereof, and a semi-fluorinated alkane compound.

[0101] Also provided herein are dispensers comprising the compositions described herein. In one example of Fig. 1, an example dispenser 10 contains a liquid 14 of the compositions described herein. Applicant discovered that the compositions described herein can, in some instances, be less stable in low density polyethylene (LDPE) and in poplypropylene (PP) than in other materials such as glass or polyethylene terephthalate (PET). Without being bound by theory it is believed that LDPE and PET material absorb one or more components of the compositions described herein, thereby reducing the content of the active pharmaceutical ingredient (API) over time.

[0102] The dispenser 10 includes a container portion 18 having an interior wall 22 defining an interior volume 26 and adapted to contact and store a liquid 14 within at least a portion of the interior volume 26; a dispensing portion 30 adapted to dispense one or more drops of a liquid 14 out of the container portion 18; and, contained within the interior volume 26. a liquid 14 comprising compositions as described herein, or a composition comprising an active pharmaceutical ingredient (API) selected from aceclidine and lifitegrast, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof, a semifluorinated alkane (SFA), and an alcohol selected from phenethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, polyethylene glycol, n-butanol, and combinations thereof.

[0103] In some instances, the interior wall 22 of the dispenser 10 comprises less than about 10%, less than about 5%, or less than about 1% of one or more of low-density polyethylene (LDPE) or polypropylene (PP). In some instances, the interior wall 22 does not comprise low density polyethylene (LDPE) or polypropylene (PP). In some instances, the interior wall 22 comprises glass or polyethylene terephthalate. In some instances, the interior wall 22 consists essentially of glass or polyethylene terephthalate (PET).

[0104] In some instances, the concentration of the API in the compositions of the liquid 14 remains more than 90% of the initial API concentration after storage in the dispenser 10 for a period of 6 months. In some instances, the concentration of the API in the compositions of the liquid 14 remains more than 90% of the initial API concentration after storage in the dispenser 10 for a period of 12 months.

[0105] In some instances, the container portion 18 and the dispensing portion 30 can each, independently, comprise or consist of the same material or different materials. In some instances, the container portion 18 and the dispensing portion 30 can each, independently, consist essentially of glass or polyethylene terephthalate (PET). In some instances, the dispensing portion 30 can comprise low density polyethylene (LDPE) or polypropylene (PP), particularly where the compositions of the liquid 14 do not typically come into contact with the dispensing portion 30 during normal storage of the compositions of the liquid 14, but come into contact with the dispensing portion 30 briefly during dispensation, such as when a drop is passing through the dispensing portion 30 from the container portion 18 during administration to an eye of a subject. Without being bound by theory', it is believed such limited contact of the compositions of the liquid 14 with LDPE or PET will have little or no effect on the compositions of the liquid 14.

[0106] In some instances, the dispenser 10 is adapted to dispense drops each independently having a volume of from about 5 pl to about 40 pl.

[0107] The compositions described herein can, in some instances, be conveniently presented in a unit dosage form or a multi-dosage form (e.g., the dispenser 10). In some embodiments, compositions and formulations described herein can be conveniently presented in a dosage form (unit or multiple) that can be used with or in an automated dosing apparatus or regimen.

[0108] In some instances, the dispenser 10 may optionally have a cap 34 that is removable from the container portion 18. For example, the cap 34 can cover the dispensing portion 30 during storage.

[0109] This disclosure also includes pharmaceutical kits useful, for example, in the treatment of disorders, diseases and conditions referred to herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as. for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit. The kit may optionally include an additional therapeutic agent as described herein.

[0110] In some embodiments, a kit can comprise a dispensing device preloaded with a composition as described herein.

[0111] Also provided herein are methods for treating diseases or conditions using the compositions, dispensers, and methods described herein. In some instances, the diseases or conditions can be related to skin or dermal tissues, mucosal membranes, oral tissues, esophageal tissues, lung tissues, or other bodily tissues.

[0112] Also provided herein are methods for treating ocular diseases or conditions using the compositions, dispensers, and methods described herein. In some instances, the ocular diseases or conditions can be related to the cornea or comeal tissues. In some instances, the ocular disease or condition is preferably treated with a composition that is absorbed (e.g., selectively absorbed) transcomeally.

[0113] Also provided herein are methods for inducing one or more symptoms of miosis in a subject using the compositions, dispensers, and methods described herein. Also provided herein are methods for inducing miosis in a subject using the compositions, dispensers, and methods described herein.

[0114] Exemplary7, nonlimiting ocular diseases that can be treated with the compositions, dispensers, and methods described herein include chemical bums or a disease selected from keratoconus. thin corneas, keratitis, infectious keratitis including bacterial or fungal keratitis, comeal ulcer, bullous keratopathy and other forms of corneal edema, keratolysis, an autoimmune disease, a cicatricizing disease such as Ocular Cicatricial Pemphigoid, Stevens Johnson Syndrome, Lupus Erythematosus. Rheumatoid Arthritis, comeal ectasia including cornea ectasia appearing after laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK), post-refractive ectasia, comeal degeneration, brittle cornea syndrome, Ehlers-Danlos Syndrome Type VI, comeal neovascularization, corneal melting including Comeal Melting in Boston Keratoprosthesis Type I, hyperopia, hyperopic astigmatism, myopia, astigmatism, myopic astigmatism, myopic regression, keratopathy, comeal astigmatism, unstable cornea, or pellucid marginal degeneration (PMD).

[0115] In some instances, the disease or condition can be a front of eye disease or condition. Exemplary, nonlimiting front of 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, presbyopia, myopia, ocular rosacea, dry eye disease, meibomian gland dysfunction, blepharitis, allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis, pterygium, pinguecula, comeal transplant rejection, graft versus host disease, ocular allergy, uveitis, anterior uveitis, Behcet's disease, Sjogren'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 bums, stem cell deficiency, neovascular glaucoma, Steven Johnson syndrome, tumor in the eye, aphakia, pseudophakia, astigmatism, blepharospasm, cataract, conjunctival diseases, comeal diseases, comeal ulcer, eyelid diseases, lacrimal apparatus diseases, pupil disorders, refractive disorders, and strabismus.

[0116] In some instances, the disease or condition can be a back of eye disease or condition.

[0117] In some instances, the methods can include a method for treating, slowing the progression of, or reducing one or more symptoms of an ocular condition in a subject, or inducing one or more symptoms of miosis in a subject, comprising administering the compositions described herein to the eye of a subject. In some instances, the methods can include a method of delivering an API to an eye of a subject comprising administering the compositions or topical ophthalmological compositions described herein. Administering can in some instances include contacting the eye with the composition.

[0118] In some instances, compositions described herein can contain APIs, such as, e.g., a muscarinic cholinergic receptor agonists such as, for example, aceclidine, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof, that can treat ocular diseases or conditions such as presbyopia, myopia, refractive errors of the eye, Sjogren's syndrome, glaucoma, conjunctivitis, lacrimal gland disease, or esotropia. Also provided herein are methods for treating ocular diseases or conditions using the compositions and methods described herein. In some instances, the ocular diseases or conditions can be presbyopia. In some instances, the ocular diseases or conditions can be myopia, refractive errors of the eye, Sjogren's syndrome, glaucoma, conjunctivitis, lacrimal gland disease, or esotropia.

[0119] In some instances, methods are providing for administering, to the eye of a subject, an effective amount of a muscarinic cholinergic receptor agonist as API using the compositions described herein. In some instances, the compositions described herein can be in the form of an eye drop. In some instances, the methods can further comprise applying the eye drop to an eye of the subject.

[0120] In some instances, a subj ect treated in accordance with a method described herein is in need of transcomeal absorption of an API. In some instances, a subject treated in accordance with a method described herein has failed to respond to treatment with an aqueous composition comprising the API or a salt thereof. In some instances, a subject treated in accordance with a method described herein has had an adverse side effect from the API or a salt thereof after receiving an aqueous composition comprising the API or a salt thereof. In some instances, a subject treated in accordance with a method described herein is highly sensitive to an aqueous composition comprising the API or a salt thereof. Also provided herein are methods for treating ocular diseases or conditions using the compounds, compositions, and methods described herein. In some instances, the ocular diseases or conditions can be related to the cornea or comeal tissues. Exemplary, nonlimiting ocular diseases that can be treated with compositions and methods described herein include chemical bums or a disease selected from keratoconus, thin corneas, keratitis, infectious keratitis including bacterial or fungal keratitis, comeal ulcer, bullous keratopathy and other forms of comeal edema, keratolysis, an autoimmune disease, a cicatricizing disease such as Ocular Cicatricial Pemphigoid, Stevens Johnson Syndrome, Lupus Ery thematosus, Rheumatoid Arthritis, comeal ectasia including cornea ectasia appearing after laser-assisted in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK), post-refractive ectasia, comeal degeneration, brittle cornea syndrome, Ehlers-Dani os Syndrome Type VI, comeal neovascularization, comeal melting including Comeal Melting in Boston Keratoprosthesis Type I, hyperopia, hyperopic astigmatism, myopia, astigmatism, myopic astigmatism, myopic regression, keratopathy, comeal astigmatism, unstable cornea, or pellucid marginal degeneration (PMD).

[0121] Also provided herein are methods for inducing miosis in a subject using the compounds, compositions, and methods described herein.

[0122] In some instances, the methods further comprise (a) (i) selecting a subject in need of transcomeal absorption of an API; or (ii) selecting a subject having an ocular condition, wherein the ocular condition is in need of transcomeal absorption of an API.

[0123] In some instances of the methods, the API is selectively delivered to the cornea of the subject.

[0124] In some instances of the methods, the subject has failed to respond to treatment with an aqueous composition comprising the API of the composition.

[0125] Failure to respond to treatment includes disease progression and failure to achieve clinically significant symptom reduction(s) after treatment. In some instances of the methods, the subject has had an adverse side effect from the API after receiving an aqueous composition comprising the API or a salt thereof. An adverse side effect from the API includes adverse side effects attributed to the API (or the salt thereof) and not to other components or features of a composition comprising the API (e.g., a preservative or pH).

[0126] In some instances of the methods, the subject is highly sensitive to an aqueous composition comprising the API or a salt thereof.

[0127] In some instances, the API can be present in an effective amount (e.g., a therapeutically effective amount). Effective doses may vary, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of cousage with other therapeutic treatments such as use of other agents and the judgment of the treating physician. For example, in some embodiments, where the compositions described herein may be used to treat a disease in an eye of the patient, such as myopia, the treating physician may adjust the dosage and dosage regimen based on the current progression of the disease in the patient, the patient’s age, or other related factors.

[0128] In some instances, the API is administered at a dose 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 the API when administered as an aqueous topical ophthalmological composition for the same method of use. The decrease in dose is not due to differences in weight between free base fonn and acid form of an API. For example, in some instances of a method of treating an ocular condition in a subject, the API is administered to the subject at a dose at least 30% less than a dose of the API in an aqueous topical ophthalmological composition for treating the ocular condition.

[0129] In some instances, the API dosages can be administered on a daily basis (<?.g., as a single dose or as two or more divided doses, e.g., once daily, two times daily, three times daily, or four times daily) or non-daily basis (e.g., every other day, every two days, every' three days, once weekly, twice weekly, once every two weeks, once a month). In some instances, the API dosages can be administered once every about 6 to about 8 hours. In some instances, the API dosages can be administered three times a day. In some instances, the API dosages can be administered once a day.

[0130] The invention will be further described in the following examples, which do not limit the scope of the invention.

[0131] It is to be understood that while the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

[0132] EXAMPLES l.Sohibility of Aceclidine in Exemplary Compositions

[0133] 1.1 Chromatographic conditions

[0134] Instrument: Agilent-8860(CGC-001)

[0135] 1.2 Experimental Procedure

[0136] Aceclidine was added to alcohols at varying concentrations and mixed. The aceclidine / alcohol mixture was then added to F6H8 at varying dilutions and mixed well with magnetic stirring. The obtained mixture was filtered through 0.22pm filter and concentration of solubilized aceclidine in the filtrated solutions was determined by chromatography as described above. 1.3 Results

[0137] Z.Solubility of Lifitegrast in Exemplary Compositions

[0138] 2.1 Chromatographic conditions Chromatographic column: Agilent ZORBAX SB-C18. 4.6*250mm.5iim

[0139] Mobile phase A: 0, 1% Phosphoric Acid-H2O

[0140] Mobile phase B: Acetonitrile

[0141] Flow rate: 1.0 mL / min Wavelength: UV / 220nm

[0142] Injection volume: 10 uL Column temperature: 35°C

[0143] Since the auxiliary peaks of MCM and MC8-2 overlapped with the main peaks in the above gradient method, the analytical methods for MCM and MC8-2 were adjusted as follows:

[0144] Chromatographic column: Agilent ZORBAX SB-C18. 4.6*250mm.5um Mobile phase A: 0, 1% Phosphoric Acid-H2O

[0145] Mobile phase B: Acetonitrile

[0146] Flow rate: 1.0 mL / min Wavelength: UV / 220nm

[0147] Injection volume: 10 uL Column temperature: 35°C

[0148] 2.2 Experimental Procedure

[0149] Lifitegrast was added to alcohols at vary ing concentrations and mixed. The obtained mixture was filtered through 0.22pm filter and concentration of solubilized aceclidine in the filtrated solutions was determined by chromatography as described above.

[0150] 2.3 Results

Claims

WHAT IS CLAIMED IS:

1. A composition comprising: an active pharmaceutical ingredient (API) selected from aceclidine and lifitegrast, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof; an alcohol selected from phenethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, polyethylene glycol, n-butanol, and combinations thereof; and a semi-fluorinated alkane compound.

2. The composition of claim 1, wherein the composition is non-aqueous.

3. The composition of any one of claims 1-2, wherein the semi-fluorinated alkane compound is selected from the group consisting of perfluorobutylpentane (F4H5), perfluorobutylhexane (F4H6), perfluorohexylbutane (F6H4), perfluorohexylhexane (F6H6), perfluorohexyloctane (F6H8), and perfluorohexyl decane (F6H10).

4. The composition of any one of claims 1-3, wherein the alcohol is selected from phenethyl alcohol, ethanol, and isopropanol.

5. The composition of any one of claims 1-4, wherein the alcohol is present in a concentration of from about 0.1% to about 99% (w / w), from about 0.1% to about 80% (w / w), from about 0. 1 % to about 50% (w / w), from about 0. 1 % to about 30% (w / w), from about0. 1 % to about 20% (w / w), from about 0.1 % to about 15% (w / w), from about 0.1 % to about 10% (w / w), from about 0.1% to about 5% (w / w), about 20% (w / w), about 15% (w / w), about 10% (w / w), about 5% (w / w), about 3% (w / w), about 1% (w / w), about 0.9% (w / w). about 0.8% (w / w), about 0.7% (w / w), about 0.6% (w / w), about 0.5% (w / w), about 0.4% (w / w), about 0.3% (w / w), about 0.2% (w / w), or about 0.1% (w / w).

6. The composition of any one of claims 1-5, wherein the semi-fluorinated alkane compound is present in a concentration of from about 1% to about 99.9% (w / w), from about 20% to about 99.9% (w / w), from about 50% to about 99.9% (w / w), from about 70% to about 99.9% (w / w), from about 80% to about 99.9% (w / w), from about 85% to about 99.9% (w / w),from about 90% to about 99.9% (w / w), from about 95% to about 99.9% (w / w), about 80% (w / w), about 85% (w / w), about 90% (w / w), about 95% (w / w), about 97% (w / w). about 99% (w / w), about 99.1% (w / w), about 99.2% (w / w) ,about 99.3% (w / w) , about 99.4% (w / w), about 99.5% (w / w), about 99.6% (w / w), about 99.7% (w / w), about 99.8% (w / w), or about 99.9% (w / w).

7. The composition of any one of claims 1-6. wherein the API is present in a concentration of from about 0.0001 % to about 20% (w / w), from about 0.001 % to 15% (w / w), from about 0.001% to 10% (w / w), from about 0.001% to 5% (w / w), from about 0.01% to 5% (w / w), or from about 0.01% to 4% (w / w).

8. The composition of any one of claims 1-7, wherein the API is in a free base or salt form.

9. The composition of any one of claims 1-8, wherein the alcohol is ethanol.

10. The composition of any one of claims 1-8, wherein the alcohol is phenethyl alcohol.

11. The composition of any one of claims 1-10, wherein the semi-fluorinated alkane compound is perfluorohexyloctane (F6H8).

12. The composition of any one of claims 1-10, wherein the semi-fluorinated alkane compound is perfluorobutylpentane (F4H5).

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

14. The composition of any one of claims 1-13, wherein the composition comprises: from about 0.0001% to about 20% (w / w) of the active pharmacal ingredient (API);from about 0. 1% to about 10% (w / w) of the alcohol, optionally about 0. 1% to about 5% (w / w) of the alcohol, about 0. 1% to about 3% (w / w) of the alcohol about 0.1% to about 2.5% (w / w) of the alcohol, about 0.1% to about 1% (w / w) of the alcohol, or about 0.1% to about 0.5% (w / w) of the alcohol; and from about 90% to about 99.9% (w / w) of the semi -fluorinated alkane compound.

15. The composition of any one of claims 1-14, wherein the composition consists of or consists essentially of: the active pharmaceutical ingredient (API); the alcohol; and the semi-fluorinated alkane compound.

16. A method for delivering an API selected from aceclidine, lifitegrast, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof, to a subject comprising dissolving the API in a composition comprising: an alcohol selected from phenethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, and polyethylene glycol; and a semi-fluorinated alkane compound, to form an API composition, and administering the API composition to the subject.

17. The method of claim 16, comprising dissolving the API in the alcohol to form a first composition; and mixing the first composition with the semi-fluorinated alkane compound, to form the API composition.

18. The method of claim 17, wherein the API is lifitegrast or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.

19. The method of claim 17, wherein the API is aceclidine or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.

20. The method of any one of claims 18-19, wherein administering the API composition to the subject comprises administering the API composition to skin or mucosal membrane of the subject, to an eye of the subject, or to a lung of the subject.

21. A method for delivering an API to a target tissue of a subj ect, wherein the target tissue is selected from skin, mucosal membrane, eye tissue, lung tissue, or a tissue of the oral cavity or esophagus, comprising administering any one of the compositions of 1-15 to said target tissue of the subject.

22. The method of claim 21, wherein the API is lifitegrast or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.

23. The method of claim 21, wherein the API is aceclidine or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.

24. A method for treating, slowing the progression of, or reducing one or more symptoms of a condition in a subject, or inducing one or more symptoms of miosis in a subject, comprising administering the composition of any one of claims 1-15 to the subject.

25. A method for treating, slowing the progression of, or reducing one or more symptoms of an ocular condition in a subject, or inducing one or more symptoms of miosis in a subject, comprising administering the composition of any one of claims 1-15 to an eye of the subject.

26. The method of claim 25, wherein the ocular condition is selected from neurotrophic keratitis, glaucoma, elevated intraocular pressure, ocular hypertension, presbyopia, myopia, ocular rosacea, dry eye disease, meibomian gland dysfunction, blepharitis, allergic conjunctivitis, atopic keratoconjunctivitis, vernal keratoconjunctivitis,pterygium, pinguecula, comeal transplant rejection, graft versus host disease, ocular allergy, uveitis, anterior uveitis, Behcet's disease, Sjogren'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 or an associated disease or symptom thereof, contact lens induced neovascularization, ulceration, alkali bums, stem cell deficiency, neovascular glaucoma. Steven Johnson syndrome, tumor in the eye, aphakia, pseudophakia, astigmatism, blepharospasm, cataract, conjunctival diseases, comeal diseases, comeal ulcer, eyelid diseases, lacrimal apparatus diseases, pupil disorders, refractive disorders, and strabismus.

27. A method for slowing presbyopia progression in a subject, comprising administering the composition of any one of claims 1-15 to an eye of the subject, wherein the API is a muscarinic receptor antagonist.

28. The method of claim 27, wherein the API is selected from aceclidine or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.

29. A method for treating, slowing the progression of, or reducing one or more symptoms of presbyopia or glaucoma in a subject, or for inducing miosis in a subject, comprising administering the composition of any one of claims 1-15 to an eye of the subject, wherein the API comprises a muscarinic cholinergic receptor agonist.

30. The method of any one of claims 24 to 29, wherein the subject is in need of transcomeal absorption of an API; wherein the subject has failed to respond to treatment with an aqueous composition comprising the API; wherein the subject has had an adverse side effect from the API after receiving an aqueous composition comprising the API; and / or wherein the subject is highly sensitive to an aqueous composition comprising the API; optionally wherein the API is in a free base form; optionally wherein the composition is administered to the eye of the subject about every about 6 to about 24 hours or one to three times a day, and / oroptionally wherein the composition is administered at a dose 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 ophthalmological composition comprising the API used for the same ocular condition or purpose.

31. A method of administering to a subject a topical ophthalmological composition for selective transcomeal absorption, the method comprising administering to an eye of the subject the composition of any one of claims 1-15; optionally wherein the composition is non-aqueous; and optionally wherein the API is in free base form.

32. A method of treating an ocular condition in a subject, the method comprising:(a) (i) selecting a subject in need of transcomeal absorption of an API; or (ii) selecting a subject having an ocular condition, wherein the ocular condition is in need of transcomeal absorption of an API; and(b) administenng to an eye of the subject the composition of any one of claims 1-15; optionally wherein the composition is non-aqueous; and optionally wherein the API is in free base form.

33. A method of selectively delivering an API to a cornea of an eye of a subject, the method comprising administering to the eye of the subject the composition of any one of claims 1-15; optionally wherein the composition is non-aqueous; and optionally wherein the API is in free base form.

34. A method for making the composition of any one of claims 1-15, comprising dissolving the API in a composition comprising: an alcohol selected from phenethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, polyethylene glycol, n-butanol, and combinations thereof; and a semi-fluorinated alkane compound.

35. The method of claim 34, comprising dissolving the API in the alcohol to form a first composition; and mixing the first composition with the semi -fluorinated alkane compound.

36. The composition of any one of claims 1-15, or the method of any one of claims 16-35, wherein the composition is in the form of a solution, suspension, emulsion, or implant.

37. A dispenser comprising: 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; and any one of the compositions of claims 1-15, 36, or 53-62, contained within the interior volume.

38. The dispenser of claim 37, wherein the interior wall comprises less than about 10% of one or more of low-density polyethylene (LDPE) or polypropylene (PP).

39. The dispenser of any one of claims 37-38, wherein the interior wall does not comprise low density polyethylene (LDPE) or polypropylene (PP).

40. The dispenser of any one of claims 37-38, wherein the interior wall comprises glass or polyethylene terephthalate.

41. The dispenser of any one of claims 37-40, wherein the interior wall consists essentially of glass or polyethylene terephthalate (PET).

42. The dispenser of any one of claims 37-41, wherein a concentration of the API remains more than 90% of an initial API concentration after storage in the dispenser for a period of at least 6 months, or wherein a concentration of the API remains more than 90% of an initial API concentration after storage in the dispenser for a period of at least 12 months or wherein a concentration of the API remains more than 90% of an initial API concentration after storage in the dispenser for at least a period of 24 months.

43. The dispenser of any one of claims 37-42, wherein the dispenser further comprises:a dispensing portion adapted to dispense one or more drops of a liquid out of the container portion; and wherein the container portion and the dispensing portion each, independently, consist essentially of glass or polyethylene terephthalate (PET).

44. The dispenser of any one of claims 37-43, wherein the dispenser further comprises: a dispensing portion adapted to dispense one or more drops of a liquid out of the container portion; and wherein the volume of the one or more drops each independently is from about 5 pl to about 40 pl.

45. A method for treating, slowing the progression of, or reducing one or more symptoms of dry eye disease, meibomian gland disfunction, or inflammatory dry eye in a subject, comprising administering the composition of any one of claims 1-16 to an eye of the subject, wherein the API is lifitegrast, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof.

46. The method of any one of claims 20-35 or 45, wherein the composition is administered to an eye of the subject, and wherein the API is absorbed transcomeally in the eye.

47. The method of any one of claims 20-35 or 45, wherein the composition is administered to an eye of the subject, and wherein the API is selectively absorbed transcomeally in the eye as compared to periorbitally.

48. The method of any one of claims 20-35 or 45-47, wherein the composition is non-aqueous; optionally wherein the composition is an emulsion.

49. The method of any one of claims 20-35 or 45-48, wherein the composition is non-aqueous, and wherein the composition is administered at a dose 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 composition comprising the API for treating, slowing the progression of. or reducing one or more symptoms of the ocular condition.

50. The method of any one of claims 20-35 or 45-49, wherein the composition is administered to the subject: (i) every' about 6 to about 8 hours or three times a day, (ii) once a day, or (iii) twice a day.51 . The method of any one of claims 20-35 or 45-50, wherein the API is in a free base form.

52. A method of formulating a topical ophthalmological composition for transcomeal absorption, the method comprising combining an active pharmaceutical ingredient (API) selected from aceclidine and lifitegrast, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof; an alcohol selected from phenethyl alcohol, ethanol, isopropanol, glycerol, propylene glycol, polyethylene glycol, n-butanol, and combinations thereof; and a semi -fluorinated alkane compound.

53. The composition of any one of claims 1-15 or 36, or the method of any one of claims 16-18, 20-22. 24-26, 30-36, or 45-52, wherein: the API is lifitegrast, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof; the alcohol is present in an amount of from about 0.1% to about 20% (w / w), optionally from about 0.1% to about 10% (w / w), from about 0.1% to about 5% (w / w), from about 0. 1% to about 1% (w / w), optionally selected from 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 1.5% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w), about 4% (w / w), about 5% (w / w), about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), or about 10% (w / w); and the semi-fluorinated alkane compound is present in an amount of from about 50% to about 95% (w / w), optionally selected from about 50% (w / w).about 55% (w / w), about 60% (w / w), about 65% (w / w), about 70% (w / w), about 75% (w / w), about 80% (w / w), about 85% (w / w), about 90%(w / w), or about 95% (w / w).

54. The composition or method of claim 53, wherein the semi-fluorinated alkane compound is selected from perfluorobutylpentane (F4H5) and perfluorohexyloctane (F6H8).

55. The composition or method of any one of claims 53-54, wherein the alcohol is ethanol.

56. The composition or method of any one of claims 53-55, wherein the lifitegrast or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof is present in the composition in an amount of from about 0.1 to about 100 mg / ml, optionally from about 0.5 to about 50 mg / ml, optionally from about 1 to about 20 mg / ml.

57. The composition or method of any one of claims 53-55, wherein the lifitegrast or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof is present in the composition in an amount of from about 0.1% to about 20 % (w / w), optionally from about 1% to about 10% (w / w), optionally about 5% (w / w).

58. The composition of any one of claims 1-15 or 36, or the method of any one of claims 16-17, 19-21, 23-36, or 45-52, wherein: the API is aceclidine, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof; the alcohol is present in an amount of from about 0.1% to about 20% (w / w), optionally from about 0.1% to about 10% (w / w). from about 0.1% to about 5% (w / w), from about 0. 1% to about 1% (w / w), optionally selected from 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 1.5% (w / w), about 2% (w / w), about 2.5% (w / w), about 3% (w / w), about 4% (w / w), about 5% (w / w),about 6% (w / w), about 7% (w / w), about 8% (w / w), about 9% (w / w), or about 10% (w / w); and the semi-fluorinated alkane compound is present in an amount of from about 80% to about 99% (w / w), optionally selected from about 80% (w / w), about 85% (w / w), about 90% (w / w), or about 95% (w / w).

59. The composition or method of claim 58, wherein the semi -fluorinated alkane compound is selected from perfluorobutylpentane (F4H5) and perfluorohexyloctane (F6H8).

60. The composition or method of any one of claims 58-59, wherein the alcohol is ethanol.

61. The composition or method of any one of claims 58-60, wherein the aceclidine, or a derivative, analogue, pharmaceutically acceptable salt, free base form, racemic mixture, or diastereomer or enantiomer thereof is present in the composition in an amount of from about 1 to about 30 mg / ml, optionally from about 5 to about 20 mg / ml, optionally from about 10 to about 15 mg / ml.

62. The composition or method of any one of claims 58-60, wherein the API is present in the composition in an amount of from about 0.1% to about 10 % (w / w), optionally from about 1% to about 3% (w / w), optionally selected from about 1%, about 1.5%, or about 1.75% (w / w).

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