WO2024108095A1 - Semifluorinated alkane antibiotic combination compositions for treatment of ocular disorders - Google Patents

Abstract

Disclosed herein are ophthalmic compositions, such as nonaqueous liquid ophthalmic compositions, comprising at least one antibiotic, such as doxycycline, and at least one semifluorinated alkane, such as 1-perfluorohexyloctane (F6H8), as well as methods of treatment or prevention of at least one ocular disorder, such as blepharitis, with such compositions. The ophthalmic compositions may further be provided in a container closure system, such as a polypropylene (PP) bottle, or in a kit.

Description

SEMIFLUORINATED ALKANE ANTIBIOTIC COMBINATION COMPOSITIONS

FOR TREATMENT OF OCULAR DISORDERS

[001] This application claims the benefit under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 63/426,166 filed November 17, 2022, which application is incorporated by reference herein in its entirety.

[002] Disclosed herein are ophthalmic compositions, such as nonaqueous liquid ophthalmic compositions, comprising at least one antibiotic, such as doxycycline, and at least one semifluorinated alkane, such as 1 -perfluorohexyloctane (F6H8). The ophthalmic compositions may be used to treat and/or temporarily prevent at least one ocular di sorder, such as blepharitis, in a single-dose unit composition. The ophthalmic compositions are stable for each active ingredient, provide efficient drug delivery, and are well tolerated by the eye. The ophthalmic compositions may be provided in a container closure system, such as a polypropylene (PP) bottle, or in a kit.

[003] Typically, ophthalmic compositions are administered as eye drops, with one or more drops of the composition being applied to an eye of the subject suffering from or susceptible to ocular disorders one or more times per day, although the frequency of administration of such compositions may be dependent on multiple factors, including the makeup of the particular composition and the condition for which the compositions are used.

[004] Of particular importance for efficacy and commercialization of ophthalmic compositions is stability. Maintenance of efficacy and stability of ophthalmic compositions may be required to meet various federal health and safety regulations, e.g., potency, impurities, shelf life testing, sterility, etc. For example, ophthalmic compositions may be required to contain expiration dates posted on their container, which may be predicated on the stability of the active ingredients and other conditions inherent in the formulation and environmental exposures of the product.

[005] Furthermore, it may be desirable for an ophthalmic composition to include a plurality of active agents. In such situations, it may be difficult or uneconomical to meet a particular shelf life target or regulatory requirements due to some instability of one or more of the combination of the active agents or other interaction with components of a formulation. This may be the result of some chemical reactivity or incompatibility of one or more of the active agents, for example, which leads to degradation of one or more of the active agents. Such degradation shortens the shelf life of the composition and may render the formulation pharmaceutically ineffective or non-compliant with federal regulatory requirements.

[006] Certain antibiotics, such as the tetracycline derivative doxycycline, are known to be effective against bacteria and/or to have inflammatory properties useful in the effective treatment of at least one ocular disorder, but are not sufficiently stable, for example in an aqueous solution at neutral pH, and are therefore unsuitable for use in traditional ophthalmic compositions, such as ready-to-use aqueous liquid ophthalmic compositions administered as eye drops. Antibiotics, like this, are only suitable for use in products that are either reconstituted in an aqueous drop just prior to use, or are formulated in a non-aqueous ointment vehicle and packaged in oxygen impermeable tubes.. There is, thus, a need for improved ophthalmic compositions comprising antibiotic agents such as doxycycline, where the product is ready-to- use without a need for reconstitution and can be conveniently delivered as a drop. For example, an antibiotic suspension in a nonaqueous liquid ophthalmic composition that may be administered as eye drops.

[007] The present inventors have surprisingly discovered that improved, stable ophthalmic compositions may be provided comprising (a) at least one antibiotic and (b) at least one semifluorinated alkane. Without wishing to be bound by theory, it is believed that, not only does the at least one semifluorinated alkane provide its own ocular disorder treatment and/or prevention effect, but it also acts as a stable, non-aqueous vehicle or carrier for the at least one antibiotic. It is thus the unique combination of the at least one antibiotic and the at least one semifluorinated alkane that provides the improved, stable ophthalmic compositions described herein. In some embodiments, the ophthalmic compositions may be nonaqueous liquid compositions comprising (a) at least one antibiotic, such as doxycycline, and (b) at least one semifluorinated alkane, such as 1-perfluorohexyloctane (F6H8).

[008] Further disclosed herein are methods for the treatment and/or temporary prevention of at least one ocular disorder, such as blepharitis, comprising administering to a patient in need thereof an effective amount of an ophthalmic compositi on comprising (a) at least one antibiotic, such as doxycycline, and (b) at least one semifluorinated alkane, such as 1- perfluorohexyloctane (F6H8).

[009] These and other features, aspects, and advantages of the disclosure will be apparent from a reading of the following.

[0010] BRIEF DESCRIPTION OF THE FIGURES [0011] Figure 1 depicts mean doxycycline concentration in tissue of the conjunctiva following topical ocular dosing of the inventive and comparative compositions of Example 3. [0012] Figure 2 depicts mean doxycycline concentration in tissue of the lid margins following topical ocular dosing of the inventive and comparative compositions of Example 3. [0013] Figure 3 depicts mean doxycycline concentration in ti ssue of the meibomian glands following topical ocular dosing of the inventive and comparative compositions of Example 3. [0014] Figure 4 depicts mean doxycycline concentration in plasma following topical ocular dosing of the inventive and comparative compositions of Example 3.

[0015] Figure 5 depicts doxycycline Cmax and AUC_0-last in tissue of the conjunctiva following topical ocular dosing of the inventive and comparative compositions of Example 3. [0016] Figure 6 depicts doxycycline Cmax and AUC_0-last in tissue of the lid margins following topical ocular dosing of the inventive and comparative compositions of Example 3. [0017] Figure 7 depicts doxycycline Cmax and AUC_0-last in tissue of the meibomian glands following topical ocular dosing of the inventive and comparative compositions of Example 3. [0018] Figure 8 depicts doxycycline Cmax and AUC_0-last in plasma following topical ocular dosing of the inventive and comparative compositions of Example 3.

[0019] Definitions of certain terms as used in this application are provided below. Unless defined otherwise, all technical and scientific terms used herein have the normal and common meaning that would be commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0020] As used herein, “a” or “an” entity refers to one or more of that entity, e.g., “a compound” refers to one or more compounds or at least one compound unless stated otherwise. As such, the terms “a” (or “an”), “one or more”, and “at least one” are used interchangeably herein.

[0021] As used herein, the term “about” means approximately, in the region of, roughly, or around. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is used herein to modify a numerical value above and below the stated value by a variance of 5%. Numeric values modified by the term “about” include the specific identified value. For example, “about 100” means a number ranging from 95 to 105, including 95, 100, and 105. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein.

[0022] As used herein, “administration” of a compound or composition to a patient refers to any route of introducing or delivering the compound or composition to a subject. Administration includes self-administration and the administration by another.

[0023] As used herein, a “condition,” “disorder,” or “disease” relates to any unhealthy or abnormal state.

[0024] As used herein, an “effective amount” or “effective dose” refers to an amount of a compound or composition that treats and/or temporarily prevents, upon single or multiple dose administration, a patient suffering from a disorder, disease, or condition. An effective amount can be determined by the attending diagnostician through the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount, a number of factors are considered by the attending diagnostician, including, but not limited to: the species of patient; its size, age, and general health; the specific condition, disorder, or disease involved; the degree of or involvement or the severity of the condition, disorder, or disease, the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation admini stered; the dose regimen selected; the use of concomitant m edication; and other relevant circumstances.

[0025] As used herein, a composition is “free” of a component when said component is not intentionally added during manufacture of the composition.

[0026] As used herein, the term “in combination with,” when referring to two or more compounds, agents, or additional active pharmaceutical ingredients, means the administration of two or more compounds, agents, or active pharmaceutical ingredients to the patient prior to, concurrent with, or subsequent to each other during a treatment period. Unless specified otherwise, the two or more compounds, agents, or active pharmaceutical ingredients may be administered on different schedules during the treatment period, such as, e.g., with one or more compounds, agents, or active pharmaceutical ingredients being administered once a day and one or more other compounds, agents, or active pharmaceutical ingredients being administered twice a day.

[0027] As used herein, the terms “patient,” “subject,” “individual,” and the like, as used herein, are interchangeable and refer to any animal, which may be a human or a non-human animal. [0028] As used herein, the terms “prevention” of or “preventing” a disorder, disease, or condition refers to reduction of or reducing the occurrence of the disorder, disease, or condition in a treated sample relative to an untreated control sample, and includes delaying onset, progression, or reduction of severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0029] As used herein, the term “ocular disorder” refers to any of the signs, symptoms, and/or underlying cause(s) of any physiological disorder that affects the eye or vision.

[0030] As used herein, a “pharmaceutically acceptable excipient” refers to a earner or an excipient that is useful in preparing a pharmaceutical composition. For example, a pharmaceutically acceptable excipient is generally safe and includes carriers and excipients that are generally considered acceptable for mammalian pharmaceutical use. As a non-limiting example, pharmaceutically acceptable excipients may be solid, semi-solid, or liquid materials which, in the aggregate, can serve as a vehicle or medium for active ingredients. Some examples of pharmaceutically acceptable excipients are found in Remington’s Pharmaceutical Sciences and the Handbook of Pharmaceutical Excipients and include diluents, vehicles, carriers, ointment bases, binders, disintegrates, lubricants, glidants, sweetening agents, flavoring agents, gel bases, sustained release matrices, stabilizing agents, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coating agents, and others. [0031] As used herein, a composition according to the present disclosure is “stable” if the at least one antibiotic within the composition degrades by less than about 10% after being stored at about 25 °C for 10 weeks, as measured by high-performance liquid chromatography (HPLC) or an equivalent appropriate technique such as that within the U.S. Pharmacopeia.

[0032] As used herein, the term “treat,” “treating,” or “treatment,” when used in connection with a disorder or condition, includes any effect, e.g., lessening, reducing, modulating, ameliorating, or eliminating, that results in the improvement of the disorder or condition. Improvements in or lessening the severity of any symptom of the disorder or condition can be readily assessed according to standard methods and techniques known in the art.

[0033] As will be understood by one of ordinary skill in the art, each range disclosed herein includes all possible subranges as well as individual numerical values within that range, including endpoints. As a non-limiting example, a range of “0.001% to 0.02%” includes and would be understood to specifically disclose subranges such as “0.004% to 0.01%,” “0.005% to 0.02%,” etc., as well as all individual numbers within the disclosed range, for example, 0.001%, 0.004%, 0.005%, 0.01%, 0.02%, etc. [0034] Claims or descriptions that include “or” or “and/or” between members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all the group members are present in, employed in, or otherwise relevant to a given product or process.

[0035] The ophthalmic compositions of the present disclosure comprise (a) at least one antibiotic and (b) at least one semifluorinated alkane. The at least one antibiotic may be chosen from any antibiotic known to be effective in the treatment and/or prevention of at least one ocular disorder or any combination of such antibiotics. Unless otherwise indicated herein, the term antibiotic, as well as the named classes of antibiotics and individually named antibiotics, are to be understood to include the free base and any salts, hydrates, solvates, and hyclates thereof. For example, the term doxycycline is to be understood to include the free base and any salts, hydrates, solvates, and hyclates thereof, for example an HCL salt, mono-hydrate, or hyclate (hydrochloride hemi ethanolate hemihydrate) thereof.

[0036] In some embodiments, the at least one antibiotic is chosen from at least one aminoglycoside, at least one macrolide, at least one polypeptide, at least one quinolone, at least one lincosamide derivative, at least one tetracycline derivative, or any combination thereof. In some embodiments, the at least one antibiotic may also be anti-parasitic. In some embodiments, the at least one antibiotic may also be anti-inflammatory.

[0037] In some embodiments, the at least one antibiotic comprises at least one aminoglycoside chosen from gentamicin, tobramycin, amikacin, plazomicin, streptomycin, neomycin, paromomycin, or any combination thereof.

[0038] In some embodiments, the at least one antibiotic comprises at least one macrolide chosen from azithromycin, clarithromycin, erythromycin, or any combination thereof.

[0039] In some embodiments, the at least one antibiotic comprises at least one polypeptide chosen from actinomycin, bacitracin, colistin, and polymyxin B, or any combination thereof.

[0040] In some embodiments, the at least one antibiotic comprises at least one quinolone chosen from besifloxacin, cinoxacin, ciprofloxacin, delatloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, or any combination thereof. [0041] In some embodiments, the at least one antibiotic comprises at least one lincosamide chosen from lincomycin, clindamycin, pirlimycin, or any combination thereof.

[0042] In some embodiments, the at least one antibiotic comprises at least one tetracycline derivative chosen from doxycycline, demeclocycline, minocycline, tetracycline, or any combination thereof.

[0043] In some embodiments, the at least one antibiotic comprises at least one antibiotic chosen from azithromycin, erythromycin, besifloxacin, ciprofloxacin, bacitracin, tobramycin, clindamycin, doxycycline, or any combination thereof.

[0044] In some embodiments, the at least one antibiotic comprises doxycycline. In some embodiments, the at least one antibiotic consists essentially of doxycycline.

[0045] In some embodiments, the at least one antibiotic, for example doxycycline, is included in the composition at a concentration from about 0.005% (w/w) to about 5% (w/w), for example, from about 0.02% (w/w) to about 4% (w/w), from about 0.5% (w/w) to about 3% (w/w), or from about 0.75% (w/w) to about 2% (w/w).

[0046] The ophthalmic compositions of the present disclosure comprise at least one semifluorinated alkane (SFA). Semifluorinated alkanes are linear or branched alkanes some of whose hydrogen atoms have been replaced by fluorine. In particular, semifluorinated alkanes are compounds composed of at least one perfluorinated hydrocarbon segment and at least one non-fluorinated hydrocarbon segment. According to a nomenclature used herein, the semifluorinated alkanes may be referred to as FnHm, wherein F refers to the perfluorinated hydrocarbon segment (F-segment), H refers to the non-fluorinated hydrocarbon segment (H- segment), and n and m refer to the number of carbon atoms of those segments, respectively. For example, F3H3 is used for perfluoropropylpropane and F4H5 is used for 1- perfluorobutylpentane. This type of nomenclature is usually used for compounds having linear segments. Therefore, unless otherwise indicated, it should be assumed that F3H3 means 1- perfluoropropylpropane, rather than 2-perfluoropropylpropane, 1-perfluoroisopropylpropane, or 2-perfluoroisopropylpropane.

[0047] In some embodiments, the at least one semifluorinated alkane may have one non- fluorinated hydrocarbon segment attached to one perfluorinated hydrocarbon segment, according to the general formula FnHm. In some embodiments, the at least one semifluorinated alkane is a compound according to the formula FnHm, wherein the F-segment and the H- segment are linear or branched and wherein n and m, which may be the same or different, are independently chosen from 3 to 20 carbon atoms, for example from 3 to 10 carbon atoms, or from 4 to 8 carbon atoms. In some embodiments, the at least one semifluorinated alkane is a compound according to the formula FnHm, wherein the F- segment and the H- segment are linear and wherein n and m, which may be the same or different, are independently chosen from 3 to 20 carbon atoms, for example from 3 to 10 carbon atoms, or from 4 to 8 carbon atoms.

[0048] In some embodiments, the ratio of the carbon atoms of the F-segment to the carbon atoms of the H-segment (said ratio obtained by dividing the number of carbon atoms in the F- segment by the number of carbon atoms in the H-segment) of the at least one linear or branched semifluorinated alkane ranges between 0.5 and 3.0, for example between 0.6 and 1.0. For example, the ratio of the carbon atoms of the F-segment to the carbon atoms of the H-segment for 1 -perfluorohexyloctane (F6H8) is 0.75. In some embodiments, the at least one semifluorinated alkane is a linear semifluorinated alkane according to the formula FnHm, wherein the ratio of the carbon atoms of the F-segment to the carbon atoms of the H-segment ranges between 0.5 and 3.0, for example between 0.6 and 1.0.

[0049] In some embodiments, the at least one semifluorinated alkane may have two perfluorinated hydrocarbon segments separated by one non-fluorinated hydrocarbon segment, according to the general formula FnHmFo, wherein n, m, and o refer to the number of carbon atoms of the first perfluorinated hydrocarbon segment, the non-fluorinated hydrocarbon segment, and the second perfluorinated hydrocarbon segment, respectively. In some embodiments, the at least one semifluorinated alkane is a compound according to the formula FnHmFo, wherein the F-segments and the H-segment are linear or branched and wherein n, m, and o, which may be the same or different, are independently chosen from 3 to 20 carbon atoms, for example from 3 to 10 carbon atoms, or from 4 to 8 carbon atoms.

[0050] In some embodiments, the at least one semifluorinated alkane may be a linear semifluorinated alkane comprising a branched non-fluorinated hydrocarbon segment comprising one or more alkyl groups chosen from -CH3, -C2H5, -C3H7, -C4H9, or any combination thereof. In some embodiments, the at least one semifluorinated alkane may be a linear semifluorinated alkane comprising a branched perfluorinated hydrocarbon segment comprising one or more perfluorinated alkyl groups chosen from -CF3, -C2F5, -C3F7, -C4F9, or any combination thereof.

[0051] In some embodiments, the at least one semifluorinated alkane may comprise a combination of more than one semifluorinated alkane. [0052] In some embodiments, the at least one semifluorinated alkane is chosen from F4H4, F4H5, F4H6, F4H7, F4H8, F5H4, F5H5, F5H6, F5H7, F5H8, F6H2, F6H4, F6H6, F6H7, F6H8, F6H9, F6H10, F6H12, F8H8, F8H10, F8H12, F10H10, or any combination thereof. In some embodiments, the at least one semifluorinated alkane is chosen from F4H4, F4H5, F4H6, F5H5, F5H6, F5H7, F5H8, F6H6, F6H7, F6H8, F6H9, F6H10, F8H8, F8H10, F8H12, F10H10, or any combination thereof. In some embodiments, the at least one semifluorinated alkane is chosen from F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8, or anv combination thereof.

[0053] In some embodiments, the at least one semifluorinated alkane comprises 1- perfluorohexyl-octane (F6H8). In some embodiments, the at least one semifluorinated alkane consists essentially of 1 -perfluorohexyl-octane (F6H8).

[0054] The compositions disclosed herein may be used for the treatment or temporary prevention of at least one ocular disorder. Where the at least one ocular disorder has a bacterial infection as a cause and/or as a symptom, the at least one antibiotic in the ophthalmic composition may be chosen from at least one antibiotic known to be effective in the treatment and/or preventi on of that ocular di sorder. In view of the descripti on herein, it is within the skill of those in the art to choose an antibiotic known to be effective to treat a given ocular disorder that has a bacterial infection as a cause and/or as a symptom.

[0055] Depending on the at least one antibiotic chosen for the ophthalmic composition, the at least one semifluorinated alkane may further be chosen from any semifluorinated alkane that provides a vehicle or carrier for the at least one antibiotic that results in a stable composition. In view of the description herein, it is within the skill of those in the art to choose a semifluorinated alkane that may result in a stable composition with a chosen antibiotic.

[0056] In some embodiments, the ophthalmic composition comprises (a) at least one antibiotic chosen from at least one aminoglycoside, at least one macrolide, at least one polypeptide, at least one quinolone, at least one tetracycline derivative, or any combination thereof and (b) at least one semifluorinated alkane chosen from F4H4, F4H5, F4H6, F4H7, F4H8, F5H4, F5H5, F5H6, F5H7, F5H8, F6H2, F6H4, F6H6, F6H7, F6H8, F6H9, F6H10, F6H12, F8H8, F8H10, F8H12, F10H10, or any combination thereof.

[0057] In some embodiments, the ophthalmic composition comprises (a) at least one antibiotic chosen from azithromycin, erythromycin, besifloxacin, ciprofloxacin, bacitracin, tobramycin, clindamycin, doxycycline, or any combination thereof and (b) at least one semifluorinated alkane chosen from F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8, or any combination thereof.

[0058] In some embodiments, the ophthalmic composition comprises (a) at least one antibiotic chosen from doxycycline, demeclocycline, minocycline, tetracycline, or any combination thereof and (b) at least one semifluorinated alkane chosen from F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8, or any combination thereof.

[0059] In some embodiments, the ophthalmic composition comprises (a) at least one antibiotic comprising doxycycline and (b) at least one semifluorinated alkane comprising F6H8.

[0060] In some embodiments, the ophthalmic composition comprises (a) at least one antibiotic, wherein the at least one antibiotic consists essentially of doxycycline, and (b) at least one semifluorinated alkane, wherein the at least one semifluorinated alkane consists essentially ofF6H8.

[0061] In some embodiments, the ophthalmic compositions of the present disclosure are liquid composition. In some embodiments, the ophthalmic compositions of the present disclosure are liquid compositions comprising water. In preferred embodiments, the ophthalmic compositions of the present disclosure are liquid compositions that are substantially water-free (nonaqueous).

[0062] In some embodiments, the ophthalmic compositions of the present disclosure are stable liquid compositions. In some embodiments, the ophthalmic compositions of the present disclosure are stable nonaqueous liquid compositions.

[0063] In some embodiments, the ophthalmic compositions of the present disclosure may be administered in combinati on with an effective amount of an addi tional therapeutic agent. In some embodiments, the ophthalmic compositions of the present disclosure may be administered in combination with an effective amount of at least one additional therapeutic agent chosen from redness reduction agents, NSAIDS, steroids, antifungals, aminopenicillins, macrolides, mite-killing compounds, antihistamines, anti-inflammatory agents, anti-allergens, or any combination thereof.

[0064] In some embodiments, the ophthalmic compositions of the present disclosure further comprise, in the same composition, an effective amount of an additional therapeutic agent. In some embodiments, the ophthalmic compositions of the present disclosure further comprise an effective amount of at least one additional therapeutic agent chosen from redness reduction agents, NSAIDS, steroids, antifungals, aminopenicillins, macrolides, mite-killing compounds, antihistamines, anti-inflammatory agents, anti-allergens, or any combination thereof.

[0065] In some embodiments, the ophthalmic compositions of the present disclosure may further include at least one additional non- therapeutic component and/or pharmaceutically acceptable excipient, including, but not limited to, tonicity agents, preservatives, buffers, pH adjustors, antioxidants, delivery vehicles, stabilizers, suspending agents, viscosity-increasing agents, wetting agents, solubilizing agents, chelating agents, nitrous oxide inhibitors, isotonic agents, humectants, surfactants, and the like. The proportion and nature of any additional non- therapeutic component and/or pharmaceutically acceptable excipient may be determined by the chosen route of administration and standard pharmaceutical practice. One of ordinary skill in the art can readily select the proper form and route of administration depending upon the disorder or condition to be treated, the stage of the disorder or condition, and other relevant circumstances.

[0066] In some embodiments, the ophthalmic compositions of the present disclosure are sterile, according to USP/EP criteria. In some embodiments, sterility is conferred by any conventional method. In some embodiments, sterility is conferred by filtration. In some embodiments, sterility is conferred by irradiation. In some embodiments, sterility is conferred by heating. In some embodiments, sterility is conferred by conducting the manufacturing process under aseptic conditions.

[0067] Further disclosed herein are methods for the treatment or temporaiy prevention of at least one ocular disorder comprising administering to a patient in need thereof an effective amount of an ophthalmic composition as described above comprising (a) at least one antibiotic and (b) at least one semifluorinated alkane.

[0068] In some embodiments, the at least one ocular disorder has a bacterial infection as a cause and/or as a symptom. In some embodiments, the at least one ocular disorder has inflammation as a cause and/or as a symptom. In some embodiments, the at least one ocular disorder has both a bacterial infection and inflammation as a cause and/or as a symptom. The at least one ocular disorder may include, but is not limited to, blepharitis, dry eye, meibomian gland dysfunction, adult chlamydial ophthalmia, ocular rosacea presbyopia, recalcitrant recurrent corneal erosions, ocular cicatricial pemphigoid, Sjogren’s syndrome (SS), non-SS keratoconjunctivitis sicca (KCS), conjunctivitis, allergic conjunctivitis, endophthalmitis, keratitis, uveitis, styes, eye inflammation, eye discomfort or pain, itching of the eye, inflammatory dry eye, redness of the eye, watery eye, stinging or burning of the eye, gritty sensation of the eye, eye sensitivity to light, blurred vision, more frequent blinking, pressure behind the eye, eyelids that are greasy, crusty, itchy, swollen or sticking, and the like.

[0069] In some embodiments, the at least one ocular disorder may be chosen from blepharitis, dry eye, meibomian gland dysfunction, adult chlamydial ophthalmia, ocular rosacea presbyopia, recalcitrant recurrent corneal erosions, ocular cicatricial pemphigoid, Sjogren’s syndrome (SS), non-SS keratoconjunctivitis sicca (KCS), conjunctivitis, allergic conjunctivitis, endophthalmitis, keratitis, uveitis, or any combination thereof.

[0070] In some embodiments, the at least one ocular disorder may be chosen from conjunctivitis, keratitis, blepharitis, or any combination thereof.

[0071] In some embodiments, the methods of the present disclosure comprise treatment or temporary' prevention of at least one ocular disorder comprising administering to a patient in need thereof an effective amount of an ophthalmic composition comprising (a) at least one antibiotic chosen from at least one aminoglycoside, at least one macrolide, at least one polypeptide, at least one quinolone, at least one tetracycline derivative, or any combination thereof and (b) at least one semifluorinated alkane chosen from F4H4, F4H5, F4H6, F4H7, F4H8, F5H4, F5H5, F5H6, F5H7, F5H8, F6H2, F6H4, F6H6, F6H7, F6H8, F6H9, F6H10, F6H12, F8H8, F8H10, F8H12, F10H10, or any combination thereof.

[0072] In some embodiments, the methods of the present disclosure comprise treatment or temporary prevention of at least one ocular disorder comprising administering to a patient in need thereof an effective amount of an ophthalmic composition comprising (a) at least one antibiotic chosen from azithromycin, erythromycin, besifloxacin, ciprofloxacin, bacitracin, tobramycin, clindamycin, doxycycline, or any combination thereof and (b) at least one semifluorinated alkane chosen from F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8, or any combination thereof.

[0073] In some embodiments, the methods of the present disclosure comprise treatment or temporary prevention of at least one ocular disorder comprising administering to a patient in need thereof an effective amount of an ophthalmic composition comprising (a) at least one antibiotic chosen from doxycycline, demeclocycline, minocycline, tetracycline, or any combination thereof and (b) at least one semifluorinated alkane chosen from F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8, or any combination thereof.

[0074] In some embodiments, the methods of the present disclosure comprise treatment or temporary prevention of at least one ocular disorder comprising administering to a patient in need thereof an effective amount of an ophthalmic composition comprising (a) at least one antibiotic comprising doxycycline and (b) at least one semifluorinated alkane comprising F6H8.

[0075] In some embodiments, the methods of the present disclosure compri se treatment or temporary prevention of at least one ocular disorder comprising administering to a patient in need thereof an effective amount of an ophthalmic composition comprising (a) at least one antibiotic, wherein the at least one antibiotic consists essentially of doxycycline, and (b) at least one semifluorinated alkane, wherein the at least one semifluorinated alkane consists essentially ofF6H8.

[0076] In some embodiments, the at least one ocular disorder is blepharitis. Blepharitis is inflammation of the eyelids, in which they often become red, irritated and itchy with dandrufflike scales that form on the eyelashes. Blepharitis is often a chronic condition that's difficult to treat. Blepharitis commonly occurs when tiny oil glands near the base of the eyelashes become clogged, causing irritation and redness. Several diseases and conditions can cause blepharitis. [0077] Blepharitis is commonly categorized into two types: anterior blepharitis and posterior blepharitis. Anterior blepharitis is commonly caused by bacteria (staphylococcal blepharitis) or dandruff of the scalp and eyebrows (seborrheic blepharitis). These bacteria are commonly found on the face and lids, but if they become excessive, or the lid area reacts poorly to their presence, an infection may occur. Less commonly, allergies or a mite infestation of the eyelashes can cause anterior blepharitis. Posterior blepharitis can occur when the glands of the eyelids irregularly produce oil (meibomian blepharitis). This creates a favorable environment for bacterial growth. Posterior blepharitis can also develop as a result of other skin conditions, such as rosacea and scalp dandruff.

[0078] Symptoms of blepharitis may include watery eyes, red eyes, a gritty, burning or stinging sensation in the eyes, eyelids that appear greasy, itchy eyelids, red and swollen eyelids, flaking of the skin around the eyes, crusted eyelashes, eyelid sticking, more frequent blinking, sensitivity to light, blurred vision that usually improves with blinking, and the like.

[0079] In some embodiments, the methods of the present di sclosure comprise treatment or temporary prevention of blepharitis comprising administering to a patient in need thereof an effective amount of an ophthalmic composition as described above comprising (a) at least one antibiotic and (b) at least one semifluorinated alkane.

[0080] In some embodiments, the methods of the present disclosure comprise treatment or temporary prevention of blepharitis comprising administering to a patient in need thereof an effective amount of an ophthalmic composition comprising (a) at least one antibiotic chosen from at least one aminoglycoside, at least one macrolide, at least one polypeptide, at least one quinolone, at least one tetracycline derivative, or any combination thereof and (b) at least one semifluorinated alkane chosen from F4H4, F4H5, F4H6, F4H7, F4H8, F5H4, F5H5, F5H6, F5H7, F5H8, F6H2, F6H4, F6H6, F6H7, F6H8, F6H9, F6H10, F6H12, F8H8, F8H10, F8H12, F10H10, or any combination thereof.

[0081] In some embodiments, the methods of the present disclosure comprise treatment or temporary prevention of blepharitis comprising administering to a patient in need thereof an effective amount of an ophthalmic composition comprising (a) at least one antibiotic chosen from azithromycin, erythromycin, besifloxacin, ciprofloxacin, bacitracin, tobramycin, clindamycin, doxycycline, or any combination thereof and (b) at least one semifluorinated alkane chosen from F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8, or any combination thereof.

[0082] In some embodiments, the methods of the present disclosure comprise treatment or temporary prevention of blepharitis comprising administering to a patient in need thereof an effective amount of an ophthalmic composition comprising (a) at least one antibiotic chosen from doxycycline, demeclocycline, minocycline, tetracycline, or any combination thereof and (b) at least one semifluorinated alkane chosen from F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8, or any combination thereof.

[0083] In some embodiments, the methods of the present disclosure comprise treatment or temporary' prevention of blepharitis comprising administering to a patient in need thereof an effective amount of an ophthalmic composition comprising (a) at least one antibiotic comprising doxycycline and (b) at least one semifluorinated alkane comprising F6H8.

[0084] In some embodiments, the methods of the present disclosure comprise treatment or temporary prevention of blepharitis comprising administering to a patient in need thereof an effective amount of an ophthalmic composition compri sing (a) at least one antibiotic, wherein the at least one antibiotic consists essentially of doxycycline, and (b) at least one semifluorinated alkane, wherein the at least one semifluorinated alkane consists essentially of F6H8.

[0085] In some embodiments, the ophthalmic compositions can be administered by any convenient route. In some embodiments, the ophthalmic compositions are any liquid form suitable for topical application. In some embodiments, the ophthalmic compositions are topically administered to the ocular surface. In some embodiments, the ophthalmic compositions are topically administered to the cornea. In some embodiments, the ophthalmic compositions are instilled into the conjunctival sac.

[0086] In some embodiments, the composition may be in the form of a liquid (such as a suspension, a solution, an emulsion, or the like) or in the form of an ointment. In some embodiments, the ophthalmic composition may be in the form of a suspension. In some embodiments, the ophthalmic composition may be in the form of a solution. In some embodiments the composition may be administered as an eye drop. In some embodiments, the ophthalmic composition may be in the form of a suspension that may be administered as an eye drop. In some embodiments, the ophthalmic composition may be in the form of a solution that may be administered as an eye drop. In some embodiments, the ophthalmic composition may be in the form of an ointment. In some embodiments, the ophthalmic composition may be administered as a spray. In some embodiments, the ophthalmic composition may be administered as artificial tears. In some embodiments, the ophthalmic composition may be in the form of a contact lens adsorbent.

[0087] Proper dosages of the ophthalmic compositions of the present disclosure are concentration-dependent. To determine the specific dose, a skilled artisan would have to take into account kinetics and absorption characteristics of the particular ingredients. In addition, the dosage may be dependent on the route of administration. The dosages may also de dependent on the degree of antibacterial and/or anti-inflammatory effect desired in a patient.

[0088] Methods of treating comprise administration of a daily dose of an ophthalmic composition of the present disclosure to a subject in need thereof. Determining and adjusting an appropriate dosing regimen (e.g., adjusting the number of doses and frequency of dosing) per day can be performed by one of ordinary skill in the relevant art, and will depend upon various factors such as the nature and progression of a disorder and/or condition associated with allergies and eye redness, the health, and/or age of the subject. In some embodiments, the ophthalmic compositions of the present disclosure are administered to a patient in a single dose per day, in two doses per day, in three doses per day, in four doses per day, etc. or up to, for example, ten doses per day. In some embodiments, the composition is administered to a patient for at least one week, at least two weeks, at least three weeks, at least one month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 12 months, at least one year, or for more than one year. [0089] Further disclosed herein are container closure systems containing an ophthalmic composition as described above comprising (a) at least one antibiotic and (b) at least one semifluorinated alkane.

[0090] The ophthalmic compositions disclosed herein may be kept in container closure systems (e.g., vials, ampoules, bottles, tubes, syringes, dispenser packages, or other suitable containers). In some embodiments, the compositions may be packaged either in a single-dose unit container closure system or multi-dose container closure system. In some embodiments, the compositions may be packaged in a single-dose unit container closure system. Container closure systems may be composed of one or more materials appropriate for its use, such as aluminum, glass, polypropylene, polyethylene (e.g., low-density polyethylene and high-density polyethylene), polyethylene terephthalate, and polyethylene terephthalate glycol. Plastic container closure systems weigh less, are more resistant to shock and other mechanical influences, cost less, and offer more design possibilities than glass. Polyethylene, e.g., low- density polyethylene (LDPE), without or with additives, and polypropylene (PP) are the plastics required by the European Pharmacopoeia. In some embodiments, the container closure system comprises polypropylene. In some embodiments, the container closure system is composed of polypropylene. In some embodiments, the container closure systems may be squeezable to allow delivery of the ophthalmic composition as drops to the eye.

[0091] In some embodiments, a single container closure system can comprise one or more compartments for containing a provided ophthalmic composition, and/or appropriate carrier for suspension or dilution. In some embodiments, a single container can be appropriate for modification such that the container can receive a physical modification so as to allow combination of compartments and/or components of individual compartments. For example, a foil or plastic bag can comprise two or more compartments separated by a perforated seal which can be broken so as to allow combination of con tents of two individual compartments once the signal to break the seal is generated.

[0092] Ophthalmic compositions disclosed herein may be prepared according to any known method for the manufacture of ophthalmic formulations or preparations. As will be appreciated by those of ordinary' skill in the art, a number of methods are known. In some embodiments, the ophthalmic compositions disclosed herein may be prepared by any conventional technique, such as, e.g., those described in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988- 1999, Marcel Dekker, New York.

[0093] In some embodiments, the ophthalmic compositions of the present disclosure are in polypropylene (PP) container closure systems (e.g., vials, ampoules, bottles, tubes, syringes, dispenser packages, or other suitable containers). Exemplary PP container closure systems include white PP bottles and natural PP bottles. PP containers are squeezable but also are semi- permeable to volatile compounds. It may be desirable for an ophthalmic composition to demonstrate stability in multiple types of container closure systems, each of a different material type.

[0094] In some embodiments, the present disclosure provides a container closure system containing an ophthalmic composition comprising (a) at least one antibiotic and (b) at least one semifluorinated alkane as disclosed above, wherein the container closure system is a PP container closure system.

[0095] The present disclosure also provides a kit comprising a formulation container containing an ophthalmic composition comprising (a) at least one antibiotic and (b) at least one semifluorinated alkane as disclosed above, wherein the container closure system is a PP container closure system. In some embodiments, kits can include a second container (the solvent container) comprising a suitable delivery vehicle for dilution or suspension of the provided ophthalmic composition in the first container (the formulation container) for preparation of administration to a subject. In some embodiments, the contents of the formulation container and contents of the solvent container combine to form at least one unit dosage form. In some embodiments, the solvent container contains a delivery vehicle that is aqueous. In some embodiments, the solvent container contains a delivery vehicle that is nonaqueous. Suitable delivery vehicle for the solvent container are detailed above.

[0096] In some embodiments, a single container can comprise one or more compartments for containing a provided ophthalmic composition, and/or appropriate vehicle carrier for suspension or dilution. In some embodiments, a single container can be appropriate for modification such that the container can receive a physical modification so as to allow combination of compartments and/or components of individual compartments. For example, a foil or plastic bag can comprise two or more compartments separated by a perforated seal which can be broken so as to allow combination of contents of tw^zo individual compartments once the signal to break the seal is generated. A kit can thus comprise such multi-compartment containers including the ophthalmic compositions disclosed herein and an appropriate solvent and/or an appropriate vehicle carrier for suspension.

[0097] Without limitation, some embodiments of the disclosure include:

[0098] Exemplary Composition Embodiments:

[0099] Embodiment 1. An ophthalmic composition comprising: (a) at least one antibiotic and (b) at least one semifluorinated alkane.

[00100] Embodiment 2. The ophthalmic composition according to Embodiment 1, wherein the at least one antibiotic is chosen from at least one aminoglycoside, at least one macrolide, at least one polypeptide, at least one quinolone, at least one tetracycline derivative, or any combination thereof.

[00101] Embodiment 3. The ophthalmic composition according to any one of Embodiments 1-2, wherein the at least one antibiotic comprises at least one aminoglycoside chosen from gentamicin, tobramycin, amikacin, plazomicin, streptomycin, neomycin, paromomycin, or any combination thereof.

[00102] Embodiment 4. The ophthalmic composition according to any one of Embodiments 1- 2, wherein the at least one antibiotic comprises at least one macrolide chosen from azithromycin, clarithromycin, erythromycin, or any combination thereof.

[00103] Embodiment 5. The oph th almi c composition according to any one of Embodiments 1-2, wherein the at least one antibiotic comprises at least one polypeptide chosen from actinomycin, bacitracin, colistin, and polymyxin B, or any combination thereof.

[00104] Embodiment 6. The ophthalmic composition according to any one of Embodiments 1-2, wherein the at least one antibiotic comprises at least one quinolone chosen from besifloxacin, cinoxacin, ciprofloxacin, delafloxacin, gatifloxacin, gemifloxacin, levofloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, or any combination thereof. [00105] Embodiment 7. The ophthalmic composition according to any one of Embodiments 1-2, wherein the at least one antibiotic is chosen from azithromycin, erythromycin, besifloxacin, ciprofloxacin, bacitracin, tobramycin, clindamycin, doxycycline, or any combination thereof.

[00106] Embodiment 8. The ophthalmic composition according to any one of Embodiments 1 -2, wherein the at least one antibiotic comprises at least one tetracycline derivative chosen from doxycycline, demeclocycline, minocycline, tetracycline, or any combination thereof.

[00107] Embodiment 9. The ophthalmic composition according to any one of Embodiments 1-2 or 8, wherein the at least one antibiotic comprises doxycycline. [00108] Embodiment 10. The ophthalmic composition according to any one of Embodiments 1-2 or 8-9, wherein the at least one antibiotic consists essentially of doxycycline. [00109] Embodiment 11. The ophthalmic composition according to any one of Embodiments 1-10, wherein the at least one antibiotic is included in the composition at a concentration from about 0.005% (w/w) to about 5% (w/w), for example, from about 0.02% (w/w) to about 4% (w/w), from about 0.5% (w/w) to about 3% (w/w), or from about 0.75% (w/w) to about 2% (w/w).

[00110] Embodiment 12. The ophthalmic composition according to any one of Embodiments 1-11, wherein the at least one semifluorinated alkane is a compound composed of at least one perfluorinated hydrocarbon segment (F-segment) and at least one nonfluorinated hydrocarbon segment (H- segment).

[00111] Embodiment 13. The ophthalmic composition according to any one of Embodiments 1-12, wherein the at least one semifluorinated alkane is a compound composed of F-segments and H-segments according to the formula FnHm, wherein the F-segments and the H-segments are linear or branched and wherein n and m, which may be the same or different, are independently chosen from 3 to 20 carbon atoms, or from 3 to 10 carbon atoms, or from 4 to 8 carbon atoms.

[00112] Embodiment 14. The ophthalmic composition according to any one of Embodiments 1-12, wherein the at least one semifluorinated alkane is a compound composed of F-segments and H-segments according to the formula FnHm, wherein the F-segments and the H-segments are linear and wherein n and m, which may be the same or different, are independently chosen from 3 to 20 carbon atoms, or from 3 to 10 carbon atoms, or from 4 to 8 carbon atoms.

[00113] Embodiment 15. The ophthalmic composition according to any one of Embodiments 1-12, wherein the at least one semifluorinated alkane is a compound composed of F-segments and H-segments according to the formula FnHmFo, wherein the F-segments and H-segments are linear or branched and wherein n, m, and o, which may be the same or different, are independently chosen from 3 to 20 carbon atoms, or from 3 to 10 carbon atoms, or from 4 to 8 carbon atoms.

[00114] Embodiment 16. The ophthalmic composition according to any one of Embodiments 1-13, wherein the ratio of the carbon atoms of the F-segment to the carbon atoms of the H-segment of the at least one linear or branched semifluorinated alkane ranges between 0.6 and 3.0 or between 0.6 and 1.0. [00115] Embodiment 17. The ophthalmic composition according to any one of Embodiments 1-14, wherein the ratio of the carbon atoms of the F-segment to the carbon atoms of the H-segment of the at least one linear semifluorinated alkane ranges between 0.6 and 3.0 or between 0.6 and 1.0.

[00116] Embodiment 18. The ophthalmic composition according to any one of Embodiments 1-12, wherein the at least one semifluorinated alkane is chosen from F4H4, F4H5, F4H6, F4H7, F4H8, F5H4, F5H5, F5H6, F5H7, F5H8, F6H2, F6H4, F6H6, F6H7, F6H8, F6H9, F6H10, F6H12, F8H8, F8H10, F8H12, F10H10, or any combination thereof.

[00117] Embodiment 19. The ophthalmic composition according to any one of Embodiments 1-12, wherein the at least one semifluorinated alkane is chosen from F4H4, F4H5, F4H6, F5H5, F5H6, F5H7, F5H8, F6H6, F6H7, F6H8, F6H9, F6H10, F8H8, F8H10, F8H12, F10H10, or any combination thereof.

[00118] Embodiment 20. The ophthalmic composition according to any one of Embodiments 1-12, wherein the at least one semifluorinated alkane is chosen from F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8, or any combination thereof.

[00119] Embodiment 21. The ophthalmic composition according to any one of Embodiments 1-12, wherein the at least one semifluorinated alkane comprises 1- perfluorohexyl-octane (F6FI8).

[00120] Embodiment 22. The ophthalmic composition according to any one of Embodiments 1-12, wherein the at least one semifluorinated alkane consists essentially of 1- perfluorohexyl-octane (F6H8).

[00121] Embodiment 23. The ophthalmic composition according to any one of Embodiments 1-22, wherein (a) the at least one antibiotic is chosen from at least one aminoglycoside, at least one macrolide, at least one polypeptide, at least one quinolone, at least one tetracycline derivative, or any combination thereof and (b) the at least one semifluorinated alkane is chosen from F4H4, F4H5, F4H6, F4H7, F4H8, F5H4, F5H5, F5H6, F5H7, F5H8, F6H2, F6H4, F6H6, F6H7, F6H8, F6H9, F6H10, F6H12, F8H8, F8H10, F8H12, F10H10, or any combination thereof.

[00122] Embodiment 24. The ophthalmic composition according to any one of Embodiments 1-23, wherein (a) the at least one antibiotic is chosen from azithromycin, eiythromycin, besifloxacin, ciprofloxacin, bacitracin, tobramycin, clindamycin, doxycycline, or any combination thereof and (b) the at least one semifluorinated alkane is chosen from F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8, or any combination thereof. [00123] Embodiment 25. The ophthalmic composition according to any one of Embodiments 1-23, wherein (a) the at least one antibiotic is chosen from doxycycline, demeclocycline, minocycline, tetracycline, or any combination thereof and (b) the at least one semifluorinated alkane is chosen from F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8, or any combination thereof.

[00124] Embodiment 26. The ophthalmic composition according to any one of Embodiments 1-25, wherein (a) the at least one antibiotic comprises doxycycline and (b) the at least one semifluorinated alkane comprises F6H8.

[00125] Embodiment 27. The ophthalmic composition according to any one of Embodiments 1 -26, wherein (a) the at least one antibiotic consists essentially of doxycycline and (b) the at least one semifluorinated alkane consists essentially of F6H8.

[00126] Embodiment 28. The ophthalmic composition according to any one of Embodiments 1-27, wherein the composition is liquid.

[00127] Embodiment 29. The ophthalmic composition according to any one of

Embodiments 1-28, wherein the composition is nonaqueous.

[00128] Embodiment 30. The ophthalmic composition according to any one of

Embodiments 1-29, wherein the composition is in the form of a suspension, a solution, or an emulsion.

[00129] Embodiment 31. The ophthalmic composition according to any one of

Embodiments 1-30, wherein the composition is stable.

[00130] Embodiment 32. The ophthalmic composition according to any one of

Embodiments 1-31, wherein the composition further comprises at least one additional therapeutic agent.

[00131] Embodiment 33. The ophthalmic composition according to any one of Embodiments 1-32, wherein the composition further comprises at least one non-therapeutic component and/or pharmaceutically acceptable excipient.

[00132] Embodiment 34. The ophthalmic composition according to any one of Embodiments 1-33, wherein the composition further comprises at least one additional therapeutic agent chosen from redness reduction agents, NSAIDS, steroids, antifungals, aminopenicillins, macrolides, mite-killing compounds, antihistamines, anti-inflammatory agents, anti-allergens, or any combination thereof.

[00133] Embodiment 35. The ophthalmic composition according to any one of Embodiments 1-34, wherein the composition further comprises at least one non-therapeutic component and/or pharmaceutically acceptable excipient chosen from tonicity agents, preservatives, buffers, pH adjustors, antioxidants, delivery vehicles, stabilizers, suspending agents, viscosity-increasing agents, wetting agents, solubilizing agents, chelating agents, nitrous oxide inhibitors, isotonic agents, humectants, surfactants, or any combination thereof. [00134] Exemplary Method of Treatment Embodiments:

[00135] Embodiment 36. A method for the treatment or temporary prevention of at least one ocular disorder comprising administering to a patient in need thereof an effective amount of an ophthalmic composition comprising (a) at least one antibiotic and (b) at least one semifluorinated alkane.

[00136] Embodiment 37. The method according to Embodiment 36, wherein the ophthalmic composition is the ophthalmic composition according to any of Embodiments 1-35.

[00137] Embodiment 38. The method according to any one of Embodiments 36-37, wherein the at least one ocular disorder is chosen from blepharitis, dry eye, meibomian gland dysfunction, adult chlamydial ophthalmia, ocular rosacea presbyopia, recalcitrant recurrent comeal erosions, ocular cicatricial pemphigoid, Sjogren’s syndrome (SS), non-SS keratoconjunctivitis sicca (KCS), conjunctivitis, allergic conjunctivitis, endophthalmitis, keratitis, uveitis, styes, eye inflammation, eye discomfort or pain, itching of the eye, inflammatory dry eye, redness of the eye, watery' eye, stinging or burning of the eye, gritty sensation of the eye, eye sensitivity to light, blurred vision, more frequent blinking, pressure behind the eye, eyelids that are greasy, crusty, itchy, swollen or sticking, or any combination thereof.

[00138] Embodiment 39. The method according to any one of Embodiments 36-38, wherein the at least one ocular disorder is chosen from blepharitis, dry eye, meibomian gland dysfunction, adult chlamydial ophthalmia, ocular rosacea presbyopia, recalcitrant recurrent comeal erosions, ocular cicatricial pemphigoid, Sjogren’s syndrome (SS), non-SS keratoconjunctivitis sicca (KCS), conjunctivitis, allergic conjunctivitis, endophthalmitis, keratitis, uveitis, or any combination thereof.

[00139] Embodiment 40. The method according to any one of Embodiments 36-39, wherein the at least one ocular disorder is chosen from conjunctivitis, keratitis, blepharitis, or any combination thereof.

[00140] Embodiment 41. A method for the treatment or temporary prevention of blepharitis comprising administering to a patient in need thereof an effective amount of an ophthalmic composition comprising (a) at least one antibiotic and (b) at least one semifluorinated alkane. [00141] Embodiment 42. The method according to Embodiment 41 , wherein the ophthalmic composition is the ophthalmic composition according to any of Embodiments 1-35.

[00142] Embodiment 43. The method according to any one of Embodiments 36-42, wherein the ophthalmic composition is topically administered to the ocular surface of the patient, or topically administered to the cornea of the patient, or instilled into the conjunctival sac of the patient.

[00143] Embodiment 44. The method according to any one of Embodiments 36-43, wherein the ophthalmic composition is administered in the form of a suspension, an ointment, a solution, or a spray.

[00144] Embodiment 45. The method according to any one of Embodiments 36-44, wherein the ophthalmic composition is administered in the form of a suspension that may be administered as an eye drop.

[00145] Embodiment 46. The method according to any one of Embodiments 36-45, wherein the ophthalmic composition is administered to the patient in a single dose per day, in two doses per day, in three doses per day, in four doses per day, or in up to ten doses per day.

[00146] Embodimen t 47. The method according to any one of Embodiments 36-46, wherein the ophthalmic composition is administered to the patient for at least one week, at least two weeks, at least three weeks, at least one month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, at least 12 months, at least one year, or for more than one year.

[00147] Embodiment 48. The method according to any one of Embodiments 36-47, wherein the ophthalmic composition is administered to the patient in combination with an effective amount of at least one additional therapeutic agent.

[00148] Embodiment 49. The method according to any one of Embodiments 36-48, wherein the ophthalmic composition is administered to the patient in combination with an effective amount of at least one additional therapeutic agent chosen from redness reduction agents, NSAIDS, steroids, antifungals, aminopenicillins, macrolides, mite-killing compounds, antihistamines, anti-inflammatory agents, anti-allergens, or any combination thereof.

[00149] Exemplary Container Closure Systems and Kits:

[00150] Embodiment 50. A container closure system containing an ophthalmic composition comprising (a) at least one antibiotic and (b) at least one semifluorinated alkane. [00151] Embodiment 51. The container closure system of Embodiment 50, wherein the ophthalmic composition is the ophthalmic composition according to any of Embodiments 1- 35.

[00152] Embodiment 52. The container closure system according to any one of claims 50-

51, wherein the container closure system is chosen from vials, ampoules, bottles, tubes, syringes, and dispenser packages.

[00153] Embodiment 53. The container closure system according to any one of claims 50-

52, wherein the container closure system is a polypropylene (PP) container closure system.

[00154] Embodiment 54. A kit comprising: (i) a formulation container closure system containing an ophthalmic composition comprising (a) at least one antibiotic and (b) at least one semifluorinated alkane and (ii) a formulation container closure system containing a delivery vehicle for dilution or suspension of the ophthalmic composition in the formulation container. [00155] Embodiment 55. The kit of Embodiment 54, wherein the ophthalmic composition is the ophthalmic composition according to any of Embodiments 1-35.

[00156] Embodiment 56. The kit according to any one of claims 54-55, wherein the formulation container closure system is chosen from vials, ampoules, bottles, tubes, syringes, and dispenser packages.

[00157] Embodiment 57. The kit according to any one of claims 54-56, wherein the formulation container closure system is a PP container closure system.

EXAMPLES

[00158] The following examples are intended to be illustrative and are not meant in any way to limit the scope of the disclosure.

Example 1 (background):

[00159] Tables 1 and 2 below show in vitro activity of the minimum inhibitory concentrations of different antibiotics frequently used in the management of Staphylococcal blepharitis (Source: Poster #3543816. 2021 Annual Meeting of the Association for Research in Vision and Ophthalmology (ARVO) May 1-7): [00160]

Table 1

[00161]

Table 2

Example 2 (background):

[00162] According to the FDA label information for Monodox® Doxycycline Monohydrate Capsules, following a 200 mg oral dose of doxycycline monohydrate, 24 normal adult volunteers averaged the following serum concentration values reported in Table 3 below: [00163]

TaMe 3

[00164] The Cmax value was reported as 3.61 mcg/mL (± 0.9 sd). The Tmax value was reported as 2.60 hr (± 1.10 sd). The half-life value was reported as 16.33 hr (± 4.53 sd).

Example 3:

[00165] Ocular tissue concentrations of doxycycline in male New Zealand White rabbits were measured following a single bilateral topical ocular administration of two doxycycline compositions. Three samples from a lot of each composition were prepared and analyzed by HPLC to measure the amount of doxycycline. The first composition (Inventive Composition Group 1) was a nonaqueous suspension in accordance with the present application, comprising both at least one antibiotic (doxyclycline) and at least one semifluorinated alkane (F6H8), the contents of which are shown in Table 4 below:

[00166]

Table 4

[00167] The second composition (Comparative Composition Group 2) was a comparative ointment comprising doxycycline, but without at least one semifluorinated alkane, the contents of which are shown in Table 5 below: [00168]

Table 5

[00169] The object of the study was to evaluate the relative ocular tissue concentrations of the two compositions. The ointment composition was chosen as the control comparator because ointment compositions tend to have long residence times, and the ointment composition was therefore expected to show an acceptable amount of drug delivery of the doxycycline for comparison to the inventive composition.

[00170] Plasma, as well as the three following types of tissues were selected for analyzing the resultant doxycycline concentrations following administration: (i) conjunctiva (because doxycycline will be administered topically); (ii) lid margin (because bacterial infection and inflammation occur in the eyelids); and (iii) upper and lower meibomian glands (pooled) (because bacterial infection occurs secondary to meibomian gland dysfunction). The concentrations were measured at the following time points (post-dose): 15, 30, 60, 120 and 480 minutes. The compositions were administered to the rabbits according to Table 6:

[00171]

Table 6

[00172] The resultant mean concentrations of doxycycline in the rabbits following the topical ocular dosing of the two compositions are shown in Table 7: [00173]

TaMe 7

[00174] Results from Table 7 are also shown in Figures 1-4.

[00175] The resultant pharmacokinetic parameters of the doxycycline in the rabbits following the topical ocular dosing of the two compositions are shown in Table 8:

[00176]

Table 8

Notes

Inv. Grp 1 = Inventive Composition (Group 1)

- Comp. Grp 2 = Comparative Composition (Group 2)

- NC: Not Calculated R²<0.7

- NR: Not Reported

* Based on final two timepoints

- # Plasma

- Terminal t1/2 values for the ocular matrices were calculated for those ocular tissues and reported when R²>0.7 for the terminal phase. Based on this criteria, the terminal t1/2 was not reported for the suspension group lid margins and meibomian glands as the apparent terminal phase extended beyond the final collection timepoint of 8 hours.

[00177] Results from Table 8 are also shown in Figures 5-8.

[00178] Given the long residence times of ointments like the comparative composition, it was surprising that the inventive composition had greater exposure in terms of mean concentration of doxycycline than comparative composition in all ocular tissues examined, despite containing less doxycycline per unit. In conjunctiva, the inventive composition measured 52.3μg*h/g and 0.213 μg*h/g/μg vs. 13.8μg*h/g and 0.045 μg*h/g/μg for the comparative composition. In lid margin, the inventive composition measured 76.8 μg*h/g and 0.137 μg*h/g/μg vs. 11.7 μg*h/g and 0.038 μg*h/g/μg for the comparative composition. In meibomian glands, the inventive composition measured 6.44 ng*h/g and 0.026 μg*h/g/μg vs. 2.45 μg*h/g and 0.008 μg*h/g/μg for the comparative composition.

[00179] In contrast, the comparative composition treatment had greater systemic exposure in plasma than the inventive composition (6.3 for the comparative composition vs. 3.08 ng*h/ml for the inventive composition).

[00180] The results above show that tissue concentrations achieved with the inventive compositions were higher than or equal to the minimum inhibitory concentration (MIC90) reported for in vitro activity of doxycycline against Staphylococcal Blepharitis (0.25ug/ml) and thus support use of the inventive composition for treatment or prevention of blepharitis in a patient.

[00181] It is also believed that the anti-inflammatory properties of the inventive composition could further be useful in treating inflammation associated with blepharitis.

Claims

What is claimed is:

1. An ophthalmic composition comprising: (a) at least one antibiotic and (b) at least one semifluorinated alkane.

2. The ophthalmic composition according to claim 1, wherein the at least one antibiotic is chosen from at least one aminoglycoside, at least one macrolide, at least one polypeptide, at least one quinolone, at least one tetracycline derivative, or any combination thereof.

3. The ophthalmic composition according to any one of claims 1-2, wherein the at least one antibiotic is chosen from azithromycin, erythromycin, besifloxacin, ciprofloxacin, bacitracin, tobramycin, clindamycin, doxycycline, or any combination thereof.

4. The ophthalmic composition according to any one of claims 1 -2, wherein the at least one antibiotic is chosen from doxycycline, demeclocycline, minocycline, tetracycline, or any combination thereof.

5. The ophthalmic composition according to any one of claims 1-4, wherein the at least one antibiotic comprises doxycycline.

6. The ophthalmic composition according to any one of claims 1-5, wherein the at least one antibiotic consists essentially of doxycycline.

7. The ophthalmic composition according to any one of claims 1-6, wherein the at least one antibiotic is included in the composition at a concentration of from about 0.005% (w/w) to about 5% (w/w).

8. The ophthalmic composition according to any one of claims 1-7, wherein the at least one semifluorinated alkane is a compound composed of at least one perfluorinated hydrocarbon segment (F-segment) and at least one non-fluorinated hydrocarbon segment (H-segment) according to the formula FnHm, wherein the F-segments and the H-segments are linear or branched and wherein n and m, which may be the same or different, are independently chosen from 3 to 20 carbon atoms.

9. The ophthalmic composition according to any one of claims 1-8, wherein the at least one semifluorinated alkane is chosen from F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8, or any combination thereof.

10. The ophthalmic composition according to any one of claims 1-9, wherein the at least one semifluorinated alkane comprises 1 -perfluorohexyl-octane (F6H8).

11. The ophthalmic composition according to any one of claims 1-10, wherein the at least one semifluorinated alkane consists essentially of 1 -perfluorohexyl-octane (F6H8).

12. The ophthalmic composition according to claim 1 , wherein (a) the at least one antibiotic is chosen from azithromycin, erythromycin, besifloxacin, ciprofloxacin, bacitracin, tobramycin, clindamycin, doxycycline, or any combination thereof and (b) the at least one semifluorinated alkane is chosen from F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8, or any combination thereof.

13. The ophthalmic composition according to claims 1, wherein (a) the at least one antibiotic is chosen from doxycycline, demeclocycline, minocycline, tetracycline, or any combination thereof and (b) the at least one semifluorinated alkane is chosen from F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8, or any combination thereof.

14. The ophthalmic composition according to claim 1 , wherein (a) the at least one antibiotic comprises doxycycline and (b) the at least one semifluorinated alkane comprises F6H8.

15. The ophthalmic composition according to claim 1 , wherein (a) the at least one antibiotic consists essentially of doxycycline and (b) the at least one semifluorinated alkane consists es sentially of F6H8.

16. The ophthalmic composition according to any one of claims 1-15, wherein the composition is liquid.

17. The ophthalmic composition according to any one of claims 1-16, wherein the composition is nonaqueous.

18. The ophthalmic composition according to any one of claims 1-17, wherein the composition is stable.

19. The ophthalmic composition according to any one of claims 1-18, 'wherein the composition further comprises at least one non-therapeutic component and/or pharmaceutically acceptable excipient.

20. The ophthalmic composition according to any one of claims 1-19, wherein the composition further comprises at least one additional therapeutic agent chosen from redness reduction agents, NSAIDS, steroids, antifungals, aminopenicillins, macrolides, mite-killing compounds, antihistamines, anti-inflammatory agents, anti-allergens, or any combination thereof.

21. A method for the treatment or temporary prevention of at least one ocular disorder comprising administering to a patient in need thereof an effective amount of an ophthalmic composition comprising (a) at least one antibiotic and (b) at least one semifluorinated alkane.

22. The method according to claim 21 , wherein (a) the at least one antibiotic is chosen from azithromycin, erythromycin, besifloxacin, ciprofloxacin, bacitracin, tobramycin, clindamycin, doxycycline, or any combination thereof and (b) the at least one semifluorinated alkane is chosen from F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8, or any combination thereof.

23. The method according to claim 21 , wherein (a) the at least one antibiotic is chosen from doxycycline, demeclocycline, minocycline, tetracycline, or any combination thereof and (b) the at least one semifluorinated alkane is chosen from F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8, or any combination thereof.

24. The method according to claim 21, wherein (a) the at least one antibiotic comprises doxycycline and (b) the at least one semifluorinated alkane comprises F6H8.

25. The method according to claim 21, wherein (a) the at least one antibiotic consists essentially of doxycycline and (b) the at least one semifluorinated alkane consists essentially ofF6H8.

26. The method according to any one of claims 22-26, wherein the ophthalmic composition is nonaqueous.

27. The method according to any one of claims 21-26, wherein the at least one ocular disorder is chosen from blepharitis, dry eye, meibomian gland dysfunction, adult chlamydial ophthalmia, ocular rosacea presbyopia, recalcitrant recurrent corneal erosions, ocular cicatricial pemphigoid, Sjogren’s syndrome (SS), non-SS keratoconjunctivitis sicca (KCS), conjunctivitis, allergic conjunctivitis, endophthalmitis, keratitis, uveitis, styes, eye inflammation, eye discomfort or pain, itching of the eye, inflammatory dry eye, redness of the eye, watery eye, stinging or burning of the eye, gritty sensation of the eye, eye sensitivity to light, blurred vision, more frequent blinking, pressure behind the eye, eyelids that are greasy, crusty, itchy, swollen or sticking, or any combination thereof.

28. The method according to any one of claims 21-27, wherein the at least one ocular disorder is chosen from blepharitis, dry eye, meibomian gland dysfunction, adult chlamydial ophthalmia, ocular rosacea presbyopia, recalcitrant recurrent corneal erosions, ocular cicatricial pemphigoid, Sjogren’s syndrome (SS), non-SS keratoconjunctivitis sicca (KCS), conjunctivitis, allergic conjunctivitis, endophthalmitis, keratitis, uveitis, or any combination thereof.

29. The method according to any one of claims 21-28, wherein the at least one ocular disorder is chosen from conjunctivitis, keratitis, blepharitis, or any combination thereof.

30. The method according to any one of claims 21-29, wherein the at least one ocular disorder is blepharitis.

31. The method according to any one of claims 21 -30, wherein the ophthalmic composition is administered to the patient in combination with an effective amount of at least one additional therapeutic agent chosen from redness reduction agents, NSAIDS, steroids, antifungals, aminopenicillins, macrolides, mite-killing compounds, antihistamines, anti-inflammatory agents, anti-allergens, or any combination thereof.

32. The method according to any one of claims 21-31, wherein the ophthalmic composition is topically administered to the ocular surface of the patient, or topically administered to the cornea of the patient, or instilled into the conjunctival sac of the patient.

33. The method according to any one of claims 21-32, wherein the ophthalmic composition is administered in the form of a suspension as eye drops.

34. The method according to any one of claims 21-33, wherein the ophthalmic composition is administered to the patient in at least a single dose per day.

35. The method according to any one of claims 21-34, wherein the ophthalmic composition is administered to the patient for at least one week.

36. A method for the treatment or temporary prevention of blepharitis comprising administering to a patient in need thereof an effective amount of an ophthalmic composition comprising (a) at least one antibiotic chosen from azithromycin, erythromycin, besifloxacin, ciprofloxacin, bacitracin, tobramycin, clindamycin, doxycycline, or any combination thereof and (b) at least one semifluorinated alkane chosen from F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8, or any combination thereof.

37. The method according to claim 36, wherein (a) the at least one antibiotic comprises doxycycline and (b) the at least one semifluorinated alkane comprises F6FI8.

38. The method according to claim 36, wherein (a) the at least one antibiotic consists essentially of doxycycline and (b) the at least one semifluorinated alkane consists essentially ofF6H8.

39. The method according to any one of claims 36-38, wherein the ophthalmic composition is nonaqueous.

40. The method according to any one of claims 36-39, wherein the ophthalmic composition is administered to the patient in combination with an effective amount of at least one additional therapeutic agent chosen from redness reduction agents, NSAIDS, steroids, antifungals, aminopenicillins, macrolides, mite-killing compounds, antihistamines, anti-inflammatory agents, anti-allergens, or any combination thereof.

41. The method according to any one of claims 36-40, wherein the ophthalmic composition is topically administered to the ocular surface of the patient, or topically administered to the comea of the patient, or instilled into the conjunctival sac of the patient.

42. The method according to any one of claims 36-41 , wherein the ophthalmic composition is administered in the form of a suspension as eye drops.

43. The method according to any one of claims 36-42, wherein the ophthalmic composition is administered to the patient in at least a single dose per day.

44. The method according to any one of claims 36-44, w'herein the ophthalmic composition is administered to the patient for at least one week.