Hemifluorinated alkane small molecule lfa-1 antagonist compositions for treating ocular disorders

Abstract

Disclosed herein are ophthalmic compositions, such as non-aqueous liquid ophthalmic compositions, comprising lifitegrast and at least one semifluorinated alkane, such as 1-perfluorohexyloctane (F6H8); and methods of treating or preventing at least one ocular condition, such as dry eye disease, with such compositions. The ophthalmic compositions can be further provided in a container closure system, such as a polypropylene (PP) bottle or in a kit.

Description

[0001] This application claims the benefit of U.S. Patent Application 63 / 600,337, filed November 17, 2023, the entire contents of which are incorporated herein by reference.

[0002] This document discloses ophthalmic compositions, such as non-aqueous liquid ophthalmic compositions, comprising at least one small molecule lymphocyte function-associated antigen 1 (LFA-1) antagonist, such as lifitegrast, and at least one semi-fluorinated alkane, such as 1-perfluorohexyloctane (F6H8). These ophthalmic compositions can be used to treat and / or temporarily prevent ophthalmic conditions, such as dry eye, in the form of single-dose or multi-dose unit compositions. The ophthalmic compositions are stable for each active ingredient, provide efficient drug delivery, and are well-tolerated by the eye. The ophthalmic compositions are available in sealed single-dose units or in multi-dose container sealing systems (such as polypropylene (PP) bottles). Background Technology

[0003] Dry eye syndrome (also known as keratoconjunctivitis sicca) is a multifunctional condition affecting both the tear film and ocular surface, causing discomfort, visual impairment, and often even ocular surface damage. Tear hyperosmolarity and tear film instability are considered key mechanisms in the etiology of this disease and appear to reinforce each other. Hyperosmolarity can be caused by excessive tear film evaporation or reduced water flow. It activates an inflammatory cascade and releases inflammatory mediators into the tear film, with multiple pathophysiological effects ultimately leading to further increased tear film evaporation and tear film instability. Thus, tear film instability can be a consequence of hyperosmolarity. Alternatively, tear film instability can also develop through its own etiological pathways, such as via abnormalities in the lipid layer composition (e.g., from meibomian gland disorders).

[0004] The inflammatory cycle is one of the key processes that maintains and potentially develops dry eye disease. Depending on the severity of the condition, patients often develop reversible squamous metaplasia and punctate erosions of the ocular epithelium. Secondary complications that dry eye disease may cause include filamentous keratitis, microbial keratitis, corneal neovascularization, and ocular surface keratosis.

[0005] Dry eye disease is currently classified into two main types: dehydrating dry eye disease (DED) and evaporative dry eye disease (DED). These conditions are not necessarily mutually exclusive.

[0006] Within the categories of dehydrated forms of dry eye disease, there are two main subtypes: Sjögren and non-Sjögren. Patients with Sjögren syndrome suffer from an autoimmune disease in which the lacrimal glands are invaded by activated T cells, leading not only to keratoconjunctivitis sicca but also to xerostomia. Sjögren syndrome can be primary or caused by other autoimmune diseases such as systemic lupus erythematosus or rheumatoid arthritis. Non-Sjögren patients with dehydrated DED typically have lacrimal gland insufficiency, lacrimal duct obstruction, or reflex hyposecretion.

[0007] The second major category, evaporative dry eye (DED), also exhibits heterogeneity and can develop due to a variety of underlying causes. Causes associated with increased tear film evaporation loss include meibomian gland disorders, palpebral fissure abnormalities, blinking disorders (such as in Parkinson's disease), or ocular surface disorders (such as in allergic conjunctivitis). In particular, meibomian gland disorders are commonly associated with evaporative dry eye. For example, meibomian gland dysfunction can lead to changes in the quantitative or qualitative secretion of lipid components required for the tear film. This, in turn, leads to the failure to form a stable and continuous tear film, followed by evaporation loss and hyperosmolarity. Meibomian gland dysfunction is often characterized by glandular obstruction and blockage resulting from hyperkeratosis of the glands and increased tarsal viscosity. Dysfunction can be caused by primary eyelid margin-related diseases or secondary diseases resulting from systemic conditions such as rosacea or seborrheic dermatitis.

[0008] Typically, ophthalmic compositions for treating dry eye are administered as eye drops, with one or more drops applied once or more daily to the eye of a subject suffering from or susceptible to the eye condition. However, the frequency of administration of such compositions can depend on a variety of factors, including the composition of the particular composition.

[0009] Stability is of particular importance for the efficacy and commercialization of ophthalmic compositions. Maintaining the efficacy and stability of ophthalmic compositions may be necessary to meet various federal health and safety regulations, such as potency, impurities, shelf-life testing, sterility, etc. For example, ophthalmic compositions may need to contain an expiration date affixed to their container, which can be predicted based on the stability of the active ingredient and other conditions inherent in the formulation, as well as the product's environmental exposure.

[0010] More importantly, the medication solution in the eye drop bottle can be contaminated during use when the dropper tip comes into contact with the dropper tip due to contact with hands or tears. Because the possibility of contamination after opening the bottle is high, regulations require the addition of antimicrobial agents in multi-dose eye drop formulations. Several preservatives have been studied and used in commercial formulations, including alcohols, parabens, EDTA, chlorhexidine, and quaternary ammonium compounds. In addition to antimicrobial efficacy, preservatives must also possess suitable physical properties for incorporation into the formulation, such as chemical and thermal stability, compatibility with other compounds in the eye drop container and formulation, and (more importantly) negligible toxicity to ocular tissues.

[0011] In patients suffering from chronic conditions such as dry eye disease who require daily eye drops for years to decades, the likelihood of preservative-induced eye damage is particularly high. In fact, most preservatives are problematic for dry eye patients because they can negatively impact the ocular surface, thus negating the intended therapeutic effect. This is especially important for patients with moderate to severe dry eye symptoms who may require frequent use to relieve symptoms, and for those who need multiple preservative-preserved topical medications.

[0012] As an alternative, single-dose containers for administering non-preservative formulations have been developed. However, these containers are less cost-effective and less convenient for patient handling compared to conventional multi-dose bottles. The formulations of the present invention can be packaged as single-dose or multi-dose products. Single-dose products are sterile before opening the package, and all compositions in the package are intended for single application to one or both eyes of the patient. Using antimicrobial preservatives to maintain the sterility of the compositions after opening the package is generally unnecessary.

[0013] Multidose products are also sterile before opening the packaging. However, because the container of a composition may be opened multiple times before all the composition in the container is consumed, multidose products must have sufficient antimicrobial activity to ensure that the composition is not contaminated by microorganisms due to repeated opening and handling of the container. The required level of antimicrobial activity for this purpose is well known to those skilled in the art and is specified in official publications such as the United States Pharmacopeia (“USP”) and corresponding publications in other countries. These publications provide detailed descriptions of specifications for the preservation of ophthalmic pharmaceutical products against microbial contamination and procedures for evaluating the preservative efficacy of specific formulations, and are incorporated herein by reference. In the United States, the preservative efficacy standard is generally referred to as the “USP PET” requirement. (“PET” stands for “Preservative Efficacy Test”.) The use of single-dose packaging eliminates the need for antimicrobial preservatives in the composition, a significant advantage from a medical perspective, as conventional antimicrobial agents used to preserve ophthalmic compositions (such as benzalkonium chloride) can cause eye irritation, particularly in patients with dry eye disease. However, currently available single-dose packaging arrangements, such as small-volume plastic bottles prepared through a process called “forming, filling, and sealing,” present several disadvantages for both manufacturers and consumers. A major drawback of single-dose packaging systems is the significantly larger amount of packaging material required, which is wasteful, expensive, and inconvenient for consumers. Furthermore, there is a risk that consumers, after applying one or two drops to the eye, may not discard the single-dose container as instructed, but instead preserve the opened container and any remaining composition for later use. This improper use of single-dose products creates a risk of microbial contamination, and if the contaminated composition is applied to the eyes, there is a associated risk of eye infections.

[0014] Rifelast (the active ingredient in Xiidra®) is a novel small molecule lymphocyte function-associated antigen 1 (LFA-1) antagonist, recently approved by the US Food and Drug Administration for the treatment of signs and symptoms of dry eye disease. It has the following structure: The current understanding of rifaspire's mechanism of action is that it reduces T-cell-mediated dry eye-related inflammation by blocking the interaction between integrin LFA-1 and intercellular adhesion molecule 1 (ICAM-1), thereby preventing the activation and migration of inflammatory cells. Xiidra is currently available as a non-preservative 5.0% ophthalmic solution in single-dose units and is administered twice daily (bid, approximately 12 hours apart) to each eye.

[0015] As with all medications, rifamil should be provided in a chemically pure and stable form, and in a physical form suitable for administration to the subject. Various solutions to enhance the stability of rifamil include incorporating various buffers and / or antioxidants (e.g., thiosulfate) or spraying the formulation with an inert gas.

[0016] Although Xiidra has successfully met the needs of many patients with dry eye disease, there is still a need for improved treatments for dry eye disease, especially those that are stable and have low concentrations or are essentially free of potentially irritating antioxidants and / or preservatives.

[0017] Public content The inventors have unexpectedly discovered that improved, stable ophthalmic compositions comprising (a) rifelast; and (b) at least one semi-fluorinated alkane are available. These compositions are preferably free of preservatives and / or antioxidants. Without wishing to be bound by theory, it is believed that at least one semi-fluorinated alkane not only provides its own therapeutic and / or preventative effects on ocular conditions (thus overlapping with disease cycles that influence inflammation and tear evaporation), but also acts as a stable, non-aqueous medium or carrier for rifelast. The non-aqueous nature of some embodiments of the invention also allows for a reduction or elimination of the need for other components, such as antioxidants and / or preservatives. Therefore, the improved, stable ophthalmic compositions described herein are provided by a unique combination of rifelast and at least one semi-fluorinated alkane. Furthermore, the compositions achieve ocular exposure similar to aqueous rifelast compositions, but at only one-third the dosage. In some embodiments, the ophthalmic composition may be a non-aqueous liquid composition comprising (a) rifelast and (b) at least one semi-fluorinated alkane, such as 1-perfluorohexyloctane (F6H8).

[0018] This article also discloses a method for treating and / or temporarily preventing dry eye disease, the method comprising administering an effective amount of an ophthalmic composition to a patient in need, the ophthalmic composition comprising (a) rifelast and (b) at least one semi-fluorinated alkane, such as 1-perfluorohexyloctane (F6H8).

[0019] Similarly, the following are provided: an ophthalmic composition for use in methods of treating or temporarily preventing dry eye disease, said ophthalmic composition comprising (a) rifelast and (b) at least one semi-fluorinated alkane; and the use of (a) rifelast and (b) at least one semi-fluorinated alkane in the manufacture of the ophthalmic composition for treating or temporarily preventing dry eye disease.

[0020] This document also discloses a method for preparing an ophthalmic composition, the method comprising the steps of: (a) providing a first composition comprising rifelast and at least one semi-fluorinated alkane, such as 1-perfluorohexyloctane (F6H8), wherein the rifelast has at least partially precipitated within the first composition; and (b) stirring the first composition to obtain a suspension of rifelast, thereby providing the ophthalmic composition. This method is typically carried out in a container-sealed system (such as a bottle), and stirring is performed by hand shaking (or continuous inversion) to redisperse the at least partially precipitated suspension, from which microdroplets can then be dispensed.

[0021] This document also discloses a method for preparing an ophthalmic composition, the method comprising the step of mixing rifaspirate with at least one semi-fluorinated alkane (such as perfluorohexyloctane). A method for packaging the ophthalmic composition is also disclosed, the method comprising the steps of: (a) providing a suspension of rifaspirate in at least one semi-fluorinated alkane (such as perfluorohexyloctane); (b) placing some or all of the suspension into an open container; and (c) sealing the container. Step (a) may involve mixing rifaspirate with at least one semi-fluorinated alkane to form a suspension.

[0022] The use of SFAs (such as F6H8) as a preservative for rifaspirant in ophthalmic compositions (and particularly in multi-dose ophthalmic compositions, for example, located within a container sealing system, such as a bottle) is also disclosed.

[0023] These and other features, aspects and advantages of this disclosure will become apparent from the following reading.

[0024] definition The following provides definitions for certain terms used in this application. Unless otherwise defined, all technical and scientific terms used herein have the common and usual meanings that would be understood by one of ordinary skill in the art to which this disclosure pertains.

[0025] Unless otherwise stated, as used herein, “a” or “an” entity means one or more of the entities described, for example, “a compound” means one or more compounds or at least one compound. Thus, the terms “a” (or “an”), “one or more” and “at least one” are used interchangeably herein.

[0026] As used herein, the term “about” means approximately, roughly, approximately, or roughly. When the term “about” is used in conjunction with a numerical range, it modifies the range by extending the boundaries to include values ​​above and below the stated value. Generally, the term “about” is used herein to modify a numerical value to a deviation of 5% higher or lower than the stated value. Numerical values ​​modified by the term “about” include specific, defined values. For example, “about 100” means a value in the range of 95 to 105, inclusive of 95, 100, and 105. Unless otherwise stated herein, the ranges of values ​​listed herein are intended only as a way of abbreviating each individual value falling within that range, and each individual value is incorporated into the specification as if it were listed separately herein.

[0027] As used herein, “administering” a compound or composition to a patient means any route by which the compound or composition is introduced or delivered to a subject. Administration includes self-administration and administration by another person.

[0028] As used in this article, “illness,” “symptom,” or “disease” refers to any unhealthy or abnormal condition.

[0029] As used herein, "effective amount" or "effective dose" refers to the amount of a compound or composition that, after a single or multiple doses, treats a patient and / or temporarily prevents the patient from developing a disease, condition, or disorder. The effective amount can be determined by the attending physician using known techniques and by observing results obtained under similar conditions. In determining the effective amount, the attending physician considers many factors, including but not limited to: the patient's species; their body type, age, and general health; the specific disease, condition, or disorder involved; the extent or severity of the disease, condition, or disorder, and the individual patient's response; the specific compound administered; the mode of administration; the bioavailability characteristics of the administered formulation; the chosen dosing regimen; the use of concomitant medications; and other relevant factors.

[0030] As used herein, a composition is "free of" a component when that component is not intentionally added during the manufacture of the composition.

[0031] As used herein, when referring to two or more compounds, agents, or other active pharmaceutical ingredients, the term "in combination with" means administering two or more compounds, agents, or active pharmaceutical ingredients to the patient before, simultaneously with, or after each other during the treatment period. Unless otherwise stated, two or more compounds, agents, or active pharmaceutical ingredients may be administered on different schedules during the treatment period, such as one or more compounds, agents, or active pharmaceutical ingredients being administered once a day, while another one or more compounds, agents, or active pharmaceutical ingredients are administered twice a day.

[0032] As used herein, the terms “patient,” “subject,” “individual,” etc., are interchangeable and refer to any animal, which may be human or non-human. The compositions of the present invention are particularly suitable for use in humans.

[0033] As used herein, the term “prevention” means reducing the occurrence of a disease, ailment, or disorder in a treated sample relative to an untreated control sample, and includes delaying the onset, progression, or severity of one or more symptoms of a disease or disorder relative to an untreated control sample.

[0034] As used in this article, the term “eye condition” refers to any sign, symptom and / or one or more underlying causes of any physiological condition affecting the eye or vision.

[0035] As used herein, “pharmaceuticalally acceptable excipient” refers to a carrier or excipient that can be used to prepare a pharmaceutical composition. For example, pharmaceutically acceptable excipients are generally safe and include carriers and excipients generally considered acceptable for use in mammalian pharmaceuticals. As a non-limiting example, pharmaceutically acceptable excipients can be solid, semi-solid, or liquid materials that generally act as a medium or carrier for the active ingredient. Examples of pharmaceutically acceptable excipients can be found in Remington's Pharmaceutical Sciences and the Handbook of Pharmaceutical Excipients, and include diluents, mediums, carriers, ointment bases, binders, disintegrants, lubricants, glidants, sweeteners, flavorings, gel bases, sustained-release bases, stabilizers, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coating agents, etc.

[0036] As used herein, a composition according to this disclosure is "stable" if, as measured by high performance liquid chromatography (HPLC) or an equivalent appropriate technique such as that in the United States Pharmacopeia, the rifaspirant in the composition degrades by less than about 10% after storage at about 25°C for 10 weeks.

[0037] As used herein, when used in conjunction with a condition or ailment, the term "treat / treating / treatment" includes any effect that causes improvement in the condition or ailment, such as relief, reduction, regulation, improvement, or elimination. Any improvement in the symptoms of a condition or ailment, or a reduction in its severity, can be readily assessed using standard methods and techniques known in the art.

[0038] As will be understood by those skilled in the art, each range disclosed herein includes all possible subranges and individual numerical values ​​within that range, including endpoints. As a non-limiting example, the range "0.001% to 0.02%" includes and should be understood to specifically disclose subranges such as "0.004% to 0.01%", "0.005% to 0.02%", etc., and all individual numbers within the disclosed range, such as 0.001%, 0.004%, 0.005%, 0.01%, 0.02%, etc.

[0039] Unless the context clearly indicates otherwise, a claim or description including "or" or "and / or" among the group members is considered to satisfy the requirement that one, more than one, or all of the group members are present in, used in, or otherwise related to a given product or method. This disclosure includes embodiments in which exactly one group member is present in, used in, or otherwise related to a given product or method. This disclosure also includes embodiments in which more than one or all of the group members are present in, used in, or otherwise related to a given product or method.

[0040] Detailed public information The ophthalmic composition disclosed herein comprises (a) rifelast and (b) at least one semi-fluorinated alkane.

[0041] In some embodiments, rifastard is included in the composition at concentrations of about 0.005% (w / w) to about 5% (w / w), such as about 0.02% (w / w) to about 4% (w / w), about 0.5% (w / w) to about 3% (w / w), or about 0.75% (w / w) to about 2% (w / w). In some preferred embodiments, the concentration is less than 5.0%, such as about 4.5%, about 4.0%, or about 3.5%.

[0042] The ophthalmic compositions disclosed herein comprise rifelast. This rifelast is typically included in the form of free rifelast acid, but in some embodiments may be included in the form of a pharmaceutically acceptable salt. In the case of the use of a salt, the concentration of rifelast disclosed herein is calculated based on the amount of free rifelast acid.

[0043] The ophthalmic compositions disclosed herein comprise at least one semi-fluorinated alkane (SFA). The semi-fluorinated alkane is a straight-chain or branched-chain alkane in which some of its hydrogen atoms have been replaced by fluorine. Specifically, the semi-fluorinated alkane is a compound consisting of at least one perfluorinated hydrocarbon segment and at least one non-fluorinated hydrocarbon segment. According to the nomenclature used herein, a semi-fluorinated alkane may be referred to as FnHm, where 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 in these segments, respectively. For example, F3H3 is used for perfluoropropylpropane and F4H5 for 1-perfluorobutylpentane. This type of nomenclature is generally used for compounds having straight-chain segments. Therefore, unless otherwise indicated, F3H3 should be assumed to refer to 1-perfluoropropylpropane, and not 2-perfluoropropylpropane, 1-perfluoroisopropylpropane, or 2-perfluoroisopropylpropane.

[0044] In some embodiments, according to the general formula FnHm, at least one semi-fluorinated alkane may have a non-fluorinated hydrocarbon segment connected to a perfluorinated hydrocarbon segment. In some embodiments, at least one semi-fluorinated alkane is a compound according to the formula FnHm, wherein the F-segment and H-segment are straight-chain or branched chains, and wherein n and m may be the same or different, independently selected from 3 to 20 carbon atoms, for example 3 to 10 carbon atoms or 4 to 8 carbon atoms. In some embodiments, at least one semi-fluorinated alkane is a compound according to the formula FnHm, wherein the F-segment and H-segment are straight-chain and wherein n and m may be the same or different, independently selected from 3 to 20 carbon atoms, for example 3 to 10 carbon atoms or 4 to 8 carbon atoms.

[0045] In some embodiments, the ratio of F-segment carbon atoms to H-segment carbon atoms (obtained by dividing the number of carbon atoms in the F-segment by the number of carbon atoms in the H-segment) of at least one straight-chain or branched semi-fluorinated alkane ranges from 0.5 to 3.0, for example, from 0.6 to 1.0. For example, the ratio of F-segment carbon atoms to H-segment carbon atoms in 1-perfluorohexyloctane (F6H8) is 0.75. In some embodiments, at least one semi-fluorinated alkane is a straight-chain semi-fluorinated alkane according to the formula FnHm, wherein the ratio of F-segment carbon atoms to H-segment carbon atoms ranges from 0.5 to 3.0, for example, from 0.6 to 1.0.

[0046] In some embodiments, according to the general formula FnHmFo, at least one semi-fluorinated alkane may have two perfluorinated segments separated by a non-fluorinated segment, wherein n, m, and o refer to the number of carbon atoms in the first perfluorinated segment, the non-fluorinated segment, and the second perfluorinated segment, respectively. In some embodiments, at least one semi-fluorinated alkane is a compound according to the formula FnHmFo, wherein the F-segment and H-segment are straight-chain or branched chains, and wherein n, m, and o may be the same or different, and are independently selected from 3 to 20 carbon atoms, for example, 3 to 10 carbon atoms or 4 to 8 carbon atoms.

[0047] In some embodiments, at least one semi-fluorinated alkane may be a straight-chain semi-fluorinated alkane comprising a branched non-fluorinated hydrocarbon segment, said branched non-fluorinated hydrocarbon segment comprising one or more alkyl groups selected from the group consisting of -CH3, -C2H5, -C3H7, -C4H9, or any combination thereof. In some embodiments, at least one semi-fluorinated alkane may be a straight-chain semi-fluorinated alkane comprising a branched perfluorinated hydrocarbon segment, said branched perfluorinated hydrocarbon segment comprising one or more perfluorinated alkyl groups selected from the group consisting of -CF3, -C2F5, -C3F7, -C4F9, or any combination thereof.

[0048] In some embodiments, at least one semifluorinated alkane may comprise a combination of more than one semifluorinated alkane.

[0049] In some embodiments, at least one semi-fluorinated alkane is selected 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, at least one semi-fluorinated alkane is selected from F4H4, F4H5, F4H6, F5H5, F5H6, F5H7, F5H8, F6H6, F6H7, F6H8, F6H9, F6H10, F8H8, F8H10, F8H12, F10H10, or any combination thereof. In some embodiments, at least one semifluorinated alkane is selected from F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8 or any combination thereof.

[0050] In some embodiments, at least one semi-fluorinated alkane comprises 1-perfluorohexyl-octane (F6H8). In some embodiments, at least one semi-fluorinated alkane is substantially composed of 1-perfluorohexyl-octane (F6H8). In some embodiments, the ophthalmic composition is substantially composed of (a) rifelast and (b) no more than two semi-fluorinated alkanes, such as 1-perfluorohexyl-octane and one other SFA. In some embodiments, the ophthalmic composition is substantially composed of (a) rifelast and (b) 1-perfluorohexyl-octane.

[0051] In some embodiments, the ophthalmic composition generally comprises: (a) rifexazone and (b) one or two perfluorohexyl-octanes. In some embodiments, the ophthalmic composition generally comprises: (a) rifexazone, (b) 1-perfluorohexyl-octane, and (c) 2-perfluorohexyl-octane. Component (a) may be present in up to 5% (w / w) (e.g., 1-5%) of the composition. Component (b) may be present in up to 99.5% (w / w) (e.g., 95-99.5%) of the composition. Component (c) may be present in up to 2% (w / w) (e.g., 0.05-1.5%) of the composition.

[0052] The compositions disclosed herein can be used to treat or temporarily prevent dry eye disease. They can be used to treat the signs and symptoms of dry eye disease.

[0053] In some embodiments, the ophthalmic composition comprises (a) rifexazone; and (b) at least one semi-fluorinated alkane selected 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.

[0054] In some embodiments, the ophthalmic composition comprises (a) rifelast; and (b) at least one semi-fluorinated alkane selected from F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8, or any combination thereof.

[0055] In some embodiments, the ophthalmic composition comprises (a) rifelast; and (b) at least one semi-fluorinated alkane comprising F6H8.

[0056] In some embodiments, the ophthalmic composition comprises (a) rifelast; and (b) at least one semi-fluorinated alkane, wherein the at least one semi-fluorinated alkane is substantially composed of F6H8.

[0057] In some embodiments, the ophthalmic composition comprises (a) rifaspire; and (b) no more than two semi-fluorinated alkanes.

[0058] In embodiments containing "no more than two" or "at most two" semi-fluorinated alkanes, these semi-fluorinated alkanes may be a single SFA (e.g., 1-perfluorohexyl-octane) or a mixture of two structural isomers of the SFA (e.g., a mixture of 1-perfluorohexyl-octane and 2-perfluorohexyl-octane). In such isomer mixtures, a straight-chain SFA (e.g., 1-perfluorohexyl-octane) may be present in excess compared to a branched-chain SFA (e.g., 2-perfluorohexyl-octane). For example, the SFA component may consist of 95% (w / w) or more of 1-perfluorohexyl-octane, such as at least 96%, at least 97%, at least 98%, or at least 99% of 1-perfluorohexyl-octane, with the balance being 2-perfluorohexyl-octane.

[0059] In some embodiments, the ophthalmic compositions of this disclosure are liquid compositions. In some embodiments, the ophthalmic compositions of this disclosure are liquid compositions containing water. In a preferred embodiment, the ophthalmic compositions of this disclosure are substantially anhydrous (non-aqueous) liquid compositions.

[0060] In some embodiments, the ophthalmic compositions of this disclosure are stable liquid compositions. In some embodiments, the ophthalmic compositions of this disclosure are stable non-aqueous liquid compositions.

[0061] In some embodiments, the ophthalmic composition of this disclosure may be administered in combination with an effective amount of another therapeutic agent. In some embodiments, the ophthalmic composition of this disclosure may be administered in combination with an effective amount of at least one other therapeutic agent selected from: erythematous agents, NSAIDs, steroids, antifungal agents, aminopenicillins, macrolides, acaricides, antihistamines, anti-inflammatory agents, anti-allergic agents, antibiotics, or any combination thereof.

[0062] In some embodiments, the ophthalmic composition of this disclosure further comprises an effective amount of another therapeutic agent in the same composition. In some embodiments, the ophthalmic composition of this disclosure further comprises an effective amount of at least one other therapeutic agent selected from: erythematous agents, NSAIDs, steroids, antifungal agents, aminopenicillins, macrolides, acaricides, antihistamines, anti-inflammatory agents, anti-allergic agents, antibiotics, or any combination thereof.

[0063] In some embodiments, the ophthalmic compositions of this disclosure may further include at least one other non-therapeutic component and / or pharmaceutically acceptable excipient, including but not limited to tonics, preservatives, buffers, pH adjusters, antioxidants, delivery mediators, stabilizers, suspending agents, thickeners, wetting agents, solubilizers, chelating agents, nitric oxide inhibitors, isotonic agents, humectants, surfactants, etc. The proportions and properties of any other non-therapeutic component and / or pharmaceutically acceptable excipient can be determined by the chosen route of administration and standard pharmaceutical practice. Those skilled in the art can readily select appropriate forms and routes of administration based on the condition or disease to be treated, the stage of the condition or disease, and other relevant circumstances.

[0064] In some embodiments, when stored at 40°C for one month, the total lifacitin degradation products formed in the formulation of the present invention are less than 1.0%. In some other embodiments, when stored at 40°C for one month, the total lifacitin degradation products are less than about 0.9%, about 0.8%, about 0.7%, about 0.6%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, or about 0.1%.

[0065] In some other embodiments, when stored at a temperature of 40°C for about two months, about three months, about four months, about five months, or about six months, the total rifelast degradation products formed in the formulation of the present invention are less than 1.0%.

[0066] In some cases, pharmaceutically acceptable formulations expire in approximately 1 to 5 years. In some cases, formulations expire in approximately 1, 2, 3, or 4 years. In some cases, formulations expire in more than 5 years. In some cases, formulations expire in less than one year. In some cases, formulations expire in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 months.

[0067] In some cases, the total lifastard degradation products at product expiration are in the range of more than 0.1-10%. In other cases, the total degradation products at expiration are approximately 0.01-1, approximately 0.01-2, approximately 0.01-3, approximately 0.01-4, approximately 0.01-5, approximately 0.01-6, approximately 0.01-7, approximately 0.01-8 or approximately 0.01-9, approximately 1-2, approximately 1-3, approximately 1-4, approximately 1-5, approximately 1-6, approximately 1-7, approximately 1-8, approximately 1-9, approximately 2-3, approximately 3-4, approximately 2-5, approximately 2-6, approximately 2-7, approximately 2- 8. Approximately 2-9, approximately 3-4, approximately 3-5, approximately 3-6, approximately 3-7, approximately 3-8, approximately 3-9, approximately 3-10, approximately 4-5, approximately 4-6, approximately 4-7, approximately 4-8, approximately 4-9, approximately 4-10, approximately 5-6, approximately 5-7, approximately 5-8, approximately 5-9, approximately 5-10, approximately 6-7, approximately 6-8, approximately 6-9, approximately 6-10, approximately 7-8, approximately 7-9, approximately 7-10, approximately 8-9, approximately 8-10, or approximately 9-10%. In some embodiments, at expiration, the total amount of degradation products is approximately 1%, approximately 2%, approximately 3%, approximately 4%, approximately 5%, approximately 6%, approximately 7%, approximately 8%, approximately 9%, or approximately 10%. In some implementations, the total amount of degradation products at expiration is about 0.01%, about 0.05%, about 0.1%, about 0.15%, about 0.2%, about 0.25%, about 0.3%, about 0.35%, about 0.40%, about 0.45%, about 0.50%, about 0.55%, about 0.60%, about 0.65%, about 0.70%, about 0.75%, about 0.80%, about 0.85%, about 0.90%, about 0.95%, or about 1.0%.

[0068] In some embodiments of the present invention, the formulation of rifetazone contains one or more antioxidants to prevent oxidative degradation of rifetazone. In some embodiments, the one or more antioxidants comprise thiosulfate. In some embodiments, the one or more antioxidants used in the formulation of rifetazone comprise sodium thiosulfate. In some embodiments, the antioxidants used in the formulation of rifetazone comprise metabisulfite. In some embodiments, the antioxidant comprises sodium bisulfate.

[0069] Other antioxidants that can be used to form the pharmaceutical formulations of the present invention include, but are not limited to, propyl, octyl, and dodecyl gallic acid esters, butylated hydroxyanisole (BHA, typically available as a mixture of ortho- and meta-isomers), green tea extract, uric acid, cysteine, pyruvate, nordihydroguaiac acid, ascorbic acid, salts of ascorbic acid (such as palmitic ascorbate and sodium ascorbate), ascorbic acid glucosamine, vitamin E (i.e., tocopherol, such as α-tocopherol), derivatives of vitamin E (e.g., tocopherol acetate), retinoids (such as retinoic acid, retinol, trans-retinol, cis-retinol, mixtures of trans-retinol and cis-retinol, 3-dehydroretinol), and derivatives of vitamin A (e.g., retinyl acetate, retinaldehyde, and retinyl palmitate, also known as tetinyl). The antioxidants include palmitate, sodium citrate, sodium sulfite, lycopene, anthocyanins, bioflavonoids (e.g., hesperidin, naringin, rutin, and quercetin), superoxide dismutase, glutathione peroxidase, butylated hydroxytoluene (BHT), indole-3-methanol, pycnogenol, melatonin, sulforaphane, pregnenolone, fatty acids, and 4-hydroxy-5-methyl-3[2H]-furanone. In various embodiments, one or more of the above antioxidants are excluded, or are present alone or in combination in amounts less than effective.

[0070] In some embodiments, the amount of antioxidant used is in the range of about 0.01-0.5% w / v. In some embodiments, the amount of antioxidant used is in the range of about 0.1-about 0.5%, about 0.2-about 0.5%, about 0.3-about 0.5%, about 0.4-about 0.5%, about 0.01-about 0.4%, about 0.1-about 0.4%, about 0.2-about 0.4%, about 0.3-about 0.4%, about 0.01-about 0.3%, about 0.1-about 0.3%, about 0.2-about 0.3%, about 0.01-about 0.2%, about 0.1-about 0.2%, or about 0.01-about 0.1%. In some embodiments, sodium thiosulfate is present in an amount that provides antioxidant stability to the formulation, and the amount of sodium thiosulfate as a weight percentage of all total antioxidants is greater than 50% by weight.

[0071] In some embodiments, vitamin E and / or vitamin E derivatives are present in an amount that provides antioxidant stability to the formulation, and the amount of vitamin E and / or vitamin E derivatives as a weight percentage of all total antioxidants is greater than 50% by weight.

[0072] As mentioned above, it is also possible to provide antioxidant-free pharmaceutical formulations of the present invention, thereby simplifying their preparation and avoiding potential irritation caused by antioxidant chemicals. The ability to maintain a stable form of rifelast in the compositions of the present invention, despite the absence of antioxidants, is particularly surprising because oxygen is highly soluble in SFA (and especially in F6H8). Xiidra products include sodium thiosulfate as an antioxidant.

[0073] It is also possible to provide preservative-free pharmaceutical formulations of the present invention even when provided in multi-dose containers, thereby simplifying their preparation and, as discussed above, avoiding potential irritation caused by known preservatives. Not wishing to be bound by theory, it is believed that SFA can provide preservative action in the composition and provide therapeutic ocular effects.

[0074] Preferred compositions of the present invention are free of antioxidants and external preservatives (i.e., SFAs are considered preservatives in addition to one or more SFAs). The compositions may also be water-free.

[0075] In some cases, rifaspirant formulations are stored at temperatures ranging from -5 to 65°C. In other cases, the formulations may be stored at approximately 0°C, approximately 5°C, approximately 10°C, approximately 15°C, approximately 20°C, approximately 25°C, approximately 30°C, approximately 35°C, approximately 40°C, approximately 45°C, approximately 50°C, approximately 55°C, approximately 60°C, or approximately 65°C. In various embodiments, the composition is stored at or below ambient temperature.

[0076] In some embodiments, the ophthalmic compositions of this disclosure are sterile in accordance with USP / EP guidelines. In some embodiments, sterility is imparted by any conventional method. In some embodiments, sterility is imparted by filtration. In some embodiments, sterility is imparted by irradiation. In some embodiments, sterility is imparted by heating. In some embodiments, sterility is imparted by a manufacturing process performed under sterile conditions.

[0077] This article also discloses a method for treating or temporarily preventing at least one eye condition, the method comprising administering to a patient in need an effective amount of the ophthalmic composition as described above, the ophthalmic composition comprising (a) rifelast; and (b) at least one semi-fluorinated alkane.

[0078] At least one eye condition may include, but is not limited to, dry eye disease, dry eye syndrome, meibomian gland dysfunction, adult chlamydial ophthalmia, ocular erythematous presbyopia, refractory recurrent corneal erosion, ocular cicatricial pemphigoid, Sjögren's syndrome (SS), non-SS keratoconjunctivitis sicca (KCS), conjunctivitis, allergic conjunctivitis, endophthalmitis, keratitis, uveitis, stye, ocular inflammation, eye discomfort or pain, itchy eyes, inflammatory dry eye syndrome, red eyes, tearing, stinging or burning eyes, gritty sensation in the eyes, photophobia, blurred vision, more frequent blinking, pressure behind the eyes, oily eyelids, crusting, itching, swelling or adhesions, etc.

[0079] In some implementations, at least one ocular condition may be selected from dry eye disease, dry eye syndrome, meibomian gland dysfunction, adult chlamydial ophthalmia, ocular erythematous presbyopia, refractory recurrent corneal erosion, ocular cicatricial pemphigoid, Sjögren's syndrome (SS), non-SS keratoconjunctivitis sicca (KCS), conjunctivitis, allergic conjunctivitis, endophthalmitis, keratitis, uveitis, or any combination thereof.

[0080] In some implementations, at least one ocular condition may be selected from conjunctivitis, keratitis, dry eye disease, or any combination thereof.

[0081] In some embodiments, at least one eye condition is dry eye disease. In some embodiments, dry eye disease is dehydration-related dry eye disease. In other embodiments, it is evaporative dry eye disease. In yet another embodiment, it is both dehydration-related dry eye disease and evaporative dry eye disease.

[0082] In some embodiments, dry eye disease has high osmotic pressure as a cause and / or as a symptom. In some embodiments, dry eye disease has tear film instability as a cause and / or as a symptom. In some embodiments, dry eye disease has both high osmotic pressure and tear film instability as a cause and / or as a symptom.

[0083] In some embodiments, the methods of this disclosure include treating or temporarily preventing dry eye disease, including administering an effective amount of the ophthalmic composition as described above to a patient in need, the ophthalmic composition comprising (a) rifaspire; and (b) at least one semi-fluorinated alkane.

[0084] In some embodiments, the methods of this disclosure include treating or temporarily preventing dry eye disease, including administering an effective amount of an ophthalmic composition to a patient in need, the ophthalmic composition comprising (a) rifelast; and (b) at least one semi-fluorinated alkane selected 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.

[0085] In some embodiments, the methods of this disclosure include treating or temporarily preventing dry eye disease, including administering an effective amount of an ophthalmic composition to a patient in need, the ophthalmic composition comprising (a) rifelast; and (b) at least one semi-fluorinated alkane selected from F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8, or any combination thereof.

[0086] In some embodiments, the methods of this disclosure include treating or temporarily preventing dry eye disease, including administering an effective amount of an ophthalmic composition to a patient in need, the ophthalmic composition comprising (a) rifelast; and (b) at least one semi-fluorinated alkane selected from F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8, or any combination thereof.

[0087] In some embodiments, the methods of this disclosure include treating or temporarily preventing dry eye disease, including administering an effective amount of an ophthalmic composition to a patient in need, said ophthalmic composition comprising (a) rifaspire; and (b) at least one semi-fluorinated alkane comprising F6H8.

[0088] In some embodiments, the methods of this disclosure include treating or temporarily preventing dry eye disease, including administering an effective amount of an ophthalmic composition to a patient in need, said ophthalmic composition comprising (a) rifelast; and (b) at least one semi-fluorinated alkane, said at least one semi-fluorinated alkane being substantially composed of F6H8.

[0089] In the case of a suspension in which the composition of the present invention is, it should be redispersed before use. Therefore, prior to the administration step, the method may include a step of redispersing rifaspirate in a liquid phase (e.g., SFA). For example, redispersing may be achieved by shaking (or inverting) a container sealing system (such as a bottle) several times, and then the suspension can be dispensed as microdroplets. Product information included in the composition may include a written statement informing the subject to perform this redispersing (e.g., shaking before use), or informing a medical professional to provide such advice to the subject.

[0090] If the subject wears contact lenses, it may be necessary to remove the contact lenses before applying the composition of the present invention to one or more of the subject's eyes. Therefore, the method may include a contact lens removal step prior to the application step. The time for re-wearing the contact lenses may be delayed, for example, by waiting at least 30 minutes after applying the composition. Product information included in the composition may include a written statement informing the subject to perform this contact lens removal and postpone re-wearing, or informing a medical professional to provide such advice to the subject.

[0091] In some embodiments, the ophthalmic composition further comprises a preservative. In some embodiments, the preservative is selected from benzalkonium chloride, cetrimonium, sodium perborate, the stable oxychloride complex SofZia, polyquaternium-1, chlorobutanol, disodium edetate, polyhexamethylene biguanide, or combinations thereof.

[0092] In some embodiments, the ophthalmic composition further comprises a buffer. In some embodiments, the buffer is selected from borates, borate-polyol complexes, phosphate buffers, citrate buffers, acetate buffers, carbonate buffers, organic buffers, amino acid buffers, or combinations thereof.

[0093] In some embodiments, the ophthalmic composition comprises rifaspirant and an SFA component, as well as an oil. The oil should be miscible with one or more SFA components. For example, the oil may be a mineral oil (such as light mineral oil), a triglyceride (such as a medium-chain triglyceride), or a tocopherol (such as α-tocopherol). Thus, the composition may consist of up to two SFAs (e.g., F6H8), rifaspirant (e.g., a free acid), and an oil component (e.g., mineral oil, triglyceride, or tocopherol).

[0094] In some embodiments, the ophthalmic composition may be administered by any convenient route. In some embodiments, the ophthalmic composition is in any liquid form suitable for topical application. In some embodiments, the ophthalmic composition is applied topically to the ocular surface. In some embodiments, the ophthalmic composition is applied topically to the cornea. In some embodiments, the ophthalmic composition is instilled into the conjunctival sac.

[0095] In some embodiments, the composition may be in liquid form (such as a suspension, solution, emulsion, etc.) or in ointment form. In some embodiments, the ophthalmic composition may be in suspension form. In some embodiments, the ophthalmic composition may be in solution form. In some embodiments, the composition may be applied as eye drops. In some embodiments, the ophthalmic composition may be in suspension form applicable as eye drops. In some embodiments, the ophthalmic composition may be in solution form applicable as eye drops. In some embodiments, the ophthalmic composition may be in ointment form. In some embodiments, the ophthalmic composition may be applied as a spray. In some embodiments, the ophthalmic composition may be applied as artificial tears. In some embodiments, the ophthalmic composition may be in contact lens absorbent form.

[0096] As a typical form of eye drop application for the treatment or temporary prevention of dry eye, one or more drops of the composition are applied to the eye of the subject. The microdroplets may have a volume of 25 μL or less, and can be as small as 8–15 μL, for example, between 11–12 μL. These microdroplets are smaller than the volume present in Xiidra products (35 μL) and reduce nasolacrimal drainage, thereby reducing the sensation of unpleasant taste.

[0097] After applying eye drops, nasolacrimal compression, obstruction, or blockage (e.g., by applying pressure to the lacrimal sac at the inner corner of the eye) can be helpful. This procedure reduces the amount of fluid entering the nasolacrimal duct and flowing into the throat, which can cause an unpleasant taste.

[0098] The appropriate dosage of the ophthalmic compositions disclosed herein is concentration-dependent. To determine a specific dosage, a skilled technician will have to consider the kinetic and absorption characteristics of the particular ingredient. Furthermore, the dosage may depend on the route of administration. The dosage may also depend on the degree of antibacterial and / or anti-inflammatory effect required by the patient.

[0099] Treatment methods include administering a daily dose of the ophthalmic composition of this disclosure to a subject in need. Determining and adjusting an appropriate daily dosing regimen (e.g., adjusting the number of doses and frequency of administration) can be performed by a person skilled in the art and will depend on a variety of factors, such as the nature and progression of the condition and / or disease associated with allergies and red eyes, the subject's health, and / or age. In some embodiments, the ophthalmic composition of this disclosure is administered to a patient in a single daily dose, two daily doses, three daily doses, four daily doses, or up to, for example, ten daily doses. 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 two months, at least three months, at least four months, at least five months, at least six months, at least twelve months, at least one year, or more than one year. When using eye drops, a single dose is typically a single microdrop per eye.

[0100] This document also discloses a container sealing system containing the ophthalmic composition described above, the ophthalmic composition comprising (a) rifelast and (b) at least one semi-fluorinated alkane.

[0101] The ophthalmic compositions disclosed herein can be contained in a container sealing system (e.g., vial, ampoule, bottle, tube, syringe, dispenser package, or other suitable container). In some embodiments, the compositions can be packaged in a single-dose unit container sealing system or a multi-dose container sealing system. In some embodiments, the compositions can be packaged in a single-dose unit container sealing system. The container sealing system can be composed of one or more materials suitable for its use, such as aluminum, glass, polypropylene, polyethylene (e.g., low-density polyethylene and high-density polyethylene), polyethylene terephthalate, and polyethylene terephthalate diol. Plastic container sealing systems are lighter, more resistant to impact and other mechanical effects, less expensive, and offer more design possibilities than glass. Polyethylene (e.g., low-density polyethylene (LDPE)) (without or with additives) and polypropylene (PP) are plastics required by the European Pharmacopoeia. In some embodiments, the container sealing system comprises polypropylene. In some embodiments, the container sealing system is composed of polypropylene (e.g., a polypropylene bottle). In some embodiments, the container sealing system is compressible to allow delivery of the ophthalmic composition to the eye in droplet form (e.g., by hand). Therefore, the container sealing system may have an outlet for forming microdroplets. This outlet facilitates droplet-by-drop dispensing of the composition from the container. The outlet can be protected with a screw cap when not in use. Thus, the ophthalmic composition is located in a polypropylene bottle (e.g., a translucent or clear polypropylene bottle) that can be squeezed by hand to expel the ophthalmic composition droplet by drop through the outlet.

[0102] In some embodiments, a single-container sealing system may include one or more compartments for containing the provided ophthalmic composition and / or a suitable carrier for suspension or dilution. In some embodiments, the individual container may be adapted to be physically modified to allow for combination of compartments and / or components of individual compartments. For example, an aluminum foil or plastic bag may include two or more compartments separated by a perforated seal that can be broken upon generating a signal to rupture the seal, thereby allowing the contents of two individual compartments to be combined.

[0103] The ophthalmic compositions disclosed herein can be prepared according to any known method for manufacturing ophthalmic preparations or formulations. As will be understood by those skilled in the art, many methods are known. In some embodiments, the ophthalmic compositions disclosed herein can be prepared by any conventional technique, such as those described in Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. DB Troy, Lippincott Williams & Wilkins, Philadelphia (or 23rd edition, 2020, ed. A. Adejare) and Encyclopedia of Pharmaceutical Technology, ed. J. Swarbrick and J.C. Boylan, 1988–1999, Marcel Dekker, New York (or 4th edition, 2013, ed. J. Swarbrick).

[0104] In some embodiments, the pharmaceutical composition further comprises a surfactant to disperse insoluble components or improve solubility. Numerous ocular surfactants are disclosed in US2019 / 0328773, which is incorporated herein by reference. Several of these surfactants are listed below. Other surfactants and related scopes are listed in US2018 / 0221407A1, which is also incorporated herein by reference.

[0105] The composition may also include one or more auxiliary solubilizers, such as surfactants. Surfactants can be varied and may include any compound that is surface-active or capable of forming micelles. Surfactants can be used to help dissolve excipients or surfactants, disperse solids or liquids in the composition, enhance wetting, modify droplet size, stabilize emulsions, or for many other purposes. Examples of surfactants may include, but are not limited to, surfactants of the following classes: alcohols, such as polyvinyl alcohol; amine oxides; block polymers; carboxylated alcohols or alkylphenol ethoxylates; carboxylic acids / fatty acids; ethoxylated alcohols; ethoxylated alkylphenols; ethoxylated arylphenols; ethoxylated fatty acids; ethoxylated fatty acid esters or oils (animal and vegetable oils); fatty acid esters; fatty acid methyl ester ethoxylates; glycerides; glycol esters; lanolin-based derivatives; lecithin and lecithin derivatives; lignin and lignin derivatives; methyl esters; monoglycerides and derivatives of glycerol; polyethylene glycol; polymeric surfactants, such as Soluplus® (from BASF); propoxylated and ethoxylated fatty acids, alcohols, or alkylphenols; protein-based surfactants; sarcosine derivatives; sorbitol derivatives; sucrose and glucose esters and derivatives; and saponins. In some embodiments, the surfactant may include polyethylene glycol (15)-hydroxystearate (CAS No. 70142-34-6, available from BASF at SOLUTOL HS 15®), polyoxyethylene-polyoxypropylene block copolymer (CAS No. 9003-11-6, available from BASF at PLURONIC® F-68), polyoxyethylene 40 stearate (POE40 stearate), polysorbate 80 or polyoxyethylene (80) sorbitan monooleate (CAS No. 9005-65-6), sorbitan monostearate (CAS No. 1338-41-6, available from Croda International PLC at SPANTM 60), or polyoxyethylene glycerol triricinoleate 35 (CAS No. 61791-12-6, available from BASF at CREMOPHOR EL®), ethoxylated castor oil, such as Cremophor EL. (CAS No. 61791-12-6). Suitable auxiliary solubilizers include, but are not limited to, povidone and acrylates (e.g., PEMULEN®).

[0106] In some embodiments, the surfactant is a nonionic surfactant, which in some cases may include polyoxyethylene dehydrated sorbitan monooleate (polysorbate-80) represented by CAS number 9005-65-6, such as Tween® 80, available from Sigma-Aldrich. In some embodiments, the nonionic surfactant includes polyoxyethylene lauryl ether represented by CAS number 9002-92-0, such as Brij® 35, available from Sigma-Aldrich. In some embodiments, the nonionic surfactant polyol includes polyethylene glycol-Wock-poly(propylene glycol)-Wock-poly(ethylene glycol) represented by CAS number 9003-11-6, such as Pluronic™ F-127, available from BASF SE. This article considers other nonionic surfactants, including but not limited to ethoxylates, fatty alcohol ethoxylates, alkylphenol ethoxylates, fatty acid ethoxylates, specialty ethoxylated fatty acid esters and oils, ethoxylated amines and / or fatty acid amides, terminal-blocking ethoxylates, fatty acid esters of polyhydroxy compounds, fatty acid esters of glycerol, fatty acid esters of sorbitol, Tween, fatty acid esters of sucrose, alkyl polyglucosides, amine oxides, sulfoxides, and phosphine oxides.

[0107] The amount of surfactant can be varied. In some embodiments, the surfactant can be used at a concentration of about 0.05% w / v to about 5.0% w / v, preferably from 0.05% w / v to about 0.5% w / w.

[0108] The surfactants incorporated into the composition are not limited by category. Various classes of surfactants can be incorporated, including but not limited to anionic, cationic, amphoteric, and nonionic surfactants. It should also be understood that multiple combinations of surfactants may be included.

[0109] In some embodiments, the ophthalmic compositions of this disclosure are contained in a polypropylene (PP) container sealing system (e.g., vials, ampoules, bottles, tubes, syringes, dispenser packs, or other suitable containers). Exemplary PP container sealing systems include white PP bottles and natural PP bottles. PP containers are compressible and semi-permeable to volatile compounds. It may be necessary for the ophthalmic compositions to demonstrate stability in multiple types of container sealing systems, each with different material types.

[0110] In the case of ophthalmic compositions supplied in multi-dose container sealing systems such as PP bottles, the volume of the ophthalmic composition will typically be large enough to provide at least 10 doses, for example, at least 10 microdroplets, such as at least 100 microdroplets. The volume of the composition may be at least 0.5 mL, for example >1 mL or >1.5 mL or more. For example, a PP bottle may contain at least 2 mL of the composition.

[0111] The compositions provided herein may optionally include an effective amount of a flavor masking agent. In some embodiments, the formulation of rifaspirant does not contain a flavor masking agent. A flavor masking agent is one or more agents or compounds that optionally together successfully mask or mask the (potentially) unpleasant taste of one or more components of the compositions provided herein when present in an effective amount. In some embodiments, the composition contains two or more flavor masking agents, such as polyol sweeteners and high-intensity sweeteners. In some embodiments, the composition includes only a single flavor masking agent, without any other sweeteners, flavorings, or flavor masking agents. In some embodiments, the flavor masking agent is sodium (tri) citrate, sodium citrate, sodium chloride, sodium bicarbonate, and combinations thereof. In some embodiments, the flavor masking agent is a polyol sweetener. Specific examples of a class of polyol sweeteners include sugars, particularly sugars selected from the group consisting of: dextrose, sucrose, maltose, fructose, lactose, and combinations thereof. Another specific example of a different category of polyol sweeteners includes sugar alcohols, particularly those selected from the group consisting of xylitol, sorbitol, mannitol, maltitol, isomaltol, isomaltitol, erythritol, lactitol, maltodextrin, hydrogenated starch hydrolysate, D-xylose, trehalose, and combinations thereof. In some embodiments, the flavor masking agent is a high-intensity sweetener or flavoring agent. High-intensity sweeteners available can be selected from the following groups: sucralose, neotame, aspartame, salts of acesulfame (especially potassium salt of acesulfame (acesulfame K)), alitame, saccharin and its salts, cyclohexane and its salts, glycyrrhizin, dihydrochalcone (e.g., NHDC), thaumatin, monellin, steviol glycosides, twinsweet (aspartame-acesulfame salt), and combinations thereof. Other examples of suitable flavor masking agents include salts of gluconic acid, such as sodium gluconate.

[0112] In some embodiments, the flavor masking agent in the composition is sucralose (e.g., in the absence of other sweeteners, flavorings, or flavor masking agents). In some embodiments, the flavor masking agent may be present in the composition in an amount from about 0.01% w / v to about 1.00% w / v. In some embodiments, the compositions provided herein have a flavor masking agent concentration of about 0.01% w / v to about 0.05% w / v, about 0.05% w / v to about 0.10% w / v, about 0.10% w / v to about 0.50% w / v, about 0.50% w / v to about 1.00% w / v, or greater than 1.00% w / v. In some embodiments, the compositions provided herein have a flavor masking agent concentration of about 0.02% w / v, about 0.05% w / v, about 0.10% w / v, about 0.20% w / v, or about 0.30% w / v.

[0113] In some embodiments, this disclosure provides a container sealing system containing an ophthalmic composition comprising (a) rifelast and (b) at least one semi-fluorinated alkane as disclosed above, wherein the container sealing system is a PP container sealing system.

[0114] This disclosure also provides a pillbox comprising a formulation container containing an ophthalmic composition as disclosed above, the ophthalmic composition comprising (a) rifaspire and (b) at least one semi-fluorinated alkane, wherein the container sealing system is a PP container sealing system. In some embodiments, the pillbox may include a second container (solvent container) containing a delivery medium suitable for diluting or suspending the ophthalmic composition provided in the first container (formulation container) to prepare for administration to a subject. In some embodiments, the contents of the formulation container and the contents of the solvent container are combined to form at least one unit dosage form. In some embodiments, the solvent container contains an aqueous delivery medium. In some embodiments, the solvent container contains a non-aqueous delivery medium. Delivery media suitable for solvent containers have been detailed above.

[0115] In some embodiments, a single container may include one or more compartments for containing the provided ophthalmic composition and / or a suitable media carrier for suspension or dilution. In some embodiments, the single container may be adapted to be physically modified to allow for combination of compartments and / or components of individual compartments. For example, an aluminum foil or plastic bag may include two or more compartments separated by a perforated seal that can be broken upon generating a signal to break the seal, thereby allowing the contents of two individual compartments to be combined. Thus, a pillbox may include such a multi-compartment container comprising the ophthalmic composition disclosed herein, along with a suitable solvent and / or a suitable media carrier for suspension. Attached Figure Description

[0116] Figure 1 The cumulative rifaspirant concentration (μg / g) in EpiCorneal™ tissues after 4 hours is shown.

[0117] Figure 2 The concentration of rifaspirant in the cornea over time (0–8 hours) is shown (ng / g).

[0118] Example F6H8 anti-corrosion activity The antimicrobial properties of F6H8 were evaluated according to Ph. Eur. 5.1.3. The results are as follows:

[0119] F6H8 meets the acceptance criteria for this assay, namely (a) the concentration of viable bacteria shows a decrease of at least 2 logs from the initial count at 6 hours, a decrease of at least 3 logs at 24 hours, and no recovery at 28 days; and (b) the concentrations of yeast and mold show a decrease of at least 2 logs from the initial count at 7 days, and no increase at 28 days. Therefore, F6H8 meets the antimicrobial effectiveness requirements without the need for external preservatives.

[0120] This result can be explained by the lack of water activity in the F6H8 liquid. The addition of solid rifelast does not introduce water activity and therefore this mixture will not support microbial growth.

[0121] suspension Rifalast free acid was added to F6H8 in various proportions, including (w / w) 0.25%, 1%, 2%, 2.5%, 4%, 5%, and 10%. Rifalast is insoluble in F6H8 and forms a suspension. When left to stand, rifalast settles to form a sediment.

[0122] Rifastard is stable in suspension. During storage at 40°C, the rifastard level in the 4% suspension (i.e., 96% (w / w) F6H8, 4% (w / w) rifastard) remained unchanged.

[0123] Similar results were observed in the 2% suspension. No significant impurities were observed when stored at 25°C for 3 months. A slight increase in impurities was observed after 3 months at 40°C, but it was not significant. Therefore, rifelast and F6H8 are chemically compatible. The same compatibility can be predicted using other SFAs, as they do not contain any other reactive groups.

[0124] The rifelast / F6H8 suspension was supplemented with α-tocopherol or tocopherol acetate as an antioxidant (e.g., 2% rifelast, 93% F6H8, 5% tocopherol acetate). After 1 month of storage at 40°C, the levels of rifelast-derived impurities did not show a significant difference with or without the presence of antioxidants (e.g., the 2% emulsion with 5% tocopherol acetate had a rifelast level of 99.92% at time zero, and this remained the case after 3 months at 40°C). No oxidation-derived degradation products were detected with or without antioxidants. Therefore, rifelast and F6H8 are compatible and no additional antioxidants are required.

[0125] Suspensions containing 2% or 5% rifamil were centrifuged at 500, 750, or 1000 rpm for 1 hour to accelerate the sedimentation of the rifamil powder. The ease and efficiency of redispersibility were assessed by hand agitation of the sediment (to simulate conditions for patient use). After centrifugation at 500 rpm, the powder could be resuspended by a single gentle inversion. After centrifugation at 750 or 1000 rpm, resuscitation required several gentle inversions or two or three hand agitations. Therefore, the suspensions demonstrated acceptable redispersibility for patient use.

[0126] The suspension was filled into a polypropylene bottle with a dropper outlet, and the droplets were weighed. A single F6H8 droplet weighed 15.91 mg (standard deviation 0.55 mg) and had a volume of 11.35 μL. A 5% rifaspirant suspension droplet weighed 15.93 mg (standard deviation 0.43 mg) and had a volume of 11.85 μL. Therefore, the suspension droplets showed acceptable dose homogeneity within the bottle, and rifaspirant did not impede the ability of F6H8 to form droplets.

[0127] The droplets of the F6H8 suspension are approximately 3 times smaller than the aqueous droplets of Xiidra™ (5% rifelast solution), and therefore the amount of rifelast delivered by a single droplet of the 5% suspension is less than the amount delivered by a single Xiidra™ droplet.

[0128] Eye irritation assessment Ocular tolerability of rifaspire / F6H8 suspension (5%) was assessed, including evaluation of stinging / burning reactions relative to commercially available rifaspire solution (Xiidra™) and commercially available F6H8 product (Miebo™). NZW rabbits (n=3 per group) received topical ocular doses four times daily for 5 days (40 μL per dose = 160 μL per eye per day). Ocular irritation was assessed as follows: (a) macroscopic examination (Draize scoring) was performed after the fourth daily dose, and if irritation was detected, the examination was repeated the following morning; and (b) microscopic examination was performed on days 0 and 5 using a slit lamp and indirect ophthalmoscopy. Stinging / burning was assessed after the second and fourth daily doses, the cumulative duration of blinking / strabismus was recorded, and other indicators (e.g., eye rubbing) were also noted.

[0129] The suspension was well tolerated, and no significant toxicological findings were observed 5 days after administration.

[0130] The maximum weighted score for the stimulus in any animal was 4 (out of a maximum of 110). The suspension was well tolerated, and any negative effects (redness, discharge, conjunctival congestion) were transient and did not increase in severity during the duration of the study.

[0131] Epicorneal Organizational Model The EpiCorneal 3D human tissue model (MatTek) provides a predictive non-animal model for evaluating ophthalmic drug delivery. This model was used to assess the effect of F6H8 on the permeability of rifaspire and the dose-dependent nature of its permeability characteristics.

[0132] Seven formulations were tested: four suspensions (0.25%, 1%, 2.5%, and 5%), a second 1% suspension, and two aqueous solutions (1% and 5%). A 12 μL volume was administered to the model, and permeability was assessed (200 μL samples were collected from the recipient at 15, 30, 60, 120, 180, and 240 minutes to measure the concentration of permeated rifaspirate), and the concentration of rifaspirate in EpiCorneal tissue was assessed after 240 minutes.

[0133] Compared to the solution, the suspension exhibited lower rifaspirate permeability but higher tissue accumulation. In the suspension case, a dose-dependent increase in tissue accumulation was observed from 0.25% to 2.5%. Figure 1 The cumulative lifacitin concentration in EpiCorneal tissue after 4 hours is shown, indicating that both 1% suspensions provide approximately the same performance as the 5% aqueous solution, and the 5% suspension provides higher tissue accumulation compared to the 5% solution. The slower penetration into the recipient using the suspension can be explained by the fact that solid lifacitin needs to dissolve before it can penetrate.

[0134] Ocular pharmacokinetic studies In vivo pharmacokinetic studies were used to evaluate the dose-dependent ocular bioavailability of lifaspirant / F6H8 suspension in Dutch belted rabbits. Four suspensions (10%, 5%, and 2 x 1%) were tested and compared with a 5% aqueous solution. The dose volume of suspension per eye was 12 μL and the solution volume was 35 μL. Samples were collected from the cornea, bulbar conjunctiva, aqueous humor, anterior sclera, and palpebral conjunctiva at 0.25, 1, 3, and 8 hours. Corneal results were obtained in... Figure 2 As shown in the image.

[0135] In 1-5% suspensions, dose-proportionate ocular exposure of rifaspire was observed, with exposure increasing proportionally at 10% suspensions.

[0136] The area under the rifafil concentration-time curve (AUC) from 0 to 8 hours was calculated using linear trapezoidal interpolation in WinNonlin. 0-8小时 The values ​​relative to the aqueous solution (100%) are as follows:

[0137] Administering 12 μL of the 5% suspension yielded the most similar ocular exposure as administering 35 μL of the 5% solution. Therefore, the amount of rifaspire administered could be reduced by 3-fold while achieving the same ocular exposure.

[0138] Numbered implementation plan Some implementations disclosed herein include, but are not limited to: Exemplary composition implementation schemes: Implementation Scheme 1. An ophthalmic composition comprising: (a) rifelast and (b) at least one semi-fluorinated alkane.

[0139] Implementation Scheme 2. An ophthalmic composition comprising generally: (a) rifelast and (b) at least one semi-fluorinated alkane.

[0140] Implementation Scheme 3. An ophthalmic composition according to any one of Implementation Schemes 1-2, wherein the rifaspirant is included in the composition at a concentration of about 0.005% (w / w) to about 5% (w / w), for example about 0.02% (w / w) to about 4% (w / w), about 0.5% (w / w) to about 3% (w / w), or about 0.75% (w / w) to about 2% (w / w).

[0141] Implementation Scheme 4. An ophthalmic composition according to any one of Implementation Schemes 1-3, 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).

[0142] Implementation Scheme 5. An ophthalmic composition according to any one of Implementation Schemes 1-4, wherein the at least one semifluorinated alkane is a compound of formula FnHm consisting of an F-segment and an H-segment, wherein the F-segment and the H-segment are straight-chain or branched chains and wherein n and m may be the same or different, and are independently selected from 3 to 20 carbon atoms, 3 to 10 carbon atoms, or 4 to 8 carbon atoms.

[0143] Implementation Scheme 6. An ophthalmic composition according to any one of Implementation Schemes 1-5, wherein the at least one semifluorinated alkane is a compound of formula FnHm consisting of an F-segment and an H-segment, wherein the F-segment and the H-segment are straight-chain and wherein n and m may be the same or different, and are independently selected from 3 to 20 carbon atoms, 3 to 10 carbon atoms, or 4 to 8 carbon atoms.

[0144] Implementation Scheme 7. An ophthalmic composition according to any one of Implementation Schemes 1-6, wherein the at least one semifluorinated alkane is a compound of formula FnHmFo consisting of an F-segment and an H-segment, wherein the F-segment and H-segment are straight-chain or branched chains and wherein n, m and o may be the same or different, and are independently selected from 3 to 20 carbon atoms, 3 to 10 carbon atoms, or 4 to 8 carbon atoms.

[0145] Implementation Scheme 8. An ophthalmic composition according to any one of Implementation Schemes 1-7, wherein the ratio of the carbon atom of the F-segment to the carbon atom of the H-segment of the at least one straight-chain or branched-chain semifluorinated alkane is in the range of 0.6 to 3.0 or 0.6 to 1.0.

[0146] Implementation Scheme 9. An ophthalmic composition according to any one of Implementation Schemes 1-8, wherein the ratio of the carbon atom of the F-segment to the carbon atom of the H-segment of the at least one linear semi-fluorinated alkane is in the range of 0.6 to 3.0 or 0.6 to 1.0.

[0147] Implementation Scheme 10. An ophthalmic composition according to any one of Implementation Schemes 1-9, wherein the at least one semifluorinated alkane is selected 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.

[0148] Implementation Scheme 11. An ophthalmic composition according to any one of Implementation Schemes 1-10, wherein the at least one semifluorinated alkane is selected from F4H4, F4H5, F4H6, F5H5, F5H6, F5H7, F5H8, F6H6, F6H7, F6H8, F6H9, F6H10, F8H8, F8H10, F8H12, F10H10 or any combination thereof.

[0149] Implementation Scheme 12. An ophthalmic composition according to any one of Implementation Schemes 1-11, wherein the at least one semifluorinated alkane is selected from F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8 or any combination thereof.

[0150] Implementation Scheme 13. An ophthalmic composition according to any one of Implementation Schemes 1-12, wherein the at least one semifluorinated alkane comprises 1-perfluorohexyl-octane (F6H8).

[0151] Implementation Scheme 14. An ophthalmic composition according to any one of Implementation Schemes 1-13, wherein the at least one semifluorinated alkane is substantially composed of 1-perfluorohexyl-octane (F6H8).

[0152] Implementation Scheme 15. An ophthalmic composition according to any one of Implementation Schemes 1-14, wherein the at least one semifluorinated alkane comprises perfluorobutylpentane (F4H5).

[0153] Implementation Scheme 16. The ophthalmic composition according to Implementation Scheme 15, wherein the at least one semifluorinated alkane is substantially composed of perfluorobutylpentane (F4H5).

[0154] Implementation Scheme 17. An ophthalmic composition according to any one of Implementation Schemes 1-16, wherein the composition is a liquid.

[0155] Implementation Scheme 18. An ophthalmic composition according to any one of Implementation Schemes 1-17, wherein the composition is non-aqueous.

[0156] Implementation Scheme 19. An ophthalmic composition according to any one of Implementation Schemes 1-18, wherein the composition is in the form of a suspension, solution or emulsion.

[0157] Implementation Scheme 20. An ophthalmic composition according to any one of Implementation Schemes 1-19, wherein the composition is in suspension form.

[0158] Implementation Scheme 21. An ophthalmic composition according to any one of Implementation Schemes 1-20, wherein the composition is stable.

[0159] Implementation Scheme 22. An ophthalmic composition according to any one of Implementation Schemes 1 and 3-21, wherein the composition further comprises at least one non-therapeutic component and / or a pharmaceutically acceptable excipient, said at least one non-therapeutic component and / or pharmaceutically acceptable excipient being selected from tension agents, preservatives, buffers, pH adjusters, antioxidants, delivery mediators, stabilizers, suspending agents, thickeners, wetting agents, solubilizers, chelating agents, nitric oxide inhibitors, isotonic agents, humectants, surfactants, or any combination thereof.

[0160] Implementation Scheme 23. An ophthalmic composition according to any one of Implementation Schemes 1-22, wherein the composition is substantially free of antioxidants.

[0161] Implementation Scheme 24. An ophthalmic composition according to any one of Implementation Schemes 1-23, wherein the composition is substantially free of preservatives.

[0162] Exemplary treatment method implementation plan: Implementation Scheme 25. A method for treating or temporarily preventing at least one eye condition, the method comprising administering an effective amount of an ophthalmic composition to a patient in need, the ophthalmic composition comprising (a) rifelast and (b) at least one semi-fluorinated alkane.

[0163] Implementation Scheme 26. The method according to Implementation Scheme 25, wherein the ophthalmic composition is the ophthalmic composition according to any one of Implementation Schemes 1-24.

[0164] Implementation Scheme 27. The method according to any one of Implementation Schemes 25-26, wherein the at least one ocular condition is selected from dry eye disease, dry eye syndrome, meibomian gland dysfunction, adult chlamydial ophthalmia, ocular erythematous presbyopia, refractory recurrent corneal erosion, ocular cicatricial pemphigoid, Sjögren's syndrome (SS), non-SS keratoconjunctivitis sicca (KCS), conjunctivitis, allergic conjunctivitis, endophthalmitis, keratitis, uveitis, stye, ocular inflammation, ocular discomfort or pain, ocular itching, inflammatory dry eye syndrome, ocular redness, tearing, ocular stinging or burning, gritty sensation in the eyes, photophobia, blurred vision, more frequent blinking, pressure behind the eyes, oily eyelids, crusting, itching, swelling or adhesions, or any combination thereof.

[0165] Implementation Scheme 28. The method according to any one of Implementation Schemes 25-27, wherein the at least one ocular condition is selected from dry eye disease, dry eye syndrome, meibomian gland dysfunction, adult chlamydial ophthalmia, ocular erythematous presbyopia, refractory recurrent corneal erosion, ocular cicatricial pemphigoid, Sjögren's syndrome (SS), non-SS keratoconjunctivitis sicca (KCS), conjunctivitis, allergic conjunctivitis, endophthalmitis, keratitis, uveitis, or any combination thereof.

[0166] Implementation Scheme 29. The method according to any one of Implementation Schemes 25-28, wherein the at least one ocular condition is selected from conjunctivitis, keratitis, dry eye disease, or any combination thereof.

[0167] Implementation Scheme 30. A method for treating or temporarily preventing dry eye disease, the method comprising administering an effective amount of an ophthalmic composition to a patient in need, the ophthalmic composition comprising (a) rifelast and (b) at least one semi-fluorinated alkane.

[0168] Implementation Scheme 31. The method according to Implementation Scheme 30, wherein the ophthalmic composition is the ophthalmic composition according to any one of Implementation Schemes 1-24.

[0169] Implementation Scheme 32. The method according to any one of Implementation Schemes 25-31, wherein the ophthalmic composition is applied topically to the ocular surface of the patient, or topically applied to the cornea of ​​the patient, or instilled into the conjunctival sac of the patient.

[0170] Implementation Scheme 33. The method according to any one of Implementation Schemes 25-32, wherein the ophthalmic composition is applied in the form of a suspension, ointment, solution or spray.

[0171] Implementation Scheme 34. The method according to any one of Implementation Schemes 25-33, wherein the ophthalmic composition is applied in the form of a suspension that can be applied as eye drops.

[0172] Implementation Scheme 35. The method according to any one of Implementation Schemes 25-34, wherein the ophthalmic composition is administered to the patient in a single daily dose, two daily doses, three daily doses, four daily doses, or up to ten daily doses.

[0173] Implementation Scheme 36. The method according to any one of Implementation Schemes 25-35, 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 two months, at least three months, at least four months, at least five months, at least six months, at least twelve months, at least one year, or more than one year.

[0174] Implementation Scheme 37. An ophthalmic composition comprising (a) rifelast and (b) at least one semi-fluorinated alkane, the ophthalmic composition being used in a method for treating or temporarily preventing at least one eye condition (e.g., according to any one of Implementation Schemes 25-36).

[0175] Implementation Scheme 38. Use of (a) rifelast and (b) at least one semi-fluorinated alkane in the manufacture of an ophthalmic composition (e.g., according to any one of Implementation Schemes 25-36) for the treatment or temporary prevention of at least one eye condition.

[0176] Exemplary container sealing systems and pillboxes: Implementation Scheme 39. A container sealing system comprising an ophthalmic composition comprising (a) rifelast and (b) at least one semi-fluorinated alkane.

[0177] Implementation Scheme 40. The container sealing system as described in Implementation Scheme 39, wherein the ophthalmic composition is the ophthalmic composition according to any one of Implementation Schemes 1-24.

[0178] Implementation Scheme 41. A container sealing system according to any one of Implementation Schemes 39-40, wherein the container sealing system is selected from vials, ampoules, bottles, tubes, syringes, and dispenser packaging.

[0179] Implementation Scheme 42. The container sealing system according to any one of Implementation Schemes 39-41, wherein the container sealing system is a polypropylene (PP) container sealing system.

[0180] Implementation Scheme 43. A pillbox comprising: (i) a formulation container sealing system containing an ophthalmic composition comprising (a) rifaspirant and (b) at least one semi-fluorinated alkane; and (ii) a formulation container sealing system containing a delivery medium for diluting or suspending the ophthalmic composition in the formulation container.

[0181] Implementation Scheme 44. The medicine box as described in Implementation Scheme 43, wherein the ophthalmic composition is the ophthalmic composition according to any one of Implementation Schemes 1-24.

[0182] Implementation Scheme 45. A medicine box according to any one of Implementation Schemes 43-44, wherein the formulation container sealing system is selected from vials, ampoules, bottles, tubes, syringes, and dispenser packaging.

[0183] Implementation Scheme 46. The medicine box according to any one of Implementation Schemes 43-45, wherein the preparation container sealing system is a PP container sealing system.

[0184] It should be understood that the work of the inventors is described by way of example only, and modifications may be made while remaining within the scope and spirit of the invention.

Claims

1. An ophthalmic composition comprising: (a) rifelast and (b) at least one semi-fluorinated alkane.

2. The ophthalmic composition of claim 1, wherein the ophthalmic composition generally comprises: (a) rifexister and (b) at least one semi-fluorinated alkane.

3. The ophthalmic composition of claim 2, wherein the ophthalmic composition generally comprises: (a) Rifexazone and (b) no more than two types of semi-fluorinated alkanes.

4. The ophthalmic composition according to any one of claims 1-3, wherein the at least one semi-fluorinated alkane is selected 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; for example, the composition comprises no more than two semi-fluorinated alkanes.

5. The ophthalmic composition according to any one of claims 1-4, wherein the at least one semifluorinated alkane is 1-perfluorohexyl-octane (F6H8).

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

7. The ophthalmic composition according to any one of claims 1 and 4-6, wherein the composition further comprises at least one non-therapeutic component and / or a pharmaceutically acceptable excipient, said at least one non-therapeutic component and / or pharmaceutically acceptable excipient being selected from: tension agents, preservatives, buffers, pH adjusters, antioxidants, delivery mediators, stabilizers, suspending agents, thickeners, wetting agents, solubilizers, chelating agents, nitric oxide inhibitors, isotonic agents, humectants, surfactants, or any combination thereof.

8. The ophthalmic composition according to any one of claims 1-7, wherein the composition is in suspension form.

9. The ophthalmic composition according to any one of claims 1-8, wherein the composition is substantially free of antioxidants and / or substantially free of preservatives.

10. The ophthalmic composition according to any one of claims 1-9, wherein the composition is non-aqueous.

11. An ophthalmic composition, said ophthalmic composition generally comprising: (a) Rifelast and (b) Perfluorohexyloctane.

12. The ophthalmic composition of claim 11, wherein rifelast is present at 2-5% (w / w), for example at 5% (w / w).

13. A method for treating or temporarily preventing at least one eye condition, the method comprising administering an effective amount of an ophthalmic composition to a patient in need, the ophthalmic composition comprising (a) rifelast and (b) at least one semi-fluorinated alkane.

14. A method for treating or temporarily preventing dry eye disease, the method comprising administering an effective amount of an ophthalmic composition to a patient in need, the ophthalmic composition comprising (a) rifelast and (b) at least one semi-fluorinated alkane selected from F4H5, F4H6, F5H6, F5H7, F6H6, F6H7, F6H8 or any combination thereof.

15. The method of claim 13, wherein the at least one eye condition is dry eye disease.

16. The method according to any one of claims 13-15, wherein the ophthalmic composition is the ophthalmic composition according to any one of claims 1-12.

17. The method according to any one of claims 13-16, wherein the ophthalmic composition is applied topically to the ocular surface of the patient, or topically applied to the cornea of ​​the patient, or instilled into the conjunctival sac of the patient.

18. The method according to any one of claims 13-17, wherein the ophthalmic composition is applied in the form of eye drops.

19. The method of claim 18, wherein the ophthalmic composition is administered in the form of a single microdroplet per eye, the microdroplet having a volume of 8-15 μL.

20. The method according to any one of claims 13-19, wherein the ophthalmic composition is administered to the patient in a single daily dose, two daily doses, three daily doses, four daily doses, or up to ten daily doses.

21. A container sealing system comprising an ophthalmic composition comprising (a) rifelast and (b) at least one semi-fluorinated alkane.

22. The container sealing system of claim 21, wherein the container sealing system is a bottle having an outlet for forming microdroplets, such as a polypropylene (PP) bottle.

23. The container sealing system of claim 22, wherein the bottle contains at least 1 mL of the ophthalmic composition, and wherein the ophthalmic composition is preservative-free.

24. The container sealing system according to any one of claims 21-23, wherein the ophthalmic composition is the ophthalmic composition according to any one of claims 1-12.

25. A method for preparing an ophthalmic composition, the method comprising the following steps: (a) Providing a first composition comprising rifelast and F6H8, wherein the rifelast has at least partially settled; (b) Stirring the first composition to obtain a suspension of rifaspire, thereby providing the ophthalmic composition.

26. The method of claim 25, wherein the first composition is located in a bottle and / or the stirring is achieved by hand shaking or continuous inversion.

27. A method for preparing an ophthalmic composition, the method comprising the step of mixing rifelast with perfluorohexyloctane.

28. A method for packaging an ophthalmic composition, the method comprising the steps of: (a) providing a suspension of rifelast in perfluorohexyloctane; (b) placing some or all of the suspension into an open container; and (c) closing the container.

29. The method of claim 28, wherein step (a) may involve mixing rifelast with perfluorohexyloctane to form the suspension.

30. Use of perfluorohexyl octane as a preservative for rifaspirant in ophthalmic compositions.

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