Semi-fluorinated compounds and compositions thereof

Abstract

The present invention relates to semi-fluorinated compounds and compositions comprising semi-fluorinated compounds, and their use as medicaments for topical application to the eye.

Description

[0001] This application is a divisional application with an application date of September 29, 2016, application number 202010471109.9, and invention name “Semifluorinated compounds and compositions thereof”.

[0002] The application with the application date of September 29, 2016, application number 202010471109.9, and invention name “Semifluorinated compounds and their compositions” is a divisional application of the Chinese national phase application with the application date of September 29, 2016, application number 201680056188.9, and invention name “Semifluorinated compounds and their compositions”. Technical Field

[0003] The present invention is in the field of compositions comprising semifluorinated compounds and their use in ocular administration. Background Art

[0004] Semifluorinated alkanes are compounds containing at least one non-fluorinated hydrocarbon segment and at least one perfluorinated hydrocarbon segment. n (CH2) m A linear, unbranched semifluorinated alkane of CH3, wherein n and m are integers representing the number of carbon atoms in each chain segment, is used in various applications, such as commercially for unfolding and re-coating the retina, as a long-term tamponade as a vitreous humor substitute (H. Meinert et al., European Journal of Ophthalmology, Vol. 10(3), pp. 189-197, 2000), and as an eluate for residual silicone oil after vitreoretinal surgery.

[0005] Formula CF3(CF2) n (CH2) m Semifluorinated alkanes of CH3 are described elsewhere.

[0006] WO2011 / 073134 discloses a CF3(CF2) n (CH2) m A solution of cyclosporine in a semifluorinated alkane of CH3, optionally in the presence of a cosolvent such as ethanol, wherein the semifluorinated alkane is used as a liquid drug delivery vehicle for cyclosporine for the topical treatment of keratoconjunctivitis sicca.

[0007] WO2014 / 041055 describes the formula CF3(CF2) n (CH2) m CH3 (which may alternatively be represented as F(CF2) n (CH2) mH) of semifluorinated alkanes. These mixtures are described as being ophthalmically usable as tear film substitutes or for the treatment of patients suffering from dry eye and / or meibomian gland dysfunction.

[0008] The nomenclature commonly used for semifluorinated compounds having linear and unbranched segments is FnHm, wherein F denotes a perfluorinated hydrocarbon segment, H denotes a non-fluorinated segment, and n and m define the number of carbon atoms of the respective segments. For example, F3H3 is used for the perfluoropropylpropane CF3(CF2)2(CH2)2CH3, i.e. 1 -perfluoropropylpropane.

[0009] However, semifluorinated alkanes of the formula CF3-(CF2)5-CH(CH3)-(CH2)5-CH3 and compositions comprising CF3(CF2)5(CH2)7CH3 and CF3-(CF2)5-CH(CH3)-(CH2)5-CH3 have not been described, in particular not for ophthalmic applications. It is therefore an object of the present application to provide compositions comprising such compounds, in particular with respect to their use in compositions for ophthalmic applications. SUMMARY

[0010] In a first aspect, the present application relates to a composition comprising CF3(CF2)5(CH2)7CH3 and CF3-(CF2)5-CH(CH3)-(CH2)5-CH3. In particular, the present application relates to a composition comprising at least about 80 wt% of CF3(CF2)5(CH2)7CH3, and in another aspect to a composition comprising up to about 25 wt% of CF3-(CF2)5-CH(CH3)-(CH2)5-CH3.

[0011] In another aspect, the present application relates to a composition comprising said compounds in the form of a clear liquid solution.

[0012] In a further aspect, the present application provides the use of a composition comprising CF3(CF2)5(CH2)7CH3 and CF3-(CF2)5-CH(CH3)-(CH2)5-CH3 for the treatment of dry eye disease and / or meibomian gland dysfunction and any symptoms or conditions associated with these disorders.

[0013] In another aspect, the present application provides a method of treating dry eye disease and / or meibomian gland dysfunction and any symptoms or conditions associated therewith, comprising topically administering said composition to the lacrimal sac, into the lower eyelid, onto the surface of the eye or to the ocular tissue.

[0014] In a further aspect, the present application provides a kit comprising a composition of the present application, the composition being contained in a container comprising a dispensing device suitable for topically administering said composition to the eye or ocular tissue. BRIEF DESCRIPTION OF DRAWINGS

[0015] Figure 1 is a graph depicting the evaporation time of a composition consisting of the compounds CF3(CF2)5(CH2)7CH3 and CF3-(CF2)5-CH(CH3)-(CH2)5-CH3 as a function of the percentage of the compound CF3-(CF2)5-CH(CH3)-(CH2)5-CH3 in the composition.

[0016] Figure 2 is a graph depicting the measured refractive index of a composition consisting of the compounds CF3(CF2)5(CH2)7CH3 and CF3-(CF2)5-CH(CH3)-(CH2)5-CH3 as a function of the percentage of the compound CF3-(CF2)5-CH(CH3)-(CH2)5-CH3 in the composition.

[0017] Figure 3 Graph representing the results obtained from an ex vivo eye irritation test (EVEIT) comparison of compositions of CF3(CF2)5(CH2)7CH3 and CF3-(CF2)5-CH(CH3)-(CH2)5-CH3, a hyaluronic acid standard reference, and a 0.01% BAC positive control. DETAILED DESCRIPTION

[0018] In a first aspect, the present invention relates to a composition comprising CF3(CF2)5(CH2)7CH3 and CF3-(CF2)5-CH(CH3)-(CH2)5-CH3.

[0019] Based on the hydrocarbon alkane root, the compound CF3-(CF2)5-CH(CH3)-(CH2)5-CH3 can also be referred to as 2-perfluorohexyl octane. This compound has a stereocenter at the 2-alkyl position. As understood herein, the general formula encompasses both enantiomers, enriched mixtures of both enantiomers, and racemic mixtures. The compound CF3(CF2)5(CH2)7CH3 can alternatively be referred to as 1-perfluorohexyl octane, or F6H8 using the nomenclature FnHm, where n is an integer representing the number of carbon atoms in the linear, unbranched perfluorinated segment, and m is an integer representing the number of carbon atoms in the linear, unbranched hydrocarbon segment.

[0020] Particularly preferred compositions of the present invention are those that contain at least about 80% by weight of CF3(CF2)5(CH2)7CH3. In other embodiments, the composition contains at least about 90% by weight, or at least about 95% by weight, or at least 97% by weight of CF3(CF2)5(CH2)7CH3. In another preferred embodiment of the present invention, the composition contains up to about 25% by weight of CF3-(CF2)5-CH(CH3)-(CH2)5-CH3. In other embodiments, the composition contains up to about 10% by weight, or up to about 5% by weight, or up to about 3% by weight of the compound CF3-(CF2)5-CH(CH3)-(CH2)5-CH3.

[0021] As used herein, the term wt% refers to the weight of a component as a percentage of the weight of the composition as a whole. The term about before a parameter such as wt% includes the exact value as well as any value that falls within the degree of variability normally observed in the measurement and determination of that parameter, including those determined using standard techniques and equipment known in the art and field.

[0022] In a further preferred embodiment, the composition of the present invention comprises about 97 weight percent CF3(CF2)5(CH2)7CH3 and up to about 3 weight percent CF3-(CF2)5-CH(CH3)-(CH2)5-CH3. In yet another embodiment, the composition may comprise about 98 weight percent CF3(CF2)5(CH2)7CH3 and up to about 1 weight percent CF3-(CF2)5-CH(CH3)-(CH2)5-CH3.

[0023] The composition comprising the semifluorinated alkanes as defined above is preferably in liquid form and is preferably formulated as a clear liquid solution. In this context, clear means the absence of dispersed solid or liquid particles that would cause turbidity. In other words, the clear solution is a pure single-phase liquid system, except for the possible presence of small and technically irrelevant amounts of particulate impurities.

[0024] In optional embodiments, the composition may be formulated for administration as a gel, suspension, microemulsion, or spray.Preferably, the composition is provided in sterile form.

[0025] Furthermore, the composition is preferably formulated as a liquid solution exhibiting a refractive index close to that of water, which is 1.333, at room temperature (RT). In a particularly preferred embodiment, the refractive index of the liquid solution at 20° C. is in the range of about 1.30 to about 1.35 as measured by a refractometer.

[0026] The compositions as defined above may also contain other excipients as needed or available, such as one or more acids, bases, electrolytes, buffers, solutes, antioxidants, stabilizers, and, if desired, preservatives. In a preferred embodiment, the compositions as described herein are substantially free of water and / or substantially free of preservatives, such as benzalkonium chloride.

[0027] In another embodiment of the present invention, the above-described composition is substantially free of the following ingredients: (a) polymers, (b) perfluorinated compounds, and / or (c) dissolved pharmacologically active ingredients that are not semifluorinated alkanes. Such compositions are also preferably formulated as clear liquid solutions. In another embodiment, the composition as described in any embodiment herein can be substantially free of any form of pharmacologically active ingredient that is not a semifluorinated alkane.

[0028] As understood herein, the term "substantially free" with respect to a component of a composition means that the component is present in no more than a trace amount, and if present in a trace amount, the component provides no technical contribution to the composition.

[0029] Examples of polymers that are preferably absent from the compositions of the present invention include silicone polymers (polymeric siloxanes), polyether polymers, and fluorinated or perfluorinated derivatives thereof.

[0030] Examples of perfluorinated compounds (ie, compounds in which all hydrogen atoms are replaced by fluorine and which are preferably absent in the compositions of the present invention) include perfluorinated alkanes, such as perfluorodecalin, and halogenated perfluorinated alkanes, such as perfluorooctyl bromide.

[0031] The compositions of the present invention are also substantially free of dissolved pharmacologically active ingredients (which are not semifluorinated alkanes). As used herein, the term "pharmacologically active ingredient" refers to any type of pharmaceutically active compound or drug, i.e., a pharmaceutically active compound or drug that produces a pharmacological effect and is therefore useful for preventing, diagnosing, stabilizing, treating, or generally managing a condition or disease.

[0032] In a preferred embodiment, the composition according to the present invention consists essentially of CF3(CF2)5(CH2)7CH3 and CF3-(CF2)5-CH(CH3)-(CH2)5-CH3. Preferably, the composition consists essentially of about 97% by weight of CF3(CF2)5(CH2)7CH3 and up to about 3% by weight of CF3-(CF2)5-CH(CH3)-(CH2)5-CH3.

[0033] As used herein, the term "consisting essentially of is so-called closed language, meaning that only the recited ingredients are present. In contrast, the terms "comprising," "including," and "containing" are used herein as so-called open language, meaning that additional ingredients may also be present.

[0034] However, the compounds of the present invention and compositions containing them have beneficial therapeutic effects at the site of administration even in the absence of other pharmacologically active ingredients.

[0035] The composition as defined above is preferably formulated to have a dynamic viscosity of no more than 10 mPa·s, and preferably no more than 4 mPa·s, measured at standard ambient temperature and pressure (25° C., 1 atmosphere). Preferably, the composition has a dynamic viscosity of from 1 mPa·s to 4 mPa·s. The viscosity of the composition can be measured using any standard viscometer device known in the art, for example, using a glass tube or capillary viscometer.

[0036] The compositions described herein are useful in medical applications, particularly in ophthalmology, particularly for topical administration to the eye, such as to the lacrimal sac, to the interior of the lower eyelid, to the surface of the eye, or to any ocular tissue or anatomical structure associated with the eyeball that is amenable to topical administration.

[0037] It has been found that the compositions of the present invention are useful for treating diseases and conditions that would benefit from stabilization of the tear film and the tear film lipid layer and lubrication of the ocular surface. Thus, the compositions of the present invention are particularly suitable for treating dry eye (keratoconjunctivitis sicca) and / or meibomian gland dysfunction (MGD) and any symptoms thereof or any symptoms associated therewith.

[0038] Dry eye, also known as keratoconjunctivitis sicca, can be divided into two categories: aqueous dry eye and evaporative dry eye. These conditions are not necessarily mutually exclusive. Aqueous dry eye is commonly observed in patients with Sjögren's syndrome or those with tear gland insufficiency, tear duct obstruction, or reflex hyposecretion. Evaporative dry eye, on the other hand, has a different underlying cause and is associated with increased / abnormal evaporative loss of the tear film, for example due to meibomian gland disease, eyelid aperture disease, blink disorders, or ocular surface disease.

[0039] Symptoms of dry eye disease include dry, itchy, gritty, sandy, or foreign body sensation in the eyes; pain, soreness, stinging, or burning; itching, increased need to blink, eyestrain, photophobia, blurred vision, redness and inflammation of eye tissues, excessive mucus discharge and crusting / coagulation, contact lens intolerance, and excessive reflex tearing.

[0040] Meibomian gland insufficiency (MGD) is a condition in which the meibomian glands do not produce enough oil, or the oily secretion is poor quality or abnormal. Typically, the opening of the oil gland may become blocked or clogged, causing the gland to produce less oil. The oil secreted from the gland may be grainy (crusty) or otherwise abnormal and may irritate the eye or ocular tissue. In its early stages, patients are often asymptomatic, but if left untreated, MGD can cause or worsen dry eye symptoms and eyelid inflammation. The oil glands become blocked due to thickening of the secretion. Chronically blocked glands eventually become unable to produce oil, which can lead to permanent changes in the tear film and dry eyes.

[0041] Symptoms of meibomian gland dysfunction include dryness, burning, itching, stickiness / crusting, watering, light sensitivity, red eyes, foreign body sensation, chalazions / styes, or intermittent blurred vision.

[0042] In a preferred embodiment, the composition of the present invention as described above is used for topical ocular treatment of evaporative dry eye and / or meibomian gland dysfunction (MGD), and for treating or preventing any symptom or condition associated therewith. In another embodiment, the composition as described herein can be used as a lubricant for the ocular surface to improve one or more symptoms associated with dry eye and to moisturize the ocular surface.

[0043] In another preferred embodiment of the present invention, the compounds and compositions thereof as described above are used for topical ocular treatment of corneal injuries. Thus, the compounds and compositions are actively supporting the corneal healing process of corneal injuries (e.g. corneal erosion).

[0044] In a further embodiment, the treatment of the conditions (e.g., corneal damage) and diseases and their associated symptoms as described above is preferably performed by administering to a patient in need thereof an effective amount of the above-described composition comprising CF3(CF2)5(CH2)7CH3 and CF3-(CF2)5-CH(CH3)-(CH2)5-CH3, for example, wherein the composition comprises up to about 25% by weight of CF3-(CF2)5-CH(CH3)-(CH2)5-CH3.

[0045] The advantages of the above-mentioned compounds and compositions in the context of use according to the present invention are believed to relate to their properties that are particularly suitable for ophthalmic application. The refractive index of the compounds of the present invention is very close to that of water, which means that there will be no or minimal impact on the patient's vision after administration, unlike ophthalmic compositions based on oily vehicles that may cause blurred vision upon administration. The generally low viscosity and low surface tension of these compounds, and especially their high wetting and spreading ability, also ensure that they are quickly accommodated and adapted to administration on the surface of the eye.

[0046] As will be more clearly shown in the examples below, the compositions of the present invention were found to be biocompatible and did not show significant cytotoxic effects. Furthermore, it has been demonstrated that these compositions are not only well tolerated in the eye and have no effect on vision, but also provide a beneficial effect in terms of ocular lubrication and tear film stabilization in the form of relieving symptoms in patients with mild to moderate symptoms associated with dry eye. Patients with dry eye and / or dysfunctional meibomian glands often express opaque and thicker meibum, which can lead to an abnormal lipid layer in the tear film. Without wishing to be bound by theory, it is believed that the physicochemical properties of the compounds contained in the compositions of the present invention can play a role in stabilizing the lipid layer of the tear film, for example by dissolving certain lipid components or improving the fluidity of the lipid layer, and can provide a lubricating effect on the eye.

[0047] In another aspect, the present invention provides a method for treating dry eye and any symptoms or conditions associated therewith, comprising topically applying a composition of the present invention to the tear sac, to the interior of the lower eyelid, to the surface of the eye, or to ocular tissue. Preferably, the composition can be applied to the eye or ocular tissue up to four times daily.

[0048] In addition, the present invention provides a kit comprising any one of the compositions described above and a container for containing the composition. The container preferably comprises a dispensing device suitable for topically applying the composition to the eye sac, lower eyelid to the eye or ocular tissue, such as an eye dropper.

[0049] In a further preferred embodiment, the dispensing device comprises a dropper of a certain size so as to dispense drops having a volume of 8 μL to 15 μL, preferably about 8 μL to 12 μL, and more preferably about 10 μL. With small drop volumes, accurate dosing of the eye can be achieved and excessive drainage of a large portion of the composition from the eye after administration can be avoided.

[0050] Furthermore, the compositions of the present invention may be applied to the eye or ocular tissue up to four times daily; preferably, one drop (approximately 8 to 15 μL) is administered per eye per dose. Treatment may continue for at least six weeks. In one embodiment of the present invention, the composition is administered three to four times daily, with one drop (approximately 8 to 15 μL), preferably about 10 μL, administered per eye per dose.

[0051] Example CF3-(CF2)5-CH(CH3)-(CH2)5-CH3(2-perfluorohexyl-octane, C 14 F 13 H 17 ) The compound CF3-(CF2)5-CH(CH3)-(CH2)5-CH3 can be prepared as follows: perfluorohexyl iodide is subjected to free radical addition to 1-octene in the presence of a free radical initiator (herein, perfluorohexyl iodide is mixed with 1-octene and a free radical initiator that is AIBN, and the resulting solution is maintained at 80°C for 30 minutes and cooled), and then the resulting iodine adduct is reduced with a hydride (i.e., LiAlH4) or by hydrogenation (i.e., catalytic hydrogenation in the presence of a catalyst such as Pd / C) to form 2-perfluorohexyl-octane, which is then purified by fractional distillation.

[0052] CF3-(CF2)5-CH(CH3)-(CH2)5-CH3: 1 H-NMR (CDCl3, 400 MHz): 2.17-2.33 (m, 1H,CH), 1.67-1.77 (m, 2H, CH2), 1.25-1.40 (m, 8H, CH2), 1.15 (d, 3H, CH3), 0.9(t, 3H, CH3) In vitro cytotoxicity assay The cytotoxicity of a composition comprising 1.3 wt% CF3-(CF2)5-CH(CH3)-(CH2)5-CH3 and 95.8 wt% CF3(CF2)5(CH2)7CH3 was evaluated by a cell growth inhibition assay, which predicts cytotoxic or necrotic effects with good correlation with animal experiments and high sensitivity.

[0053] The composition was extracted with cell culture medium (DMEM supplemented with 10% FBS) for approximately 24 hours under agitation. The resulting extract was then incubated with mouse cell line L929 cells for 68-72 hours and then analyzed for protein content using a BCA (bicinchoninic acid) assay as a measure of cytotoxicity. No inhibition of cell growth or cell lysis was observed.

[0054] A similar in vitro cytotoxicity assay was performed on a composition comprising about 23.7 wt % CF3-(CF2)5-CH(CH3)-(CH2)5-CH3 and about 75.6 wt % F6H8.

[0055] Tear film analysis study A composition containing 98.3% by weight of CF3(CF2)5(CH2)7CH3 and 1.2% by weight of CF3-(CF2)5-CH(CH3)-(CH2)5-CH3 was tested in an observational study of patients with mild to moderate evaporative dry eye. The clear, colorless liquid composition was provided in a 5 ml bottle equipped with a dropper sized to dispense approximately 10 μl drops into the eye sac. Patients wearing contact lenses were excluded from the study. After obtaining informed consent, patients were advised to instill 3-4 drops in both eyes daily, converting to a daily dose of 30 μl-40 μl. Patients returned for follow-up after 5 to 7 weeks. Clinical data were collected from 29 patients at baseline and at 5-7 weeks of follow-up.

[0056] a) Tear film analysis Tear film fluidity and tear film stability improved during the study period, as evidenced by increases in Schirmer I and TFBUT. Retrospective statistical analysis reinforced this observation, as the difference in TFBUT between baseline and follow-up was highly significant (paired two-sided t-test: p = 0.0026 (right eye) and p = 0.0006 (left eye)). No changes in tear osmolarity were detected.

[0057] The subjective dry eye questionnaire (Ocular Surface Disease Index, OSDI) showed a reduction in the severity of patients' subjective symptoms after a period of 5-7 weeks using a composition comprising 98.3 wt% CF3(CF2)5(CH2)7CH3 and 1.2 wt% CF3-(CF2)5-CH(CH3)-(CH2)5-CH3, as evidenced by lower scores in follow-up and retrospective statistical analysis (paired two-sided t-test: p<0.0001).

[0058]

[0059] b) Corneal staining (Oxford grading scheme) Corneal fluorescein staining is an indicator of corneal damage (loss of cell-to-cell connections). Data showed a reduction in corneal damage after 5-7 weeks of treatment, as evidenced by a shift in the number of patients diagnosed with grade 1 or 2 at baseline to grade 0 at follow-up. This difference in initial damage was statistically significant, as shown by the Wilcoxon signed-rank test: p = 0.0013 (right eye) and p = 0.0041 (left eye).

[0060]

[0061] c) Physician symptom assessment At baseline and follow-up, the physicians asked the patients whether they were currently experiencing typical dry eye symptoms. As can be seen in the table below, fewer DED-related symptoms were reported after 5-7 weeks of treatment.

[0062]

[0063] d) Meibum secretion analysis In healthy eyes, meibum is a clear fluid secreted from the meibomian glands. More opaque and thicker meibum is an indicator of meibomian gland dysfunction. Descriptive examinations of patients' meibum were performed at baseline and during follow-up. The data obtained showed improvement in meibum quality in many cases. In seven cases, treatment induced a decrease in expressible meibum (from clear meibum to absence).

[0064]

[0065] e) Safety parameters No changes in visual acuity or intraocular pressure were observed, indicating that use of the composition comprising 98.3 wt % CF3(CF2)5(CH2)7CH3 and 1.2 wt % CF3-(CF2)5-CH(CH3)-(CH2)5-CH3 for 5-7 weeks is safe and does not interfere with these ophthalmic parameters.

[0066]

[0067] Differential scanning calorimetry Differential scanning calorimetry (DSC 1, Mettler Toledo, Greifensee, Switzerland) was used to characterize the structural and phase behavior of mixtures of CF3(CF2)5-CH(CH3)-(CH2)5-CH3 and CF3(CF2)5(CH2)7CH3. Transformation data were obtained using DSC by temperature scanning at a heating rate of 1°C / min. Sealed standard aluminum crucibles (40 μl, Mettler Toledo) were used.

[0068]

[0069]

[0070] The presence of CF3(CF2)5-CH(CH3)-(CH2)5-CH3 in a mixture of CF3(CF2)5-(CH2)7-CH3(F6H8) results in a significant decrease in the melting temperature. The enthalpy of fusion is also reduced, indicating that the semifluorinated alkane does not crystallize. This difference has beneficial effects on the application of the compound to the eye as a tear substitute or lubricant; for example, in terms of its ability to mix with and modulate the tear film lipid layer. Furthermore, this effect can be advantageously modulated by varying the amount of the compound in the ophthalmic composition of the present invention.

[0071] DSC measurements were also performed on a series of mixtures of 23.74 wt% F3(CF2)5-CH(CH3)-(CH2)5-CH3 and CF3(CF2)5(CH2)7CH3 with tetradecane (C14). Transition data were obtained using temperature scans (heating rates of 0.2°C / min, 0.5°C / min, and 1°C / min). The end temperature was determined using a heating rate extrapolated to 0°C / min, while the start temperature was determined using the average value from three measurements. A decrease in the enthalpy of fusion was observed compared to the mixture of tetradecane and pure CF3(CF2)5(CH2)7CH3, indicating that some tetradecane was dissolved in the liquid portion of CF3(CF2)5-CH(CH3)-(CH2)5-CH3 and that this compound had a stronger solubilizing ability than CF3(CF2)5(CH2)7CH3.

[0072] Refractive index and evaporation time .

[0073] The evaporation time of mixtures of the semifluorinated alkanes CF₃(CF₂)₅(CH₂)ₐCH₃ and CF₃(CF₂)₅-CH(CH₃)-(CH₂)₅-CH₃ was evaluated. A 10 μL droplet of each mixture was placed on a glass surface at room temperature. The time until evaporation was recorded using video monitoring.

[0074]

[0075] It was observed that an increase in the percentage of semifluorinated alkane CF3(CF2)5-CH(CH3)-(CH2)5-CH3 decreased the evaporation time of the mixture ( Figure 1 By varying the amount of such semifluorinated alkane present in the mixture, the composition can be adjusted and fine-tuned to the requirements of the intended ophthalmic use, such as extending or reducing the residence time of the composition on the ocular surface.

[0076] The refractive index of the mixture was also determined. For ophthalmic compositions to be applied topically, the refractive index of the composition should preferably be similar to or adjusted to the refractive index of the eye or lens, for example, as close as possible to the refractive index of physiological tear fluid. If the refractive index of the composition is not similar, the patient may experience blurred or impaired vision when applied to the ocular surface. The amount of semifluorinated alkane CF3(CF2)5-CH(CH3)-(CH2)5-CH3 was observed to have an effect on the refractive index (see Figure 2 , which depicts an increase in refractive index value with increasing 2-perfluorohexyloctane content). By varying the amount of this semifluorinated alkane in the mixture, it is also possible to tailor the composition to the requirements of the intended ophthalmic use, for example, to patients with altered tear composition and refractive index due to ocular conditions and / or age.

[0077] Ex vivo eye irritation test (EVEIT) For the two compositions containing CF3(CF2)5(CH2)7CH3, i.e., the compositions consisting of a mixture of the semifluorinated alkanes CF3(CF2)5(CH2)7CH3 and CF3(CF2)5-CH(CH3)-(CH2)5-CH3 (composition A with 0.17% by weight of CF3(CF2)5-CH(CH3)-(CH2)5-CH3 and composition B with 64% by weight of CF3(CF2)5-CH(CH3)-(CH2)5-CH3), hyaluronic acid (HYLO-COMOD ® ) as a reference and 0.01% BAC (benzalkonium chloride) as a positive control, an in vitro eye irritation test (EVEIT) similar to that described in M. Frentz et al, Altern. to Lab. Anim., 2008 (36) p 25-32; and N. Schrage et al, Graefes Arch Clin Exp Ophthalmol 2012 (250), 1330-1340) was used to compare the corneal healing process.

[0078] Methods. Rabbit corneas were obtained and placed in an artificial anterior chamber, which was slowly filled with serum-free minimal essential medium (Eagle's MEM) containing Earle's salts and nutrient-rich HEPES buffer. The medium was continuously replenished by a micropump to mimic the physiological conditions of the eye. The incubation chamber was maintained at 32°C in a normal atmosphere without supplemental CO2 and >95% relative humidity. In addition to testing two corneas (n=2) for a positive control, five corneas (n=5) were used per test substance.

[0079] After stabilization in the culture chamber for 12 hours, the corneas were evaluated microscopically and corneas with intact epithelium and no opacity were selected. Four small scratches (2.3-4.3 mm) were applied to the surface of the selected corneas using a corneal drill. 2 All defects were monitored by sodium fluorescein staining (0.17% in water) and microscopy.

[0080] The test substance was applied 1 hour after induction of corneal erosion and applied six times a day to the top of the cornea (30-50 μL every four hours). A soft-top cannula for continuous suction was placed at the bottom of the corneal scleral area in the culture chamber to remove any excess fluid. The experiment was terminated after 3 days of application. Biomicroscopic images of the cornea were taken daily using a phase contrast microscope integrated camera (KY-F1030U, JVC, (BadVilbel, DE), mounted on a Z16 APO microscope (Wetzlar, DE)) to record the corneal healing process. All defects were monitored by sodium fluorescein staining (0.17% aqueous solution), and yellow-green fluorescence indicated the area of ​​epithelial defects. The erosion size was determined using the software tool of the microscope (DISKUS). At the end of 3 days, the experiment was terminated and all corneas were fixed in 3.7% formaldehyde and stained with hematoxylin-eosin dye for microscopic evaluation. In order to monitor the metabolic activity of the cornea, glucose and lactate concentrations were photometrically quantified in the outflow medium from the artificial anterior chamber.

[0081] Results Compared with the standard reference hyaluronic acid composition (HYLO-COMOD ® ), similar positive effects were observed for both semifluorinated alkane mixtures (compositions A and B as described above) in terms of the corneal treatment process after induction of corneal erosion.

[0082] Corneal erosion size measurements / mean mm 2 (SD)

[0083] Histological observations on day 3

[0084] No significant differences in active corneal healing were observed between composition B, comprising 64% by weight of the semifluorinated alkane CF3(CF2)5-CH(CH3)-(CH2)5-CH3, based on the total weight of the composition, and composition A. For both compositions, as for the reference composition, mechanically induced epithelial erosion was found to be significantly reduced and essentially absent after the second day of treatment. Figure 3 Depicted are the results of corneal erosion size measurements for the test composition, reference, and positive control from days 0-3 of the EVEIT experiment.

[0085] As shown in the table above, microscopic histological examination of cross sections of the corneas at the end of the experiment on day 3 showed no significant residual defects or differences in the corneas treated with compositions A, B and the reference HYLO-COMOD ® There were no significant residual defects or differences in the treated corneas.

[0086] Furthermore, no corneal toxicity was observed for these compositions, as indicated by the metabolic activity based on glucose / lactate measurements.

[0087] In sharp contrast, the positive control comprising 0.01 % preservative BAC was observed to induce an increasing epithelial damage over the three days of the experiment.

[0088] The present application also comprises the following embodiments: 1. A composition comprising CF3(CF2)5(CH2)7CH3 and CF3-(CF2)5-CH(CH3)-(CH2)5-CH3.

[0089] 2. The composition according to embodiment 1, comprising at least about 80 wt% of CF3(CF2)5(CH2)7CH3.

[0090] 3. The composition according to embodiment 1, comprising at most about 25 wt% of CF3-(CF2)5-CH(CH3)-(CH2)5-CH3.

[0091] 4. The composition according to any one of the preceding embodiments, comprising about 97 wt% of CF3(CF2)5(CH2)7CH3 and at most about 3 wt% of CF3-(CF2)5-CH(CH3)-(CH2)5-CH3.

[0092] 5. The composition according to any one of the preceding embodiments, formulated as a transparent liquid solution.

[0093] 6. The composition according to any one of the preceding embodiments, which is essentially free of: (a) polymers, (b) perfluorinated compounds, and / or (c) dissolved pharmacologically active ingredients.

[0094] 7. The composition according to any one of the preceding embodiments, having a dynamic viscosity of not more than 10 mPa-s, and preferably not more than 4 mPa-s, at ambient temperature and pressure.

[0095] 8. The composition according to any one of the preceding embodiments, for use as a medicament.

[0096] 9. The composition of embodiment 8, wherein the composition is topically administered to the tear sac, the interior of the lower eyelid, the surface of the eye, or ocular tissue.

[0097] 10. The composition of embodiment 9, comprising administering the composition up to 4 times per day.

[0098] 11. The composition of any one of embodiments 8 to 10, for use in treating keratoconjunctivitis sicca and / or meibomian gland dysfunction or symptoms or conditions associated therewith.

[0099] 12. The composition of any one of embodiments 8 to 11 for use in treating corneal damage.

[0100] 13. The composition of any one of embodiments 8 to 11 for use as a lubricant for the surface of the eye.

[0101] 14. A kit comprising a composition according to any one of the preceding embodiments and a container for containing the composition, wherein the container comprises a dispensing device suitable for topical application of the composition to the lacrimal sac, the interior of the lower eyelid, the surface of the eye, or ocular tissue.

[0102] 15. The kit of embodiment 14, wherein the dispensing device comprises a dropper sized to dispense droplets having a volume of 8 μL to 15 μL.

Claims

1. A composition comprising CF3(CF2)5(CH2)7CH3 and CF3-(CF2)5-CH(CH3)-(CH2)5-CH3.

2. The composition of claim 1 comprising at least about 80 wt% CF3(CF2)5(CH2)7CH3.

3. The composition of claim 1 comprising up to about 25 wt% CF3-(CF2)5-CH(CH3)-(CH2)5-CH3.

4. The composition of any one of the preceding claims, comprising about 97 wt% CF3(CF2)5(CH2)7CH3 and up to about 3 wt% CF3-(CF2)5-CH(CH3)-(CH2)5-CH3.

5. A composition according to any one of the preceding claims, formulated as a clear liquid solution.

6. A composition according to any one of the preceding claims, which is substantially free of: (a) polymers, (b) perfluorinated compounds, and / or (c) Dissolved pharmacologically active ingredient.

7. A composition according to any preceding claim, having a dynamic viscosity at ambient temperature and pressure of not more than 10 mPa·s, and preferably not more than 4 mPa·s.

8. A composition according to any one of the preceding claims for use as a medicament.

9. The composition of claim 8, wherein the composition is topically applied to the lacrimal sac, the interior of the lower eyelid, the surface of the eye, or ocular tissue.

10. The composition of claim 9, comprising administering the composition up to 4 times per day.

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