US 20190038555A1 ( 19) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 / 0038555 A1 Lin et al. (43 ) Pub . Date: Feb . 7 , 2019 (54 ) BICONTINUOUS MICROEMULSIONS AND Related U . S . Application Data METHODS OF USE THEREOF (60 ) Provisional application No .62 / 300 ,245 , filed on Feb . (71 ) Applicant: The Regents of the University of 26 , 2016 . California , Oakland , CA ( US ) Publication Classification ( 72 ) Inventors : Meng C . Lin , Dublin , CA (US ) ; (51 ) Int. CI. Tatyana F . Svitova , Emeryville , CA A61K 9 / 107 ( 2006 .01 ) A61K 9 / 00 ( 2006 .01 ) (US ) :) U . S . C1. (21 ) Appl. No. : 16 /068 , 535 CPC ...... A61K 9 / 1075 ( 2013 . 01 ) ; A61K 9 / 0048 (2013 . 01 ) ( 22 ) PCT Filed : Feb . 24 , 2017 ( 57) ABSTRACT ( 86 ) PCT No. : PCT /US17 / 19425 The present disclosure provides bicontinuous microemul $ 371 (c )( 1) , sions, and methods of using the bicontinuous microemul ( 2 ) Date : Jul. 6 , 2018 sions in the treatment of dry eye . Patent Application Publication Feb . 7 , 2019 Sheet 1 of 7 US 2019 /0038555 A1

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BICONTINUOUS MICROEMULSIONS AND as described above or elsewhere herein , to the surface of the METHODS OF USE THEREOF eye , thereby reducing evaporation of the aqueous tear film from the surface of the eye . The present disclosure provides CROSS -REFERENCE a method of treating dry eye in an eye of an individual, the [0001 ] This application claims the benefit of U . S . Provi method comprising applying a bicontinuous microemulsion , sional Patent Application No . 62 / 300 , 245 , filed Feb . 26 , as described above or elsewhere herein , to the surface of the 2016 , which application is incorporated herein by reference eye of the individual. In some cases , the bicontinuous in its entirety . microemulsion comprises . In some cases, the bicon tinuous microemulsion comprises solid dehydrated lanolin . INTRODUCTION [0005 ] The present disclosure provides a bicontinuous [ 0002 ] The sensation of ocular discomfort referred to as microemulsion comprising : a ) an aqueous phase compris “ dry eye” can be caused by various factors . The principle ing : i) sodium chloride; ii ) sea salt; iii ) ascorbic acid ; and iv ) causative factors are : a ) inadequate tear production attrib trehalose ; and b ) a lipid phase comprising i ) sphingomyelin ; utable to aging , medical procedures performed on the cor ii ) phosphatidylcholine ; iii ) fish ; iv ) ; and v ) olive nea , or other conditions; b ) environmental irritants ( e . g . , oil, wherein the osmolarity of the microemulsion is from 270 dust , smoke , wind , sun , low humidity ) ; and c ) eye strain mOsm to 320 mOsm , and wherein the microemulsion has a attributable to extended viewing of computer monitors , or to pH of from 7 . 2 to 7 .4 . In some cases , the ratio of aqueous other workplace environment- related factors . phase to lipid phase is from about 10 : 1 to 1 : 10 ( v / v ) . In some cases , the ratio of aqueous phase to lipid phase is from about SUMMARY 5 : 1 to 1 :5 ( v / v ) . In some cases, the ratio of aqueous phase to [ 0003 ] The present disclosure provides bicontinuous lipid phase is from about 3 : 1 to 1 : 3 ( v / v ) . In some cases , the microemulsions, and methods of using the bicontinuous bicontinuous microemulsion comprises lactoferrin . In some microemulsions in the treatment of dry eye . cases, the ratio of sphingomyelin to phosphatidylcholine is [0004 ] The present disclosure provides a bicontinuous from 4 : 1 to 1 : 1 ( w / v ) . In some cases , the ratio of palm oil to microemulsion comprising : a ) an aqueous phase compris is from 3 : 1 to 1 :3 ( v / v ) . In some cases, the ratio of ing: i ) sodium chloride ; ii ) sea salt ; iii ) ascorbic acid ; and iv ) solid and liquid oils to beeswax is from about 4 : 1 : 0 . 1 to trehalose ; and b ) a lipid phase comprising one or more of: i ) 1 : 1 : 0 . 3 . In some cases , the ratio of and sphingomyelin ; ii) phosphatidylcholine ; iii ) ; iv ) oil to beeswax is from 4 : 1: 0 . 1 to 1: 1: 0 .3 . In some cases , coconut oil ; v ) grapeseed oil ; vi) beeswax ; vii ) ghee ; and the ratio of aqueous phase to lipid phase is from about 2 .5 : 1 viii ) lanolin , wherein the osmolarity of the microemulsion is to 3 : 1 ( v / v ) . In some cases, the ratio of palm oil and olive oil from 270 mOsm to 320 mOsm , and wherein the microemul to fish oil is from 10 : 1 to 6 : 1 palm oil + olive oil: fish oil . In sion has a pH of from 7 . 2 to 7 . 4 . In some cases , the ratio of some cases , the ratio of solid oils and liquid oils to fish oil aqueous phase to lipid phase is from about 10 : 1 to 1 : 10 (v / v ) . is from 10 : 1 to 6 : 1 . In some cases , the ratio of coconut oil In some cases, the ratio of aqueous phase to lipid phase is and grape to fish oil is from 10 : 1 to 6 : 1 . In some from about 5 : 1 to 1 :5 ( v / v ). In some cases , the ratio of cases , the bicontinuous emulsion is sterile . In some cases , aqueous phase to lipid phase is from about 3 : 1 to 1 : 3 ( v / v ) . the bicontinuous microemulsion comprises coconut oil . In In some cases, the ratio of aqueous phase to lipid phase is some cases, the ratio of palm oil/ coconut oil and olive oil to from about 2 . 5 : 1 to 3 : 1 ( v / v ). In some cases, the lipid phase fish oil is from 10 : 1 to 6 : 1 palm oil + olive oil : fish oil . In some of the bicontinuous microemulsion comprises palm oil and cases , the ratio of coconut oil and grape seed oil to fish oil fish oil . In some cases , the lipid phase of the bicontinuous is from 10 : 1 to 6 : 1 coconut oil + grape seed oil : fish oil. In microemulsion comprises palm oil, fish oil , and coconut oil. some cases , the ratio of coconut oil to grape seed to fish oil In some cases , the lipid phase of the bicontinuous micro is from 10 : 1 to 6 : 1 coconut oil + grape seed oil: fish oil. In emulsion comprises grapeseed oil , coconut oil, beeswax , some cases, the ratio of coconut oil to grape seed oil is from sphingomyelin , and phosphatidylcholine . In some cases , the 3 : 1 to 1 : 3 (v /v ) . In some cases , the ratio of coconut oil to lipid phase of the bicontinuous microemulsion comprises grape seed oil is from 5 : 1 to 1 : 5 ( v / v ) . In some cases , the palm oil , beeswax , lecithin , and phosphatidylcholine . In ratio of coconut oil to grape seed oil is from 2 . 5 : 1 to 3 : 1 some cases , the lipid phase of the bicontinuous microemul ( v / v ) . ) . In some cases , the ratio of coconut oil to grape seed sion comprises ghee , lecithin , and phosphatidylcholine . In oil is from 10 : 1 to 1 : 10 ( V / v ) . some cases, the bicontinuous microemulsion further com [ 0006 ] The present disclosure provides a container com prises beeswax . In some cases , the bicontinuous microemul prising a bicontinuous microemulsion as described above or sion further comprises palm oil . In some cases , the bicon elsewhere herein . In some cases , the container is an eye tinuous microemulsion further comprises olive oil. In some dropper . In some cases , the container is sterile ; and the cases, the bicontinuous microemulsion further comprises bicontinuous emulsion is sterile. The present disclosure palm oil and olive oil . In some cases, the bicontinuous provides a method of reducing evaporation of an aqueous microemulsion further comprises ghee . In some cases , the tear film from the surface of an eye, the method comprising bicontinuous emulsion is sterile . The present disclosure applying a bicontinuous microemulsion , as described above provides a container comprising a bicontinuous microemul or elsewhere herein , to the surface of the eye, thereby sion as described above or elsewhere herein . In some cases , reducing evaporation of the aqueous tear film from the the container is an eyedropper. In some cases , the container surface of the eye . The present disclosure provides a method is sterile ; and the bicontinuous emulsion is sterile . The of treating dry eye in an eye of an individual , the method present disclosure provides a method of reducing evapora comprising applying a bicontinuous microemulsion , as tion of an aqueous tear film from the surface of an eye , the described above or elsewhere herein , to the surface of the method comprising applying a bicontinuous microemulsion , eye of the individual. US 2019 /0038555 A1 Feb . 7 , 2019

[ 0007 ] Aspects , including embodiments , of the present [ 0023 ] Aspect 16 . The bicontinuous microemulsion of any subject matter described above may be beneficial alone or in one of aspects 1 - 7 , wherein the lipid phase comprises combination , with one or more other aspects or embodi nonpolar lipids and polar lipids in a ratio of from about 10 : 1 ments . Without limiting the foregoing description , certain to 4 : 1 ( v / v ) . non - limiting aspects of the disclosure numbered 1 - 32 are [ 0024 ] Aspect 17 . The bicontinuous microemulsion of any provided below . As will be apparent to those of skill in the one of aspects 1 - 7 , wherein the lipid phase comprises art upon reading this disclosure , each of the individually grapeseed oil, coconut oil , beeswax , sphingomyelin , and numbered aspects may be used or combined with any of the phosphatidylcholine . preceding or following individually numbered aspects. This f0025 ] Aspect 18 . The bicontinuous microemulsion of any is intended to provide support for all such combinations of one of aspects 1 - 7 , wherein the lipid phase comprises palm aspects and is not limited to combinations of aspects explic oil, beeswax , lecithin , and phosphatidylcholine . itly provided below : [0026 ] Aspect 19 . The bicontinuous microemulsion of any [0008 ] Aspect 1 . A bicontinuous microemulsion compris one of aspects 1 - 7 , wherein the lipid phase comprises ghee , ing : a ) an aqueous phase comprising one or more of: i ) lecithin , and phosphatidylcholine. sodium chloride; ii ) sea salt ; iii ) ascorbic acid ; and iv ) [ 0027 ] Aspect 20 . The bicontinuous microemulsion of any trehalose ; and b ) a lipid phase comprising one or more of: i ) one of aspects 1 - 7 , wherein the lipid phase comprises ghee , sphingomyelin ; ii ) phosphatidylcholine; iii) fish oil; iv ) palm lecithin , sphingomyelin , and phosphatidylcholine . oil ; v ) olive oil ; vi) coconut oil ; vii ) grapeseed oil ; viii ) bees [0028 Aspect 21. The bicontinuous microemulsion of any wax ; xi) ghee ; and x ) lanolin , wherein the osmolarity of the one of aspects 1 - 7 , wherein the lipid phase comprises microemulsion is from 270 mOsm to 320 mOsm , and grapeseed oil , beeswax , lecithin , and sphingomyelin . wherein the microemulsion has a pH of from 7 . 2 to 7 . 4 . [0029 ] Aspect 22 . The bicontinuous microemulsion of any one of aspects 1 - 7 , wherein the lipid phase comprises [0009 ] Aspect 2 . The bicontinuous microemulsion of grapeseed oil , coconut oil, beeswax , lecithin , and sphingo aspect 1 , wherein the ratio of aqueous phase to lipid phase myelin . is from about 10 : 1 to 1 : 10 ( v / v ) . (0030 ) Aspect 23 . The bicontinuous microemulsion of any [0010 ] Aspect 3 . The bicontinuous microemulsion of one of aspects 1 - 7 , wherein the lipid phase comprises ghee , aspect 1 , wherein the ratio of aqueous phase to lipid phase lecithin , and sphingomyelin . is from about 5 : 1 to 1 : 5 ( v / v ) . [ 0031 ] Aspect 24 . The bicontinuous microemulsion of any [ 0011 ] Aspect 4 . The bicontinuous microemulsion of one of aspects 1 - 7 , wherein the lipid phase comprises aspect 1 , wherein the ratio of aqueous phase to lipid phase coconut oil and grapeseed oil . is from about 3 : 1 to 1 : 3 ( v / v ) . [0032 ] Aspect 25 . The bicontinuous microemulsion of [0012 ] Aspect 5 . The bicontinuous microemulsion of aspect 1 , wherein the lecithin is egg yolk lecithin . aspect 1 , wherein the ratio of aqueous phase to lipid phase [0033 ] Aspect 26 . The bicontinuous microemulsion of any is from about 2 .5 : 1 to 3 : 1 ( v /v ). one of aspects 1 - 25, wherein the bicontinuous emulsion is 10013 ] Aspect 6 . The bicontinuous microemulsion of any sterile . one of aspects 1 -5 , comprising lactoferrin . [0034 ] Aspect 27 . A formulation comprising the bicon [ 0014 ] Aspect 7 . The bicontinuous microemulsion of any tinuous microemulsion of any one of aspects 1 - 26 , wherein one of aspects 1 - 6 , wherein the lipid phase comprises the formulation is a liquid , a gel, a semi- solid , or an sphingomyelin and phosphatidylcholine . ointment. [ 0015 ] Aspect 8 . The bicontinuous microemulsion of (0035 ] Aspect 28 . A container comprising the bicontinu aspect 7 , wherein the ratio of sphingomyelin to phosphati ous microemulsion of any one of aspects 1 - 26 or the dylcholine is from 4 : 1 to 1 : 1 ( w / v ) . formulation of aspect 27 . [0036 ] Aspect 30 . The container of aspect 28 , wherein the [ 0016 ] Aspect 9 . The bicontinuous microemulsion of any container comprises an eyedropper . one of aspects 1 - 6 , wherein the lipid phase comprises palm [ 0037 ] Aspect 31. A method of reducing evaporation of an oil and olive oil. aqueous tear film from the surface of an eye , the method [0017 ] Aspect 10 . The bicontinuous microemulsion of comprising applying the bicontinuousmicroemulsion of any aspect 9 , wherein the ratio of palm oil to olive oil is from 3 : 1 one of aspects 1 - 26 or the formulation of aspect 27 to the to 1 : 3 ( v / v ) . surface of the eye, thereby reducing evaporation of the [0018 ] Aspect 11. The bicontinuousmicroemulsion of any aqueous tear film from the surface of the eye . one of aspects 1 - 6 , wherein the lipid phase comprises palm [ 0038 ] Aspect 32 . A method of treating dry eye in an eye oil , olive oil, and fish oil . of an individual , the method comprising applying the bicon [ 0019 ] Aspect 12. The bicontinuous microemulsion of tinuous microemulsion of any one of aspects 1 - 26 or the aspect 11, wherein the ratio of palm oil and olive oil to fish formulation of aspect 27 to the surface of the eye of the oil is from 10 : 1 to 6 : 1 palm oil + olive oil : fish oil. individual. [ 0020 ] Aspect 13. The bicontinuousmicroemulsion of any one of aspects 1- 7, comprising coconut oil . BRIEF DESCRIPTION OF THE DRAWINGS [ 0021] Aspect 14 . The bicontinuous microemulsion of any f0039 ] FIG . 1 depicts surface pressure as a function of one of aspects 1 - 7 , wherein the lipid phase comprises model tear lipid (MTL ) film thickness for three different coconut oil or palm oil; olive oil ; and fish oil . MTL mixtures . [0022 ] Aspect 15 . The bicontinuous microemulsion of [0040 ] FIG . 2 depicts sessile drop of model tear electro aspect 14 , wherein the ratio of palm oil/ coconut oil and olive lytes (MTE ) solution evaporation at 35° C ., 75 % relative oil to fish oil is from 10 : 1 to 6 : 1 palm oil /coconut oil + olive humidity (RH ) without lipid films and with ~ 90 -nm thick oil : fish oil . model lipid films. US 2019 /0038555 A1 Feb . 7 , 2019

[0041 ] FIG . 3 depicts MTE solution evaporative flux at in a single embodiment. Conversely , various features of the 35 .5° C ., 75 % RH without lipid films and with model lipid invention , which are , for brevity , described in the context of films of varying thickness . a single embodiment, may also be provided separately or in [ 0042 ] FIG . 4 depicts the surface pressure ( in mN /m ) of a any suitable sub -combination . All combinations of the microemulsion of the present disclosure and human tear embodiments pertaining to the invention are specifically lipid , of various thicknesses . embraced by the present invention and are disclosed herein [ 0043] FIG . 5 depicts the relative evaporation rate (as a just as if each and every combination was individually and percent of MTE ) of: 1 ) various model systems; 2 ) a bicon explicitly disclosed . In addition , all sub - combinations of the tinuous microemulsion of the present disclosure ; and 3) various embodiments and elements thereof are also specifi human tears . cally embraced by the present invention and are disclosed ( 0044 ) FIG . 6 depicts tear - lipid - film quality in a control herein just as if each and every such sub - combination was eye and a test eye ( 1 second after blink ) 2 hours after individually and explicitly disclosed herein . administration of a bicontinuous microemulsion of the pres [ 0051 ] The publications discussed herein are provided ent disclosure . solely for their disclosure prior to the filing date of the [0045 ] FIG . 7 depicts tear- lipid - film quality in a control present application . Nothing herein is to be construed as an eye and a test eye (6 seconds after blink ) 2 hours after admission that the present invention is not entitled to ante administration of a bicontinuous microemulsion of the pres date such publication by virtue of prior invention . Further, ent disclosure . the dates of publication provided may be different from the [ 0046 ] Before the present invention is further described , it actual publication dates which may need to be independently is to be understood that this invention is not limited to confirmed . particular embodiments described , as such may , of course , vary . It is also to be understood that the terminology used DETAILED DESCRIPTION herein is for the purpose of describing particular embodi ments only , and is not intended to be limiting, since the [0052 ] The present disclosure provides bicontinuous scope of the present invention will be limited only by the microemulsions , and methods of using the bicontinuous appended claims. microemulsions in the treatment of dry eye . [ 0047] Where a range of values is provided , it is under stood that each intervening value , to the tenth of the unit of Microemulsions the lower limit unless the context clearly dictates otherwise , between the upper and lower limit of that range and any [0053 ] The present disclosure provides bicontinuous other stated or intervening value in that stated range , is microemulsions for use in treating dry eye . A bicontinuous encompassed within the invention . The upper and lower microemulsion of the present disclosure comprises : a ) an limits of these smaller ranges may independently be aqueous phase ; and b ) a lipid phase . The oils and lipids included in the smaller ranges , and are also encompassed blended in a bicontinuous microemulsion of the present within the invention , subject to any specifically excluded disclosure include only naturally -occurring components that limit in the stated range . Where the stated range includes one are chemically identical to counterpart components found in or both of the limits , ranges excluding either or both of those human tear lipids . Because a bicontinuous microemulsion of included limits are also included in the invention . the present disclosure comprises components found in [ 0048 ] Unless defined otherwise , all technical and scien human tear lipids , the lipid phase and the aqueous phase of tific terms used herein have the samemeaning as commonly a bicontinuous microemulsion of the present disclosure are understood by one of ordinary skill in the art to which this spontaneously arranged into nanometer - sized aggregates invention belongs . Although any methods and materials possessing the structure and dimensions similar to that of similar or equivalent to those described herein can also be human tear - lipid films. used in the practice or testing of the present invention , the [0054 ] A bicontinuous microemulsion of the present dis preferred methods and materials are now described . All closure comprises droplets having an average diameter in publications mentioned herein are incorporated herein by the range of from 25 nm to 200 nm , or from 50 nm to 150 reference to disclose and describe the methods and /or mate nm . rials in connection with which the publications are cited . [0055 ] The present disclosure provides a bicontinuous 10049] It must be noted that as used herein and in the microemulsion comprising : a ) an aqueous phase compris appended claims, the singular forms “ a ," " an ,” and “ the ” ing : i ) sodium chloride ; ii ) sea salt ; iii ) ascorbic acid ; and iv ) include plural referents unless the context clearly dictates trehalose ; and b ) a lipid phase comprising one or more of: i) otherwise . Thus, for example , reference to " a bicontinuous sphingomyelin ; ii ) phosphatidylcholine; iii ) fish oil ; iv ) palm microemulsion ” includes a plurality of such microemulsions oil; v ) olive oil; vi) coconut oil ; vii ) grapeseed oil ; viii ) and reference to " the ocular disorder ” includes reference to beeswax ; ix ) ghee ; and x ) solid dehydrated lanolin , wherein one or more ocular disorders and equivalents thereof known the osmolarity of the microemulsion is from 270 mOsm to to those skilled in the art , and so forth . It is further noted that 320 mOsm , and wherein the microemulsion has a pH of the claims may be drafted to exclude any optional element. from 7 .2 to 7. 4 . In some cases, the ratio of aqueous phase to As such , this statement is intended to serve as antecedent lipid phase is from about 10 : 1 to 1 : 10 ( v / v ) . In some cases, basis for use of such exclusive terminology as “ solely, ” the ratio of aqueous phase to lipid phase is from about 9 : 1 “ only ” and the like in connection with the recitation of claim to 1 : 9 ( v / v ) . In some cases, the ratio of aqueous phase to lipid elements , or use of a " negative ” limitation . phase is from about 5 : 1 to 1 : 5 ( v / v ) . In some cases , the ratio [0050 ] It is appreciated that certain features of the inven of aqueous phase to lipid phase is from about 3 : 1 to 1 : 3 tion , which are , for clarity , described in the context of (v / v ) . In some cases, the ratio of aqueous phase to lipid separate embodiments , may also be provided in combination phase is from about 2 . 5 : 1 to 3 : 1 ( v / v ) . US 2019 /0038555 A1 Feb . 7 , 2019

[0056 ] In some cases, the bicontinuous microemulsion ous phase and a lipid phase in a ratio of 2 . 5 :1 (v /v ) aqueous further comprises beeswax . In some cases, the bicontinuous phase: lipid phase . In some cases , a bicontinuous microemul microemulsion comprises palm oil . In some cases, the sion of the present disclosure comprises an aqueous phase bicontinuous microemulsion comprises olive oil. In some and a lipid phase in a ratio of 2 : 1 ( v / v ) aqueous phase : lipid cases , the bicontinuous microemulsion comprises palm oil phase . In some cases , a bicontinuous microemulsion of the and olive oil. In some cases, the bicontinuous microemul present disclosure comprises an aqueous phase and a lipid sion comprises coconut oil. In some cases, the bicontinuous phase in a ratio of 1 : 1 ( v / v ) aqueous phase: lipid phase . In microemulsion comprises solid dehydrated lanolin . In some some cases , a bicontinuous microemulsion of the present cases , the bicontinuous microemulsion comprises coconut disclosure comprises an aqueous phase and a lipid phase in oil and grape seed oil . In some cases , the bicontinuous a ratio of 1 : 1 . 5 ( v / v ) aqueous phase : lipid phase . In some microemulsion further comprises coconut oil, grape seed oil, cases , a bicontinuous microemulsion of the present disclo and beeswax . In some cases , the bicontinuous microemul sure comprises an aqueous phase and a lipid phase in a ratio sion comprises ghee ( i . e . clarified ) . In some cases , the of 1 : 2 ( v / v ) aqueous phase : lipid phase . In some cases , a bicontinuous microemulsion comprises solid dehydrated bicontinuous microemulsion of the present disclosure com lanolin . prises an aqueous phase and a lipid phase in a ratio of 1 : 2 . 5 [ 0057 ] In some cases, the bicontinuous emulsion is sterile . ( v / v ) aqueous phase : lipid phase . In some cases , a bicontinu The present disclosure provides a container comprising a ous microemulsion of the present disclosure comprises an bicontinuous microemulsion as described above or else aqueous phase and a lipid phase in a ratio of 1 : 3 ( v /v ) where herein . In some cases , the container is an eyedropper. aqueous phase : lipid phase . In some cases, the bicontinuous microemulsion formulation is filled into an eyedropper bottle . In some cases , the Aqueous Phase bicontinuous microemulsion is packaged in an eyedropper [0063 ] The aqueous phase of a bicontinuous microemul bottle with a screw - top dropper. In some cases, the container sion of the present disclosure comprises one or more of: a is sterile ; and the bicontinuous emulsion is sterile . salt, a buffering agent, an anti - oxidant, and an aqueous phase 10058 ] The pH of a bicontinuous microemulsion of the thickener. In some cases , the aqueous phase of a bicontinu present disclosure is in the range of from about 7 . 0 to 7 . 5 , ous microemulsion of the present disclosure comprises a salt from about 7 . 0 to 7 . 3 , from about 7 . 1 to about 7 . 4 , from and a buffering agent . In some cases, the aqueous phase of about 7 . 2 to about 7 . 5 , or from 7 . 3 to 7 . 4 . a bicontinuous microemulsion of the present disclosure 100591. A bicontinuous microemulsion of the present dis comprises salt , a buffering agent, and an anti- oxidant . In closure has an osmolarity of from 200 mOsm to 400 mOsm , some cases , the aqueous phase of a bicontinuous micro from 220 mOsm to 380 mOsm , from 240 mOsm to 360 emulsion of the present disclosure comprises salt , a buffer mOsm , from 260 mOsm to 340 mOsm , or from 270 mOsm ing agent, an anti -oxidant , and a thickener . to 320 mOsm . [ 0064 ] As noted above , in some cases , the aqueous phase 10060 ] A bicontinuous microemulsion of the present dis of a bicontinuous microemulsion of the present disclosure closure can form a lipid film on an eye , where the lipid film comprises a salt . In some cases , the salt is sodium chloride . has a thickness of from 30 nm to 100 nm , e . g . , from 30 nm In some cases , the salt is sea salt . In some cases , the aqueous to 50 nm , from 50 nm to 60 nm , from 60 nm to 70 nm , from phase of a bicontinuous microemulsion of the present dis 70 nm to 80 nm , from 80 nm to 90 nm , or from 90 nm to 100 closure includes both sodium chloride and sea salt . In some nm . cases , a bicontinuous microemulsion of the present disclo [0061 ] A bicontinuous microemulsion of the present dis sure comprises 0 . 5 % ( w / w ) sodium chloride and 0 . 4 % ( w / w ) closure does not contain mineral oil . A bicontinuous micro sea salt. emulsion of the present disclosure does not contain white [0065 ] As noted above , in some cases, the aqueous phase petrolatum . A bicontinuous microemulsion of the present of a bicontinuous microemulsion of the present disclosure disclosure does not contain crude oil - derived organic sol comprises an anti- oxidant . In some cases , the anti - oxidant is vents or petroleum - derived organic solvents . ascorbic acid . In some cases, the anti -oxidant is folic acid . 10062 ] A bicontinuous microemulsion of the present dis In some cases , the anti -oxidant is . In some cases, closure comprises an aqueous phase and a lipid phase . In the anti - oxidant is citric acid . In some cases , the anti - oxidant some cases , a bicontinuous microemulsion of the present is beta carotene . In some cases , the anti -oxidant is gluta disclosure comprises an aqueous phase and a lipid phase in thione . a ratio of from 10 : 1 ( v / v ) to 1 : 10 ( v / v ) aqueous phase : lipid [0066 ] As noted above , in some cases, the aqueous phase phase . In some cases, a bicontinuous microemulsion of the of a bicontinuous microemulsion of the present disclosure present disclosure comprises an aqueous phase and a lipid comprises a buffering agent . In some cases, the buffering phase in a ratio of from 5 : 1 ( v / v ) to 1 : 5 ( v / v ) aqueous agent is ascorbic acid . In some cases, the buffering agent is phase : lipid phase . In some cases , a bicontinuous microemul citric acid . In some cases , the buffering agent is glycolic sion of the present disclosure comprises an aqueous phase acid . In some cases , the buffering agent is glycine . and a lipid phase in a ratio of from 3 : 1 ( v / v ) to 1 : 3 ( v / v ) 10067 ] As noted above , in some cases , the aqueous phase aqueous phase: lipid phase . In some cases, a bicontinuous of a bicontinuous microemulsion of the present disclosure microemulsion of the present disclosure comprises an aque comprises an aqueous phase thickener . In some cases , the ous phase and a lipid phase in a ratio of from 2 : 1 ( v / v ) to 1 : 2 aqueous phase thickener is monosaccharide . In some cases , ( v /v ) aqueous phase: lipid phase . In some cases, a bicontinu the aqueous phase thickener is a glucose . In some cases , the ous microemulsion of the present disclosure comprises an aqueous phase thickener is a trehalose . In some cases , the aqueous phase and a lipid phase in a ratio of 3 : 1 ( v / v ) aqueous phase thickener is disaccharide . In some cases , the aqueous phase : lipid phase . In some cases , a bicontinuous aqueous phase thickener is lactose . In some cases, the microemulsion of the present disclosure comprises an aque aqueous phase thickener is maltose . In some cases , the US 2019 /0038555 A1 Feb . 7 , 2019 aqueous phase thickener is galactose . In some cases, the palm oil and olive oil. In some cases, the lipid phase of a aqueous phase thickener is mannose . In some cases , the bicontinuous microemulsion of the present disclosure com aqueous phase thickener is polysaccharide . In some cases, prises coconut oil and grape seed oil. In some cases , the lipid the aqueous phase thickener is dextran . In some cases, the phase of a bicontinuous microemulsion of the present dis aqueous phase thickener is agarose . In some cases , the closure comprises coconut oil , grape seed oil, and beeswax . aqueous phase thickener is starch . In some cases, the aque In some cases , the lipid phase of a bicontinuous microemul ous phase thickener is guar gum . sion of the present disclosure comprises ghee , beeswax and [ 0068 ] In some cases , the aqueous phase of a bicontinuous fish oil. In some cases, the lipid phase of a bicontinuous microemulsion of the present disclosure comprises : i ) microemulsion of the present disclosure comprises palm oil, sodium chloride ; ii ) sea salt; iii) ascorbic acid ; and iv ) olive oil , and fish oil. In some cases, the lipid phase of a trehalose . In some cases , a bicontinuous microemulsion of bicontinuous microemulsion of the present disclosure com the present disclosure comprises : i ) sodium chloride 0 . 5 % prises sphingomyelin , phosphatidylcholine , fish oil, palm ( w / w ); ii ) sea salt 0 .4 % (w /w ); iii ) ascorbic acid ; and iv ) oil , and olive oil . In some cases , the lipid phase of a trehalose . In some cases, the aqueous phase of a bicontinu bicontinuous microemulsion of the present disclosure com ous microemulsion of the present disclosure comprises : i ) prises sphingomyelin , phosphatidylcholine, fish oil, coconut sodium chloride ( 5 % ) ; ii ) sea salt ( 4 % ), buffered to pH 7 . 0 oil , and grape seed oil. In some cases , the lipid phase of a to 7 . 5 with ascorbic acid , citric acid , or NaH2PO4. In some bicontinuous microemulsion of the present disclosure com cases , the aqueous phase includes lactoferrin . In some cases , prises sphingomyelin , phosphatidylcholine, fish oil , palm the aqueous phase includes mucin . In some cases , the oil , and grape seed oil . aqueous phase includes alginate . In some cases , the aqueous phase includes a polysaccharide . [0072 ] The lipid phase of a bicontinuous microemulsion of the present disclosure can comprise non - polar lipids and Lipid Phase polar lipids . In some cases , the ratio of non - polar lipids to polar lipids in the lipid phase is from 10 : 1 to 4 : 1 , e . g . , from [0069 ] The lipid phase of a bicontinuous microemulsion of 10 : 1 to 8 : 1 , from 8 : 1 to 6 : 1 , or from 6 : 1 to 4 : 1 . the present disclosure comprises one or more lipids that are naturally present in human tears. [0073 ] As noted above , in some cases , the lipid phase of [0070 ] The lipid phase of a bicontinuous microemulsion of a bicontinuous microemulsion of the present disclosure the present disclosure comprises one or more of: i ) sphin comprises sphingomyelin . The sphingomyelin can be pres gomyelin ; ii ) phosphatidylcholine ; iii ) fish oil; iv ) palm oil ; ent in the microemulsion in an amount of from 5 % to 25 % v ) olive oil; vi) coconut oil ; vii ) grapeseed oil; viii ) bees by weight, from 10 % to 20 % by weight, or from 10 % to 15 % wax ; xi) ghee ; and x ) lanolin . In some cases , a bicontinuous by weight. As noted above , in some cases, the lipid phase of microemulsion of the present disclosure specifically a bicontinuous microemulsion of the present disclosure excludes one or more of: i ) sphingomyelin ; ii ) phosphati comprises phosphatidylcholine . The phosphatidylcholine dylcholine ; iii ) fish oil; iv ) palm oil ; v ) olive oil ; vi) coconut can be present in the microemulsion in an amount of from oil ; vii) grapeseed oil; viii ) bees wax ; xi) ghee; and x ) 5 % to 25 % by weight, from 10 % to 20 % by weight, or from lanolin . For example , in some cases, a bicontinuous micro 10 % to 15 % by weight. emulsion of the present disclosure specifically excludes [ 0074 ] As noted above , in some cases , the lipid phase of palm oil. a bicontinuous microemulsion of the present disclosure [ 0071 ] In some cases, the lipid phase of a bicontinuous comprises sphingomyelin and phosphatidylcholine . In some microemulsion of the present disclosure comprises sphin cases , a bicontinuous microemulsion of the present disclo gomyelin . In some cases , the lipid phase of a bicontinuous sure comprises sphingomyelin and phosphatidylcholine in a microemulsion of the present disclosure comprises phospha ratio of from 4 : 1 to 1 : 1 sphingomyelin :phosphatidylcholine . tidylcholine ( lecithin ) . In some cases , the lipid phase of a In some cases, a bicontinuous microemulsion of the present bicontinuous microemulsion of the present disclosure com disclosure comprises sphingomyelin and phosphatidylcho prises sphingomyelin and phosphatidylcholine. The sphin line in a ratio of from 3 : 1 to 1 : 1 sphingomyelin : phosphati gomyelin and lecithin can be from any of a variety of dylcholine . In some cases , a bicontinuous microemulsion of sources , which may include cow milk , egg yolk , liver, the present disclosure comprises sphingomyelin and phos porcine brain , and soy . In some cases, the lecithin is egg yolk phatidylcholine in a ratio of from 2 : 1 to 1 : 1 sphingomyelin : lecithin . In some cases , the sphingomyelin is egg yolk phosphatidylcholine. In some cases , a bicontinuous micro sphingomyelin . In some cases , the lipid phase of a bicon emulsion of the present disclosure comprises sphingomyelin tinuous microemulsion of the present disclosure comprises and phosphatidylcholine in a ratio of from 3 : 1 to 2 : 1 fish oil. In some cases, the lipid phase of a bicontinuous sphingomyelin : phosphatidylcholine . In some cases , a bicon microemulsion of the present disclosure comprises palm oil . tinuous microemulsion of the present disclosure comprises In some cases , the lipid phase of a bicontinuous microemul sphingomyelin and phosphatidylcholine in a ratio of 4 : 1 sion of the present disclosure comprises olive oil . In some sphingomyelin : phosphatidylcholine . In some cases, a bicon cases , the lipid phase of a bicontinuous microemulsion of the tinuous microemulsion of the present disclosure comprises present disclosure comprises coconut oil . In some cases , the sphingomyelin and phosphatidylcholine in a ratio of 3 : 1 lipid phase of a bicontinuous microemulsion of the present sphingomyelin :phosphatidylcholine . In some cases , a bicon disclosure comprises grape seed oil . In some cases, the lipid tinuous microemulsion of the present disclosure comprises phase of a bicontinuous microemulsion of the present dis sphingomyelin and phosphatidylcholine in a ratio of 2 : 1 closure comprises beeswax . In some cases , the lipid phase of sphingomyelin :phosphatidylcholine . In some cases, a bicon a bicontinuous microemulsion of the present disclosure tinuous microemulsion of the present disclosure comprises comprises ghee . In some cases , the lipid phase of a bicon sphingomyelin and phosphatidylcholine in a ratio of 1 : 1 tinuous microemulsion of the present disclosure comprises sphingomyelin : phosphatidylcholine . US 2019 /0038555 A1 Feb . 7 , 2019

[0075 ] As noted above , in some cases , the lipid phase of palm oil : fish oil. In some cases, the palm oil and the fish oil a bicontinuous microemulsion of the present disclosure are present in a bicontinuous microemulsion of the present comprises palm oil and olive oil . In some cases, the palm oil disclosure in a ratio of 6 : 1 palm oil : fish oil . and the olive oil are present in a bicontinuous microemul [0080 ] As noted above, in some cases , the lipid phase of sion of the present disclosure in a ratio of from 1 : 3 to 3 : 1 a bicontinuous microemulsion of the present disclosure palm oil: olive oil . In some cases , the palm oil and the olive comprises coconut oil and fish oil . In some cases, the oil are present in a bicontinuous microemulsion of the coconut oil and the fish oil are present in a bicontinuous present disclosure in a ratio of 1 : 3 palm oil: olive oil . In some microemulsion of the present disclosure in a ratio of from cases , the palm oil and the olive oil are present in a 8 : 1 to 6 : 1 palm oil : fish oil . In some cases, the coconut oil and bicontinuous microemulsion of the present disclosure in a the fish oil are present in a bicontinuous microemulsion of ratio of 1 : 2 palm oil :olive oil. In some cases , the palm oil and the present disclosure in a ratio of 8 : 1 coconut oil: fish oil . In the olive oil are present in a bicontinuous microemulsion of some cases , the coconut oil and the fish oil are present in a the present disclosure in a ratio of 1 : 1 palm oil: olive oil . In bicontinuous microemulsion of the present disclosure in a some cases , the palm oil and the olive oil are present in a ratio of 7 : 1 coconut oil : fish oil . In some cases, the coconut bicontinuous microemulsion of the present disclosure in a oil and the fish oil are present in a bicontinuous microemul ratio of 2 : 1 palm oil : olive oil. In some cases , the palm oil and sion of the present disclosure in a ratio of 6 : 1 coconut oil : fish the olive oil are present in a bicontinuous microemulsion of oil . the present disclosure in a ratio of 3 : 1 palm oil : olive oil . [0081 ] As noted above, in some cases , the lipid phase of [ 0076 ] As noted above , in some cases , the lipid phase of a bicontinuous microemulsion of the present disclosure a bicontinuous microemulsion of the present disclosure comprises palm oil , olive oil , and fish oil. In some cases, the comprises coconut oil and grape seed oil. In some cases , the palm oil , olive oil , and fish oil are present in a bicontinuous coconut oil and the grape seed oil are present in a bicon microemulsion of the present disclosure in a ratio of from tinuous microemulsion of the present disclosure in a ratio of 10 : 1 to 8 : 1 ( palm oil + olive oil ) : fish oil . As noted above , in from 10 :1 to 1: 10 coconut oil :grape seed oil. In some cases, some cases , the lipid phase of a bicontinuous microemulsion the coconut oil and the grape seed oil are present in a of the present disclosure comprises palm oil, olive oil , and bicontinuous microemulsion of the present disclosure in a fish oil. In some cases, the palm oil , olive oil , and fish oil are ratio of from 1 : 3 to 3 : 1 coconut oil: grape seed oil . In some present in a bicontinuous microemulsion of the present cases , the coconut oil and the grape seed oil are present in disclosure in a ratio of 10 : 1 (palm oil + olive oil ) : fish oil . In a bicontinuous microemulsion of the present disclosure in a some cases , the palm oil , olive oil, and fish oil are present ratio of 1 : 3 coconut oil : grape seed oil. In some cases , the in a bicontinuous microemulsion of the present disclosure in coconut oil and the grape seed oil are present in a bicon a ratio of 9 : 1 (palm oil olive oil ) : fish oil . In some cases , the tinuous microemulsion of the present disclosure in a ratio of palm oil , olive oil , and fish oil are present in a bicontinuous 1 : 2 coconut oil: grape seed oil . In some cases , the coconut oil microemulsion of the present disclosure in a ratio of 8 : 1 and the grape seed oil are present in a bicontinuous micro (palm oil + olive oil ) : fish oil . emulsion of the present disclosure in a ratio of 1 : 1 coconut [ 0082] As noted above, in some cases , the lipid phase of oil : grape seed oil. In some cases, the coconut oil and the a bicontinuous microemulsion of the present disclosure grape seed oil are present in a bicontinuous microemulsion comprises coconut oil , olive oil, and fish oil. In some cases , of the present disclosure in a ratio of 2 : 1 coconut oil : grape the coconut oil, olive oil , and fish oil are present in a seed oil. In some cases , the coconut oil and the grape seed bicontinuous microemulsion of the present disclosure in a oil are present in a bicontinuous microemulsion of the ratio of from 10 : 1 to 8 : 1 ( coconut oil olive oil ) : fish oil. As present disclosure in a ratio of 3 : 1 coconut oil oil : grape seed noted above , in some cases, the lipid phase of a bicontinuous oil . microemulsion of the present disclosure comprises coconut [0077 ] Grapeseed oil can comprise about 60 % to 80 % oil , olive oil , and fish oil . In some cases , the coconut oil , ; from 14 % to 16 % ; from 5 % to 8 % olive oil , and fish oil are present in a bicontinuous micro ; from 4 % to 5 % ; and from about emulsion of the present disclosure in a ratio of 10 : 1 ( coconut 0 .05 % to 0 . 5 % alpha - linolenic acid . See , e . g ., Moret at al . oil + olive oil ): fish oil . In some cases, the coconut oil , olive (2000 ) J. American Oil Chemists ' Society 77 : 1289 . oil, and fish oil are present in a bicontinuous microemulsion [0078 ] Beeswax comprises esters and various of the present disclosure in a ratio of 9 : 1 ( coconut oil + olive long - chain alcohols. For example, beeswax can comprise oil ) : fish oil . In some cases , the coconut oil , olive oil, and fish palmitate , palmitoleate, and oleate esters of long - chain ( e . g . , oil are present in a bicontinuous microemulsion of the from 30 to 32 carbons ) aliphatic alcohols . Principle com present disclosure in a ratio of 8 : 1 (coconut oil + olive oil ) : ponents can be triacontanyl palmitate and cerotic acid , fish oil . which can be present in a ratio of 6 : 1 triacontanyl palmitate : [0083 ] In some cases, the lipid phase thickener is coconut cerotic acid . See , e . g ., Tulloch ( 1970 ) Lipids 5 : 247. oil . In some cases, the lipid phase contains palm oil , where [ 0079 ] As noted above, in some cases, the lipid phase of the palm oil is a source of beta -carotenes . a bicontinuous microemulsion of the present disclosure [0084 ] Phosphatidylcholines include, e . g ., L - a phosphati comprises palm oil and fish oil. In some cases , the palm oil dylcholines ; 1 - oleoyl- 2 -palmitoyl - phosphatidylcholine; and and the fish oil are present in a bicontinuous microemulsion the like. Lecithin can comprise phospholipids such as phos of the present disclosure in a ratio of from 8 : 1 to 6 : 1 palm phatidylcholine, phosphatidylethanolamine, phosphati oil : fish oil. In some cases, the palm oil and the fish oil are dylinositol, phosphatidylserine , and phosphatidic acid . In present in a bicontinuous microemulsion of the present some cases, the lecithin included in a bicontinuous micro disclosure in a ratio of 8 : 1 palm oil : fish oil. In some cases, emulsion of the present disclosure includes multiple forms the palm oil and the fish oil are present in a bicontinuous of lecithin . Sphingomyelin , lecithin , and phosphatidylcho microemulsion of the present disclosure in a ratio of 7 : 1 line that may be included in a bicontinuous microemulsion US 2019 /0038555 A1 Feb . 7 , 2019 of the present disclosure can be heterogeneous mixtures . and fish oil are present in a bicontinuous microemulsion of Sphingomyelin , lecithin , and phosphatidylcholine that may the present disclosure in a ratio of 5 : 1 ( coconut oil + grape be included in a bicontinuous microemulsion of the present seed oil ) : fish oil. In some cases, the coconut oil, grape seed disclosure can be purified , e . g . , from 50 % to 60 % , from 60 % oil , and fish oil are present in a bicontinuous microemulsion to 70 % , from 70 % to 80 % , from 80 % to 90 % , from 90 % to of the present disclosure in a ratio of 4 : 1 ( coconut oil + grape 95 % , from 95 % to 98 % , or more than 98 % , pure . seed oil ) : fish oil. 10085 ) In some cases, the lipid phase of a bicontinuous [0088 ] In some cases, the coconut oil , grape seed oil , and microemulsion of the present disclosure comprises palm oil, fish oil are present in a bicontinuous microemulsion of the olive oil , and flax seed oil . In some cases, the lipid phase of present disclosure in a ratio of 3 : 1 ( coconut oil + grape seed a bicontinuous microemulsion of the present disclosure oil) : fish oil . comprises palm oil, olive oil , and grape seed oil (as a source [0089 ] As noted above , in some cases , the lipid phase of of omega - 3 , 6 and 9 fatty acids) . In some cases, the lipid a bicontinuous microemulsion of the present disclosure phase of a bicontinuous microemulsion of the present dis comprises coconut oil , grape seed oil, and beeswax . In some closure comprises palm oil, olive oil, and Sea Buckthorn oil cases , the coconut oil, grape seed oil , and beeswax are (Omega - 7, palmitoleic and cis - vaccenic acids) . present in a bicontinuous microemulsion of the present [0086 ] As noted above, in some cases, the lipid phase of disclosure in a ratio of from 10 : 1 to 8 : 1 ( coconut oil + grape a bicontinuous microemulsion of the present disclosure seed oil ): beeswax . In some cases , the coconut oil, grape comprises palm oil , grape seed oil , and fish oil . In some seed oil, and beeswax are present in a bicontinuous micro cases , the palm oil, grape seed oil , and fish oil are present in emulsion of the present disclosure in a ratio of from 10 : 1 to a bicontinuous microemulsion of the present disclosure in a 3 : 1 ( coconut oil + grape seed oil ) : beeswax . In some cases , ratio of from 10 : 1 to 8 : 1 (palm oil + grape seed oil ) : fish oil. the ratio of solid oils and liquid oils to beeswax is from about As noted above , in some cases, the lipid phase of a bicon 4 : 1 : 0 . 1 to 1 : 1 : 0 . 3 . In some cases , the ratio of coconut oil and tinuous microemulsion of the present disclosure comprises grape seed oil to bees wax is from 4 : 1 : 0 . 1 to 1 : 1 : 0 . 3 . palm oil , grape seed oil, and fish oil. In some cases , the palm [0090 ] As noted above , in some cases , the lipid phase of oil, grape seed oil, and fish oil are present in a bicontinuous a bicontinuous microemulsion of the present disclosure microemulsion of the present disclosure in a ratio of 10 : 1 comprises coconut oil, grape seed oil, and bees wax . In some (palm oil + grape seed oil ) : fish oil. In some cases, the palm cases , the coconut oil , grape seed oil , and beeswax are oil, grape seed oil, and fish oil are present in a bicontinuous present in a bicontinuous microemulsion of the present microemulsion of the present disclosure in a ratio of 9 : 1 disclosure in a ratio of 10 : 1 ( coconut oil + grape seed oil ): ( palm oil + grape seed oil ) : fish oil. In some cases, the palm bees wax . In some cases , the coconut oil, grape seed oil , and oil, grape seed oil , and fish oil are present in a bicontinuous beeswax are present in a bicontinuous microemulsion of the microemulsion of the present disclosure in a ratio of 8 : 1 present disclosure in a ratio of 1 : 1 ( coconut oil + grape seed ( palm oil + grape seed oil ): fish oil . oil ) : beeswax . In some cases , the coconut oil, grape seed oil , [0087 ] As noted above, in some cases, the lipid phase of and beeswax are present in a bicontinuous microemulsion of a bicontinuous microemulsion of the present disclosure the present disclosure in a ratio of 8 : 1 ( coconut oil + grape comprises coconut oil , grape seed oil, and fish oil. In some seed oil) : beeswax . In some cases , the coconut oil , grape cases, the coconut oil , grape seed oil, and fish oil are present seed oil , and beeswax are present in a bicontinuous micro in a bicontinuous microemulsion of the present disclosure in emulsion of the present disclosure in a ratio of 7 : 1 ( coconut a ratio of from 10 : 1 to 8 : 1 (coconut oil + grape seed oil ) : fish oil + grape seed oil) : beeswax . In some cases , the coconut oil , oil. In some cases , the coconut oil, grape seed oil , and fish grape seed oil, and beeswax are present in a bicontinuous oil are present in a bicontinuous microemulsion of the microemulsion of the present disclosure in a ratio of 6 : 1 present disclosure in a ratio of from 10 : 1 to 3 : 1 ( coconut ( coconut oil + grape seed oil ) : beeswax . In some cases , the oil + grape seed oil ) : fish oil . In some cases , the ratio of solid coconut oil , grape seed oil, and beeswax are present in a oils and liquid oils to fish oil is from 10 : 1 to 6 : 1 . In some bicontinuous microemulsion of the present disclosure in a cases , the ratio of coconut oil and grape seed oil to fish oil ratio of 5 : 1 (coconut oil + grape seed oil ) : beeswax . In some is from 10 : 1 to 6 : 1 . As noted above , in some cases, the lipid cases , the coconut oil, grape seed oil, and beeswax are phase of a bicontinuous microemulsion of the present dis present in a bicontinuous microemulsion of the present closure comprises coconut oil, grape seed oil , and fish oil. In disclosure in a ratio of 4 : 1 ( coconut oil + grape seed oil) : some cases, the coconut oil , grape seed oil , and fish oil are beeswax . In some cases , the coconut oil , grape seed oil , and present in a bicontinuous microemulsion of the present beeswax are present in a bicontinuous microemulsion of the disclosure in a ratio of 10 : 1 ( coconut oil + grape seed oil ) : fish present disclosure in a ratio of 3 : 1 ( coconut oil + grape seed oil. In some cases , the coconut oil , grape seed oil , and fish oil ) : beeswax . oil are present in a bicontinuous microemulsion of the present disclosure in a ratio of 1 : 1 (coconut oil + grape seed Additional Components oil ): fish oil . In some cases , the coconut oil , grape seed oil, [0091 ] In addition to the above- noted components , a and fish oil are present in a bicontinuous microemulsion of bicontinuous microemulsion of the present disclosure will in the present disclosure in a ratio of 8 : 1 ( coconut oil + grape some cases comprise one or more additional components . In seed oil ) : fish oil . In some cases , the coconut oil , olive oil, some cases , a bicontinuous microemulsion of the present and fish oil are present in a bicontinuous microemulsion of disclosure comprises human lactoferrin ( e . g . , human milk the present disclosure in a ratio of 7 : 1 (coconut oil + olive lactoferrin ) . In some cases , a bicontinuous microemulsion of oil ) : fish oil . In some cases , the coconut oil , olive oil , and fish the present disclosure comprises human lactoferrin ( e . g . , oil are present in a bicontinuous microemulsion of the human milk lactoferrin ) in an amount of from 0 .01 % to 1 . 0 % present disclosure in a ratio of 6 : 1 ( coconut oil + grape seed ( w / w ) , e . g . , from 0 .01 % ( w / w ) to 0 . 1 % ( w / w ) , from 0 . 1 % oil) : fish oil. In some cases , the coconut oil , grape seed oil, ( w / w ) to 0 . 5 % ( w / w ) , or from 0 .5 % (w /w ) to 1 .0 % ( w / w ). US 2019 /0038555 A1 Feb . 7 , 2019

[0092 ] In some cases, the aqueous phase of a bicontinuous [0098 ] Microemulsions 2 - 16 (“ Examples 2 - 16 " ) are microemulsion of present disclosure comprises Niacina described below . These microemulsions are examples of mide . In some cases, the aqueous phase of a bicontinuous bicontinuous microemulsions of the present disclosure , and microemulsion comprises Quercetin . In some cases , the are not meant to be limiting . aqueous phase of a bicontinuous microemulsion Lutein . In some cases , the aqueous phase of a bicontinuous micro Example 2 emulsion comprises Zeaxanthin . [0099 ] Example 2 provides bicontinuous microemulsion EXEMPLARY FORMULATINS formulation 1 consisting of: [0100 ] 1 . 8 parts of isotonic aqueous phase , containing [0093 ] Provided herein are exemplary bicontinuous 5 % of sodium chloride, 4 % of sea salt, buffered with microemulsion formulations . In some cases, a bicontinuous NaH , PO4 to pH 7 . 3 microemulsion of the present disclosure is in the form of a [0101 ] 2 . 2 parts of Lipid phase , containing 8 parts of solution . In some cases, a bicontinuous microemulsion is in nonpolar lipids ( 1 part of Grapeseed oil , 2 parts of the form of a suspension . In some cases , the suspension is in coconut oil, 0 .2 parts of beeswax ) and 2 parts of polar an aqueous liquid or non - aqueous liquid . Formulations lipids ( 4 parts of Sphingomyelin and 6 parts of L - a suitable for injectable use include sterile aqueous solutions . Phosphatidylcholines ). In some cases, a bicontinuous microemulsion of the present disclosure is in the form of an ointment . In some cases , the Example 3 bicontinuous microemulsion is applied to the surface of an eye in the form of a solution ( e . g ., an emulsion , a suspen [0102 ] Example 3 provides bicontinuous microemulsion sion ) or an ointment (particularly , an ointment for eyes ) . In formulation 2 consisting of 99. 9 % natural food - quality some cases , a non - limiting example of how an ointment can organic ingredients which includes: be prepared includes using a widely used basal agent such as [0103 ] 1 : 9 parts of isotonic aqueous phase , containing ghee or beeswax . Petrochemicals such as white Vaseline or 5 % of sodium chloride , 4 % of sea salt , buffered with liquid paraffin are excluded . In some cases, the solution or NaH , PO4 to pH 7 . 3 , containing 0 . 9 mg/ml of human ointment is sterile . A bicontinuous emulsion of the present milk lactoferrin and 0 . 03 mg/ ml of Bovine mucin . disclosure can be formulated as a liquid , a gel , a semi- solid , [0104 ] 2 : 1 parts of Lipid phase , containing 8 parts of a solid , an ointment, and the like ; in some cases , the nonpolar lipids ( 1 part of organic Grapeseed oil, 3 parts formulation is sterile . of organic coconut oil , 0 . 2 parts of organic beeswax ) [0094 ] The following are non - limiting examples of bicon and 2 parts of polar lipids ( 4 parts of lecithin and 1 part tinuous microemulsions of the present disclosure and their of L - a Phosphatidylcholines ) . In some cases , the leci preparation . thin is egg yolk lecithin . Example 1 Example 4 10095 ] A bicontinuous microemulsion of the present dis [0105 ] Example 4 provides bicontinuous microemulsion 3 closure can be prepared in the following manner Aqueous consisting of 99. 9 % natural food - quality organic ingredi and lipid phases can be heated to 36 -45° C . in separate vials ents , which includes: for 20 minutes . The aqueous and lipid phases can then be f0106 ] 1 . 9 parts of isotonic aqueous phase, containing 5 % placed in one vial and homogenized in an ultrasound bath at of sodium chloride, 4 % of sea salt , buffered with citric acid medium to high intensity until totally emulsified . Prepared to pH 7 . 3 emulsions can be stored at 4° C . and brought to room [0107 ] 2 . 1 parts of Lipid phase , containing 7. 5 parts of temperature prior to use . In some cases, no phase separation nonpolar lipids ( 1 part of organic Grapeseed oil, 3 parts of and emulsion creaming occurs during cold storage for at organic coconut oil , 0 . 2 parts of organic beeswax ) and 2 . 5 least one month . parts of polar lipids ( 5 parts of lecithin and 1 parts of L - a [0096 ] Moreover , different formulations can be targeted to Phosphatidylcholines ) . In some cases, the lecithin is egg specific dry - eye related deficiencies . For example , formula yolk lecithin . tions can be designed for aqueous - deficient and meibomian gland dysfunction (MGD )- symptomatic or lipid - deficient Example 5 patients . [0108 ] Example 5 provides bicontinuous microemulsion 4 [0097 ] Table 1 , shown below , provides the aqueous and consisting of 99. 9 % natural food - quality organic ingredi lipid ranges for aqueous -deficient and MGD lipid -deficient ents , which includes: symptoms. [0109 ] 1 . 9 parts of isotonic aqueous phase, containing 5 % of sodium chloride , 4 % of sea salt, buffered with ascorbic TABLE 1 acid to pH 7 . 3 . Aqueous phase range , Lipid phase range , [0110 ] 2 . 1 parts of Lipid phase , containing 8 parts of Symptoms parts parts nonpolar lipids ( 1 part of organic Grapeseed oil, 3 parts of Aqueous -deficient 9 - 15 1 - 2 . 5 organic coconut oil, 0 . 2 parts of organic beeswax ) and 2 MGD 1 - 5 5 - 9 parts of polar lipids (5 parts of lecithin and 1 parts of L - a Phosphatidylcholines ) . In some cases , the lecithin is egg yolk lecithin . US 2019 /0038555 A1 Feb . 7 , 2019

Example 6 parts of lecithin , 1 part of Sphingomyelin , and 1 part of L - a [0111 ] Example 6 provides bicontinuous microemulsion 5 Phosphatidylcholines) . In some cases, the lecithin is egg consisting of 99 . 9 % natural food -quality organic ingredi yolk lecithin . In some cases, the sphingomyelin is egg yolk ents , which includes : sphingomyelin . [ 0112 ] 1. 9 parts of isotonic aqueous phase , containing 5 % Example 11 of sodium chloride , 4 % of sea salt , buffered with ascorbic acid to pH 7 . 3 . [0126 ] Example 11 provides bicontinuous microemulsion [ 0113 ] 2 . 1 part of Lipid phase , containing 8 parts of 10 consisting of 99. 9 % natural food - quality organic ingre nonpolar lipids ( 9 parts Organic Red palm oil and 1 part of dients , which includes : organic beeswax ) and 2 parts of polar lipids ( 2 parts of [0127 ] 1 . 9 parts of isotonic aqueous phase , containing 5 % lecithin and 1 part of L - a Phosphatidylcholines ) . In some of sodium chloride , 4 % of sea salt , 0 . 5 % of Manugel cases , the lecithin is egg yolk lecithin . (alginate , polysaccharide ) buffered with citric acid to pH 7 . 3 . 10128 ] 2 . 2 parts of Lipid phase , containing 8 parts of Example 7 nonpolar lipids (lipids (2 part of organic Grapeseed oil, 2 [0114 ] Example 7 provides bicontinuous microemulsion 6 parts of organic coconut oil , 0 . 4 parts of organic beeswax ) ) consisting of 99 . 9 % natural food -quality organic ingredi and 2 parts of polar lipids ( 5 parts of lecithin , 1 part of ents , which includes: Sphingomyelin ). In some cases , the lecithin is egg yolk [0115 ] 1 . 9 parts of isotonic aqueous phase , containing 5 % lecithin . In some cases , the sphingomyelin is egg yolk of sodium chloride , 4 % of sea salt , buffered with ascorbic sphingomyelin . acid to pH 7 . 3 . [0116 ] 2 . 1 part of Lipid phase , containing 8 parts of Example 12 nonpolar lipids ( Organic Ghee ) and 2 parts of polar lipids (5 [0129 ] Example 12 provides bicontinuous microemulsion parts of lecithin and 1 part of L -a Phosphatidylcholines ). In 11 for aqueous- deficiency symptoms consisting of 99. 9 % some cases, the lecithin is egg yolk lecithin . natural food - quality organic ingredients , which includes: 0130 1 . 9 parts of isotonic aqueous phase , containing 5 % Example 8 of sodium chloride , 4 % of sea salt , 0 . 5 % of Manugel [0117 ] Example 8 provides bicontinuousmicroemulsion 7 ( polysaccharide) buffered with citric acid to pH 7 . 3 . consisting of 99. 9 % natural food - quality organic ingredi [0131 ] 2 . 1 parts of Lipid phase , containing 8 parts of ents , which includes : nonpolar lipids ( 2 part of organic Grapeseed oil, 2 parts of [0118 ] 1 . 8 parts of isotonic aqueous phase , containing 5 % organic coconut oil, 0 . 4 parts of organic beeswax ) ) and 2 of sodium chloride , 4 % of sea salt , buffered with ascorbic parts of polar lipids (5 parts of lecithin , 1 part of Sphingo acid to pH 7 . 3 . myelin ). In some cases, the lecithin is egg yolk lecithin . In [ 0119 ] 2 . 2 parts of Lipid phase, containing 8 parts of some cases , the sphingomyelin is egg yolk sphingomyelin . nonpolar lipids (Organic Ghee ) and 2 parts of polar lipids ( 4 parts of lecithin , 1 part of Sphingomyelin , and 1 part of L - a Example 13 Phosphatidylcholines) . In some cases, the lecithin is egg [0132 ] Example 13 provides bicontinuous microemulsion yolk lecithin . In some cases , the sphingomyelin is egg yolk 12 for MGD lipid - deficiency symptoms consisting of 99 . 9 % sphingomyelin . natural food - quality organic ingredients : [0133 ] 1 . 1 parts of isotonic aqueous phase, containing 5 % Example 9 of sodium chloride , 4 % of sea salt , 0 . 5 % of Manugel [0120 ] Example 9 provides bicontinuous microemulsion 8 (polysaccharide ) buffered with ascorbic acid to pH 7 . 3 . consisting of 99 . 9 % natural food -quality organic ingredi [0134 ] 2 . 4 parts of Lipid phase , containing 8 parts of ents , which includes: nonpolar lipids (Ghee ) and 2 parts of polar lipids ( 5 parts of [ 0121] 1 . 9 parts of isotonic aqueous phase , containing 5 % lecithin , 1 part of Sphingomyelin ) . In some cases , the of sodium chloride, 4 % of sea salt , and 3 % of Trehalose , lecithin is egg yolk lecithin . In some cases , the sphingomy buffered with ascorbic acid to pH 7 . 3 . elin is egg yolk sphingomyelin . [0122 ] 2 . 2 parts of Lipid phase , containing 8 parts of nonpolar lipids (Organic Ghee ) and 2 parts of polar lipids (4 Example 14 parts lecithin , 1 part of Sphingomyelin , and 1 parts of L - a [0135 ] Different formulations targeting specific dry -eye Phosphatidylcholines) . In some cases, the lecithin is egg related deficiency, namely , specifically designed for patients yolk lecithin . In some cases , the sphingomyelin is egg yolk of Asian and Caucasian decent have been suggested . sphingomyelin . [0136 ] Moreover, different formulations targeting specific dry -eye related deficiency were suggested , as shown in Example 10 Table 2 below : [0123 ] Example 10 provides bicontinuous microemulsion 9 consisting of 99. 9 % natural food - quality organic ingredi TABLE 2 ents, which includes : Aqueous phase Lipid phase Including Including [ 0124 ] 1 . 9 parts of isotonic aqueous phase , containing 5 % Race range , parts range , parts Nonpolar parts Polar parts of sodium chloride , 4 % of sea salt , 1 % of sodium alginate , Asian 1 - 10 9 - 1 8 - 9 2 - 1 buffered with citric acid to pH 7. 3 . Caucasian 1 - 4 4 - 1 7 - 8 3 - 2 [0125 ] 2 . 1 parts of Lipid phase , containing 8 parts of nonpolar lipids (Organic Ghee ) and 2 parts of polar lipids ( 4 US 2019 /0038555 A1 Feb . 7 , 2019

Example 15 ration rate in an untreated eye ( e . g ., an untreated eye of the same individual under the same conditions ). [0137 ] Example 15 provides bicontinuous microemulsion [0146 ] An individual suitable for treatment with a bicon 13 for Asian subjects consisting of 99 . 9 % natural food tinuous microemulsion of the present disclosure is an indi quality organic ingredients , which include: vidual who is experiencing dry eye . The dry eye can be due [0138 ] 1 . 8 parts of isotonic aqueous phase , containing 5 % to any of a number of factors , including , but not limited to , of sodium chloride , 4 % of sea salt , buffered with citric acid inadequate tear production attributable to aging, medical to pH 7 . 3 . procedures performed on the cornea , or other conditions; [0139 ] 2 . 2 parts of Lipid phase , containing 8 . 5 parts of exposure of the eye to environmental irritants ( e . g ., dust , nonpolar lipids ( 2 parts of organic Grapeseed oil, 2 parts of smoke , wind , sun , low humidity ) ; and eye strain attributable organic coconut oil, 0 . 4 parts of organic beeswax )) and 1 . 5 to extended viewing of computer monitors , or to other parts of polar lipids ( 5 parts of lecithin , 1 part of Sphingo workplace environment- related factors . In some cases, the myelin ) . In some cases , the lecithin is egg yolk lecithin . In individual is a human . some cases, the sphingomyelin is egg yolk sphingomyelin . 10147 ] A bicontinuous microemulsion of the present dis closure can be applied to the surface of an eye in an amount Example 16 of from 2 ul to 10 ul, e . g . , from 2 ul to 3 ul, from 3 ul to 4 [0140 ] Example 16 provides bicontinuous microemulsion ul, from 4 ul to 5 ul, or from 5 ul to 10 ul. 14 for Caucasian subjects . consisting of 99. 9 % natural [0148 ] A bicontinuous microemulsion of the present dis food - quality organic ingredients , which include: closure can be applied to the surface of an eye at any desired [0141 ] 1 . 9 parts of isotonic aqueous phase, containing 5 % frequency, e . g ., from 1 time per hour to 12 times per hour, of sodium chloride , 4 % of sea salt , 0 . 5 % of Manugel from 1 time per hour to 1 time per every 2 hours, from once ( polysaccharide) buffered with citric acid to pH 7 . 3 . Manu every 2 hours to once every 4 hours, from once every 4 hours gel is an alginate , a naturally occurring polysaccharide; to once every 8 hours , or from once every 8 hours to once every 12 hours . A bicontinuous microemulsion of the pres suitable sources include, e .g ., seaweed . ent disclosure can be applied to the surface of an eye at a [ 0142 ] 2 . 1 parts of Lipid phase , containing 3 parts of frequency of from once every 12 hours to once a day , once nonpolar lipids ( 2 part of organic Grapeseed oil, 2 parts of every 3 days , once a week , etc . organic coconut oil, 0 . 4 parts of organic beeswax ) ) and 1 [0149 ] A bicontinuous microemulsion of the present dis parts of polar lipids ( 3 parts of lecithin , 1 part of Sphingo closure can be applied to the surface of an eye for any myelin and 1 part of L - a Phosphatidylcholines ) . In some desired duration , e . g ., from one hour to 12 hours , from 12 cases , the lecithin is egg yolk lecithin . In some cases , the hours to one day , from 1 day to 7 days , from 1 week to 4 sphingomyelin is egg yolk sphingomyelin . weeks, from 1 month to 6 months, from 6 months to 1 year, or longer than 1 year. Containers [ 0143 ] The present disclosure provides a container com EXAMPLES prising a bicontinuous microemulsion of the present disclo [ 0150 ] The following examples are put forth so as to sure . In some cases , the container is sterile , and the bicon provide those of ordinary skill in the art with a complete tinuous microemulsion of the present disclosure is sterile . In disclosure and description of how to make and use the some cases, the container is an eyedropper . present invention , and are not intended to limit the scope of what the inventors regard as their invention nor are they Methods intended to represent that the experiments below are all or [ 0144 ] The present disclosure provides methods of treat the only experiments performed . Efforts have been made to ing dry eye by reducing evaporation of an aqueous tear film ensure accuracy with respect to numbers used ( e . g . amounts , from the surface of an eye , the methods generally involving temperature , etc . ) but some experimental errors and devia administering , to an ocular surface of an individual having tions should be accounted for. Unless indicated otherwise , dry eye , an effective amount of a bicontinuous microemul parts are parts by weight, molecular weight is weight aver sion of the present disclosure to the eye of an individual in age molecular weight, temperature is in degrees Celsius , and need thereof ( e . g ., to the surface of the eye ) . The present pressure is at or near atmospheric . Standard abbreviations disclose provides methods of reducing the rate of evapora may be used , e .g ., bp , base pair (s ); kb , kilobase (s ); pl, tion of tears from an eye in an individual, e . g ., from an eye picoliter ( s ); s or sec , second ( s ); min , minute( s ) ; h or hr, in a human ; the methods generally involve applying an hour ( s ); aa, amino acid ( s ) ; kb , kilobase ( s ) ; bp , base pair ( s ) ; effective amount of a bicontinuous microemulsion of the nt, nucleotide( s) ; i. m ., intramuscular ( ly ); i. p ., intraperitoneal present disclosure to the surface of the eye of the individual . (ly ) ; s . c . , subcutaneous ( ly ) ; and the like . [ 0145 ] In some cases , an effective amount of a bicontinu Example 1 ous microemulsion of the present disclosure is an amount that reduces the evaporation rate of the aqueous tear film 10151] FIG . 1 depicts surface pressure as a function of from the surface of the eye . In some cases, an effective model tear lipid (MTL ) film thickness for three different amount of a bicontinuous microemulsion of the present MTL mixtures . disclosure is an amount that reduces the evaporation rate of [0152 ] FIG . 2 depicts sessile drop of model tear electro the aqueous tear film from the surface of the eye by at least lytes (MTE ) solution evaporation at 35° C ., 75 % RH without 25 % , at least 30 % , at least 40 % , at least 50 % , at least 60 % , lipid films and with ~ 90 - nm thick model lipid films. DPPC : at least 75 % , at least 2 - fold , at least 3 -fold , at least 4 - fold , Dipalmitoylphosphatidylcholine; DSPC : 1 , 2 -distearoyl - sn at least 5 - fold , or more than 5 - fold , compared to the evapo glycero - 3 - phosphocholine ; SpL : sphingolipid US 2019 /0038555 A1 Feb . 7 , 2019

[0153 ] FIG . 3 depicts MTE solution evaporative flux at VA was not changed before and after exposure of the Test 35 .5° C ., 75 % RH without lipid films and with model lipid solution , whereas it decreased with Retain solution Imme films of varying thickness . diately upon instillation , the masked subject reported long lasting blurriness with Retain solution compared with tran Example 2 sient blurred vision , which dissipated within 30 sec , with the [0154 ] Microemulsion 1 contains only lipids and electro Test solution . No discomfort was reported upon instillation lytes naturally occurring in human tears . Microemulsion 1 of Test or Control solutions. Subject reported less vision has the interfacial pressure dynamics closely mimicking that fluctuation in the Test eye. No corneal staining or conjunc of human tear lipids . The data are shown in FIG . 4 . FIG . 4 tival redness was observed after application of a formulation depicts surface pressure (mN / m ) as a function of lipid - film of the present disclosure to the eye . thickness for 1 ) human tear lipids ; and 2 ) microemulsion # 1 . [0155 ] FIG . 5 provides a comparison of relative evapora Case # 3 tion rates of model systems, microemulsion # 1 , commercial [0161 ] Case # 3 was an asymptomatic female . The test eye drops , and human tears in vivo . Microemulsion # 1 solution was microemulsion # 2 . The controls were Retain reduces the evaporative flux to the level close to human tears and saline solutions . in vivo . Evaporation rates of human tears in vivo were taken [0162 ] Clinical results were very similar to those found in from : 1 ) Peng et al . ( 2014 ) Industrial & Engineering Chem Case # 2 . However , the impact was not as great in this istry Research 53 : 18130 ; and 2 ) Guillon and Maissa ( 2010 ) asymptomatic subject compared with the symptomatic sub Contact Lens & Anterior Eye 33 : 171. ject. One notable finding is that even given the smaller magnitudes of improvement in tear - film stability from Base Example 3 line or compared with the Control solutions , the improve [0156 ] This example provides contralateral (Control solu ment was long lasting ( > 12 hrs ) . Therefore , this asymptom tions in one eye and Test solutions in the fellow eve ) case atic subject could discern a difference in comfort between studies in which in vivo performance of formulations of the Test and Control eyes for at least 24 hours . No corneal present disclosure was observed , measured , and analyzed . staining or conjunctival redness was observed after appli No corneal staining or conjunctival redness was observed cation of a formulation of the present disclosure to the eye. after application of a formulation of the present disclosure . 10163 ]. In summary , the test formulations stabilized tear film with long - lasting effect while not compromising vision Case # 1 quality . The test formulations can greatly reduce ocular discomfort due to dryness and tear - film instability . In addi [0157 ] Case # 1 was an asymptomatic female . The test tion , these microemulsion drops can improve ocular imaging solution was bicontinuous microemulsion # 1 . The controls quality ( anterior and posterior segments ) by stabilizing the were retain and saline solutions . air - tear film interface of the optical path . This is because the f0158 ] When compared to both Control solutions , the Test tear - lipid - film quality was substantially improved after Test solution provided a long - lasting stability of the tear film up formulation drop instillation , as demonstrated in FIG . 6 and to 18 hrs with corresponding greater tear - lipid thickness as FIG . 7 . The lipid film of the Test eye becamemore uniform measured by interferometry , while the Control eye had in thickness and more evenly distributed over the entire decreased tear- lipid thickness . The masked subject reported cornea . These improvements, far more pronounced in the better ocular comfort in the eye that was exposed to the Test eyes of the symptomatic subject , are the most likely reasons solution compared to Baseline (no instilled solutions) and of enhanced visual acuity as well as improved ocular both Control solutions. Visual acuity was improved from imaging quality . One example of ocular imaging of the 20 / 25 to 20 / 20 in test eyes in comparison with no changes anterior segment that can be benefited from a stabilized with Saline control solution and decline to 20 / 30 in Retain air - tear film interface is corneal topography . A stable air -tear control solution . No corneal staining or conjunctival redness film interface can lead to a better approximation of the was observed after application of a formulation of the corneal power, leading to improved accuracy of calculated present disclosure to the eye . crystalline lens powers prior to a cataract surgery . 0164 ] While the present invention has been described Case # 2 with reference to the specific embodiments thereof, it should [0159 ] Case # 2 was a symptomatic female . The test solu be understood by those skilled in the art that various changes tion was microemulsion # 2 . The controls were Retain and may be made and equivalents may be substituted without saline solutions. departing from the true spirit and scope of the invention . In 10160 ] Compared to both Control solutions, the masked addition , many modifications may be made to adapt a subject reported much better comfort in the eye that was particular situation , material, composition of matter, pro exposed to the Test solution , and the effect lasted 6 hours. cess, process step or steps, to the objective , spirit and scope The subject also reported better comfort compared with of the present invention . All such modifications are intended Baseline and the effect lasted for 6 hrs . For the eye exposed to be within the scope of the claims appended hereto . to the Test solution , the stability of the tear film improved from 2 s at baseline to 5 s ( 30 min and 4 hrs after instilling What is claimed is : Test solution ) , whereas the Control had deteriorating tear 1 . A bicontinuous microemulsion comprising : film stability during the same time period for both Control a ) an aqueous phase comprising one or more of: solutions . The improved tear- film stability corresponded to i) sodium chloride ; improved functional vision . For example , low contrast ii ) sea salt ; visual acuity (VA ) was improved from 20 /60 at baseline to iii ) ascorbic acid ; and 20 / 40 ( 30 min , 2hr and 4hrs after instillation ). High contrast iv ) trehalose ; and US 2019 /0038555 A1 Feb . 7 , 2019

b ) a lipid phase comprising one or more of: 16 . The bicontinuous microemulsion of any one of claims i ) sphingomyelin ; 1 -7 , wherein the lipid phase comprises nonpolar lipids and ii ) phosphatidylcholine ; polar lipids in a ratio of from about 10 : 1 to 4 : 1 ( v / v ) . iii ) fish oil ; 17 . The bicontinuous microemulsion of any one of claims iv ) palm oil ; 1 -7 , wherein the lipid phase comprises grapeseed oil, coco v ) olive oil, nut oil , beeswax , sphingomyelin , and phosphatidylcholine . vi) coconut oil ; 18 . The bicontinuous microemulsion of any one of claims vii ) grapeseed oil ; 1 - 7 , wherein the lipid phase comprises palm oil, beeswax , viii ) bees wax ; lecithin , and phosphatidylcholine . xi) ghee ; and 19 . The bicontinuous microemulsion of any one of claims x ) lanolin , 1 - 7 , wherein the lipid phase comprises ghee, lecithin , and wherein the osmolarity of the microemulsion is from 270 phosphatidylcholine. mOsm to 320 mOsm , and wherein the microemulsion has a pH of from 7 . 2 to 7 . 4 . 20 . The bicontinuous microemulsion of any one of claims 2 . The bicontinuous microemulsion of claim 1 , wherein 1 -7 , wherein the lipid phase comprises ghee , lecithin , sphin the ratio of aqueous phase to lipid phase is from about 10 : 1 gomyelin , and phosphatidylcholine . to 1: 10 ( v / v ). 21 . The bicontinuous microemulsion of any one of claims 3 . The bicontinuous microemulsion of claim 1 , wherein 1 - 7 , wherein the lipid phase comprises grapeseed oil , bees the ratio of aqueous phase to lipid phase is from about 5 : 1 wax , lecithin , and sphingomyelin . to 1 :5 ( v / v ) . 22 . The bicontinuous microemulsion of any one of claims 4 . The bicontinuous microemulsion of claim 1 , wherein 1 - 7 , wherein the lipid phase comprises grapeseed oil, coco the ratio of aqueous phase to lipid phase is from about 3 : 1 nut oil , beeswax , lecithin , and sphingomyelin . to 1 : 3 ( v / v ) . 23. The bicontinuous microemulsion of any one of claims 5 . The bicontinuous microemulsion of claim 1 , wherein 1 - 7 , wherein the lipid phase comprises ghee , lecithin , and the ratio of aqueous phase to lipid phase is from about 2 . 5 : 1 sphingomyelin . to 3 :1 ( v / v ) . 24 . The bicontinuousmicroemulsion of any one of claims 6 . The bicontinuous microemulsion of any one of claims 1 - 7 , wherein the lipid phase comprises coconut oil and 1 - 5 , comprising lactoferrin . grapeseed oil . 7 . The bicontinuous microemulsion of any one of claims 25 . The bicontinuous microemulsion of claim 1 , wherein 1 -6 , wherein the lipid phase comprises sphingomyelin and the lecithin is egg yolk lecithin . phosphatidylcholine . 26 . The bicontinuous microemulsion of any one of claims 8 . The bicontinuous microemulsion of claim 7 , wherein 1 - 25 , wherein the bicontinuous emulsion is sterile . the ratio of sphingomyelin to phosphatidylcholine is from 27 . A formulation comprising the bicontinuous micro 4 : 1 to 1: 1 (w / v ). emulsion of any one of claims 1 - 26 , wherein the formulation 9 . The bicontinuous microemulsion of any one of claims is a liquid , a gel, a semi- solid , or an ointment. 1 - 6 , wherein the lipid phase comprises palm oil and olive oil. 28 . A container comprising the bicontinuous microemul 10 . The bicontinuous microemulsion of claim 9 , wherein sion of any one of claims 1 - 26 or the formulation of claim the ratio of palm oil to olive oil is from 3 : 1 to 1 : 3 ( v / v ) . 27 . 11. The bicontinuousmicroemulsion of any one of claims 29 . The container of claim 28 , wherein the container 1 - 6 , wherein the lipid phase comprises palm oil , olive oil , comprises an eyedropper. and fish oil. 12 . The bicontinuous microemulsion of claim 11 , wherein 30 . A method of reducing evaporation of an aqueous tear the ratio of palm oil and olive oil to fish oil is from 10 : 1 to film from the surface of an eye , the method comprising 6 : 1 palm oil + olive oil: fish oil . applying the bicontinuous microemulsion of any one of 13 . The bicontinuous microemulsion of any one of claims claims 1 -26 or the formulation of claim 27 to the surface of 1 - 7 , comprising coconut oil . the eye , thereby reducing evaporation of the aqueous tear 14 . The bicontinuous microemulsion of any one of claims film from the surface of the eye . 1 - 7 , wherein the lipid phase comprises coconut oil or palm 31. A method of treating dry eye in an eye of an indi oil ; olive oil ; and fish oil . vidual, the method comprising applying the bicontinuous 15 . The bicontinuous microemulsion of claim 14 , wherein microemulsion of any one of claims 1 - 26 or the formulation the ratio of palm oil/ coconut oil and olive oil to fish oil is of claim 27 to the surface of the eye of the individual . from 10 : 1 to 6 : 1 palm oil/ coconut oil + olive oil : fish oil .