Patent Publication Number: US-2021186913-A1

Title: Compositions and methods for treating the eye

Description:
CROSS REFERENCE TO RELATED APPLICATION 
     The present application is a divisional application of U.S. patent application Ser. No. 16/519,166 filed Jul. 23, 2019, which claims the benefit of the United States provisional patent application 62/703,943, filed Jul. 27, 2018, the entirety of which application is hereby incorporated by reference herein as if fully set forth herein. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to compositions comprising one or more extracts and/or compounds having retinol-like activity and properties and methods of using the compositions to treat the eye. 
     BACKGROUND OF THE INVENTION 
     “Dry eye is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.” Craig, J. P. et al. TFOS DEWS II definition and classification report.  Ocul Surf.  2017; 15: 276-283. Dry eye can result from abnormal or inadequate tear formation, and deficiency in mucin secretion (i.e., keratoconjunctivitis sicca). Dry eye symptoms can be manifest as a result of various underlying disorders such as autoimmune disorders that damage lacrimal (i.e., tear-producing) glands, such as rheumatoid arthritis, Sjögren&#39;s syndrome, systemic lupus erythematosus, and systemic sclerosis and sarcoidosis. Dry eye can also be induced following eye surgery, such as Lasik® surgery. Dry eye is estimated to affect more than 13 million individuals in the United States. 
     Regardless of the underlying pathology, dry eye commonly involves the rapid breakdown of the pre-ocular tear film, resulting in dehydration of the exposed outer surface. Normal tear formation is required to keep the cornea and conjunctiva moist, and this in turn helps to prevent ulceration of both, as well as to maintain corneal transparency. In addition, tears facilitate movement of the eyelid over the eye surface (e.g., blinking) and removal of foreign substances from the eye. Tears also normally contain lysozyme which is useful in preventing infection in the eye. Dry eye can be associated with mild discomfort to severe pain in the eye. When it occurs for prolonged periods of time, it can cause blurred vision, grittiness and/or burning sensation, and itchiness. If the condition is allowed to persist without treatment, it can further lead to corneal ulcers and/or scarring. 
     Dry eye symptoms include eye pain or fatigue, increased blinking, and bloodshot eyes. Further, bacteria may enter through a scratch and cause infection, and if the scratch is deep enough it can even affect the vision of the person. In addition to eyestrain, causes of dry eye include Sjogren&#39;s syndrome, Stevens-Johnson syndrome, burns and injury to the eye, and side effects of hypotensive drugs, tranquilizers, eyedrops for treating glaucoma, and other such drugs. 
     Tear film is the bodies&#39; natural defense against dry eye. The tear film contains ocular mucins and is essential for maintaining the homeostasis of the wet ocular surface. Mucins are produced, among other places, by corneal epithelial cells in the eye. Mucins are glycoproteins expressed by epithelial tissues of mucosal surfaces. They protect tissues by functioning as antioxidants and providing lubrication. Mucin genes associated with the tear film include MUC1, MUC2, MUC4, MUC5AC, MUC5B, MUC7 and MUC16. 
     Mucin is also useful as an antimicrobial, for general wound healing, and is essential for overall eye health maintenance. 
     There is therefore a need for an ophthalmic pharmaceutical composition that would promote and/or improve the production and/or release of mucin from and/or in the cornea. 
     The present inventors have discovered compounds and/or extracts having retinol-like properties and/or benefits which can induce, promote and/or improve production/release/delivery/excretion of mucin from and/or in the cornea. 
     Accordingly, an aspect of the present invention relates to compositions comprising a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or benefits to induce, promote and/or improve the production/release/delivery/excretion of mucin from and/or in the cornea. 
     Another aspect of the present invention relates to compositions comprising a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or benefits which induce, promote and/or improve production/release/delivery/excretion of mucin from and/or in the cornea, which compositions can be administered to patients having a MUC5AC concentration in tears lower than 6 (or about 6), optionally 8 (or about 8), nanograms per milligram of proteins, such that the concentration of MUC5AC in the tears is raised to (or, is made to be) equal to or greater than 8 (or about 8) nanograms to 15 (or about 15) nanograms, optionally from 9 (or about 9) nanograms to 12 (or about 12) nanograms, per milligram of proteins. 
     In certain embodiments, the above-described concentration of MU5AC in the tears (i.e., equal to or greater than 8 (or about 8) nanograms to 15 (or about 15) nanograms, optionally from 9 (or about 9) nanograms to 12 (or about 12) nanograms, per milligram of proteins), resulting from the compounds and/or extracts having retinol-like properties and/or benefits which induce, promote and/or improve production/release/delivery/excretion of mucin from and/or in the cornea, is maintained for a period of up to, at least, about 2 hours, optionally about 4 hours, optionally about 6 hours, optionally about 8 hours, optionally about 10 hours, optionally about 12 hours, or optionally from about 12 to about 24 hours. 
     Concentrations of MUC5AC in tears detailed above are determined using the Uchino Method (described below in the definitions). 
     Another aspect of the present invention relates to compositions comprising a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or benefits which induce, promote and/or improve production/release/delivery/excretion of mucin from and/or in the cornea for treating dry eye. 
     Another aspect of the present invention relates to methods of preventing and/or treating (e.g., reducing) eye symptoms associated with dry eye and/or resulting from decreased or low-level production/release/delivery/excretion of mucin from and/or in the cornea by administering compositions comprising a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or benefits which induce, promote and/or improve production/release/delivery/excretion of mucin from and/or in the cornea. 
     Another aspect of the present invention relates to methods of promoting healing or increasing the rate of healing of wounds in and/or on the eye (e.g., non-dry eye associated, eye trauma, postoperative surgical or nonspecific wounds) of a patient by administering compositions comprising a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or benefits which induce, promote and/or improve production/release/delivery/excretion of mucin from and/or in the cornea (i.e., which increase production/release/delivery/excretion of mucin from and/or in the cornea, in certain embodiments, beyond the concentration level of mucin produced by such patient without (or absent) administration of the compositions comprising a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or benefits which induce, promote and/or improve production/release/delivery/excretion of mucin from and/or in the cornea). 
     Another aspect of the present invention relates to methods for improving the antimicrobial properties in tears (or the tear film of the eye) of a patient by administering compositions comprising a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or benefits which induce, promote and/or improve production/release/delivery/excretion of mucin from and/or in the cornea (i.e., which increase production/release/delivery/excretion of mucin from and/or in the cornea, in certain embodiments, beyond the concentration level of mucin produced by such patient without (or absent) the administration of the compositions comprising a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or benefits which induce, promote and/or improve production/release/delivery/excretion of mucin from and/or in the cornea). 
     SUMMARY OF THE INVENTION 
     The present invention relates to methods for producing/releasing/delivering/excreting mucin from and/or in the cornea (optionally, in a patient in need of such production/release/deliverance/excretion of mucin) comprising the step of administering a composition comprising:
         i) a safe and effective amount of a compound and/or extract having retinol-like properties and/or benefits for use in treating dry eye selected from one or more of: botanical extracts, or sources of extracts, from plants of the genus  Acronychia, Licaria, Calendula  and/or  Trigonella ; bacterial extracts, or sources of extracts, of the genus  Actinomyces ; and compounds of Formula (I):       

     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein— 
                 the dotted lines represent simple or double bound; optionally one of the dotted line is a double bound; 
                 R 1  represent an H, a carbonated chain, linear, cyclic, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; 
                 R 2  represent a carbonated chain, linear, cyclic ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; optionally a methyl (—CH 3 ) or methylene (═CH 2 ) moiety; a carbonated chain, linear, ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; optionally from 1 to 10 carbon atoms; optionally 6 carbon atoms; optionally an aromatic moiety, optionally a phenyl moiety; optionally 2-methyl-prop-1,3-diene; and 
                 ii) optionally, an ophthalmologically acceptable carrier. 
               
             
           
         
       
    
     The present invention relates to methods for maintaining the concentration of MU5AC in tears within the range of equal to or greater than 8 nanograms to 15 nanograms per milligrams of protein, comprising the step of administering a composition comprising:
         i) a safe and effective amount of a compound and/or extract having retinol-like properties and/or benefits for use in treating dry eye selected from one or more of: botanical extracts, or sources of extracts, from plants of the genus  Acronychia, Licaria, Calendula  and/or  Trigonella ; bacterial extracts, or sources of extracts, of the genus  Actinomyces ; and compounds of Formula (I):       

     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein— 
                 the dotted lines represent simple or double bound; optionally one of the dotted line is a double bound; 
                 R 1  represent an H, a carbonated chain, linear, cyclic, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; 
                 R 2  represent a carbonated chain, linear, cyclic ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; optionally a methyl (—CH 3 ) or methylene (═CH 2 ) moiety; a carbonated chain, linear, ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; 
                 optionally from 1 to 10 carbon atoms; optionally 6 carbon atoms; optionally an aromatic moiety, optionally a phenyl moiety; optionally 2-methyl-prop-1,3-diene; and 
               
             
             ii) optionally, an ophthalmologically acceptable carrier. 
           
         
       
    
     The present invention relates to methods for treating a patient having decreased or low-level production/release/delivery/excretion of mucin from and/or in the cornea comprising the step of topically administering to the eye the patient a composition comprising:
         i) a safe and effective amount of a compound and/or extract having retinol-like properties and/or benefits for use in treating dry eye selected from one or more of: botanical extracts, or sources of extracts, from plants of the genus  Acronychia, Licaria, Calendula  and/or  Trigonella ; bacterial extracts, or sources of extracts, of the genus  Actinomyces ; and compounds of Formula (I):       

     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein— 
                 the dotted lines represent simple or double bound; optionally one of the dotted line is a double bound; 
                 R 1  represent an H, a carbonated chain, linear, cyclic, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; 
                 R 2  represent a carbonated chain, linear, cyclic ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; optionally a methyl (—CH 3 ) or methylene (═CH 2 ) moiety; a carbonated chain, linear, ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; optionally from 1 to 10 carbon atoms; optionally 6 carbon atoms; optionally an aromatic moiety, optionally a phenyl moiety; optionally 2-methyl-prop-1,3-diene; and 
               
             
             ii) optionally, an ophthalmologically acceptable carrier. 
           
         
       
    
     The present invention relates to methods for preventing or treating the symptoms associated with dry eye comprising the step of topically administering to a patient (optionally, in a patient need of such prevention or reduction in dry eye symptoms) a composition comprising:
         i) a safe and effective amount of a compound and/or extract having retinol-like properties and/or benefits for use in treating dry eye selected from one or more of: botanical extracts, or sources of extracts, from plants of the genus  Acronychia, Licaria, Calendula  and/or  Trigonella ; bacterial extracts, or sources of extracts, of the genus  Actinomyces ; and compounds of Formula (I):       

     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein— 
                 the dotted lines represent simple or double bound; optionally one of the dotted line is a double bound; 
                 R 1  represent an H, a carbonated chain, linear, cyclic, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; R 2  represent a carbonated chain, linear, cyclic ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; optionally a methyl (—CH 3 ) or methylene (═CH 2 ) moiety; a carbonated chain, linear, ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; optionally from 1 to 10 carbon atoms; optionally 6 carbon atoms; optionally an aromatic moiety, optionally a phenyl moiety; optionally 2-methyl-prop-1,3-diene; 
               
             
             ii) one or more demulcents or soothing agents; and 
             iii) optionally, an ophthalmologically acceptable carrier. 
           
         
       
    
     The present invention relates to methods for promoting healing or increasing the rate of healing of wounds in and/or on the eye of a patient (optionally, in a patient need of such eye wound healing), comprising the step of administering compositions (i.e., which increase production/release/delivery/excretion of mucin from and/or in the cornea, in certain embodiments, beyond the concentration level of mucin produced by such patient without (or absent) administration of the compositions comprising a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or benefits) comprising:
         i) a safe and effective amount of a compound and/or extract having retinol-like properties and/or benefits for use in treating dry eye selected from one or more of: botanical extracts, or sources of extracts, from plants of the genus  Acronychia, Licaria, Calendula  and/or  Trigonella ; bacterial extracts, or sources of extracts, of the genus  Actinomyces ; and compounds of Formula (I):       

     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein— 
                 the dotted lines represent simple or double bound; preferably one of the dotted line is a double bound; 
                 R 1  represent an H, a carbonated chain, linear, cyclic, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; 
                 R 2  represent a carbonated chain, linear, cyclic ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; preferably a methyl (—CH 3 ) or methylene (═CH 2 ) moiety; 
                 a represent a carbonated chain, linear, ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; preferably from 1 to 10 carbon atoms; more preferably 6 carbon atoms; preferably an aromatic moiety, preferably a phenyl moiety; preferably 2-methyl-prop-1,3-diene. 
               
             
             ii) optionally, an ophthalmologically acceptable carrier. 
           
         
       
    
     The present invention relates to methods for improving the antimicrobial properties in tears (or, the tear film of the eye) of a patent (optionally, in a patient need of such antimicrobial properties), comprising the step of administering compositions (i.e., which increase production/release/delivery/excretion of mucin from and/or in the cornea, in certain embodiments, beyond the concentration level of mucin produced by such patient without (or absent) administration of the compositions comprising a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or benefits) comprising:
         i) a safe and effective amount of a compound and/or extract having retinol-like properties and/or benefits for use in treating dry eye selected from one or more of: botanical extracts, or sources of extracts, from plants of the genus  Acronychia, Licaria, Calendula  and/or  Trigonella ; bacterial extracts, or sources of extracts, of the genus  Actinomyces ; and compounds of Formula (I):       

     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein— 
                 the dotted lines represent simple or double bound; preferably one of the dotted line is a double bound; 
                 R 1  represent an H, a carbonated chain, linear, cyclic, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; 
                 R 2  represent a carbonated chain, linear, cyclic ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; preferably a methyl (—CH 3 ) or methylene (═CH 2 ) moiety; 
                 a represent a carbonated chain, linear, ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; preferably from 1 to 10 carbon atoms; more preferably 6 carbon atoms; preferably an aromatic moiety, preferably a phenyl moiety; preferably 2-methyl-prop-1,3-diene. 
               
             
             ii) optionally, an ophthalmologically acceptable carrier. 
           
         
       
    
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIG. 1  depicts bar graphs showing lemon aspen extract induced MUC1, MUC4 and MUC16 gene expression in corneal epithelial cells. 
         FIG. 2  depicts bar graphs showing lemon aspen extract induced Mucin-1 secretion in corneal epithelial cells. 
     
    
    
     DETAILED DESCRIPTION OF INVENTION 
     It is believed that one skilled in the art can, based upon the description herein, utilize this invention to its fullest extent. The following specific embodiments can be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. 
     The compositions of the present invention can comprise, consist of, or consist essentially of the elements, steps and limitations of the invention described herein, as well any of the additional or optional ingredients, components, or limitations described herein. 
     The term “comprising” (and its grammatical variations) as used herein is used in the inclusive sense of “having” or “including” and not in the exclusive sense of “consisting only of.” The terms “a” and “the” as used herein are understood to encompass the plural as well as the singular. 
     Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Also, all publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety to the extent that they are not inconsistent with this specification. As used herein, all percentages are by weight of the total composition unless otherwise specified 
     As used herein, the terms “cornea” or “corneal” is, includes and/or relates to, the transparent front part of the eye that covers the iris, pupil, and anterior chamber, the layers of which transparent front part include the corneal epithelium layer (comprising corneal epithelial cells), Bowman&#39;s layer (also known as the anterior limiting membrane), Corneal stroma (also substantia propria), Descemet&#39;s membrane (also posterior limiting membrane), and Corneal endothelium (simple squamous or low cuboidal monolayer, approx. 5 μm thick, of mitochondria-rich cells). 
     As used herein, the phrase “decreased or low-level production/release/delivery/excretion of mucin from and/or in the cornea” means a concentration of MUC5AC which is less than the concentration of MUC5AC in the tears of a normal (i.e., non-diseased) person, or, in certain embodiments, less than 6, optionally less than 8, nanograms per milligram of proteins, as determined using the method described in Uchino Y, Uchino M, Yokoi N, et al. Alteration of Tear Mucin 5AC in Office Workers Using Visual Display Terminals: The Osaka Study.  JAMA Ophthalmol . n2014; 132(8):985-992. That method (the Uchino Method) is reproduced below: 
     MUC5AC Concentration in Tears
         The concentration of the secreted mucin MUC5AC in the tear samples was quantified by enzyme-linked immunoassay (E90756Hu; USCN Life Science). (See Maker A V, Katabi N, Gonen M L, et al. Pancreatic cyst fluid and serum mucin levels predict dysplasia in intraductal, papillary mucinous neoplasms of the pancreas.  Ann Surg Oncol.  2011:18(1): 199-206.) All samples were analyzed according to the manufacturer&#39;s guidelines. Absorbance was measured at 450 ran, and the standard solutions in the kit were recombinant hitman MUC5AC, A protein assay reagent kit (BCA Protein Assay Kit; Pierce) was used to determine the protein concentration in the tear samples. The MUC5AC concentration was normalized to the tear protein content and expressed as MUC5AC protein (nanograms) per tear total protein (milligrams).       

     As used herein, a composition that is “essentially free” of an ingredient means the composition that has about 2% or less of that ingredient by weight based on the total weight of the composition. Preferably, a composition that is essentially free of an ingredient has about 1% or less, more preferably about 0.5% or less, more preferably about 0.1% or less, more preferably about 0.05 or less, more preferably about 0.01% or less by weight based on the total weight of composition of the ingredient. In certain more preferred embodiments, a composition that is essentially free of an ingredient is free of the ingredient, i.e. has none of that ingredient in the composition. 
     As used herein, “ophthalmologically acceptable” means that the ingredients which the term describes are suitable for use in contact with tissues (e.g., the soft tissues of the eye or periorbital skin tissues) without undue toxicity, incompatibility, instability, irritation, allergic response, and the like. As will be recognized by one of skill in the art, ophthalmologically acceptable salts are acidic/anionic or basic/cationic salts. 
     As used herein, the term “safe and effective amount” means an amount of disclosed the extract, compound or of the composition sufficient to induce, promote and/or improve the production/release/delivery/excretion of mucin from and/or in one or more layer of the cornea, but low enough to avoid serious side effects. The safe and effective amount of the compound, extract, or composition will vary with e.g. the age, health and environmental exposure of the end user, the duration and nature of the treatment, the specific extract, ingredient, or composition employed, the particular pharmaceutically-acceptable carrier utilized, and like factors. 
     The term “retinol-like properties and/or benefits” means the properties and/or benefits induced by retinol. 
     In certain embodiments, the present invention as disclosed herein may be practiced in the absence of any compound or element (or group of compounds or elements) which is not specifically disclosed herein. 
     In general, IUPAC nomenclature rules are used herein and according to the following term definitions. 
     The term “C1-8 alkyl,” whether used alone or as part of a substituent group, refers to a saturated aliphatic branched or straight-chain monovalent hydrocarbon radical having from 1-8 carbon atoms. For example, “C1-8 alkyl” specifically includes the radicals methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, tert-butyl, 1-butyl, 1-pentyl, 2-pentyl, 3-pentyl, 1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 1-octyl, 2-octyl, 3-octyl and the like. Said term may also refer to the corresponding alkyldiyl radical. Alkyl and alkyldiyl radicals may be attached to a core molecule via a terminal carbon atom or via a carbon atom within the chain. Similarly, any number of substituent variables may be attached to an alkyl or alkyldiyl radical when allowed by available valences. 
     The term “C 1-4 alkyl,” whether used alone or as part of a substituent group, refers to a saturated aliphatic branched or straight-chain monovalent hydrocarbon radical or alkyldiyl linking group having a specified number of carbon atoms, wherein the radical is derived by the removal of one hydrogen atom from a carbon atom and the alkyldiyl linking group is derived by the removal of one hydrogen atom from each of two carbon atoms in the chain. The term “C 1-4 alkyl” refers to a radical having from 1-4 carbon atoms in a linear or branched arrangement. For example, “C 1-4 alkyl” specifically includes the radical&#39;s methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, tert-butyl, 1-butyl, and the like. Alkyl and alkyldiyl radicals may be attached to a core molecule via a terminal carbon atom or via a carbon atom within the chain. Similarly, any number of substituent variables may be attached to an alkyl or alkyldiyl radical when allowed by available valences. 
     The term “C 2-4 alkenyl” refers to an alkenyl radical having from 2-4 carbon atoms. For example, specifically includes the radicals ethenyl, propenyl, allyl (2-propenyl), butenyl and the like. As described above, an alkenyl radical may be similarly attached to a core molecule and further substituted where indicated. 
     The term “halo” as such or in combination with other terms means halogen atom, such as fluoro, chloro, bromo or iodo. 
     The term “substituted,” refers to a core molecule in which one or more hydrogen atoms have been replaced with that amount of substituents allowed by available valences. Substitution is not limited to the core molecule, but may also occur on a substituent radical, whereby the radical becomes a linking group. 
     The term “independently selected” refers to two or more substituents that may be selected from a substituent variable group, wherein the selected substituents may be the same or different. 
     The term “dependently selected” refers to one or more substituent variables that are specified in an indicated combination for substitution in a core molecule (e.g. variables that refer to groups of substituents appearing in a tabular list of compounds). 
     Acceptable salts from inorganic bases include, for example, sodium or potassium salts, and the like. Acceptable salts from organic bases include, for example, salts formed with primary, secondary, or tertiary amines, and the like. 
     Compounds/Extracts Exhibiting Retinol-Like Bioactivity and/or Properties 
     The present invention comprises compounds and/or extracts having retinol-like properties and/or benefits for use in treating dry eye including, selected from or selected from the group consisting of one or more of: botanical extracts, or sources of extracts, from plants of the genus  Acronychia, Licaria, Calendula  and/or  Trigonella ; bacterial extracts, or sources of extracts, of the genus  Actinomyces ; and compounds of Formula (I): 
     
       
         
         
             
             
         
       
     
     wherein—
         the dotted lines represent simple or double bound; optionally one of the dotted line is a double bound;   R 1  represent an H, a carbonated chain, linear, cyclic, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms;   R 2  represent a carbonated chain, linear, cyclic ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; optionally a methyl (—CH 3 ) or methylene (═CH 2 ) moiety; a carbonated chain, linear, ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; optionally from 1 to 10 carbon atoms; optionally 6 carbon atoms; optionally an aromatic moiety, optionally a phenyl moiety; optionally 2-methyl-prop-1,3-diene.
 
 Acronychia, Licaria, Calendula  and/or  Trisonella  Botanical Plant Extract(s)
       

     In certain embodiments, the compounds/extracts exhibiting retinol-like properties and/or benefits are, or comprise, extracts, or sources of extracts, of plant  Acronychia, Licaria, Calendula  and/or  Trigonella . The  Acronychia, Licaria, Calendula  or  Trigonella  extracts, or sources of such extracts, are obtained from plants of the genus  Acronychia, Licaria, Calendula  or  Trigonella.    
     Plants of the genus  Acronychia , from which extracts useful in the present invention are, obtained include, for example,  Acronychia aberrans, Acronychia acidula  (also referred herein as lemon aspen),  Acronychia acronychioides, Acronychia acuminate, Acronychia baeuerlenii, Acronychia chooreechillum, Acronychia crassipetala, Acronychia eungellensis, Acronychia imperforate, Acronychia laevis, Acronychia laurifolia, Acronychia littoralis, Acronychia oblongifolia, Acronychia octandra, Acronychia parviflora, Acronychia pauciflora, Acronychia pedunculate, Acronychia pubescens, Acronychia  species (Batavia Downs),  Acronychia suberosa, Acronychia vestita, Acronychia wilcoxiana , and combinations of two or more thereof. In one embodiment, the extract used in the present invention dis obtained from  Acronychia acidula.    
     Plants of the genus  Licaria , from which extracts useful in the present invention are obtained, include, for example,  Licaria vernicosa, Licaria brittoniana, Licaria canella, Licaria cubensis, Licaria velutina  and  Licaria triandra , and combinations of two or more thereof. There are about 40 species of genus  Licaria  reported and are endemic to Central and South Americas. In one embodiment, the extract used in the present invention is obtained from  Licaria vernicosa.    
     There are about 15-20 species of genus  Calendula  reported and are found in southwestern Asia, western Europe, Macaronesia, and the Mediterranean. Plants of the genus  Calendula , from which extracts useful in the present invention are obtained, include, for example,  Calendula arvensis  (field marigold);  Calendula maderensis  (Madeiran marigold); and  Calendula officinalis  (pot marigold) and combinations of two or more thereof. In one embodiment, the extract used in the present invention is obtained from  Calendula officinalis.    
     Plants of the genus  Trigonella  include 36 known species Plants of the genus  Trigonella , from which extracts useful in the present invention are obtained, include, for example,  Trigonella foenum - graecum, Trigonella balansae, Trigonella corniculata, Trigonella maritima, Trigonella spicata, Trigonella caerulea, Trigonella occulta, Trigonella polycerata, Trigonella Calliceras, Trigonella Cretica  and combinations of two or more thereof.  Trigonella foenum - graecum  or herb fenugreek is the best-known member of the genus  Trigonella . In one embodiment, the extract used in the present invention is obtained from  Trigonella foenum - graecum.    
     In certain embodiments, the extract used in the present invention is a mixture of extracts obtained from plants of the genus  Acronychia, Licaria, Calendula  and/or  Trigonella.    
     Extracts of  Licaria vernicosa  useful in the present invention can be obtained from the Baruch S. Blumberg Institute, Doylestown, Pa. (formerly known as IVHR). In certain embodiments, one extract comes from the woody part of the plant (E2) and the second extract was from the roots of the plant (E3). Within the nomenclature of IHVR collection, the two extracts are labeled as IHVR_40256_G10=X-005348-001E002 and as IHVR_40256_E10=X-005346-001M002 respectively. The woody parts and the roots of  Licaria vernicosa  (Mez) Kosterm. can be collected from Guyana. 504.3 g of dried, ground woody plant material can be extracted with an ample methanol, which can be dried under vacuum to afford 10.54 g of crude methanol extract (E2) for X-005348-001E002. 403.8 g of dried, ground root material can be extracted with ample methanol, which can be dried under vacuum to afford 18.11 g of crude methanol extract (E3) for X-005346-001M002. 
     In certain embodiments, the  Acronychia  and/or  Licaria  extracts useful in the present invention comprise compounds having the Formula II: 
     
       
         
         
             
             
         
       
     
     wherein:
 
R 1  is selected from the group consisting of C 1 -C 20  alkyl, C 2 -C 20  alkenyl, C 2 -C 20  alkynyl, and C 3 -C 8  cycloalkyl or aryl;
 
R 2  is selected from the group consisting of hydrogen, hydroxyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl or aryl, —OC 1 -C 6  alkyl, —OC 2 -C 6  alkenyl, —OC 2 -C 6  alkynyl, —OC 3 -C 8  cycloalkyl or aryl, thiol, —SC 1 -C 6  alkyl, —SC 2 -C 6  alkenyl, —SC 2 -C 6  alkynyl, —SC 3 -C 8  cycloalkyl or aryl, —NR 4 C 1 -C 6  alkyl, —NR 4 C 2 -C 6  alkenyl, —NR 4 C 2 -C 6  alkynyl, and —NR 4 C 3 -C 8  cycloalkyl or aryl;
 
R 3  is selected from —CO 2 H, —CO 2 R 4  or an isosteric equivalent of a carboxy group, wherein R 4  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 3 -C 8  cycloalkyl or aryl; and
 
Y is —(CH 2 —CH 2 )—, —(CH═CH)—, or —(C≡C)—;
 
or a ophthalmologically acceptable salt thereof.
 
     In certain embodiments, the  Acronychia  and/or  Licaria  extracts useful in the present invention comprises compounds having the Formula II: 
     
       
         
         
             
             
         
       
     
     wherein:
 
R 1  is selected from the group consisting of C 5 -C 16  alkyl, C 5 -C 16  alkenyl, and C 5 -C 16  alkynyl, more preferably C 5 -C 16  alkenyl, including, for example, farnesyl;
 
R 2  is selected from the group consisting of hydrogen, hydroxyl, —OC 1 -C 6  alkyl, —OC 2 -C 6  alkenyl, —OC 2 -C 6  alkynyl, —OC 3 -C 8  cycloalkyl, more preferably hydrogen, hydroxyl, —OC 1 -C 6  alkyl, even more preferably hydrogen or —OC 1 -C 3  alkyl;
 
R 3  is selected from —CO 2 H, —CO 2 R 4  wherein R 4  is C 1 -C 6  alkyl, or an isosteric equivalent of a carboxy group; and
 
Y is —(CH 2 —CH 2 )— or —(CH═CH)—;
 
or a ophthalmologically-acceptable salt thereof.
 
     In certain embodiments, at least one of the compounds of Formula II is present in the extract the  Acronychia  and/or  Licaria  at a concentration equal to or greater than 1% (or about 1%) to about 20%, or optionally from about 7% (or about 7%) to about 10% (or about 10%), by weight of the  Acronychia  and/or  Licaria  extract. 
     In certain embodiments, the compounds of Formula II useful in the present invention are in the form of an acid or alkylester selected from (or, selected from the group consisting of) 3-(4-farnesyloxyphenyl)-propionic acid, 3-(4-farnesyloxy-3-hydroxyphenyl)-propionic acid, 3-(4-farnesyloxy-3-methoxyphenyl)-propionic acid, alkylesters thereof, in particular ethyl esters thereof, and combinations of two or more thereof. 
     In certain embodiments, the compound of Formula II useful in the present invention is 3-(4-farnesyloxyphenyl)-propionic acid and/or its ethyl ester. 
     In certain embodiments, the compound of Formula II useful in the present invention is 3-(4-farnesyloxy-3-hydroxyphenyl)-propionic acid and/or its ethyl ester. 
     In certain embodiments, the compound of Formula II useful in the present invention is 3-(4-farnesyloxy-3-methoxyphenyl)-propionic acid and/or its ethyl ester. 
     Compounds and extracts derived from  Acronychia  species are described in U.S. Pat. No. 9,220,928, which patent is herein incorporated by reference in entirety. 
     In certain embodiments, the 3-(4-farnesyloxyphenyl)-propionic acid and/or its ethyl ester is present in the extract the  Acronychia  and/or  Licaria  at a concentration equal to or greater than 1% (or about 1%) to about 20%, or optionally from about 7% (or about 7%) to about 10% (or about 10%), by weight of the  Acronychia  and/or  Licaria  extract. 
     Any of a variety of extracts of  Acronychia  and/or  Licaria  may be used for embodiments where the method comprises applying such an extract. The extract may be obtained from any part of the plant such as the fruit, the seed, the bark, the leaf, the flower, the roots and the wood. 
     In certain embodiments, the extract is obtained from the fruit of the plant. Suitable extracts of  Acronychia  or  Licaria  fruit, seed, bark, leaves, flower, root, and wood may be obtained using conventional methods including, but not limited to, direct extraction of material from the biomass by grinding, macerating, pressing, squeezing, mashing, centrifuging, and/or processes such as cold percolation, agitation/distillation, microwave assisted extraction, supercritical/subcritical CO 2  compressed gas extraction with or without polar modifiers, pressurized solvent extraction, accelerated solvent extraction, pressurized or normal hot water extraction, surfactant assisted pressurized hot water extraction, oil extraction, membrane extraction, Soxhlet extraction, the gold finger distillation/extraction and/or processes disclosed, for example, in U.S. Pat. Nos. 7,442,391, 7,473,435, and 7,537,791 to Integrated Botanical Technologies, LLC, incorporated herein by reference, and the like, or by other methods such as solvent extraction, and the like. Any of a variety of solvents including polar solvents, non-polar solvents, or combinations of two or more thereof may be used in methods of comprising solvent extraction. 
     Suitable polar solvents include polar inorganic solvents such as water and the like, polar organic solvents such as alcohols and corresponding organic acids, for example C 1 -C 8  alcohols including methanol, ethanol, propanol, butanol, and the like and organic acids, including acetic acid, formic acid, propanoic acid, and the like, polyols and glycols, including C 1 -C 8  polyols/glycols and the like, and combinations of two or more thereof. Suitable non-polar solvents include non-polar organic solvents such as alkanes, including C 1 -C 8  alkanes, cycloalkanes, including C 1 -C 8  alkanes, alkyl ethers, including C 1 -C 8  alkyl ethers, Petroleum ethers, ketones, including C 1 -C 8  ketones, methylene chloride, ethyl acetate, xylene, toluene, chloroform, vegetable oil, mineral oil and the like. In another embodiment extraction may be obtained by non-polar solvents described above or supercritical fluid extraction with or without a polar modifier such as C 1 -C 8  alcohols, water, C 1 -C 8  polyols/glycols or C 1 -C 8  organic acids. 
     In one embodiment, the extract comprises an extract of  Acronychia acidula . In another embodiment, the extract of the invention comprises a combination of polar and non-polar extracts of from  Acronychia acidula  fruit. In another embodiment, the extract of the invention comprises alcoholic or glycolic extracts of  Acronychia acidula  fruit. 
     In one embodiment, the extract comprises an extract of  Licaria vernicosa . In another embodiment, the extract of the invention comprises a combination of polar and non-polar extracts of from  Licaria vernicosa  wood or  Licaria vernicosa  root. In another embodiment, the extract of the invention comprises alcoholic extracts of  Licaria vernicosa  wood or  Licaria vernicosa  root. 
     In another embodiment, the extract of the invention comprises a polar extract prepared by extracting from fruit of  Acronychia acidula , wood of  Licaria vernicosa , or root of  Licaria vernicosa  using a polar solvent comprising water, C 1 -C 8  alcohols, C 1 -C 8  polyols, C 1 -C 8  glycols, and combinations of two or more thereof. In certain embodiments, the extract is extracted using one or more C 1 -C 4  alcohols, C 1 -C 4  polyols, and/or C 1 -C 4  glycols. In certain embodiments, the extract is prepared using a solvent comprising methanol, ethanol, or a combination thereof with or without presence of water. In another embodiment, the extract is a polar extract extracted from  Acronychia acidula  fruit using a combination of alcohol and water. In yet another embodiment, the extract is a polar extract extracted from the ground wood of  Licaria vernicosa , or ground root of  Licaria vernicosa  using methanol. 
     In yet another embodiment, the extract comprises a non-polar extract prepared by extracting from  Acronychia acidula  fruit,  Licaria vernicosa  wood, or  Licaria vernicosa  root using a non-polar solvent comprising one or more C 1 -C 8  alkanes, C 1 -C 8  cycloalkanes, C 1 -C 8  alkyl ethers, C 1 -C 8  alkyl esters and/or chloroform, more preferably one or more C 1 -C 8  alkanes, C 1 -C 8  alkyl esters and/or chloroform. In yet another embodiment, the non-polar extract is extracted from  Acronychia acidula  fruit,  Licaria vernicosa  wood, or  Licaria vernicosa  root using hexanes, ethyl acetate, chloroform or mixtures of two or more thereof. In yet another embodiment, the non-polar extract is extracted from  Acronychia acidula  fruit using ethyl acetate. 
     In one embodiment, the extract comprises an extract of  Calendula officinalis . In another embodiment, the extract of the invention comprises a combination of polar and non-polar extracts of  Calendula officinalis  petals. In another embodiment, the extract of the invention comprises a non-polar extract of  Calendula officinalis  petals. 
     In one embodiment, the extract comprises an extract of  Trigonella foenum - graecum . In another embodiment, the extract of the invention comprises a combination of polar and non-polar extracts of  Trigonella foenum - graecum  leaves. In another embodiment, the extract of the invention comprises a non-polar extract of  Trigonella foenum - graecum  leaves. 
     In yet another embodiment, the  Calendula  and/or  Trigonella  extract is a non-polar extract prepared using anon-polar solvent comprising one or more C 1 -C 8  alkanes, C 1 -C 8  cycloalkanes, C 1 -C 8  alkyl ethers, C 1 -C 8  alkyl esters and/or chloroform, more preferably one or more C 1 -C 8  alkanes, C 1 -C 8  alkyl esters and/or chloroform. 
     In yet another embodiment,  Calendula  and/or  Trigonella  extract is a non-polar extract prepared using hexanes, ethyl acetate, chloroform, or mixtures of two or more thereof. In yet another embodiment, the extract is a non-polar extract prepared using ethyl acetate. 
     In one embodiment, the botanical extracts may be obtained via extraction of cell cultures of various plants, including cell cultures of the genera  Acronychia, Licaria, Calendula , or  Trigonella . The cell cultures which are extracted to obtain botanical extracts for use in the invention may be of any form including suspension cell cultures and the like. 
     Extracts of  Calendula officinalis  and of  Trigonella foenum - graecum  can be obtained from Caithness Biotechnologies Ltd, UK (http://www.caithnessbiotechnologies.com/). These extracts are part of The Phytotitre Natural Product Library available to everyone for purchase. Alternatively, the extracts can be obtained using a preparation method described by Caithness Biotechnologies Ltd. as non-polar and prepared with a mixture of methanol and methylene chloride. For detailed description please consult webpage http://caithnessbiotechnologies.com/contact.html. In a typical extraction, a preweighed dried powdered biomass is suspended and stirred in a mixture of methanol/methylene chloride (1:1) over night at ambient temperature. The suspension is then filtered, filtrate is dried under reduced pressure to a residue free of solvents. 
     In certain embodiments, the extract of the  Acronychia, Licaria, Calendula , and/or  Trigonella  is present in the compositions of the present invention in an amount of from about 0.001% to about 10%, optionally, from about 0.001% to about 5%, or, optionally, from about 0.01% to about 1%, by weight of the composition. 
     Bacterial Extract(s) of the Genus  Actinomyces  Exhibiting Retinol-Like Properties and/or Benefits 
     In certain embodiments, the compounds/extracts exhibiting retinol-like properties and/or benefits comprise bacterial extract(s) of the genus  Actinomyces . Bacteria of the genus  Actinomyces  include many species fully characterized, as well as some of them which are not well characterized, for example one species collected from USA and labeled as species A5640. A sample of this bacteria is collected, grown in culture and made into an extract. The extract is a part of natural products collection now in control of the Baruch S. Blumberg Institute, Doylestown, Pa. (formerly known as the Institute of Hepatitis Virus Research Labs (IHVR)). Within the nomenclature of IHVR collection, the extract is labeled as IHVR_39565_F7. 
     In one embodiment, the extract used in the present invention is obtained from  Actinomyces  species with a capacity to produce similar chemical composition as is produced by extract A5640. In another embodiment, the bacteria are collected in the USA and the strain is identical to previously assigned species A5640. 
     In certain embodiments, the extract of  Actinomyces  is present in the composition of the present invention in an amount of from 0.001% to 10%, optionally, from 0.001% to 5%, or, optionally, from 0.01% to 1%, by weight of the composition. 
     Compound(s) of Formula (I) Exhibiting Retinol-Like Bioactivity and/or Properties. 
     In certain embodiments, the compounds/extracts exhibiting retinol-like properties and/or benefits comprise the compounds of Formula (I). 
     
       
         
         
             
             
         
       
     
     wherein—
         the dotted lines represent simple or double bound; optionally one of the dotted line is a double bound;   R 1  represent an H, a carbonated chain, linear, cyclic, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms;   R 2  represent a carbonated chain, linear, cyclic ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; optionally a methyl (—CH 3 ) or methylene (═CH 2 ) moiety; a carbonated chain, linear, ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; optionally from 1 to 10 carbon atoms; optionally 6 carbon atoms; optionally an aromatic moiety, optionally a phenyl moiety; preferably 2-methyl-prop-1,3-diene.       

     In certain embodiments, the compounds of Formula (I) include the corresponding salts of such metal ions as, but not limited to, Li + , Na + , K + , Ca 2+ , or Mg 2+ . 
     In certain embodiments, the compounds of Formula I are: 
     
       
         
         
             
             
         
       
     
     (2E,4E,6E)-7-(1,1,2,2,3,3-hexamethyl-2,3-dihydro-1H-inden-5-yl)-3-methylocta-2,4,6-trienoic acid 
     or 
     
       
         
         
             
             
         
       
     
     4-(1-(1,1,2,2,3,3-hexamethyl-2,3-dihydro-1H-inden-5-yl)vinyl)benzoic acid and, in each case, their derivatives that display retinoid-like activity. These compounds are referred referenced in Examples 6 and 7 below as Compound 1 and Compound 2, respectively. 
     The present invention is directed to compounds of Formula I such as (2E,4E,6E)-7-(1,1,2,2,3,3-hexamethyl-2,3-dihydro-1H-inden-5-yl)-3-methylocta-2,4,6-trienoic acid and 4-(1-(1,1,2,2,3,3-hexamethyl-2,3-dihydro-1H-inden-5-yl)vinyl)benzoic acid and their derivatives that display retinoid-like activity and mixtures thereof. 
     Mixtures of any of the above the compounds/extracts/extract sources exhibiting retinol-like properties and/or benefits may also be used. 
     Compounds and extracts of Formula I are described in US Patent Publication 2019/0091122, which patent is herein incorporated by reference in entirety. 
     In certain embodiments, the compound(s) of Formula I is present in the composition of the present invention in an amount of from about 0.0001% to about 20%, optionally, from about 0.001% to about 10%, optionally, from about 0.01% to about 5%, or optionally from about 0.2 to about 2%, by weight of the composition. In yet another embodiment, the compound(s) of Formula I is present in the composition of the present invention in an amount of from about 0.0001 to about 1%, optionally from about 0.001 to about 1%, or optionally from about 0.01 to about 1%, by weight of the composition. 
     Compositions The present inventors have discovered that compounds and/or extracts having retinol-like properties and/or benefits can promote and/or improve delivery/excretion of mucin from corneal epithelial cells. 
     Permeation Enhancer 
     In certain embodiments, the compositions of the present invention optionally comprise a permeation enhancer. 
     Suitable permeation enhancers include (selected from or selected from the group consisting of) either alone or in combination, surfactants such as saponins, polyoxyethylene, polyoxyethylene ethers of fatty acids such as polyoxyethylene 4-, 9-, 10-, and 23-lauryl ether, polyoxyethylene 10- and 20-cetyl ether, polyoxyethylene 10- and 20-stearyl ether, sorbitan monooleate, sorbitan monolaurate, polyoxyethylene monolaurate, polyoxyethylene sorbitans such as polyoxyethylene sorbitan monolaurate, decamethonium, decamethonium bromide, and dodecyltrimethylammonium bromide; chelators such natural poly acids (e.g., citric acid), phosphate salts (e.g., disodium pyrophosphate), phosphonates, bisphosphonates (e.g., etridronic acid), aminocarboxylic acids (e.g., ethylenediaminetetraacetic acid (EDTA) and disodium EDTA) and ethylenediamine-N,N′-disuccinic acid (EDDS)); bile salts and acids such as cholic acid, deoxycholic acid, glycocholic acid, glycodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, sodium cholate, sodium glycocholate, glycocholate, sodium deoxy cholate, sodium taurocholate, sodium glycodeoxy cholate, sodium taurodeoxy cholate, chenodeoxycholic acid, and urosdeoxycholic acid; fusidic acid derivatives, glycyrrhizic acid, and ammonium glycyrrhizide, with saponin EDTA, fusidic acid, polyoxyethylene 9-lauryl ether, polyoxyethylene 20-stearylether, glycocholate, or mixtures of any of the above. 
     The concentration of permeation enhancer administered should be the minimum amount needed to sufficiently increase absorption of the compound and/or extract through the mucous or other barrier membranes of the eye. Generally, concentrations ranging from 0.01% (or about 0.01%), optionally, from 0.05% (or about 0.05%), optionally, from 0.1% (or about 0.1%), optionally, from 0.15% (or about 0.15%), optionally, from 0.2% (or about 0.2%), optionally, from 0.25% (or about 0.25%) to 2% (or about 2%), optionally, to 2.5% (or about 2.5%), optionally, to 3% (or about 3%), optionally, to 3.5%, (or about 3.5%), optionally, to 4% (or about 4%), optionally, to 4.5% (or about 4.5%), optionally, to 5% (or about 5%), optionally, to 5.5% (or about 5.5%), optionally, to 6% (or about 6%), optionally, to 6.5% (or about 6.5%), optionally, to 7% (or about 7%), optionally, to 7.5% (or about 7.5%), optionally, to 8% (or about 8%), optionally, to 8.5% (or about 8.5%), optionally, to 9% (or about 9%), optionally, to 9.5% (or about 9.5%), optionally, to 10% (or about 10%), optionally, to 10.5% (or about 10.5%), optionally, to 11% (or about 11%), optionally, to 11.5% (or about 11.5%), optionally, to 12% (or about 12%), optionally, to 12.5% (or about 12.5%), optionally, to 13% (or about 13%), optionally, to 13.5% (or about 13.5%), optionally, to 14% (or about 14%), optionally, to 14.5% (or about 14.5%), optionally, to 15% (or about 15%), optionally, to 15.5% (or about 15.5%), optionally, to 16% (or about 16%), optionally, to 16.5% (or about 16.5%), optionally, to 17% (or about 17%), optionally, to 17.5% (or about 17.5%), optionally, to 18% (or about 18%), optionally, to 18.5% (or about 18.5%), optionally, to 19% (or about 19%), optionally, to 19.5% (or about 19.5%), optionally, to 20% (or about 20%), of the total composition (w/v), are useful in the compositions of the present invention. 
     Ophthalmologically Acceptable Carrier 
     The compositions of the present invention also comprise an aqueous, oil-in-water emulsion, or water-in-oil emulsion carrier. The carrier is ophthalmologically acceptable. Useful oil-in-water and water-oil-carriers can be found in US Patent Publication 20030165545A1 and U.S. Pat. Nos. 9,480,645, 8,828,412 and 8,496,976, each of which patent documents are herein incorporated by reference in its entirety. 
     The ophthalmologically acceptable carrier (or, compositions of the present invention) may optionally comprise one or more additional excipients and/or one or more additional active ingredients. Examples of such optional components are described below. 
     Excipients commonly used in ophthalmic compositions include, but are not limited to, demulcents, tonicity agents, preservatives, chelating agents, buffering agents (other than and in addition to the organic acids of the present invention), and surfactants. Other excipients comprise solubilizing agents, stabilizing agents, comfort-enhancing agents, polymers, emollients, pH-adjusting agents (other than and in addition to the organic acids of the present invention), and/or lubricants. Any of a variety of excipients may be used in the compositions of the present invention including water, mixtures of water and water-miscible solvents, such as vegetable oils or mineral oils comprising from 0.5% to 5% non-toxic water-soluble polymers, natural products, such as agar and acacia, starch derivatives, such as starch acetate and hydroxypropyl starch, and also other synthetic products such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, and preferably cross-linked polyacrylic acid and mixtures thereof. 
     Demulcents or soothing agents used with embodiments of the present invention include, but are not limited to, cellulose derivatives (such hydroxy ethyl cellulose, methyl cellulose, hypromellose or mixtures thereof), hyaluronic acid, tamarind seed extract, glycerin, polyvinyl pyrrolidone, polyethylene oxide, polyethylene glycol, propylene glycol and polyacrylic acid and mixtures thereof. In certain embodiments, one or more of hyaluronic acid, propylene glycol, tamarind seed extract, glycerin and/or polyethylene glycol 400 are the demulcents or soothing agents. In certain embodiments, the demulcent or soothing agent is selected from hyaluronic acid, tamarind seed extract or mixtures thereof. 
     Compositions of the present invention are ophthalmologically suitable for application to a subject&#39;s eyes. The term “aqueous” typically denotes an aqueous formulation wherein the excipient is &gt;about 50%, more preferably &gt;about 75% and in particular &gt;about 90% by weight water. In certain embodiments, the compositions of the present invention are essentially free of compounds which irritate the eye. In certain embodiments, the compositions of the present invention are essentially free of free fatty acids and C 1  to C 4  alcohols. In certain embodiments, the compositions of the present invention are comprise less than 40% (or about 40%), optionally, less than 35% (or about 35%), optionally, less than 30% (or about 30%), optionally less than 25% (or about 25%), optionally, less than 20% (or about 20%), optionally, less than 15% (or about 15%), optionally less than 10% (or about 10%), or optionally, less than 5% (or about 5%), by weight of the total composition, of a non-alcohol, organic excipient or solvent. These drops may be delivered from a single dose ampoule which may preferably be sterile and thus render bacteriostatic components of the formulation unnecessary. Alternatively, the drops may be delivered from a multi-dose bottle which may preferably comprise a device which extracts any preservative from the composition as it is delivered, such devices being known in the art. 
     In certain embodiments, the compositions of the present invention are isotonic, or slightly hypotonic in order to combat any hypertonicity of tears caused by evaporation and/or disease. This may require a tonicity agent to bring the osmolality of the formulation to a level at or near 210-320 milliosmoles per kilogram (mOsm/kg). The compositions of the present invention generally have an osmolality in the range of 220-320 mOsm/kg, or, optionally, have an osmolality in the range of 235-300 mOsm/kg. The ophthalmic compositions will generally be formulated as sterile aqueous solutions. 
     The osmolality of the compositions of the present invention may be adjusted with tonicity agents to a value which is compatible with the intended use of the compositions. For example, the osmolality of the composition may be adjusted to approximate the osmotic pressure of normal tear fluid, which is equivalent to about 0.9 w/v % of sodium chloride in water. Examples of suitable tonicity adjusting agents include, without limitation, sodium, potassium, calcium and magnesium chloride; dextrose; glycerin; propylene glycol; mannitol; sorbitol and the like and mixtures thereof. In one embodiment, a combination of sodium chloride and potassium chloride are used to adjust the tonicity of the composition. 
     The compositions of the present invention can also be used to administer pharmaceutically active compounds. Such compounds include, but are not limited to, glaucoma therapeutics, pain relievers, anti-inflammatory and anti-allergy medications, and anti-microbials. More specific examples of pharmaceutically active compounds include betaxolol, timolol, pilocarpine, carbonic anhydrase inhibitors and prostaglandins; dopaminergic antagonists; post-surgical antihypertensive agents, such as para-amino clonidine (apraclonidine); anti-infectives such as ciprofloxacin, moxifloxacin, and tobramycin; non-steroidal and steroidal anti-inflammatories, such as naproxen, diclofenac, nepafenac, suprofen, ketorolac, tetrahydrocortisol and dexamethasone; dry eye therapeutics such as PDE4 inhibitors; and anti-allergy medications such as H1/H4 inhibitors, H4 inhibitors, olopatadine or mixtures thereof. 
     It is also contemplated that the concentrations of the ingredients comprising the formulations of the present invention can vary. A person of ordinary skill in the art would understand that the concentrations can vary depending on the addition, substitution, and/or subtraction of ingredients in a given formulation. 
     In certain embodiments, the compositions of the present invention may have a pH which is compatible with the intended use, and is often in the range of 4 (or about 4) to 10 (or about 10), optionally between 6 (or about 6) to 8 (to about 8), optionally between 6.5 (or about 6.5) to 7.5 (or about 7.5), or optionally between 6.8 (or about 6.8) to 7.2 (or about 7.2). 
     In certain embodiments, a variety of conventional buffers may be employed, such as phosphate, borate, citrate, acetate, histidine, tris, bis-tris and the like and mixtures thereof. Borate buffers include boric acid and its salts, such as sodium or potassium borate. Potassium tetraborate or potassium metaborate, which produce boric acid or a salt of boric acid in solution, may also be employed. Hydrated salts such as sodium borate decahydrate can also be used. Phosphate buffers include phosphoric acid and its salts; for example, M 2 HPO 4  and MH 2 PO 4 , wherein M is an alkali metal such as sodium and potassium. 
     Hydrated salts can also be used. In one embodiment of the present invention, Na 2 HPO 4 .7H 2 O and NaH 2 PO 2 .H 2 O are used as buffers. The term phosphate also includes compounds that produce phosphoric acid or a salt of phosphoric acid in solution. Additionally, organic counter-ions for the above buffers may also be employed. The concentration of buffer generally varies from about 0.01 to 2.5 w/v % and more preferably varies from about 0.05 to about 0.5 w/v %. 
     In certain embodiments, the viscosity of the compositions of the present invention range from about 1 to about 500 cps, optionally from about 10 to about 200 cps, or optionally from about 10 to about 100 cps, when measured using a TA Instrument AR 2000 rheometer. The TA Instrument AR 2000 rheometer should be used with the AR2000 flow test method of the TA Rheological Advantage software with a 40 mm steel plate geometry; the viscosity ranges should be obtained by measuring steady state flow controlling shear rate from 0 sec −1  to 200 sec −1 . 
     In certain embodiments, the compositions of the present invention are useful as, and in the form of, eye-drop solution, eye wash solution, contact lens lubricating and/or rewetting solution, spray, mist or any other manner of administering a composition to the eye. 
     The compositions of the present invention may also be useful as, and in the form of, packing solutions for contact lenses. In certain embodiments, as packing solutions, the compositions of the present invention may be sealed in blister packaging and, also, suitable for undergoing sterilization. 
     Examples of blister packages and sterilization techniques are disclosed in the following references which are hereby incorporated by reference in their entirety, U.S. Pat. Nos. D435,966; 4,691,820; 5,467,868; 5,704,468; 5,823,327; 6,050,398, 5,696,686; 6,018,931; 5,577,367; and 5,488,815. This portion of the manufacturing process presents another method of treating the ophthalmic devices with anti-allergic agent, namely adding anti-allergic agents to a solution prior to sealing the package, and subsequently sterilizing the package. This is the preferred method of treating ophthalmic devices with anti-allergic agents. 
     Sterilization can take place at different temperatures and periods of time. The preferred sterilization conditions range from about 100° C. for about 8 hours to about 150° C. for about 0.5 minute. More preferred sterilization conditions range from about 115° C. for about 2.5 hours to about 130° C. for about 5.0 minutes. The most preferred sterilization conditions are about 124° C. for about 18 minutes. 
     When used as packing solutions, the compositions of the present invention may be water-based solutions. Typical packing solutions include, without limitation, saline solutions, other buffered solutions, and deionized water. In certain embodiments, the packing solution is an aqueous solution of deionized water or saline solution containing salts including, without limitation, sodium chloride, sodium borate, sodium phosphate, sodium hydrogenphosphate, sodium dihydrogenphosphate, or the corresponding potassium salts of the same. These ingredients are generally combined to form buffered solutions that include an acid and its conjugate base, so that addition of acids and bases cause only a relatively small change in pH. In certain embodiments, the pH of the packing solution is as described above. The buffered solutions may additionally include 2-(N-morpholino)ethanesulfonic acid (MES), sodium hydroxide, 2,2-bis(hydroxymethyl)-2,2′,2″-nitrilotriethanol, n-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid, citric acid, sodium citrate, sodium carbonate, sodium bicarbonate, acetic acid, sodium acetate, ethylenediamine tetraacetic acid and the like and combinations thereof. Preferably, the solution is a borate buffered or phosphate buffered saline solution or deionized water. The particularly preferred solution contains about 500 ppm to about 18,500 ppm sodium borate, most particularly preferred about 1000 ppm of sodium borate. 
     If any ingredients incorporated into the packing solutions are subject to oxidative degradation, agents that stabilize packing solutions containing such ingredients may be added. Such “oxidative stabilization agents” include but are not limited to chelants such as EDTA, Dequest, Desferal, silica, chitin derivatives such as chitosan, cellulose and its derivatives, and N,N,N′,N′,N″,N″-hexa(2-pyridyl)-1,3,5-tris(aminomethyl)benzene, and certain macrocyclic ligands such as crown ethers, ligand containing knots and catenands. See, David A. Leigh et al Angew. Chem Int. Ed., 2001, 40, No. 8, pgs. 1538-1542 and Jean-Claude Chambron et al. Pure &amp; Appl. Chem., 1990, Vol. 62, No. 6, pgs. 1027-1034. Oxidative stabilization agents may include other compounds that inhibit oxidations such as those selected from the group consisting of 2,2′,2″,6,6′,6″-Hexa-(1,1-dimethylethyl)4,4′,4″-[(2,4,6-trimethyl-1,3,5-benzenetriyl)-trismethylene]-triphenol (Irganox 1330), 1,3,5tris[3,5-di(1,1-dimethylethyl)4-hydroxybenzyl]-1H,3H,5H-1,3,5-triazine-2,4,6-trione, pentaerythrityl tetrakis[3-[3,5-di(1,1-dimethylethyl)-4-hydroxyphenyl]-propionate], octadecyl-3-[3,5-di(1,1-dimethylethyl)-4-hydroxyphenyl]-propionate, tris[2,4-di(1,1-dimethylethyl)-phenyl]-phosphite, 2,2′-di(octadecyloxy)-5,5′-spirobi(1,3,2-dioxaphosphorinane), dioctadecyl disulphide, didodecyl-3,3′-thiodipropionate, dioctadecyl-3,3′-thiodipropionate, butylhydroxytoluene, ethylene bis[3,3-di[3-(1,1-dimethylethyl)-4-hydroxyphenyl]butyrate] and mixtures thereof. The preferred oxidative stabilization agents are diethylenetriaminepentaacetic acid (“DTP A”), or salts of DTP A such as CaNa3DTPA, ZnNa3DTPA, and Ca2DTPA. See, U.S. App. Pat. No. 60/783,557 filed on, Mar. 17, 2006, entitled “Methods for Stabilizing Oxidatively Unstable Pharmaceutical Compositions” and its corresponding non-provisional filing which are hereby incorporated by reference in their entirety. In certain embodiments, the concentration of oxidative stabilization agents in the solution be from about 2.5 μmoles/liter to about, 5000 μmoles/liter, optionally, from about 20 μmoles/liter to about 1000 μmoles/liter, optionally from about 100 μmoles/liter to about 1000 μmoles/liter, or optionally from about 100 μmoles/liter to about 500 μmoles/liter. 
     In particular embodiments, the compositions of the present invention are formulated for administration at any frequency of administration, including once a week, once every five days, once every three days, once every two days, twice a day, three times a day, four times a day, five times a day, six times a day, eight times a day, every hour, or greater frequency. Such dosing frequency is also maintained for a varying duration of time depending on the therapeutic needs of the user. The duration of a particular therapeutic regimen may vary from one-time dosing to a regimen that extends for months or years. One of ordinary skill in the art would be familiar with determining a therapeutic regimen for a specific indication. 
     The composition and products containing such compositions of this invention may be prepared using methodology that is well known by an artisan of ordinary skill. 
     EXAMPLES 
     Any compositions of the present invention as described in following examples illustrate specific embodiments of compositions of the present invention but are not intended to be limiting thereof. Other modifications can be undertaken by the skilled artisan without departing from the spirit and scope of this invention. 
     The following test methods were used in the Examples: 
     Example 1 
     Compositions of Lemon aspen extract showed an increase of MUC1, MUC4 and MUC16 gene expressions in human epicorneal 3D tissues when treated in the medium. 
     EpiCorneal 3D human tissues were purchased from MatTek Company (Ashland, Mass., USA). Upon receiving, epicorneal 3D human tissues, they were incubated in MatTek assay medium overnight following the manufacturer&#39;s instruction. The epicorneal 3D human tissues were divided into three treatment groups with at least three tissues per group. Lemon aspen extract were added, respectively, into the culture medium containing the human epicorneal tissues of two of the treatment groups to produce media concentrations of 0.001% or 0.01% (w/v), respectively. The epicorneal tissues in all four treatment groups were allowed to incubate for two days. The extract of lemon aspen used in the and extracted and supplied by Southern Cross Botanicals (Knockrow Nsw, Australia. After the two days&#39; incubation, gene expressions of mucin 1 (MUC1), mucin 4 (MUC4) and mucin 16 (MUC16) were analyzed. After two days&#39; incubation, the human epicorneal 3D tissues were cut in halves and half of the tissues were lysed in 350 μL lysis buffer, consisting of 100 parts RLT buffer (RNeasy Mini kit, Qiagen, Valencia, Calif.), to one part 2-mercaptoethanol. RNA was extracted from the solutions using the RNeasy Mini Kit (Qiagen, Valencia, Calif.) according to manufacturer&#39;s instructions and RNA was eluted in 25 μL RNase-free water. 
     Reverse transcription (RT) was performed using the Applied Biosystems High Capacity Reverse Transcription Kit (ThermoFisher Scientific, Bridgewater, N.J.). Gene expression assays sold under the tradename TAQMAN for mucin-1 (MUC1), mucin-4 (MUC4) and mucin-16 (MUC16) polymerase (RNA) II polypeptide A (POLR2A), and Master Mix were purchased from ThermoFisher Scientific (Bridgewater, N.J.). qPCR analysis was performed using TaqMan® Master Mix (ThermoFisher Scientific, Bridgewater, N.J.), and run on a real time PCR system sold under the tradename QUANTSTUDIO 7 Flex System (ThermoFisher Scientific, Bridgewater, N.J.). The expression of the MUC1, MUC4 and MUC16 genes were normalized against the expression of the human POLR2A housekeeping gene. The fold changes were calculated in comparison to the untreated control (UT) and two-tailed two-sample Student t-tests (Microsoft Office Excel 2007; Microsoft, Redmond, Wash., USA) were performed. Results are shown in  FIG. 1 . 
     Example 2 
     Compositions of Lemon aspen extract showed an increase of mucin-1 secretion in human epicorneal 3D tissues when treated in the medium. 
     EpiCorneal 3D human tissues were purchased from MatTek Company (Ashland, Mass., USA). Upon receiving, epicorneal 3D human tissues, they were incubated in MatTek assay medium overnight following the manufacturer&#39;s instruction. The epicorneal 3D human tissues were divided into three treatment groups with at least three tissues per group. Lemon aspen extract were added, respectively, into the culture medium containing the human epicorneal tissues of two of the treatment groups to produce media concentrations of 0.001% or 0.01% (w/v), respectively. The epicorneal tissues in all four treatment groups were allowed to incubate for two days. After the two days, culture media were collected for measuring mucin 1 secretion using human mucin-1 (CA15-3) enzyme-linked immunosorbent assay (ELISA) kit (EHMUC1, ThermoFisher Scientific, Bridgewater, N.J.) following the manufacturer&#39;s protocol. To assess activity, the colorimetric change was measured using a microplate reader (SpectraMax M2E, Molecular Devices, Sunnyvale, Calif., USA). This assay employs the standard enzyme-linked immunoassay technique, so there is a linear correlation between Mucin-1 concentration in the sample and the colorimetric change. A standard curve was generated, with the Mucin-1 concentration on the x-axis and absorbance on the y-axis to indicate corresponding Mucin-1 concentration. Results are shown below in  FIG. 2 . 
     Example 3 
     Solutions can be prepared containing one or more compounds and/or extract having retinol-like properties and/or benefits of the present invention as shown in Examples 3-7. 
     Table 1 illustrates the components of such formulations (as illustrated in formulations 3A-3D), which components can be incorporated as described below using conventional mixing technology. 
                                         TABLE 1                                  3C   3D           3A   3B   Useful for Relief of   Useful for Relief of           Useful for Relief of   Useful for Relief of   Dry Eye Irritation   Dry Eye Irritation           Dry Eye Irritation   Dry Eye Irritation   for Contact Lenses   for Contact Lenses                                                         amount       amount       amount       amount           %   per batch   %   per batch   %   per batch   %   per batch       INGREDIENT   w/w   (gms)   w/w   (gms)   w/w   (gms)   w/w   (gms)                                                         Sodium   0.20   2.0   0.30   3.0   0.15   1.5   0.15   1.5       Hyaluronate       Lemon Aspen   0.10   1.0   0.01   0.10   0.10   1.0   0.01   0.10       Extract       Polysorbate 80   1.0   10.0   0.2   2.0   1.0   10.0   0.2   2.0       Polysorbate 20   5.0   50.0   1.0   10.0   2.0   20.0   1.0   10.0       Polyethylene   0.25   2.5   0.25   2.5   0   0   0   0       Glycol 400       Boric Acid   0.60   6.0   0.60   6.0   0.60   6.0   0.60   6.0       Sodium Borate   0.05   0.50   0.05   0.50   0.05   0.50   0.05   0.50       Sodium       Chloride*       Potassium   0.10   1.0   0.10   1.0   0.10   1.0   0.10   1.0       Chloride       Calcium   0.006   0.06   0.006   0.06   0.006   0.06   0.006   0.06       Chloride       Dihydrate       Magnesium   0.006   0.06   0.006   0.06   0.006   0.06   0.006   0.06       Chloride       Sodium Chlorite   0.014   0.14   0.014   0.14   0.014   0.14   0.014   0.14       Dihydrate       Polyquaternium   0.0015   0.015   0.0015   0.015   0.0015   0.015   0.0015   0.015       42 (33% aqueous)       Sodium Chlorite   0.014   0.14   0.014   0.14   0.014   0.14   0.014   0.14       Dihydrate       1N Sodium       Hydroxide       solution**       1N Hydrochloric       Acid solution**       Purified       Water***           total   100.00%   1000.0 g   100.00%   1000.0 g   100.00%   1000.00 g   100.00%   1000.00 g               *can be adjusted to tonicity of 280-290 mOsm/Kg       **can adjust to pH 7.2       ***optionally, q.s to 100% w/w            
For Examples 3A-3D: The Sodium Hyaluronate can be supplied by CONTIPRO A.S. (DOLNI, DOBROUC, CZECH REPUBLIC)
 
For Examples 3A-3D: The Lemon Aspen Extract (Abacross™  Acronychia acidula  fruit extract) can be supplied by SOUTHERN CROSS BOTANICALS (KNOCKROW NSW, AUSTRALIA).
 
For Examples 3A-3D: The Polysorbate 20 can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 3A-3D: The Polysorbate 80 can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 5A-5B: The Polyethylene Glycol 400 can be supplied by Clariant Produkte (BURGKIRCHEN, GERMANY).
 
For Examples 3A-3D: The Boric Acid can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 3A-3D: The Sodium Borate can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 3A-3D: The Sodium Chloride can be supplied by Caldic (DUSSELDORF, GERMANY).
 
For Examples 3A-3D: The Potassium Chloride can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 3A-3D: The Calcium Chloride Dihydrate can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 3A-3D: The Magnesium Chloride can be supplied by KGaA (DARMSTADT, GERMANY).
 
For Examples 3A-3D: The Polyquatemium-42 (33% aqueous) can be supplied by DSM BIOMEDICAL (BERKELEY, Calif., USA).
 
For Examples 3A-3D: The Sodium Chlorite Dihydrate can be supplied by Oxychem (WICHITA, Kans., USA)
 
For Examples 3A-3D: The 1N Sodium Hydroxide can be supplied by VWR (RADNER, Pa., USA).
 
For Examples 3A-3D: The 1N Hydrochloric acid can be supplied by VWR (RADNER, Pa., USA).
 
     Solution 3A can be Prepared as Follows: 
     1. To a 1500 ml beaker is added 800 grams of Purified Water USP.
 
2. To the above is added 10 g of Polysorbate 80 and 50 g of Polysorbate 20. The solution is mixed until both are fully mixed and dissolved.
 
3. To the above is added 1.0 g of Lemon Aspen Extract. The solution is mixed until the Lemon Aspen Extract is dissolved.
 
4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.
 
5. To the solution of Step 4 is added 2.0 grams of Sodium Hyaluronate. The solution is mixed to fully dissolve the Sodium Hyaluronate.
 
6. The following ingredients are next added sequentially, allowing for each to dissolve before adding the next: 2.5 grams Polyethylene Glycol 400, 6.0 grams Boric acid, 0.05 gram Sodium Borate, 1.0 gram Potassium Chloride, 0.06 gram Calcium Chloride Dihydrate, 0.06 gram Magnesium Chloride, and 0.0015 grams Polyquatemium-42 (aqueous).
 
7. While continuing to mix, 0.14 gram Sodium Chlorite Dihydrate is added and mixed to dissolve.
 
8. The tonicity of the formula is determined and adjusted to 280 mOsm/Kg with Sodium Chloride.
 
9. The pH of the formula is adjusted to pH of 7.2 using the 1N Sodium Hydroxide and/or 1N Hydrochloric acid.
 
10. The solution is brought to 1000.0 grams using Purified Water USP and mixed for 10 minutes to be fully uniform.
 
11. The solution is filtered using a 0.22 micron filter.
 
     Solution 3B can be Prepared as Follows: 
     1. To a 1500 ml beaker is added 800 grams of Purified Water USP.
 
2. To the above is added 2 g of Polysorbate 80 and 10 g of Polysorbate 20. The solution is mixed until both are fully mixed and dissolved.
 
3. To the above is added 0.1 g of Lemon Aspen Extract. The solution is mixed until the Lemon Aspen Extract is dissolved.
 
4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.
 
5. To the solution of Step 4 is added 3.0 grams of Sodium Hyaluronate. The solution is mixed to fully dissolve the Sodium Hyaluronate.
 
6. The following ingredients are next added sequentially, allowing for each to dissolve before adding the next: 2.5 grams Polyethylene Glycol 400, 6.0 grams Boric acid, 0.05 gram Sodium Borate, 1.0 gram Potassium Chloride, 0.06 gram Calcium Chloride Dihydrate, 0.06 gram Magnesium Chloride, and 0.0015 grams Polyquatemium-42 (aqueous).
 
7. While continuing to mix, 0.14 gram Sodium Chlorite Dihydrate is added and mixed to dissolve.
 
8. The tonicity of the formula is determined and adjusted to 280 mOsm/Kg with Sodium Chloride.
 
9. The pH of the formula is adjusted to pH of 7.2 using the 1N Sodium Hydroxide and/or 1N Hydrochloric acid.
 
10. The solution is brought to 1000.0 grams using Purified Water USP and mixed for 10 minutes to be fully uniform.
 
11. The solution is filtered using a 0.22 micron filter.
 
     Solution 3C can be Prepared as Follows: 
     1. To a 1500 ml beaker is added 800 grams of Purified Water USP.
 
2. To the above is added 10 g of Polysorbate 80 and 20 g of Polysorbate 20. The solution is mixed until both are fully mixed and dissolved.
 
3. To the above is added 1.0 g of Lemon Aspen Extract. The solution is mixed until the Lemon Aspen Extract is dissolved.
 
4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.
 
5. To the solution of Step 4 is added 1.5 grams of Sodium Hyaluronate. The solution is mixed to fully dissolve the Sodium Hyaluronate.
 
6. The following ingredients are next added sequentially, allowing for each to dissolve before adding the next: 6.0 grams Boric acid, 0.05 gram Sodium Borate, 1.0 gram Potassium Chloride, 0.06 gram Calcium Chloride Dihydrate, 0.06 gram Magnesium Chloride and 0.0015 grams Polyquatemium-42 (aqueous).
 
7. While continuing to mix, 0.14 gram Sodium Chlorite Dihydrate is added and mixed to dissolve.
 
8. The tonicity of the formula is determined and adjusted to 280 mOsm/Kg with Sodium Chloride.
 
9. The pH of the formula is adjusted to pH of 7.2 using the 1N Sodium Hydroxide and/or 1N Hydrochloric acid.
 
10. The solution is brought to 1000.0 grams using Purified Water USP and mixed for 10 minutes to be fully uniform.
 
11. The solution is filtered using a 0.22 micron filter.
 
     Solution 3D can be Prepared as Follows: 
     1. To a 1500 ml beaker is added 800 grams of Purified Water USP.
 
2. To the above is added 2 g of Polysorbate 10 and 50 g of Polysorbate 20. The solution is mixed until both are fully mixed and dissolved.
 
3. To the above is added 0.1 g of Lemon Aspen Extract. The solution is mixed until the Lemon Aspen Extract is dissolved.
 
4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.
 
5. To the solution of Step 4 is added 1.5 grams of Sodium Hyaluronate. The solution is mixed to fully dissolve the Sodium Hyaluronate.
 
6. The following ingredients are next added sequentially, allowing for each to dissolve before adding the next: 6.0 grams Boric acid, 0.05 gram Sodium Borate, 1.0 gram Potassium Chloride, 0.06 gram Calcium Chloride Dihydrate, 0.06 gram Magnesium Chloride and 0.0015 grams Polyquatemium-42 (aqueous).
 
7. While continuing to mix, 0.14 gram Sodium Chlorite Dihydrate is added and mixed to dissolve.
 
8. The tonicity of the formula is determined and adjusted to 280 mOsm/Kg with Sodium Chloride.
 
9. The pH of the formula is adjusted to pH of 7.2 using the 1N Sodium Hydroxide and/or 1N Hydrochloric acid.
 
10. The solution is brought to 1000.0 grams using Purified Water USP and mixed for 10 minutes to be fully uniform.
 
11. The solution is filtered using a 0.22 micron filter.
 
     Example 4 
     Table 2 illustrates the components of formulations of the present invention (as illustrated in formulations 4A-4D), which components can be incorporated as described below using conventional mixing technology. 
                                         TABLE 2                              4B   4C               4A   Useful for Relief of   Useful for Relief of   4D           Useful for Relief of   Dry Eye Irritation   Dry Eye Irritation   Useful for Relief of           Dry Eye Irritation   for Contact Lenses   for Contact Lenses   Dry Eye Irritation                                                         amount       amount       amount       amount           %   per batch   %   per batch   %   per batch   %   per batch       INGREDIENT   w/w   (gms)   w/w   (gms)   w/w   (gms)   w/w   (gms)                                                         Sodium   0   0   0   0   0.120   1.20   0.120   1.20       Hyaluronate       Tamarind Seed   0   0   0   0   0.200   2.00   0.200   2.00       Polysaccharide       Lemon Aspen   0.10   1.0   0.10   1.0   0.01   0.10   0.01   0.10       Extract       Polysorbate 80   1.0   10.0   1.0   10.0   0.2   2.0   0.2   2.0       Polysorbate 20   5.0   50.0   5.0   50.0   1.0   10.0   1.0   10.0       Polyethylene   0   0   0   0   0.25   2.5   0.25   2.5       Glycol 400       Glycerin   0.25   2.5   0.25   2.5   0.25   2.5   0.25   2.5       Hypromellose E3   0.198   1.98   0.198   1.98   0.198   1.98   0.198   1.98       2910       Boric Acid   0.40   4.0   0.40   4.0   0.40   4.0   0.40   4.0       Sodium Borate   0.022   0.22   0.022   0.22   0.022   0.22   0.022   0.22       Disodium   0.027   0.27   0.027   0.27   0.027   0.27   0.027   0.27       Phosphate       Sodium Citrate   0.40   4.0   0.40   4.0   0.40   4.0   0.40   4.0       Dihydrate       Sodium       Chloride*       Potassium   0.10   1.0   0.10   1.0   0.10   1.0   0.10   1.0       Chloride       50% Aqueous   0.057   0.57   0.057   0.57   0.057   0.57   0.057   0.57       Solution of       Sodium Lactate       Magnesium   0.013   0.13   0.013   0.13   0.013   0.13   0.013   0.13       Chloride       Glucose   0.0036   0.036   0.0036   0.036   0.0036   0.036   0.0036   0.036       Glycine   0.00002   0.0002   0.00002   0.0002   0.00002   0.0002   0.00002   0.0002       Ascorbic Acid   0.00001   0.0001   0.00001   0.0001   0.00001   0.0001   0.00001   0.0001       Disodium Edetate   0.01   0.1   0.05   0.5   0.01   0.1   0.05   0.5       Polyquaternium   0.0030   0.030   0.0015   0.015   0.0030   0.030   0.0015   0.015       42 (33% aqueous)       Sodium Chlorite   0.014   0.14   0.014   0.14   0.014   0.14   0.014   0.14       Dihydrate       1N Sodium       Hydroxide       solution**       1N Hydrochloric       Acid solution**       Purified       Water***           total   100.00%   1000.00 g   100.00%   1000.00 g   100.00%   1000.00 g   100.00%   1000.00 G               *can be adjusted to tonicity of 280-290 mOsm/Kg       **can adjust to pH 7.2       ***optionally, q.s to 100% w/w            
For Examples 4C-4D: The Sodium Hyaluronate can be supplied by CONTIPRO A.S. (DOLNI, DOBROUC, CZECH REPUBLIC)
 
For Examples 4C-4D: The Tamarind Seed Polysaccharide cab be supplied by INDENA (MILANO, ITALY).
 
For Examples 4A-4D: The Lemon Aspen Extract (Abacross™  Acronychia acidula  fruit extract) can be supplied by SOUTHERN CROSS BOTANICALS (KNOCKROW NSW, AUSTRALIA).
 
For Examples 4A-4D: The Polysorbate 20 can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 4A-4D: The Polysorbate 80 can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 6C-6D: The Polyethylene Glycol 400 can be supplied by Clariant Produkte (BURGKIRCHEN, GERMANY).
 
For Examples 4A-4D: The Boric Acid can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 4A-4D: The Sodium Borate can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 4A-4D: The Sodium Chloride can be supplied by Caldic (DUSSELDORF, GERMANY).
 
For Examples 4A-4D: The Potassium Chloride can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 4A-4D: The Hypromellose E3 2910 can be supplied by DOW CHEMICAL (PLAQUEMINE, LOUISIANA, USA).
 
For Examples 4A-4D: The Glycerin can be supplied by Emery Oleochemicals GmbH (DUSSELDORF, GERMANY).
 
For Examples 4A-4D: The Disodium Phosphate can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 4A-4D: The Sodium Citrate can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 4A-4D: The Sodium Lactate can be supplied as Sodium Lactate (50% aqueous) by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 4A-4D: The Glucose can be supplied by Roquette Freres (LASTREM, FRANCE).
 
For Examples 4A-4D: The Glycine can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 4A-4D: The Ascorbic Acid can be supplied by DSM NUTRITIONAL Products (DRAKEMYRE, SCOTLAND, UK).
 
For Examples 4A-4D: The Polyquatemium 42 can be supplied as Polyquatemium 42 (33% aqueous) by DSM BIOMEDICAL, (BERKELEY, Calif.).
 
For examples 4A-4D: The Disodium Edetate can be supplied by Merck NV/SA (OVERUSE, BELGIUM).
 
For Examples 4A-4D: The 1N Sodium Hydroxide can be supplied by VWR (RADNER, Pa., USA).
 
For Examples 4A-4D: The 1N Hydrochloric acid can be supplied by VWR (RADNER, Pa., USA).
 
For Examples 6A-6D: The Sodium Chlorite Dihydrate can be supplied by Oxychem (WICHITA, Kans., USA)
 
     Solution 4A can be Prepared as Follows: 
     1. To a 1500 ml beaker is added 800 grams of Purified Water USP.
 
2. To the above is added 10 g of Polysorbate 80 and 50 g of Polysorbate 20. The solution is mixed until both are fully mixed and dissolved.
 
3. To the above is added 1.0 g of Lemon Aspen Extract. The solution is mixed until the Lemon Aspen Extract is dissolved.
 
4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.
 
5. To the above is added 1.98 g of Hypromellose E3 Premium. The solution is mixed until the Hypromellose E3 Premium dissolved.
 
6. The following ingredients are next added sequentially, allowing each to dissolve before adding the next: 2.50 grams Glycerin, 4.0 grams Boric acid, 0.22 gram Sodium Borate, 0.27 gram Disodium Phosphate, 4.00 grams Sodium Citrate Dihydrate, 1 gram Potassium Chloride, 0.57 gram Sodium Lactate (50% aqueous), 0.13 gram Magnesium Chloride, 0.036 gram Glucose, 0.0002 gram Glycine, 0.0001 gram Ascorbic acid, 0.10 gram Disodium Edetate, 0.030 gram Polyquatemium-42 (33% aqueous), and 0.14 gram Sodium Chlorite.
 
7. The tonicity of the solution is determined and adjusted to 280 mOsm with Sodium Chloride.
 
8. The pH of the solution is measured and adjusted to 7.2 with 1N Sodium Hydroxide and/or 1N Hydrochloric acid.
 
9. The solution is brought to a volume of 1,000.00 grams with Purified Water and mixed for 10 minutes.
 
10. The solution is filtered using a 0.22 micron filter.
 
     Solution 4B can be Prepared as Follows: 
     1. To a 1500 ml beaker is added 800 grams of Purified Water USP.
 
2. To the above is added 10 g of Polysorbate 80 and 50 g of Polysorbate 20. The solution is mixed until both are fully mixed and dissolved.
 
3. To the above is added 1.0 g of Lemon Aspen Extract. The solution is mixed until the Lemon Aspen Extract is dissolved.
 
4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.
 
5. To the above is added 1.98 g of Hypromellose E3 Premium. The solution is mixed until the Hypromellose E3 Premium dissolved.
 
6. The following ingredients are next added sequentially, allowing each to dissolve before adding the next: 2.50 grams Glycerin, 4.0 grams Boric acid, 0.22 gram Sodium Borate, 0.27 gram Disodium Phosphate, 4.00 grams Sodium Citrate Dihydrate, 1 gram Potassium Chloride, 0.57 gram Sodium Lactate (50% aqueous), 0.13 gram Magnesium Chloride, 0.036 gram Glucose, 0.0002 gram Glycine, 0.0001 gram Ascorbic acid, 0.05 gram Disodium Edetate, 0.015 gram Polyquatemium-42 (33% aqueous), and 0.14 gram Sodium Chlorite.
 
7. The tonicity of the solution is determined and adjusted to 280 mOsm with Sodium Chloride.
 
8. The pH of the solution is measured and adjusted to 7.2 with 1N Sodium Hydroxide and/or 1N Hydrochloric acid.
 
9. The solution is brought to a volume of 1,000.00 grams with Purified Water and mixed for 10 minutes.
 
10. The solution is filtered using a 0.22 micron filter.
 
     Solution 4C can be Prepared as Follows: 
     1. To a 1500 ml beaker is added 800 grams of Purified Water USP.
 
2. To the above is added 2 g of Polysorbate 80 and 10 g of Polysorbate 20. The solution is mixed until both are fully mixed and dissolved.
 
3. To the above is added 0.1 g of Lemon Aspen Extract. The solution is mixed until the Lemon Aspen Extract is dissolved.
 
4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.
 
5. To the solution of Step 4 is added 1.2 grams of Sodium Hyaluronate. The solution is mixed to fully dissolve the Sodium Hyaluronate.
 
6. To the above is added 2.0 grams of Tamarind Seed Polysaccharide. The solution is mixed to fully dissolve the Tamarind Seed Polysaccharide.
 
7. To the above is added 1.98 g of Hypromellose E3 Premium. The solution is mixed until the Hypromellose E3 Premium dissolved.
 
8. The following ingredients are next added sequentially, allowing each to dissolve before adding the next: 2.50 grams Polyethylene Glycol 400, 2.50 grams Glycerin, 4.0 grams Boric acid, 0.22 gram Sodium Borate, 0.27 gram Disodium Phosphate, 4.00 grams Sodium Citrate Dihydrate, 1 gram Potassium Chloride, 0.57 gram Sodium Lactate (50% aqueous), 0.13 gram Magnesium Chloride, 0.036 gram Glucose, 0.0002 gram Glycine, 0.0001 gram Ascorbic acid, 0.10 gram Disodium Edetate, 0.030 gram Polyquatemium-42(33% aqueous), and 0.14 gram Sodium Chlorite.
 
9. The tonicity of the solution is determined and adjusted to 280 mOsm with Sodium Chloride.
 
10. The pH of the solution is measured and adjusted to 7.2 with 1N Sodium Hydroxide and/or 1N Hydrochloric acid.
 
11. The solution is brought to a volume of 1,000.00 grams with Purified Water and mixed for 10 minutes.
 
12. The solution is filtered using a 0.22 micron filter.
 
     Solution 4D can be Prepared as Follows: 
     1. To a 1500 ml beaker is added 800 grams of Purified Water USP.
 
2. To the above is added 2 g of Polysorbate 80 and 10 g of Polysorbate 20. The solution is mixed until both are fully mixed and dissolved.
 
3. To the above is added 0.1 g of Lemon Aspen Extract. The solution is mixed until the Lemon Aspen Extract is dissolved.
 
4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.
 
5. To the solution of Step 4 is added 1.2 grams of Sodium Hyaluronate. The solution is mixed to fully dissolve the Sodium Hyaluronate.
 
6. To the above is added 2.0 grams of Tamarind Seed Polysaccharide. The solution is mixed to fully dissolve the Tamarind Seed Polysaccharide.
 
7. To the above is added 1.98 g of Hypromellose E3 Premium. The solution is mixed until the Hypromellose E3 Premium dissolved.
 
8. The following ingredients are next added sequentially, allowing each to dissolve before adding the next: 2.50 grams Polyethylene Glycol 400, 2.50 grams Glycerin, 4.0 grams Boric acid, 0.22 gram Sodium Borate, 0.27 gram Disodium Phosphate, 4.00 grams Sodium Citrate Dihydrate, 1 gram Potassium Chloride, 0.57 gram Sodium Lactate (50% aqueous), 0.13 gram Magnesium Chloride, 0.036 gram Glucose, 0.0002 gram Glycine, 0.0001 gram Ascorbic acid, 0.10 gram Disodium Edetate, 0.015 gram Polyquatemium-42 (33% aqueous), and 0.14 gram Sodium Chlorite.
 
9. The tonicity of the solution is determined and adjusted to 280 mOsm with Sodium Chloride.
 
10. The pH of the solution is measured and adjusted to 7.2 with 1N Sodium Hydroxide and/or 1N Hydrochloric acid.
 
11. The solution is brought to a volume of 1,000.00 grams with Purified Water and mixed for 10 minutes.
 
12. The solution is filtered using a 0.22 micron hydrophilic filter.
 
     Example 5 
     Table 3 illustrates the components of formulations of the present invention (as illustrated in formulations 5A and 5B), which components can be incorporated as described below using conventional mixing technology. 
                                 TABLE 3                          5A   5B           Useful for Relief of   Useful for Relief of           Dry Eye Irritation   Dry Eye Irritation                                         amount       amount           %   per batch   %   per batch       INGREDIENT   w/w   (gms)   w/w   (gms)                                         Sodium   0.20   2.0   0.10   1.0       Hyaluronate       Tamarind Seed   0   0   0.20   2.0       Polysaccharide       Lemon Aspen   0.01   0.1   0.10   1.0       Extract       Polysorbate 80   0.2   2.0   1.0   10.0       Polysorbate 20   1.0   10.0   5.0   50.0       Polyethylene   0.25   2.5   0.25   2.5       Glycol 400       Boric Acid   0.60   6.0   0.60   6.0       Sodium Borate   0.06   0.60   0.06   0.60       Sodium       Chloride*       Super refined   0.625   6.25   0.625   6.25       Castor Oil       Lumuluse   0.50   5.0   0.50   5.0       GRH-40       Ethyl linolenate   0.10   1.0   0   0       Retinyl   0.05   0.5   0   0       Palmitate       Polyquaternium   0.0045   0.045   0.0045   0.045       42       (33% aqueous)       1N Sodium       Hydroxide       solution**       1N       Hydrochloric       Acid solution**       Purified       Water***                       Total   100.00%   1000.0 g   100.00%   1000.0 g               *can be adjusted to tonicity of 280-290 mOsm/Kg       **can adjust to pH 7.2       ***optionally, q.s to 100% w/w            
For Examples 5A-5B: The Sodium Hyaluronate can be supplied by CONTIPRO A.S. (DOLNI, DOBROUC, CZECH REPUBLIC)
 
For Examples 5A-5B: The Lemon Aspen Extract (Abacross™  Acronychia acidula  fruit extract) can be supplied by SOUTHERN CROSS BOTANICALS (KNOCKROW NSW, AUSTRALIA).
 
For Examples 5A-5B: The Polysorbate 20 can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 5A-5B: The Polysorbate 80 can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 5A-5B: The Polyethylene Glycol 400 can be supplied by Clariant Produkte (BURGKIRCHEN, GERMANY).
 
For Examples 5A-5B: The Boric Acid can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 5A-5B: The Sodium Borate can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 5A-5B: The Sodium Chloride can be supplied by Caldic (DUSSELDORF, GERMANY).
 
For Examples 5A-5B: The 1N Sodium Hydroxide can be supplied by VWR (RADNER, Pa., USA).
 
For Examples 5A-5B: The 1N Hydrochloric acid can be supplied by VWR (RADNER, Pa., USA).
 
For Examples 5A-5B: The Lumuluse GRH-40 is can be supplied by is supplied by VANTAGE (GURNEE, Ill., USA).
 
For Examples 5A-5B: The Super refined Castor Oil can be supplied by CRODA (EDISON, N.J., USA).
 
For Examples 5A-5B: The Ethyl linolenate can be supplied by SIGMA-ALDRICH (ST. LOUIS, Mo., USA).
 
For Examples 5A-5B: The Retinyl Palmitate can be supplied by SIGMA-ALDRICH (ST. LOUIS, Mo., USA).
 
For Examples 5A-5B: The Polyquatemium-42 (33% aqueous) can be supplied by DSM BIOMEDICAL (BERKELEY, Calif., USA).
 
For Example 5B: The Tamarind Seed Polysaccharide can be supplied by INDENA (MILAN, ITALY).
 
     Solution 5A can be Prepared as Follows: 
     1. To a 50 ml beaker is added 5.0 grams of Lumuluse GRH-40
 
2. While mixing, 6.25 grams of Super refined Castor Oil is added.
 
3. Next is added 1 gram of Ethyl linolenate and 0.5 gram of Retinyl Palmitate to mix until uniform.
 
4. In a separate 1500 ml beaker is added 500 grams of Purified Water.
 
5. To the above is added 2 g of Polysorbate 80 and 10 g of Polysorbate 20. The solution is mixed until both are fully dissolved.
 
6. To the above is added 0.1 gram of Lemon Aspen Extract. The solution is mixed until the Lemon Aspen Extract is dissolved.
 
7. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.
 
8. To the solution in step 7 is added 2.0 grams of Sodium Hyaluronate. The solution is mixed to fully dissolve the Sodium Hyaluronate.
 
9. The following ingredients are next added sequentially, allowing for each to dissolve before adding the next: 2.5 grams Polyethylene Glycol 400, 6.0 grams Boric acid, 0.06 gram Sodium Borate, and grams of Polyquatemium-42 (33% aqueous).
 
10. The contents of step 3 are added and mixed until uniform using a homogenizer.
 
11. The tonicity of the formula is determined and adjusted to 280 mOsm/Kg with Sodium Chloride.
 
12. The pH of the formula is adjusted to pH of 7.2 using the 1N Sodium Hydroxide and/or 1N Hydrochloric acid.
 
13. The solution is brought to 1000.0 grams using Purified Water USP and mixed for 10 minutes until fully uniform.
 
14. The solution is filtered using a 0.22 micron filter.
 
     Solution 5B can be Prepared as Follows: 
     1. To a 50 ml beaker is added 5.0 grams of Lumuluse GRH-40
 
2. While mixing, 6.25 grams of Super refined Castor Oil is added.
 
3. The uniform solution is set aside for future use.
 
4. In a separate 1500 ml beaker is added 500 grams of Purified Water.
 
5. To the above is added 10 g of Polysorbate 80 and 50 g of Polysorbate 20. The solution is mixed until both are fully dissolved.
 
6. To the above is added 1.0 gram of Lemon Aspen Extract. The solution is mixed until the Lemon Aspen Extract is dissolved.
 
7. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.
 
8. To the solution in step 7 is added 1.0 grams of Sodium Hyaluronate. The solution is mixed to fully dissolve the Sodium Hyaluronate.
 
9. Next, 2.0 grams of Tamarind Seed Polysaccharide is added. The solution is mixed to fully dissolve the Tamarind Seed Polysaccharide.
 
10. The following ingredients are next added sequentially, allowing for each to dissolve before adding the next: 2.5 grams Polyethylene Glycol 400, 6.0 grams Boric acid, 0.06 gram Sodium Borate, and 0.045 grams of Polyquatemium-42 (33% aqueous).
 
11. The contents of step 3 are added and mixed until uniform using a homogenizer.
 
12. The tonicity of the formula is determined and adjusted to 280 mOsm/Kg with Sodium Chloride.
 
13. The pH of the formula is adjusted to pH of 7.2 using the 1N Sodium Hydroxide and/or 1N Hydrochloric acid.
 
14. The solution is brought to 1000.0 grams using Purified Water USP and mixed for 10 minutes until fully uniform.
 
15. The solution is filtered using a 0.22 micron filter.
 
     Example 6 
     Table 4 illustrates the components of formulations of the present invention (as illustrated in formulations 6A and 6B), which components can be incorporated as described below using conventional mixing technology. 
                                 TABLE 4                              6B           6A   Useful for Relief of           Useful for Relief of   Dry Eye Irritation           Dry Eye Irritation   for Contact Lenses                                         amount       amount           %   per batch   %   per batch       INGREDIENT   w/w   (gms)   w/w   (gms)                                         Sodium   0.30   3.0   0.15   1.5       Hyaluronate       Actinomyces   5.0   50.0   0   0       Extract       Compound 1 ****   0   0   5.0   50.0       Polysorbate 80   1.0   10.0   1.0   10.0       Polysorbate 20   10.0   100.0   7.5   75.0       Polyethylene   0.25   2.5   0   0       Glycol 400       Boric Acid   0.60   6.0   0.60   6.0       Sodium Borate   0.05   0.50   0.05   0.50       Sodium       Chloride*       Potassium   0.10   1.0   0.10   1.0       Chloride       Calcium   0.006   0.06   0.006   0.06       Chloride       Dihydrate       Magnesium   0.006   0.06   0.006   0.06       Chloride       Sodium   0.014   0.14   0.014   0.14       Chlorite       Dihydrate       Polyquaternium   0.0015   0.015   0.0015   0.015       42       (33% aqueous)       Sodium   0.014   0.14   0.014   0.14       Chlorite       Dihydrate       1N Sodium       Hydroxide       solution**       1N       Hydrochloric       Acid solution**       Purified       Water***           Total   100.00%   1000.0 g   100.00%   1000.00 g               *adjust to tonicity of 280-290 mOsm/Kg       **adjust to pH 7.2       ***q.s to 100% w/w       **** (2E,4E,6E)-7-(1,1,2,2,3,3-hexamethyl-2,3-dihydro-1H-inden-5-yl)-3-methylocta-2,4,6-trienoic acid            
For Examples 6A-6B: The Sodium Hyaluronate can be supplied by CONTIPRO A.S. (DOLNI, DOBROUC, CZECH REPUBLIC)
 
For Example 6A: The  Actinomyces  species A5640 Extract (IHVR collection bacteria extract labeled under IHVR collection nomenclature as IHVR_39565_F7), can be supplied by Baruch S. Blumberg Institute, Doylestown, Pa.
 
For Example 6B: Compound 1 can be supplied by Sigma-Aldrich.
 
For Examples 6A-6B: The Polysorbate 20 can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 6A-6B: The Polysorbate 80 can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 8A: The Polyethylene Glycol 400 can be supplied by Clariant Produkte (BURGKIRCHEN, GERMANY).
 
For Examples 6A-6B: The Boric Acid can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 6A-6B: The Sodium Borate can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 6A-6B: The Sodium Chloride can be supplied by Caldic (DUSSELDORF, GERMANY).
 
For Examples 6A-6B: The Potassium Chloride can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 6A-6B: The Calcium Chloride Dihydrate can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 6A-6B: The Magnesium Chloride to be supplied can KGaA (DARMSTADT, GERMANY).
 
For Examples 6A-6B: The Polyquatemium-42 (33% aqueous) can be supplied by DSM BIOMEDICAL (BERKELEY, Calif., USA).
 
For Examples 6A-6B: The Sodium Chlorite Dihydrate can be supplied by Oxychem (WICHITA, Kans., USA)
 
For Examples 6A-6B: The 1N Sodium Hydroxide can be supplied by VWR (RADNER, Pa., USA).
 
For Examples 6A-6B: The 1N Hydrochloric acid can be supplied by VWR (RADNER, Pa., USA).
 
     Solution 6A can be Prepared as Follows: 
     
         
         1. To a 1500 ml beaker is added 800 grams of Purified Water USP. 
         2. To the above is added 10 g of Polysorbate 80 and 100 g of Polysorbate 20. The solution is mixed until both are fully mixed and dissolved. 
         3. To the above is added 50.0 g of  Actinomyces  Extract. The solution is mixed until the  Actinomyces  Extract is dissolved. 
         4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker. 
         5. To the solution of Step 4 is added 3.0 grams of Sodium Hyaluronate. The solution is mixed to fully dissolve the Sodium Hyaluronate. 
         6. The following ingredients are next added sequentially, allowing for each to dissolve before adding the next: 2.5 grams Polyethylene Glycol 400, 6.0 grams Boric acid, 0.05 gram Sodium Borate, 1.0 gram Potassium Chloride, 0.06 gram Calcium Chloride Dihydrate, 0.06 gram Magnesium Chloride, and 0.0015 grams Polyquatemium-42 (aqueous). 
         7. While continuing to mix, 0.14 gram Sodium Chlorite Dihydrate is added and mixed to dissolve. 
         8. The tonicity of the formula is determined and adjusted to 280 mOsm/Kg with Sodium Chloride. 
         9. The pH of the formula is adjusted to pH of 7.2 using the 1N Sodium Hydroxide and/or 1N Hydrochloric acid. 
         10. The solution is brought to 1000.0 grams using Purified Water USP and mixed for 10 minutes to be fully uniform. 
         11. The solution is filtered using a 0.22 micron filter. 
       
    
     Solution 6B can be Prepared as Follows: 
     
         
         1. To a 1500 ml beaker is added 800 grams of Purified Water USP. 
         2. To the above is added 10 g of Polysorbate 80 and 75 g of Polysorbate 20. The solution is mixed until both are fully mixed and dissolved. 
         3. To the above is added 50.0 g of Compound I. The solution is mixed until the Compound I is dissolved. 
         4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker. 
         5. To the solution of Step 4 is added 1.5 grams of Sodium Hyaluronate. The solution is mixed to fully dissolve the Sodium Hyaluronate. 
         6. The following ingredients are next added sequentially, allowing for each to dissolve before adding the next: 6.0 grams Boric acid, 0.05 gram Sodium Borate, 1.0 gram Potassium Chloride, 0.06 gram Calcium Chloride Dihydrate, 0.06 gram Magnesium Chloride and 0.0015 grams Polyquatemium-42 (aqueous). 
         7. While continuing to mix, 0.14 gram Sodium Chlorite Dihydrate is added and mixed to dissolve. 
         8. The tonicity of the formula is determined and adjusted to 280 mOsm/Kg with Sodium Chloride. 
         9. The pH of the formula is adjusted to pH of 7.2 using the 1N Sodium Hydroxide and/or 1N Hydrochloric acid. 
         10. The solution is brought to 1000.0 grams using Purified Water USP and mixed for 10 minutes to be fully uniform. 
         11. The solution is filtered using a 0.22 micron filter. 
       
    
     Example 7 
     Table 5 illustrates the components of formulations of the present invention (as illustrated in formulations 7A and 7B), which components can be incorporated as described below using conventional mixing technology. 
                                 TABLE 5                          7A               Useful for Relief of   7B           Dry Eye Irritation   Useful for Relief of           for Contact Lenses   Dry Eye Irritation                                         amount       amount           %   per batch   %   per batch       INGREDIENT   w/w   (gms)   w/w   (gms)                                         Sodium   0.120   1.20   0.120   1.20       Hyaluronate       Tamarind Seed   0.200   2.00   0.200   2.00       Polysaccharide       Actinomyces   5.0   50.0   0   0       Extract       Compound 2 ****   0   0   0.5   5.0       Polysorbate 80   1.0   10.0   1.0   10.0       Polysorbate 20   10.0   100.0   3.0   30.0       Polyethylene   0.25   2.5   0.25   2.5       Glycol 400       Glycerin   0.25   2.5   0.25   2.5       Hypromellose   0.198   1.98   0.198   1.98       E3 2910       Boric Acid   0.40   4.0   0.40   4.0       Sodium Borate   0.022   0.22   0.022   0.22       Disodium   0.027   0.27   0.027   0.27       Phosphate       Sodium Citrate   0.40   4.0   0.40   4.0       Dihydrate       Sodium       Chloride*       Potassium   0.10   1.0   0.10   1.0       Chloride       50% Aqueous   0.057   0.57   0.057   0.57       Solution of       Sodium Lactate       Magnesium   0.013   0.13   0.013   0.13       Chloride       Glucose   0.0036   0.036   0.0036   0.036       Glycine   0.00002   0.0002   0.00002   0.0002       Ascorbic Acid   0.00001   0.0001   0.00001   0.0001       Disodium   0.01   0.1   0.05   0.5       Edetate       Polyquaternium   0.0030   0.030   0.0015   0.015       42       (33% aqueous)       Sodium   0.014   0.14   0.014   0.14       Chlorite       Dihydrate       1N Sodium       Hydroxide       solution**       1N       Hydrochloric       Acid solution**       Purified       Water***           Total   100.00%   1000.00 g   100.00%   1000.00 G               *adjust to tonicity of 280-290 mOsm/Kg       **adjust to pH 7.2       ***q.s to 100.00% volume       **** 4-(1-(1,1,2,2,3,3-hexamethyl-2,3-dihydro-1H-inden-5-yl)vinyl)benzoic acid            
For Examples 7A-7B: The Sodium Hyaluronate can be supplied by CONTIPRO A.S. (DOLNI, DOBROUC, CZECH REPUBLIC)
 
For Examples 7A-7B: The Tamarind Seed Polysaccharide can be supplied by INDENA (MILANO, ITALY).
 
For Example 7A: The  Actinomyces  species A5640 Extract (IHVR collection bacteria extract labeled under IHVR collection nomenclature as IHVR_39565_F7), can be supplied by Baruch S. Blumberg Institute, Doylestown, Pa.
 
For Example 7B: Compound 2 can be supplied by Sigma-Aldrich.
 
For Examples 7A-7B: The Polysorbate 20 can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 7A-7B: The Polysorbate 80 can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 7A-7B: The Polyethylene Glycol 400 can be supplied by Clariant Produkte (BURGKIRCHEN, GERMANY).
 
For Examples 7A-7B: The Boric Acid can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 7A-7B: The Sodium Borate can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 7A-7B: The Sodium Chloride can be supplied by Caldic (DUSSELDORF, GERMANY).
 
For Examples 7A-7B: The Potassium Chloride can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 7A-7B: The Hypromellose E3 2910 can be supplied by DOW CHEMICAL (PLAQUEMINE, LOUISIANA, USA).
 
For Examples 7A-7B: The Glycerin to be supplied can Emery Oleochemicals GmbH (DUSSELDORF, GERMANY).
 
For Examples 7A-7B: The Disodium Phosphate can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 7A-7B: The Sodium Citrate can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 7A-7B: The Sodium Lactate can be supplied as Sodium Lactate (50% aqueous) by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 7A-7B: The Glucose can be supplied by Roquette Freres (LASTREM, FRANCE).
 
For Examples 7A-7B: The Glycine can be supplied by Merck KGaA (DARMSTADT, GERMANY).
 
For Examples 7A-7B: The Ascorbic Acid can be supplied by DSM NUTRITIONAL Products (DRAKEMYRE, SCOTLAND, UK).
 
For Examples 7A-7B: The Polyquatemium 42 can be supplied as Polyquatemium 42 (33% aqueous) by DSM BIOMEDICAL, (BERKELEY, Calif.).
 
For examples 7A-7B: The Disodium Edetate can be supplied by Merck NV/SA (OVERUSE, BELGIUM).
 
For Examples 7A-7B: The 1N Sodium Hydroxide can be supplied by VWR (RADNER, Pa., USA).
 
For Examples 7A-7B: The 1N Hydrochloric acid can be supplied by VWR (RADNER, Pa., USA).
 
For Examples 7A-7B: The Sodium Chlorite Dihydrate can be supplied by Oxychem (WICHITA, Kans., USA)
 
     Solution 7A can be Prepared as Follows: 
     
         
         1. To a 1500 ml beaker is added 800 grams of Purified Water USP. 
         2. To the above is added 10 g of Polysorbate 80 and 100 g of Polysorbate 20. The solution is mixed until both are fully mixed and dissolved. 
         3. To the above is added 50 g of  Actinomyces  Extract. The solution is mixed until the  Actinomyces  Extract is dissolved. 
         4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker. 
         5. To the solution of Step 4 is added 1.2 grams of Sodium Hyaluronate. The solution is mixed to fully dissolve the Sodium Hyaluronate. 
         6. To the above is added 2.0 grams of Tamarind Seed Polysaccharide. The solution is mixed to fully dissolve the Tamarind Seed Polysaccharide. 
         7. To the above is added 1.98 g of Hypromellose E3 Premium. The solution is mixed until the Hypromellose E3 Premium dissolved. 
         8. The following ingredients are next added sequentially, allowing each to dissolve before adding the next: 2.50 grams Polyethylene Glycol 400, 2.50 grams Glycerin, 4.0 grams Boric acid, 0.22 gram Sodium Borate, 0.27 gram Disodium Phosphate, 4.00 grams Sodium Citrate Dihydrate, 1 gram Potassium Chloride, 0.57 gram Sodium Lactate (50% aqueous), 0.13 gram Magnesium Chloride, 0.036 gram Glucose, 0.0002 gram Glycine, 0.0001 gram Ascorbic acid, 0.10 gram Disodium Edetate, 0.030 gram Polyquatemium-42(33% aqueous), and 0.14 gram Sodium Chlorite. 
         9. The tonicity of the solution is determined and adjusted to 280 mOsm with Sodium Chloride. 
         10. The pH of the solution is measured and adjusted to 7.2 with 1N Sodium Hydroxide and/or 1N Hydrochloric acid. 
         11. The solution is brought to a volume of 1,000.00 grams with Purified Water and mixed for 10 minutes. 
         12. The solution is filtered using a 0.22 micron filter. 
       
    
     Solution 7B can be Prepared as Follows: 
     
         
         1. To a 1500 ml beaker is added 800 grams of Purified Water USP. 
         2. To the above is added 10 g of Polysorbate 80 and 30 g of Polysorbate 20. The solution is mixed until both are fully mixed and dissolved. 
         3. To the above is added 5.0 g of Compound I. The solution is mixed until the Compound I is dissolved. 
         4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker. 
         5. To the solution of Step 4 is added 1.2 grams of Sodium Hyaluronate. The solution is mixed to fully dissolve the Sodium Hyaluronate. 
         6. To the above is added 2.0 grams of Tamarind Seed Polysaccharide. The solution is mixed to fully dissolve the Tamarind Seed Polysaccharide. 
         7. To the above is added 1.98 g of Hypromellose E3 Premium. The solution is mixed until the Hypromellose E3 Premium dissolved. 
         8. The following ingredients are next added sequentially, allowing each to dissolve before adding the next: 2.50 grams Polyethylene Glycol 400, 2.50 grams Glycerin, 4.0 grams Boric acid, 0.22 gram Sodium Borate, 0.27 gram Disodium Phosphate, 4.00 grams Sodium Citrate Dihydrate, 1 gram Potassium Chloride, 0.57 gram Sodium Lactate (50% aqueous), 0.13 gram Magnesium Chloride, 0.036 gram Glucose, 0.0002 gram Glycine, 0.0001 gram Ascorbic acid, 0.10 gram Disodium Edetate, 0.015 gram Polyquatemium-42 (33% aqueous), and 0.14 gram Sodium Chlorite. 
         9. The tonicity of the solution is determined and adjusted to 280 mOsm with Sodium Chloride. 
         10. The pH of the solution is measured and adjusted to 7.2 with 1N Sodium Hydroxide and/or 1N Hydrochloric acid. 
         11. The solution is brought to a volume of 1,000.00 grams with Purified Water and mixed for 10 minutes. 
         12. The solution is filtered using a 0.22 micron hydrophilic filter. 
       
    
     EMBODIMENTS OF THE PRESENT INVENTION 
     
         
         1. A method for producing/releasing/delivering/excreting mucin from and/or in the cornea (optionally, in a patient in need of such production/release/deliverance/excretion of mucin) comprising the step of administering a composition comprising:
       i) a safe and effective amount of a compound and/or extract having retinol-like properties and/or benefits for use in treating dry eye selected from one or more of: botanical extracts, or sources of extracts, from plants of the genus  Acronychia, Licaria, Calendula  and/or  Trigonella ; bacterial extracts, or sources of extracts, of the genus  Actinomyces ; and compounds of Formula (I):   
     
       
    
     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein— 
                 the dotted lines represent simple or double bound; optionally one of the dotted line is a double bound; 
                 R 1  represent an H, a carbonated chain, linear, cyclic, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; 
                 R 2  represent a carbonated chain, linear, cyclic ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; optionally a methyl (—CH 3 ) or methylene (═CH 2 ) moiety; a carbonated chain, linear, ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; optionally from 1 to 10 carbon atoms; optionally 6 carbon atoms; optionally an aromatic moiety, optionally a phenyl moiety; optionally 2-methyl-prop-1,3-diene; and 
               
             
             ii) optionally, an ophthalmologically acceptable carrier. 
           
         
         2. The method according to embodiment 1 (or, any of the following embodiments), wherein the compound and/or extract having retinol-like properties and/or benefits is a botanical extract, or source of extracts, from plants of the genus  Acronychia  and/or  Licaria.    
         3. The method according to embodiments 1 and/or 2 (or, any of the following embodiments), wherein the compound and/or extract having retinol-like properties and/or benefits is a botanical extract, or source of extracts, from plants of the genus  Acronychia.    
         4. The method according to anyone of, or a combination of, embodiments 1-3 (or, any of the following embodiments), wherein the botanical extract, or source of extracts, from plants of the genus  Acronychia  is selected from the group consisting of  Acronychia aberram, Acronychia acidula, Acronychia acronychioides, Acronychia acuminate, Acronychia baeuerlenii, Acronychia chooreechillum, Acronychia crassipetala, Acronychia eungellensis, Acronychia imperforate, Acronychia laevis, Acronychia laurifolia, Acronychia littoralis, Acronychia oblongifolia, Acronychia octandra, Acronychia parviflora, Acronychia pauciflora, Acronychia pedunculata, Acronychia pubescens, Acronychia  species (Batavia Downs),  Acronychia suberosa, Acronychia vestita, Acronychia wilcoxiana , and combinations of two or more thereof. 
         5. The method according to anyone of, or a combination of, embodiments 1-4 (or, any of the following embodiments), wherein the botanical extract, or source of extracts, from plants of the genus  Acronychia  is  Acronychia acidula.    
         6. The method according to anyone of, or a combination of, embodiments 1-5 (or, any of the following embodiments), wherein the botanical extract of  Acronychia  and/or  Licaria  comprises from about 1% to about 20%, by weight of the extract, of the compound of formula II 
       
    
     
       
         
         
             
             
         
       
         
         
           
             wherein: 
             R 1  is selected from the group consisting of C 1 -C 20  alkyl, C 2 -C 20  alkenyl, C 2 -C 20  alkynyl, and C 3 -C 8  cycloalkyl or aryl; 
             R 2  is selected from the group consisting of hydrogen, hydroxyl, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 8  cycloalkyl or aryl, —OC 1 -C 6  alkyl, —OC 2 -C 6  alkenyl, —OC 2 -C 6  alkynyl, —OC 3 -C 8  cycloalkyl or aryl, thiol, —SC 1 -C 6  alkyl, —SC 2 -C 6  alkenyl, —SC 2 -C 6  alkynyl, —SC 3 -C 8  cycloalkyl or aryl, —NR 4 C 1 -C 6  alkyl, —NR 4 C 2 -C 6  alkenyl, —NR 4 C 2 -C 6  alkynyl, and —NR 4 C 3 -C 8  cycloalkyl or aryl; 
             R 3  is selected from —CO 2 H, —CO 2 R 4  or an isosteric equivalent of a carboxy group, wherein R 4  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 3 -C 8  cycloalkyl or aryl; and 
             Y is —(CH 2 —CH 2 )—, —(CH═CH)—, or —(C≡C)—. 
           
         
         7. The method according to anyone of, or a combination of, embodiments 1-6 (or, any of the following embodiments), wherein the botanical extract of  Acronychia  and/or  Licaria  comprises from about 1% to about 20%, by weight of the extract, of the compound of Formula II 
       
    
     
       
         
         
             
             
         
       
         
         
           
             wherein: 
             R 1  is selected from the group consisting of C 5 -C 16  alkyl, C 5 -C 16  alkenyl, and C 5 -C 16  alkynyl, more preferably C 5 -C 16  alkenyl, including, for example, farnesyl; 
             R 2  is selected from the group consisting of hydrogen, hydroxyl, —OC 1 -C 6  alkyl, —OC 2 -C 6  alkenyl, —OC 2 -C 6  alkynyl, —OC 3 -C 8  cycloalkyl, more preferably hydrogen, hydroxyl, —OC 1 -C 6  alkyl, even more preferably hydrogen or —OC 1 -C 3  alkyl; 
             R 3  is selected from —CO 2 H, —CO 2 R 4  wherein R 4  is C 1 -C 6  alkyl, or an isosteric equivalent of a carboxy group; and 
             Y is —(CH 2 —CH 2 )— or —(CH═CH)—. 
           
         
         8. The method according to anyone of, or a combination of, embodiments 1-7 (or, any of the following embodiments), wherein the compound of formula (II) are in the form of an acid or alkylester selected from 3-(4-farnesyloxyphenyl)-propionic acid, 3-(4-farnesyloxy-3-hydroxyphenyl)-propionic acid, 3-(4-farnesyloxy-3-methoxyphenyl)-propionic acid, alkylesters thereof and combinations of two or more thereof. 
         9. The method according to according to anyone of, or a combination of, embodiments 1-8 (or, any of the following embodiments), wherein the compound of Formula II useful in the present invention is 3-(4-farnesyloxyphenyl)-propionic acid and/or its ethyl ester. 
         10. The method according to anyone of, or a combination of, embodiments 1-9 (or, any of the following embodiments), wherein the compound and/or extract having retinol-like properties and/or benefits is a botanical extract, or source of extracts, from plants of the genus  Licaria.    
         11. The method according to anyone of, or a combination of, embodiments 1-10 (or, any of the following embodiments), wherein the botanical extract, or source of extracts, from plants of the genus  Licaria  is selected from the group consisting of  Licaria vernicosa, Licaria brittoniana, Licaria canella, Licaria cubensis, Licaria velutina  and  Licaria triandra , and combinations of two or more thereof. 
         12. The method according to anyone of, or a combination of, embodiments 1-11 (or, any of the following embodiments), wherein the botanical extract, or source of extracts, from plants of the genus  Licaria  is  Licaria vernicosa.    
         13. The method according to anyone of, or a combination of, embodiments 1-12 (or, any of the following embodiments), wherein the compound and/or extract having retinol-like properties and/or benefits is a bacterial extract, or source of extracts, of the genus  Actinomyces.    
         14. The method according to anyone of, or a combination of, embodiments 1-13 (or, any of the following embodiments), wherein the compound and/or extract having retinol-like properties and/or benefits is a bacterial extract, or source of extracts, of the  Actinomyces  species A5640. 
         15. The method according to anyone of, or a combination of, embodiments 1-14 (or, any of the following embodiments), wherein the compound and/or extract having retinol-like properties and/or benefits comprises the compound of Formula (I): 
       
    
     
       
         
         
             
             
         
       
     
     wherein—
         the dotted lines represent simple or double bound; optionally, one of the dotted line is a double bound;   R 1  represent an H, a carbonated chain, linear, cyclic, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms;   R 2  represent a carbonated chain, linear, cyclic ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; a carbonated chain, linear, ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms.       16. The method according to anyone of, or a combination of, embodiments 1-15 (or, any of the following embodiments), wherein the compound of Formula I is selected from (2E,4E,6E)-7-(1,1,2,2,3,3-hexamethyl-2,3-dihydro-1H-inden-5-yl)-3-methylocta-2,4,6-trienoic acid and 4-(1-(1,1,2,2,3,3-hexamethyl-2,3-dihydro-1H-inden-5-yl)vinyl)benzoic acid and their derivatives that display retinoid-like activity and mixtures thereof.   17. A method for maintaining the concentration of MU5AC in tears within the range of equal to or greater than 8 nanograms to 15 nanograms per milligrams of protein, (optionally in a patient in need of such maintenance) comprising the step of administering a composition comprising:
       i) a safe and effective amount of a compound and/or extract having retinol-like properties and/or benefits for use in treating dry eye selected from one or more of: botanical extracts, or sources of extracts, from plants of the genus  Acronychia, Licaria, Calendula  and/or  Trigonella ; bacterial extracts, or sources of extracts, of the genus  Actinomyces ; and compounds of Formula (I):   
       

     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein— 
                 the dotted lines represent simple or double bound; 
                 R 1  represent an H, a carbonated chain, linear, cyclic, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; 
                 R 2  represent a carbonated chain, linear, cyclic ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; preferably a methyl (—CH 3 ) or methylene (═CH 2 ) moiety; 
                 a represent a carbonated chain, linear, ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; and 
               
             
             ii) optionally, an ophthalmologically acceptable carrier. 
           
         
         18. A method for treating a patient having decreased or low-level production/release/delivery/excretion of mucin from and/or in the cornea comprising the step of topically administering to the eye the patient a composition comprising:
       i) a safe and effective amount of a compound and/or extract having retinol-like properties and/or benefits for use in treating dry eye selected from one or more of: botanical extracts, or sources of extracts, from plants of the genus  Acronychia, Licaria, Calendula  and/or  Trigonella ; bacterial extracts, or sources of extracts, of the genus  Actinomyces ; and compounds of Formula (I):   
     
       
    
     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein— 
                 the dotted lines represent simple or double bound; preferably one of the dotted line is a double bound; 
                 R 1  represent an H, a carbonated chain, linear, cyclic, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; 
                 R 2  represent a carbonated chain, linear, cyclic ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; preferably a methyl (—CH 3 ) or methylene (═CH 2 ) moiety; 
                 a represent a carbonated chain, linear, ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; preferably from 1 to 10 carbon atoms; more preferably 6 carbon atoms; preferably an aromatic moiety, preferably a phenyl moiety; preferably 2-methyl-prop-1,3-diene, 
               
             
             ii) optionally, an ophthalmologically acceptable carrier. 
           
         
         19. A method for preventing or treating the symptoms associated with dry eye comprising the step of topically administering (optionally, to a patient in need of such prevention or treatment) a composition comprising:
       i) a safe and effective amount of a compound and/or extract having retinol-like properties and/or benefits for use in treating dry eye selected from one or more of: botanical extracts, or sources of extracts, from plants of the genus  Acronychia, Licaria, Calendula  and/or  Trigonella ; bacterial extracts, or sources of extracts, of the genus  Actinomyces ; and compounds of Formula (I):   
     
       
    
     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein— 
                 the dotted lines represent simple or double bound; preferably one of the dotted line is a double bound; 
                 R 1  represent an H, a carbonated chain, linear, cyclic, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; 
                 R 2  represent a carbonated chain, linear, cyclic ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; preferably a methyl (—CH 3 ) or methylene (═CH 2 ) moiety; 
                 a represent a carbonated chain, linear, ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; preferably from 1 to 10 carbon atoms; more preferably 6 carbon atoms; preferably an aromatic moiety, preferably a phenyl moiety; preferably 2-methyl-prop-1,3-diene; 
               
             
             ii) one or more demulcents or soothing agents; and 
             iii) optionally, an ophthalmologically acceptable carrier. 
           
         
         20. A method for promoting healing or increasing the rate of healing of wounds in and/or on the eye (optionally, of a patient in need of such promoted healing or increased healing rate) comprising the step of administering compositions, comprising:
       i) a safe and effective amount of a compound and/or extract having retinol-like properties and/or benefits for use in treating dry eye selected from one or more of: botanical extracts, or sources of extracts, from plants of the genus  Acronychia, Licaria, Calendula  and/or  Trigonella ; bacterial extracts, or sources of extracts, of the genus  Actinomyces ; and compounds of Formula (I):   
     
       
    
     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein— 
                 the dotted lines represent simple or double bound; preferably one of the dotted line is a double bound; 
                 R 1  represent an H, a carbonated chain, linear, cyclic, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; 
                 R 2  represent a carbonated chain, linear, cyclic ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; preferably a methyl (—CH 3 ) or methylene (═CH 2 ) moiety; 
                 a represent a carbonated chain, linear, ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; preferably from 1 to 10 carbon atoms; more preferably 6 carbon atoms; preferably an aromatic moiety, preferably a phenyl moiety; preferably 2-methyl-prop-1,3-diene. 
               
             
             ii) optionally, an ophthalmologically acceptable carrier. 
           
         
         21. A method for improving the antimicrobial properties in tears (optionally, of a patient in need of such improved properties in tears), comprising the step of administering compositions, comprising:
       i) a safe and effective amount of a compound and/or extract having retinol-like properties and/or benefits for use in treating dry eye selected from one or more of: botanical extracts, or sources of extracts, from plants of the genus  Acronychia, Licaria, Calendula  and/or  Trigonella ; bacterial extracts, or sources of extracts, of the genus  Actinomyces ; and compounds of Formula (I):   
     
       
    
     
       
         
         
             
             
         
       
         
         
           
             
               
                 wherein— 
                 the dotted lines represent simple or double bound; preferably one of the dotted line is a double bound; 
                 R 1  represent an H, a carbonated chain, linear, cyclic, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; 
                 R 2  represent a carbonated chain, linear, cyclic ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; preferably a methyl (—CH 3 ) or methylene (═CH 2 ) moiety; 
                 a represent a carbonated chain, linear, ringed, or branched, saturated or unsaturated, comprising from 1 to 20 carbon atoms; preferably from 1 to 10 carbon atoms; more preferably 6 carbon atoms; preferably an aromatic moiety, preferably a phenyl moiety; preferably 2-methyl-prop-1,3-diene. 
               
             
             ii) optionally, an ophthalmologically acceptable carrier.