RU2802365C2 - Compositions and methods of treating eye disorders - Google Patents

Abstract

FIELD: medicine, ophthalmology.

SUBSTANCE: group of inventions is intended for the treatment of an eye disease or condition. The method of producing/release/delivering/discharge of mucin from the cornea and/or into the cornea includes the step of administering a composition containing a safe and effective amount of an extract having retinol-like properties and/or beneficial effects for use in the treatment of dry eye syndrome, selected from one or more of plant extracts or sources of extracts containing Acronychia acidula. In other embodiments, a method is provided to maintain the concentration of MU5AC in tear fluid in the range of 8 to 15 ng per 1 milligram of protein or higher; a method of treating a patient with reduced or low production/release/delivery/discharge of mucin from the cornea and/or into the cornea; a method of preventing or treating symptoms of dry eye syndrome; and a method of improving the antimicrobial properties of a patient's lacrimal fluid.

EFFECT: using the invention allows to induce, stimulate and/or improve the production/release/delivery/discharge of hyaluronic acid from the cornea and/or into the cornea.

5 cl, 2 dwg, 5 tbl, 7 ex

Description

FIELD OF APPLICATION OF THE INVENTION

The present invention relates to compositions containing one or more extracts and/or compounds having retinol-like activity and properties, and methods of using these compositions for the treatment of eyes.

PREREQUISITES FOR CREATION OF THE INVENTION

“Dry eye is a multifactorial ocular surface disease that is characterized by loss of tear film homeostasis and is accompanied by ocular symptoms in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play an etiological role.” Craig, J.P. et al. TFOS DEWS II definition and classification report. Ocul Surf. 2017; 15: 276-283. Dry eye syndrome may result from abnormal or insufficient tear production and deficiency of mucin secretion (ie, keratoconjunctivitis sicca). Symptoms of dry eye syndrome can result from a variety of underlying disorders, such as autoimmune diseases that affect the lacrimal (i.e., tear-producing) glands, such as rheumatoid arthritis, Sjögren's syndrome, systemic lupus erythematosus, systemic sclerosis, and sarcoidosis. Dry eye syndrome can also occur after eye surgery, such as Lasik® surgery. It is estimated that more than 13 million people in the United States suffer from dry eye syndrome.

Regardless of the underlying pathological conditions, dry eye syndrome typically involves rapid breakdown of the preocular tear film, resulting in dehydration of the exposed outer surface. Normal tear production is necessary to maintain hydration of the cornea and conjunctiva, which in turn helps prevent ulceration and also maintain corneal clarity. In addition, tears facilitate the movement of the eyelid along the surface of the eye (for example, blinking) and the removal of foreign substances from the eye. Tear fluid also usually contains lysozyme, which helps prevent eye infections. Dry eye syndrome can cause mild discomfort to severe pain in the eye. When this happens for extended periods of time, blurred vision, graininess, and/or a burning and itching sensation may occur. If left untreated, the condition can also lead to corneal ulcers and/or scarring.

Symptoms of dry eye syndrome include eye pain or tiredness, increased blinking, and sore eyes. Additionally, bacteria can enter through scratches and cause infection, and if the scratch is deep enough, it can even affect your vision. In addition to eye strain, causes of dry eye include Sjögren's syndrome, Stevens-Johnson syndrome, burns and eye injuries, and side effects of antihypertensive drugs, tranquilizers, glaucoma eye drops, and other similar medications.

The tear film is the body's natural defense against dry eyes. The tear film contains ocular mucins and is essential for maintaining ocular moist surface homeostasis. Mucins are produced, among other things, by the epithelial cells of the cornea. Mucins are glycoproteins expressed by mucosal epithelial tissues. They protect tissue 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 used as an antimicrobial agent to heal any wounds and is essential for maintaining overall eye health.

Thus, there is a need for an ophthalmic pharmaceutical composition that would stimulate and/or improve the production and/or release of mucin from and/or into the cornea.

The present inventors have discovered compounds and/or extracts having retinol-like properties and/or beneficial effects that can induce, stimulate and/or improve the production/release/delivery/release of mucin from and/or into the cornea.

Accordingly, one aspect of the present invention relates to compositions containing a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or beneficial effects for inducing, stimulating and/or improving the production/release/delivery/excretion of mucin from the cornea and/or into the cornea.

Another aspect of the present invention relates to compositions containing a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or beneficial effects that induce, stimulate and/or improve the production/release/delivery/excretion of mucin from the cornea and /or into the cornea, wherein the compositions can be administered to patients having a tear MUC5AC concentration of less than 6 (or about 6), in some cases 8 (or about 8) nanograms per milligram of proteins such that the tear MUC5AC concentration is increased to (or became equal) from 8 (or about 8) or more nanograms to 15 (or about 15) nanograms, in some cases 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 tear fluid (i.e., equal to or greater than 8 (or about 8) nanograms to 15 (or about 15) nanograms, in some cases from 9 (or about 9) nanograms to 12 (or about 12) nanograms per milligram of proteins), resulting from compounds and/or extracts having retinol-like properties and/or beneficial effects that induce, stimulate and/or improve the production/release/delivery/release of mucin from and/or into the cornea , is maintained for a period of up to at least about 2 hours, in some cases about 4 hours, in some cases about 6 hours, in some cases about 8 hours, in some cases about 10 hours, in some cases about 12 hours, or in some cases from about 12 to about 24 hours.

MUC5AC concentrations in tear fluid, detailed above, were determined by the Uchino method (described below in definitions).

Another aspect of the present invention relates to compositions containing a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or beneficial effects that induce, stimulate and/or improve the production/release/delivery/excretion of mucin from the cornea and/ or into the cornea to treat dry eyes.

Another aspect of the present invention relates to methods of preventing and/or treating (for example, reducing) symptoms of ocular disorders associated with dry eye syndrome and/or resulting from decreased or low levels of mucin production/release/delivery/excretion from the cornea and/or cornea, by administering compositions containing a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or beneficial effects that induce, stimulate and/or improve the production/release/delivery/excretion of mucin from the cornea and/or into 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 surface of the eye (eg, non-dry eye, ocular trauma, post-operative surgical or non-specific wounds) of a patient by administering compositions containing a safe and effective amount one or more compounds and/or extracts, or sources of extracts, having retinol-like properties and/or beneficial effects that induce, stimulate and/or improve the production/release/delivery/secretion of mucin from and into the cornea (i.e., that increase producing/releasing/delivering/secreting mucin from and/or into the cornea in certain embodiments, in addition to the concentrations of mucin that are produced in such patient without (or in the absence of) administration of compositions containing a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or beneficial effects that induce, stimulate and/or improve the production/release/delivery/secretion of mucin from and/or into the cornea).

Another further aspect of the present invention relates to methods of improving the antimicrobial properties of the tear fluid (or tear film of the eye) of a patient by administering compositions containing a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or beneficial effects for inducing, stimulating and/or enhancing the production/release/delivery/release of mucin from and into the cornea (i.e., to enhance the production/release/delivery/release of mucin from and/or into the cornea in certain embodiments above a mucin concentration level, typically produced by such patient, without (or in the absence) administration of compositions containing a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or beneficial effects that induce, stimulate and/or improve production/release/delivery /release of mucin from the cornea and into the cornea).

SUMMARY OF THE INVENTION

The present invention relates to methods for producing/releasing/delivering/releasing mucin from and/or into the cornea (in some cases in a patient requiring such production/releasing/delivery/releasing 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 beneficial effects for use in the treatment of dry eye syndrome, selected from one or more of plant extracts or sources of plant extracts of the genus Acronychia, Licaria, Calendula and/or Trigonella ; Bacterial extracts or sources of extracts of bacteria of the genus Actinomyces; and compounds of formula (I):

(I),

Where -

dotted lines indicate a single or double bond; optionally one of the dotted lines represents a double bond;

R1 represents H, a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms;

R2 represents a carbon chain, linear, cyclic ring or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; optionally a methyl (-CH3) or methylene (=CH2) functional group; a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; optionally from 1 to 10 carbon atoms; optionally 6 carbon atoms; optionally an aromatic functional group, optionally a phenyl functional group; optionally 2-methyl-prop-1,3-diene; And

ii) optionally, an ophthalmologically acceptable carrier.

The present invention relates to methods of maintaining MU5AC concentrations in tear fluid in the range of 8 nanograms to 15 nanograms per milligram of protein or higher, 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 beneficial effects for use in the treatment of dry eye syndrome, selected from one or more of plant extracts or sources of plant extracts of the genus Acronychia, Licaria, Calendula and/or Trigonella ; Bacterial extracts or sources of extracts of bacteria of the genus Actinomyces; and compounds of formula (I):

(I),

Where -

dotted lines indicate a single or double bond; optionally one of the dotted lines represents a double bond;

R1 represents H, a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms;

R2 represents a carbon chain, linear, cyclic ring or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; optionally a methyl (-CH3) or methylene (=CH2) functional group; a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; optionally from 1 to 10 carbon atoms; optionally 6 carbon atoms; optionally an aromatic functional group, optionally a phenyl functional group; optionally 2-methyl-prop-1,3-diene; And

ii) optionally, an ophthalmologically acceptable carrier.

The present invention relates to methods of treating patients with reduced or low production/release/delivery/secretion of mucin from and/or into the cornea, comprising the step of locally administering to the patient a composition containing:

i) a safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects for use in the treatment of dry eye syndrome, selected from one or more of plant extracts or sources of plant extracts of the genus Acronychia, Licaria, Calendula and/or Trigonella ; Bacterial extracts or sources of extracts of bacteria of the genus Actinomyces; and compounds of formula (I):

(I),

Where -

dotted lines indicate a single or double bond; optionally one of the dotted lines represents a double bond;

R1 represents H, a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms;

R2 represents a carbon chain, linear, cyclic ring or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; optionally a methyl (-CH3) or methylene (=CH2) functional group; a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; optionally from 1 to 10 carbon atoms; optionally 6 carbon atoms; optionally an aromatic functional group, optionally a phenyl functional group; optionally 2-methyl-prop-1,3-diene; And

ii) optionally, an ophthalmologically acceptable carrier.

The present invention provides methods for preventing or treating symptoms of dry eye syndrome, comprising the step of locally administering to a patient (optionally, a patient in need of such prevention or reduction of dry eye symptoms) of a composition comprising:

i) a safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects for use in the treatment of dry eye syndrome, selected from one or more of plant extracts or sources of plant extracts of the genus Acronychia, Licaria, Calendula and/or Trigonella ; Bacterial extracts or sources of extracts of bacteria of the genus Actinomyces; and compounds of formula (I):

(I),

Where -

dotted lines indicate a single or double bond; optionally one of the dotted lines represents a double bond;

R1 represents H, a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms;

R2 represents a carbon chain, linear, cyclic ring or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; optionally a methyl (-CH3) or methylene (=CH2) functional group; a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; optionally from 1 to 10 carbon atoms; optionally 6 carbon atoms; optionally an aromatic functional group, optionally a phenyl functional group; optionally 2-methyl-prop-1,3-diene;

ii) one or more emollients or sedatives; And

iii) optionally, an ophthalmologically acceptable carrier.

The present invention relates to methods of promoting healing or increasing the rate of healing of wounds in and/or on the surface of the eye of a patient (in some cases, when the patient requires such treatment of ocular wounds), including the step of administering compositions (i.e., that increase the production/release of delivery/release of mucin from and/or within the cornea, in some embodiments, in addition to the concentration of mucin produced by such patient without (or in the absence of) administration of compositions containing a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and /or beneficial effects) containing:

i) a safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects for use in the treatment of dry eye syndrome, selected from one or more of plant extracts or sources of plant extracts of the genus Acronychia, Licaria, Calendula and/or Trigonella ; Bacterial extracts or sources of extracts of bacteria of the genus Actinomyces; and compounds of formula (I):

(I),

Where -

dotted lines indicate a single or double bond; preferably one of the dotted lines represents a double bond;

R1 represents H, a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms;

R2 represents a carbon chain, linear, cyclic ring or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; preferably a methyl (-CH3) or methylene (=CH2) functional group;

A represents a carbon chain, linear, ring or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; preferably from 1 to 10 carbon atoms; more preferably 6 carbon atoms; preferably an aromatic functional group, preferably a phenyl functional group; preferably 2-methylprop-1,3-diene.

ii) optionally, an ophthalmologically acceptable carrier.

The present invention relates to methods of improving the antimicrobial properties of the tear fluid (or tear film of the eyes) of a patient (in some cases a patient in need of such antimicrobial properties), comprising the step of administering compositions (i.e., that increase the production/release/delivery/excretion of mucin from and/or into the cornea, in certain embodiments, beyond the level of mucin concentration produced by such patient without (or in the absence of) administration of compositions containing a safe and effective amount of one or more compounds and/or extracts having retinol-like properties and/or beneficial effects) containing:

i) a safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects for use in the treatment of dry eye syndrome, selected from one or more of plant extracts or sources of plant extracts of the genus Acronychia, Licaria, Calendula and/or Trigonella ; Bacterial extracts or sources of extracts of bacteria of the genus Actinomyces; and compounds of formula (I):

(I),

Where -

dotted lines indicate a single or double bond; preferably one of the dotted lines represents a double bond;

R1 represents H, a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms;

R2 represents a carbon chain, linear, cyclic ring or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; preferably a methyl (-CH3) or methylene (=CH2) functional group;

A represents a carbon chain, linear, ring or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; preferably from 1 to 10 carbon atoms; more preferably 6 carbon atoms; preferably an aromatic functional group, preferably a phenyl functional group; preferably 2-methylprop-1,3-diene.

ii) optionally, an ophthalmologically acceptable carrier.

BRIEF DESCRIPTION OF GRAPHIC MATERIALS

In FIG. Figure 1 shows bar graphs showing the expression of the MUC1, MUC4 and MUC16 genes induced by lemon aspen extract in corneal epithelial cells.

In FIG. Figure 2 shows bar graphs showing mucin-1 secretion induced by lemon aspen extract in corneal epithelial cells.

DETAILED DESCRIPTION OF THE INVENTION

It is believed that, based on the description provided herein, one skilled in the art will be able to use this invention to its fullest extent. The following specific embodiments are to be considered as illustrative examples only and are not intended to limit the remainder of the present description in any way.

The compositions of the present invention may contain, consist of or consist essentially of the elements, steps and limitations of the invention described herein, as well as any of the additional or optional ingredients, components or limitations described herein.

As used herein, the term “comprising” (and its grammatical variations) is used broadly to mean “having” or “including”, rather than narrowly meaning “consisting only of”. As used herein, the singular forms are considered to include both the plural and the singular.

Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one skilled in the art to which the invention relates. In addition, all publications, patent applications, patents and other references mentioned herein are incorporated herein in their entirety by reference to the extent consistent with the disclosure herein. All percentages herein are by weight of the total composition unless otherwise noted.

As used herein, the term “cornea” or “corneal” includes and/or refers to the clear anterior portion of the eye that covers the iris, pupil, and anterior chamber, the layers of this clear anterior portion including a layer of corneal epithelium (containing corneal epithelial cells), Bowman's membrane (also known as the anterior limiting membrane), corneal stroma (also substantia propria), Descemet's membrane (also posterior limiting membrane), and corneal endothelium (a simple squamous or low cubic monolayer of mitochondria-rich cells whose thickness is approximately 5 µm).

As used herein, the phrase “reduced or low production/release/delivery/release of mucin from and/or into the cornea” means a concentration of MUC5AC that is less than the concentration of MUC5AC in the tear fluid of a normal (i.e., healthy) person, or, in some embodiments implementation, less than 6, in some cases less than 8 nanograms per milligram of proteins, as determined by 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. This method (Uchino method) is reproduced below:

● Concentration of MUC5AC in tear fluid

The concentration of secreted mucin MUC5AC in tear fluid samples was quantified using an enzyme-linked immunosorbent assay (E90756Hu; USCN Life Science). (See Maker AV, Katabi N, Gonen M, et al. Pancreatic cyst fluid and serum mucin levels predict dysplasia in intraductal papillary mucinous neoplasms of the pancreas glands. Ann Surg Oncol. 2011;18(1):199-206.) All samples were analyzed according to the manufacturer's instructions. Absorbance was measured at 450 nm, and the standard solutions in the kit were recombinant human MUC5AC. A protein assay reagent kit (BCA protein assay kit; Pierce) was used to determine protein concentrations in tear fluid samples. MUC5AC concentration was normalized to tear protein content and expressed as MUC5AC protein (nanograms) per total tear protein (milligrams).

As used herein, a composition “substantially free” of an ingredient means a composition containing about 2% or less of that ingredient by weight, based on the total weight of the composition. Preferably, the substantially ingredient-free composition contains 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 of the ingredient by weight, based on the total weight of the composition. In certain more preferred embodiments, the substantially ingredient-free composition is ingredient-free, i.e., the ingredient is not present in the composition.

As used herein, the term "ophthalmically acceptable" means that the ingredients to which the term refers are suitable for use in contact with tissues (e.g., the soft tissues of the eye or periorbital skin tissues) without adverse effects of nonspecific toxicity, incompatibility, instability, irritation, allergic reaction, etc. As will be appreciated by one skilled in the art, ophthalmologically acceptable salts are acidic/anionic or alkaline/cationic salts.

As used herein, the term “safe and effective amount” means an amount of the described extract, compound or composition sufficient to induce, stimulate and/or improve the production/release/delivery/secretion of mucin from one or more layers of the cornea and/or one or more layer of the cornea, but low enough to prevent serious side effects. The safe and effective amount of a compound, extract or composition will vary depending on, for example, the age, health and environmental conditions of the end user, the duration and nature of the treatment, the particular extract, ingredient or composition used, the particular pharmaceutically acceptable carrier used and similar factors.

The term “retinol-like properties and/or beneficial effects” means the properties and/or beneficial effects caused by retinol.

In certain embodiments, the present invention described herein may be practiced in the absence of any compound or element (or group of compounds or elements) not specifically referenced herein.

In general, this document applies the rules of nomenclature of the International Union of Pure and Applied Chemistry (IUPAC) in accordance with the following definitions of terms.

The term "C1-8 alkyl", used alone or as part of a substituent group, refers to a saturated aliphatic branched or straight chain monovalent hydrocarbon radical having 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, etc. The term may also refer to the corresponding alkyldiyl radical. Alkyl and alkyldiyl radicals can attach to the main molecule through a terminal carbon atom or through an intrachain carbon atom. Similarly, any number of variable substituents allowed by the available valences can be attached to an alkyl or alkyldiyl radical.

The term "C1-4 alkyl", 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, the radical being formed by the removal of one hydrogen atom from a carbon atom, and the alkyldiyl linking group is made by removing one hydrogen atom from each of the two carbon atoms in the chain. The term "C1-4 alkyl" refers to a radical having 1-4 carbon atoms in a linear or branched configuration. For example, "C1-4 alkyl" specifically includes the radicals methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, tert-butyl, 1-butyl, etc. Alkyl and alkyldiyl radicals can attach to the main molecule via a terminal carbon atom or via a carbon atom within the chain. Similarly, any number of variable substituents allowed by the available valences can be attached to an alkyl or alkyldiyl radical.

The term "C2-4 alkenyl" refers to an alkenyl radical having 2-4 carbon atoms. For example, specifically includes ethenyl, propenyl, allyl (2-propenyl), butenyl, and the like radicals. As described above, an alkenyl radical may be similarly attached to the parent molecule and further substituted where indicated.

The term "halogen", alone or in combination with other terms, means a halogen atom such as fluorine, chlorine, bromine or iodine.

The term "substituted" refers to a parent molecule in which one or more hydrogen atoms have been replaced by the number of substituents allowed by the available valences. Substitution is not limited to the main molecule, but can also occur in the substituting radical, with the radical being converted into a linking group.

The term "independently selected" refers to two or more substituents that may be selected from a group of variable substituents, and the selected substituents may be the same or different.

The term "dependently selected" refers to one or more variable substituents that are specified in a specified combination for replacement in the main molecule (for example, variables that relate to groups of substituents given in a tabular list of compounds).

Acceptable salts formed using inorganic bases include, for example, sodium or potassium salts, etc. Acceptable salts formed using organic bases include, for example, salts formed by reaction with primary, secondary or tertiary amines, etc.

Compounds/extracts having retinol-like biological activity and/or properties

The present invention includes compounds and/or extracts having retinol-like properties and/or beneficial effects for use in the treatment of dry eye syndrome, including those selected from or selected from the group consisting of one or more plant extracts or sources of plant extracts of the genus Acronychia, Licaria , Calendula and/or Trigonella; Bacterial extracts or sources of extracts of bacteria of the genus Actinomyces; and compounds of formula (I):

(I),

Where -

dotted lines indicate a single or double bond; optionally one of the dotted lines represents a double bond;

R1 represents H, a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms;

R2 represents a carbon chain, linear, cyclic ring or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; optionally a methyl (-CH3) or methylene (=CH2) functional group; a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; optionally from 1 to 10 carbon atoms; optionally 6 carbon atoms; optionally an aromatic functional group, optionally a phenyl functional group; optionally 2-methyl-prop-1,3-diene.

Acronychia, Licaria, Calendula and/or Trigonella plant extract(s)

In certain embodiments, the compounds/extracts having retinol-like properties and/or beneficial effects are or contain extracts or sources of extracts from Acronychia, Licaria, Calendula and/or Trigonella plants. 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 used in the present invention are obtained include, for example, Acronychia aberrans, Acronychia acidula (also referred to 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 pedunculata, Acronychia pubescens, Acronychia species (Batavia Downs), Acronychia suberosa, Acronychia vestita, Acronychia wilcoxiana and combinations two or more of them. In one embodiment, the extract used in the present invention was obtained from Acronychia acidula.

Plants of the genus Licaria from which extracts used in the present invention are obtained include, for example, Licaria vernicosa, Licaria brittoniana, Licaria canella, Licaria cubensis, Licaria velutina and Licaria triandra, as well as combinations of two or more of them. There are about 40 species of the genus Licaria that are endemic to Central and South America. In one embodiment, the extract used in the present invention is obtained from Licaria vernicosa.

There are about 15-20 species of the genus Calendula, which have been found in Southwest 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 (Madeira marigold); and Calendula officinalis (medicinal marigold) and combinations of two or more of them. In one embodiment, the extract used in the present invention is obtained from Calendula officinalis.

Plants of the genus Trigonella include 36 known species 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 Callices, Trigonella Cretica and combinations of two or more of them. Trigonella foenum-graecum, or fenugreek, is the best known member of the Trigonella genus. In one embodiment, the extract used in the present invention is obtained from Trigonella foenum-graecum.

In some 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.

Licaria vernicosa extracts used in the present invention are available from the Baruch S. Blumerg Institute, Doylestown, Pennsylvania (formerly known as IVHR). In some embodiments, one extract is obtained from the woody part of the plant (E2) and the second extract is obtained from the roots of the plant (E3). In the IHVR collection nomenclature, the two extracts are labeled IHVR_40256_G10=X-005348-001E002 and IHVR_40256_E10=X-005346-001M002, respectively. Woody parts and roots of Licaria vernicosa (Mez) Kosterm. can be purchased in Guyana. 504.3 g of dried ground woody plant material can be extracted with a sufficient amount of methanol, which can be dried in a vacuum to obtain 10.54 g of raw methanol extract (E2) for X-005348-001E002. 403.8 g of dried, ground root material can be extracted with sufficient methanol, which can be vacuum dried to produce 18.11 g of raw methanol (E3) for X-005346-001M002.

In some embodiments, the Acronychia and/or Licaria extracts used in the present invention contain compounds having Formula II:

wherein:

R1 is selected from the group consisting of C1 - C20 alkyl, C2 - C20 alkenyl, C2 - C20 alkynyl and C3 - C8 cycloalkyl or aryl;

R2 is selected from the group consisting of hydrogen, hydroxyl, C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C8 cycloalkyl or aryl, - OC1 - C6 alkyl, - OC2 - C6 alkenyl, - OC2 - C6 alkynyl , - OC3 - C8 cycloalkyl or aryl, thiol, - SC1 - C6 alkyl, - SC2 - C6 alkenyl, - SC2 - C6 alkynyl, - SC3 - C8 cycloalkyl or aryl, - NR4C1 - C6 alkyl, - NR4C2 - C6 alkenyl, - NR4C2 - C6 alkynyl and - NR4C3 - C8 cycloalkyl or aryl;

R3 is selected from -CO2H, -CO2R4 or the isosteric equivalent of a carboxyl group, where R4 is C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl or aryl; And

Y represents -(CH2 - CH2)-, -(CH ═ H - or -(C ═ C)-;

or an ophthalmologically acceptable salt thereof.

In some embodiments, the Acronychia and/or Licaria extracts used in the present invention contain compounds having Formula II:

wherein:

R1 is selected from the group consisting of C5 - C16 alkyl, C5 - C16 alkenyl and C5 - C16 alkynyl, more preferably C5 - C16 alkenyl, including, for example, farnesyl;

R2 is selected from the group consisting of hydrogen, hydroxyl, - OC1 - C6 alkyl, - OC2 - C6 alkenyl, - OC2 - C6 alkynyl, - OC3 - C8 cycloalkyl, more preferably hydrogen, hydroxyl, - OC1 - C6 alkyl, even more preferably - hydrogen or - OC1 - C3 alkyl;

R3 is selected from - CO2H, - CO2R4, where R4 is a C1 - C6 alkyl or the isosteric equivalent of a carboxyl group; And

Y represents -(CH2 - CH2)- or -(CH ═ CH)-;

or an ophthalmologically acceptable salt thereof.

In some embodiments, at least one of the compounds of Formula II is present in the Acronychia and/or Licaria extract at a concentration of from at least 1% (or about 1%) to about 20%, or in some cases from about 7% (or about 7% ) to about 10% (or about 10%) by weight of the Acronychia and/or Licaria extract.

In some embodiments, the compounds of formula II used in the present invention are in the form of an acid or alkyl ester 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, alkyl esters thereof, in particular ethyl esters thereof, and combinations of two or more of them.

In some embodiments, the compound of Formula II used in the present invention is 3-(4-farnesyloxyphenyl)propionic acid and/or its ethyl ester.

In some embodiments, the compound of Formula II used in the present invention is 3-(4-farnesyloxy-3-hydroxyphenyl)-propionic acid and/or an ethyl ester thereof.

In some embodiments, the compound of Formula II used in the present invention is 3-(4-farnesyloxy-3-methoxyphenyl)-propionic acid and/or its ethyl ester.

Compounds and extracts obtained from Acronychia species are described in US Patent No. 9,220,928, the contents of which are incorporated herein by reference in their entirety.

In some embodiments, 3-(4-farnesyloxyphenyl)-propionic acid and/or its ethyl ester is present in the Acronychia and/or Licaria extract at a concentration of at least 1% (or about 1%) to about 20%, or in some cases from about 7% (or about 7%) to about 10% (or about 10%) wt. Acronychia and/or Licaria extract.

Any of a variety of Acronychia and/or Licaria extracts can be used for embodiments in which the method includes applying such an extract. The extract can be obtained from any part of the plant, such as, for example, fruits, seeds, bark, leaves, flowers, roots and wood.

In some embodiments, the extract is obtained from the fruit of the plant. Suitable extracts of the fruits, seeds, bark, leaves, flowers, roots and wood of Acronychia or Licaria can be obtained using standard methods, including, without limitation, direct extraction of material from biomass by grinding, maceration, pressing, squeezing, crushing, centrifugation and/or processes such as cold percolation, stirring/distillation, microwave extraction, supercritical/subcritical CO2 gas extraction with or without polar modifiers, pressurized solvent extraction, accelerated solvent extraction, hot water extraction at elevated or normal pressure, hot water extraction under elevated pressure in the presence of a surfactant, oil extraction, membrane extraction, Soxhlet extraction, distillation/golden finger extraction, and/or methods disclosed, for example, in US Patent Nos. 7442391, 7473435 and 7537791 issued to Integrated Botanical Technologies, LLC, incorporated herein by reference, etc. or using other methods such as solvent extraction and the like. In methods involving solvent extraction, any of a variety of solvents may be used, including polar solvents, non-polar solvents, or combinations of two or more of them.

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 C1-C8 alcohols including methanol, ethanol, propanol, butanol and the like, as well as organic acids, including acetic acid, formic acid, propanoic acid, etc., polyols and glycols, including C1-C8 polyols/glycols, etc., and combinations of two or more of them. Suitable non-polar solvents include non-polar organic solvents such as alkanes, including C1-C8 alkanes, cycloalkanes, including C1-C8 cycloalkanes, alkyl ethers, including C1-C8 alkyl ethers, petroleum ethers, ketones, including C1-C8 ketones, methylene chloride, ethyl acetate, xylene , toluene, chloroform, vegetable oil, mineral oil, etc. In another embodiment, the extraction can be carried out using non-polar solvents described above, or by supercritical fluid extraction in the presence or absence of a polar modifier such as C1-C8 alcohols, water, C1-C8 polyols/glycols or C1-C8 organic acids.

In one embodiment, the extract contains an extract of Acronychia acidula. In another embodiment, the extract of the present invention contains a combination of polar and non-polar extracts from the fruit of Acronychia acidula. In another embodiment, the extract of the invention contains 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 present invention contains a combination of polar and non-polar extracts from Licaria vernicosa wood or Licaria vernicosa root. In another embodiment, the extract of the present invention contains alcoholic extracts of Licaria vernicosa wood or Licaria vernicosa root.

In another embodiment, the extract of the present invention contains a polar extract obtained by extracting from the fruit of Acronychia acidula, wood of Licaria vernicosa or root of Licaria vernicosa using a polar solvent containing water, C1 - C8 alcohols, C1 - C8 polyols, C1 - C8 glycols and combinations of two or more of them. In some embodiments, the extract is extracted using one or more C1-C4 alcohols, C1-C4 polyols, and/or C1-C4 glycols. In some embodiments, the extract is prepared using a solvent containing methanol, ethanol, or a combination thereof, in the presence or absence of water. In another embodiment, the extract is a polar extract obtained from the fruit of Acronychia acidula using a combination of alcohol and water. In yet another embodiment, the extract is a polar extract obtained from ground Licaria vernicosa wood or ground Licaria vernicosa root using methanol.

In yet another embodiment, the extract comprises a non-polar extract obtained by extracting from the fruit of Acronychia acidula, the wood of Licaria vernicosa or the root of Licaria vernicosa using a non-polar solvent containing one or more C1 - C8 alkanes, C1 - C8 cycloalkanes, C1 - C8 alkyl esters, C1 - C8 ethers and/or chloroform, more preferably one or more C1 - C8 alkanes, C1 - C8 alkyl esters and/or chloroform. In yet another embodiment, a non-polar extract is prepared from the fruit of Acronychia acidula, wood of Licaria vernicosa, or root of Licaria vernicosa using hexanes, ethyl acetate, chloroform, or mixtures of two or more of these. In yet another embodiment, a non-polar extract is prepared from the fruit of Acronychia acidula using ethyl acetate.

In one embodiment, the extract comprises Calendula officinalis extract. In another embodiment, the extract of the present invention contains a combination of polar and non-polar extracts of Calendula officinalis petals. In another embodiment, the extract of the present invention comprises a non-polar extract of Calendula officinalis petals.

In one embodiment, the extract comprises Trigonella foenum-graecum extract. In another embodiment, the extract of the present invention contains a combination of polar and non-polar extracts of Trigonella folium leaves. In another embodiment, the extract of the invention contains 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 a non-polar solvent containing one or more C1 - C8 alkanes, C1 - C8 cycloalkanes, C1 - C8 alkyl ethers, C1 - C8 alkyl esters and /or chloroform, more preferably one or more C1 - C8 alkanes, C1 - C8 alkyl esters and/or chloroform.

In yet another embodiment, the Calendula and/or Trigonella extract is a non-polar extract prepared using hexanes, ethyl acetate, chloroform, or mixtures of two or more of them. In yet another embodiment, the extract is a non-polar extract prepared using ethyl acetate.

In one embodiment, plant extracts can be obtained by extraction of cell cultures of various plants, including cell cultures of the genera Acronychia, Licaria, Calendula or Trigonella. The cell cultures that are extracted to obtain plant extracts for use in the present invention may be in any form, including suspension cell cultures and the like.

Extracts of Calendula officinalis and Trigonella foenum-graecum can be purchased from Caithness Biotechnologies Ltd, UK (http://www.caithnessbiotechnologies.com/). These extracts are part of the Phytotitre Natural Product Library, which is publicly available for purchase. Alternatively, extracts can be prepared using a preparation method described by Caithness Biotechnologies Ltd. as non-polar and prepared from a mixture of methanol and methylene chloride. For a detailed description, please refer to http://caithnessbiotechnologies.com/contact.html. Typically, in extraction, pre-weighed dried powdered biomass is suspended and stirred in methanol/methylene chloride (1:1) overnight at ambient temperature. The suspension is then filtered and the filtrate is dried under reduced pressure to a solvent-free residue.

In some embodiments, the extract of 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%, in some cases from about 0.001% to about 5%, or in some cases from about 0.01 % to about 1% wt. compositions.

Extract(s) of bacteria of the genus Actinomyces with retinol-like properties and/or beneficial effects

In some embodiments, the compounds/extracts demonstrating retinol-like properties and/or beneficial effects are or contain extract(s) of bacteria of the genus Actinomyces. Bacteria of the genus Actinomyces include many fully characterized species as well as poorly characterized ones, such as one species collected from the United States and labeled species A5640. A sample of these bacteria was collected, grown in culture and converted into an extract. The extract is part of a collection of natural products now operated by the Baruch S. Blumerg Institute, Doylestown, Pennsylvania, USA (formerly known as the Institute for Hepatitis Virus Research (IHVR)). In the nomenclature of the IHVR collection, the extract is labeled as IHVR_39565_F7.

In one embodiment, the extract used in the present invention is obtained from an Actinomyces species capable of producing a chemical composition similar to that obtained with the A5640 extract. In another embodiment, the bacteria are collected in the United States and the strain is identical to previously isolated species A5640.

In some embodiments, the Actinomyces extract is contained 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. compositions.

Compound(s) of formula (I) having retinol-like biological activity and/or properties.

In some embodiments, the compounds/extracts having retinol-like properties and/or beneficial effects are or contain compounds of formula (I).

(I),

Where -

dotted lines indicate a single or double bond; optionally one of the dotted lines represents a double bond;

R1 represents H, a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms;

R2 represents H, a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; optionally a methyl (-CH3) or methylene (=CH2) functional group; a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; optionally from 1 to 10 carbon atoms; optionally 6 carbon atoms; optionally an aromatic functional group, optionally a phenyl functional group; preferably 2-methylprop-1,3-diene.

In some embodiments, compounds of formula (I) include corresponding salts of metal ions such as, but not limited to, Li+, Na+, K+, Ca2+, or Mg2+.

In some embodiments, the compounds of formula I are:

(1)

(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

(2)

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 exhibiting retinoid-like activity . These compounds are further referred to in Examples 6 and 7 as Compound 1 and Compound 2, respectively.

The present invention relates to compounds 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, which demonstrate retinoid-like activity, and mixtures thereof.

Mixtures of any of the above compounds/extracts/extract sources having retinol-like properties and/or beneficial effects may also be used.

The compounds and extracts of Formula I are described in US Patent Publication 2019/0091122, which is incorporated herein by reference in its entirety.

In some 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%, in some cases from about 0.001% to about 10%, in some cases from about 0.01% to about 5%, or in some cases from about 0.2 to about 2% by weight. compositions. In some embodiments, the compound(s) of Formula I is contained in the composition of the present invention in an amount of from about 0.0001% to about 1%, in some cases from about 0.001% to about 1%, or in some cases from about 0.01% up to about 1% wt. compositions.

Compositions The present inventors have discovered that compounds and/or extracts having retinol-like properties and/or beneficial effects can stimulate and/or improve the delivery/release of mucin from corneal epithelial cells.

Permeability enhancer

In certain embodiments, the compositions of the present invention optionally contain a permeability enhancer.

Suitable permeability enhancers include (selected from or selected from the group consisting of), alone or in combination, surfactants such as saponins, polyoxyethylene, polyoxyethylene fatty acid ethers 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, decame bromide tonium and dodecyltrimethylammonium bromide; chelators such as natural polyacids (eg, citric acid), phosphate salts (eg, disodium pyrophosphate), phosphonates, bisphosphonates (eg, etidronic acid), aminocarboxylic acids (eg, ethylenediaminetetraacetic acid (EDTA) and disodium EDTA), and ethylenediamine-N , N'-disuccinic acid (EDDS)); bile acids and salts such as cholic acid, deoxycholic acid, glycocholic acid, glycodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, sodium cholate, sodium glycocholate, glycocholate, sodium deoxycholate, sodium taurocholate, sodium glycodeoxycholate, sodium taurodeoxycholate, chenodeoxycholic acid and ursodeoxycholic acid ; fusidic acid derivatives, glycyrrhizic acid and ammonium glycyrrhizinate with saponin-EDTA, fusidic acid, polyoxyethylene 9-lauryl ether, polyoxyethylene 20-stearyl ether, glycocholate or mixtures of any of the above.

The concentration of permeability enhancer administered should be the minimum amount necessary to sufficiently increase absorption of the compound and/or extract across the mucous membrane or other protective membranes of the eye. Typically, concentrations ranging from 0.01% (or about 0.01%), optionally from 0.05% (or about 0.05%), optionally from 0.1% (or about 0.05%), can be used in the compositions of the present invention. 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 up to 2.5% (or about 2.5%), optionally up to 3% (or about 3%), optionally up to 3.5%, (or about 3.5%), optionally up to 4% (or about 4%), optionally up to 4.5% (or about 4.5%), optionally up to 5% (or about 5%), optionally up to 5.5% (or about 5.5% ), optionally up to 6% (or about 6%), optionally up to 6.5% (or about 6.5%), optionally up to 7% (or about 7%), optionally up to 7.5% (or about 7. 5%), optionally up to 8% (or about 8%), optionally up to 8.5% (or about 8.5%), optionally up to 9% (or about 9%), optionally up to 9.5% (or about 9.5%), optionally up to 10% (or about 10%), optionally up to 10.5% (or about 10.5%), optionally up to 11% (or about 11%), optionally up to 11.5% ( or about 11.5%), optionally up to 12% (or about 12%), optionally up to 12.5% (or about 12.5%), optionally up to 13% (or about 13%), optionally up to 13.5 % (or about 13.5%), optionally up to 14% (or about 14%), optionally up to 14.5% (or about 14.5%), optionally up to 15% (or about 15%), optionally up to 15 .5% (or about 15.5%), optional up to 16% (or about 16%), optional up to 16.5% (or about 16.5%), optional up to 17% (or about 17%), optional up to 17.5% (or about 17.5%), optional up to 18% (or about 18%), optional up to 18.5% (or about 18.5%), optional up to 19% (or about 19%) , optionally up to 19.5% (or about 19.5%), optionally up to 20% (or about 20%) of the total amount of the composition (w/v).

Ophthalmologically acceptable carrier

The compositions of the present invention also contain an aqueous carrier in the form of an oil-in-water emulsion or a water-in-oil emulsion. The carrier is ophthalmologically acceptable. Useful oil-in-water and water-in-oil media can be found in US Patent Publication No. 20030165545A1 and US Patent Nos. 9480645, 8828412 and 8496976, each of which is incorporated herein by reference in its entirety.

The compositions of the present invention may in some cases contain one or more additional excipients and/or one or more additional active ingredients. Examples of such optional components are described below.

Excipients that are commonly used in ophthalmic compositions include, but are not limited to, emollients, tonicity regulators, preservatives, chelating agents, buffering agents (other than and complementary to the organic acids of the present invention), and surfactants. Other excipients contain solubilizing, stabilizing, comfort enhancing agents, polymers, emollients, pH adjusters (different from and complementary to the organic acids of the present invention) and/or lubricants. The compositions of the present invention can use any of a variety of excipients, including water, mixtures of water and water-miscible solvents such as vegetable oils or mineral oils containing from 0.5% to 5% non-toxic water-soluble polymers, natural products such as agar and gum arabic, starch derivatives such as starch acetate and hydroxypropyl starch, as well as other synthetic products such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, and preferably cross-linked polyacrylic acid, and mixtures thereof.

Emollients and soothing agents used in embodiments of the present invention include, but are not limited to, cellulose derivatives (such as hydroxyethylcellulose, methylcellulose, hypromellose, or mixtures thereof), hyaluronic acid, tamarind seed extract, glycerin, polyvinylpyrrolidone, polyethylene oxide, polyethylene glycol, propylene glycol and polyacrylic acid and mixtures thereof. In some embodiments, one or more of hyaluronic acid, propylene glycol, tamarind seed extract, glycerin, and/or polyethylene glycol 400 are emollients and soothing agents. In some embodiments, the emollient and soothing agent is selected from hyaluronic acid, tamarind seed extract, or mixtures thereof.

The compositions of the present invention are ophthalmologically acceptable for instillation into the eyes of a patient. The term “aqueous” generally means an aqueous composition in which the excipient constitutes more than about 50%, preferably more than about 75%, or in particular more than about 90% by weight of water. In some embodiments, the compositions of the present invention are substantially free of eye irritant compounds. In some embodiments, the compositions of the present invention are substantially free of free fatty acids and C1-C4 alcohols. In some embodiments, the compositions of the present invention contain less than 40% (or about 40%), in some cases less than 35% (or about 35%), in some cases less than 30% (or about 30%), in some cases less than 25% (or about 25%); in some cases less than 20% (or about 20%), in some cases less than 15% (or about 15%), in some cases less than 10% (or about 10%) or in some cases less than 5% (or about 5% ) non-alcoholic, organic filler or solvent from the total weight of the composition. These drops can be dispensed from a single dose ampoule, which may preferably be sterile, eliminating the need for bacteriostatic components in the formulation. Alternatively, the drops may be dispensed from a multi-dose vial, which may preferably contain a device that removes any preservative from the composition as it is dispensed, and such devices are known in the art.

In certain embodiments, the compositions of the present invention are of the isotonic or mildly hypotonic type to overcome any tear hypertonicity caused by dehydration and/or disease. This may require a tonicity regulator to bring the formulation's osmolality level to or around 210-320 milliosmoles per kilogram (mOsm/kg). The compositions of the present invention have an osmolality substantially in the range of 220-320 mOsm/kg, or optionally have an osmolality in the range of 235-300 mOsm/kg. The composition of ophthalmic compositions will essentially correspond to the composition of sterile aqueous solutions.

The osmolality of the compositions of the present invention can be adjusted with tonicity regulators to a value compatible with the intended use of the compositions. For example, the osmolality of the composition can be adjusted to approximate the osmotic pressure of normal tear fluid, which is equivalent to approximately 0.9% w/v sodium chloride in water. Examples of suitable tonicity regulators include, but are not limited to, sodium, potassium, calcium and magnesium chloride; dextrose; glycerol; propylene glycol; mannitol; sorbitol, etc., as well as mixtures thereof. In one embodiment, a combination of sodium chloride and potassium chloride is used to control 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, analgesics, anti-inflammatory and antiallergic drugs, and antimicrobial agents. More specific examples of pharmaceutically active compounds include betaxolol, timolol, pilocarpine, carbonic anhydrase inhibitors and prostaglandins; dopaminergic antagonists; postoperative antihypertensive agents such as para-aminoclonidine (apraclonidine); anti-infectives such as ciprofloxacin, moxifloxacin and tobramycin; non-steroidal and steroidal anti-inflammatory drugs such as naproxen, diclofenac, nepafenac, suprofen, ketorolac, tetrahydrocortisol and dexamethasone; dry eye therapeutics such as PDE4 inhibitors; and antiallergic drugs such as H1/H4 inhibitors, H4 inhibitors, olopatadine, or mixtures thereof.

It is also contemplated that the concentrations of the ingredients included in the compositions of the present invention may vary. One of ordinary skill in the art will appreciate that concentrations may vary depending on the addition, substitution and/or subtraction of ingredients in a given formulation.

In some embodiments, the compositions of the present invention may have a pH compatible with the intended use, often ranging from 4 (or about 4) to 10 (or about 10), in some cases from 6 (or about 6) to 8 (or about 8), in some cases from 6.5 (or about 6.5) to 7.5 (or about 7.5) or in some cases from 6.8 (or about 6.8) to 7.2 (or about 7.2).

In some embodiments, various conventional buffer solutions may be used, such as phosphate, borate, citrate, acetate, histidine, tris, bis-tris, etc., as well as mixtures thereof. Borate buffer solutions include boric acid and its salts such as sodium or potassium borate. Potassium tetraborate or potassium metaborate can also be used, which produce boric acid or a salt of boric acid in solution. Hydrated salts such as sodium borate decahydrate can also be used. Phosphate buffers include phosphoric acid and its salts; for example, M2HPO4 and MH2PO4, where M represents an alkali metal such as sodium and potassium. Salt hydrates can also be used. In one embodiment of the present invention, Na2HPO4.7H2O and NaH2PO2.H2O are used as buffer solutions. The term "phosphate" also includes compounds that form phosphoric acid or a salt of phosphoric acid in solution. In addition, organic counterions can also be used in the above buffer solutions. The concentration of the buffer solution generally ranges from about 0.01 to 2.5% w/v, and preferably ranges from about 0.05 to about 0.5% w/v.

In some embodiments, the viscosity of the compositions of the present invention ranges from about 1 to about 500 cP, in some cases from about 10 to about 200 cP, or in some cases from about 10 to about 100 cP when measured on a TA Instruments AR 2000 rheometer. The TA Instruments AR 2000 Rheometer must be used with the TA Rheological Advantage Software AR2000 Flow Test Method with 40mm steel plate geometry; Viscosity ranges must be obtained by measuring steady-state flow with a controlled shear rate from 0 s¯¹ to 200 s¯¹.

In some embodiments, the compositions of the present invention are used as an eye drop solution, an eye wash solution, a contact lens lubricant and/or moisturizer solution, a spray solution, an irrigation solution, or any other method of administering the composition to the eye.

The compositions of the present invention can also be used as packaging solutions for contact lenses. In some embodiments, as packaging solutions, the compositions of the present invention can be sealed in blister packs and are also suitable for sterilization.

Examples of blister packs and sterilization methods are described in the following references, which are incorporated herein by reference in their entirety; US Patents No. D435966; 4691820; 5467868; 5704468; 5823327; 6,050,398; 5,696,686; 6018931; 5577367; and 5,488,815. This part of the manufacturing process is another way of treating ophthalmic products with an antiallergic agent, namely adding antiallergic agents to the solution before sealing the package and then sterilizing the package. This method is the preferred method for treating ophthalmic products with antiallergic substances.

Sterilization can be carried out at different temperatures and for different periods of time. Preferred sterilization conditions range from about 100ºC for about 8 hours to about 150ºC for about 0.5 minutes. Preferred sterilization conditions range from about 115°C for about 2.5 hours to about 130°C for about 5.0 minutes. Preferred sterilization conditions are approximately 124ºC for approximately 18 minutes.

When used as packaging solutions, the compositions of the present invention may be aqueous. Typical packaging solutions include, but are not limited to, saline solutions, other buffer solutions, and deionized water. In some embodiments, the packaging solution is an aqueous solution in deionized water or saline containing salts, including, without limitation, sodium chloride, sodium borate, sodium phosphate, sodium hydrogenphosphate, sodium dihydrogenphosphate, or their corresponding potassium salts. These ingredients typically combine to form buffer solutions containing an acid and a conjugate base, so that the addition of acids and bases results in only a relatively small change in pH. In some embodiments, the pH of the packaging solution is as described above. Buffer solutions may further 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, ethylenediaminetetraacetic acid, etc., and combinations thereof.Preferably, the solution is borate or phosphate buffered saline or deionized water.A particularly preferred solution will contain about 500-18,500 ppm sodium borate, most preferably about 1,000 ppm sodium borate.

If any ingredients contained in packaging solutions undergo oxidative degradation, agents may be added to stabilize the packaging solutions containing such ingredients. Such "oxidation stabilizers" include, but are not limited to, chelating agents 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, as well as some macrocyclic ligands such as crown ethers, ligand-containing units and catenanes. See David A. Leigh et al Angew. Chem Int. Ed., 2001, 40, No. 8, pgs. 1538-1542 and Jean-Claude Chambron et al. Pure & Appl. Chem., 1990, Vol. 62, No. 6, pgs. 1027-1034. Stabilizers that prevent oxidation can also be other substances that inhibit oxidation, for example, substances from the group consisting of 2,2',2",6,6',6"-hexa-(1,1-dimethyl)4, 4',4"-[(2,4,6-trimethyl-1,3,5-benztriyl)-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(octadecycloxy)-5,5'-spirobi(1,3,2-dioxaphosphorine), dioctadecyl disulfide, didodecyl-3,3'-thiodipropionate, dioctadecyl-3,3'-thiodipropionate, butylhydroxytoluene , ethylene bis[3,3-di[3-(1,1-dimethylethyl)-4-hydroxyphenyl]butyrate] and mixtures thereof.Preferred oxidation stabilizers are diethylenetriaminepentaacetic acid (DTPA) or DTPA salts such as CaNa3DTPA, ZnNa3DTPA and Ca2DTPA See U.S. Patent Application No. 60/783,557, filed March 17, 2006, entitled “Methods for Stabilizing Pharmaceutical Compositions That Are Unstable to Oxidation,” and the corresponding unconditional application, which is incorporated herein by reference in its entirety. In some embodiments, the concentration of oxidation stabilizers in the solution is from about 2.5 µmol/L to about 5000 µmol/L, in some cases from about 20 µmol/L to about 1000 µmol/L, in some cases from about 100 µmol/L up to about 1000 µmol/L or in some cases from about 100 µmol/L to about 500 µmol/L.

In specific 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 once a day, five times a day, six times a day, eight times a day, every hour or more often. This dosing frequency is also maintained for periods of varying duration depending on the therapeutic needs of the patient. The duration of a particular therapeutic regimen can vary from a single-dose regimen to a regimen lasting several months or years. One of ordinary skill in the art will be familiar with the definition of a therapeutic regimen for specific indications.

The composition and products containing such compositions of this invention can be prepared using techniques well known to one of ordinary skill in the art.

EXAMPLES

Any of the compositions of the present invention described in the examples below illustrate, but are not limited to, specific embodiments of the compositions of the present invention. Other modifications may be made by one skilled in the art without departing from the spirit and scope of the present invention.

The following test methods were used in the examples.

Example 1

Lemon aspen extract compositions showed increased expression of MUC1, MUC4 and MUC16 genes in human epicorneal tissues when treated in the medium.

Human 3D epicorneal tissues were purchased from MatTek Company (Ashland, MA, USA). Once 3D human epicorneal tissues were obtained, they were incubated in MatTek assay medium overnight according to the manufacturer's instructions. Three-dimensional human epicorneal tissues were divided into three experimental groups with a minimum of three tissues in each group. Lemon aspen extract was respectively added to the culture medium containing human epicorneal tissues from the two experimental groups to obtain medium concentrations of 0.001% or 0.01% (w/v), respectively. Epicorneal tissues from all four experimental groups were incubated for two days. The lemon aspen extract used was supplied by Southern Cross Botanicals (Knockrow Nsw, Australia). After incubation for two days, the expression of mucin 1 (MUC1), mucin 4 (MUC4) and mucin 16 (MUC16) genes was analyzed. After two days of incubation, human 3D epicorneal tissues were cut in half and half the tissue was lysed in 350 μl of lysis buffer consisting of 100 parts RLT buffer (RNeasy Mini' Kit, Qiagen, Valencia, CA, USA) per part 2-mercaptoethanol. RNA was extracted from the solutions using the RNeasy mini kit (QIAGEN, Valencia, CA, USA) according to the manufacturer's instructions, and RNA was eluted in 25 μl of RNase-free water.

Reverse transcription (RT) was performed using a Biosystems High Throughput Reverse Transcription Kit (ThermoFisher Scientific, Bridgewater, NJ, USA). Gene expression assay kits sold under the trade name TAQMAN for mucin-1 (MUC1), mucin-4 (MUC4) and mucin-16 (MUC16), polypeptide A (RNA) polymerase (RNA) II (POLR2A) and master mix purchased from ThermoFisher Scientific (Bridgewater, NJ). The qPCR assay was performed using TaqMan® Master Mix (ThermoFisher Scientific, Bridgewater, NJ, USA) and performed on a real-time PCR system commercially available under the trade name QUANTSTUDIO 7 Flex System (ThermoFisher Scientific, NJ, USA). Bridgewater, New Jersey, USA). The expression of the MUC1, MUC4 and MUC16 genes was normalized to the expression of the constitutive human RNA gene POLR2A. Fold changes were calculated compared to untreated control (UT) and a two-tailed two-sample Student's t test (Microsoft Office Excel 2007; Microsoft, Redmond, WA, USA). The results are shown in Fig. 1.

Example 2

Lemon aspen extract compositions showed an increase in mucin-1 secretion in human epicorneal tissues when treated in the medium.

Human 3D epicorneal tissues were purchased from MatTek Company (Ashland, MA, USA). Once 3D human epicorneal tissues were obtained, they were incubated in MatTek assay medium overnight according to the manufacturer's instructions. Three-dimensional human epicorneal tissues were divided into three experimental groups with a minimum of three tissues in each group. Lemon aspen extract was respectively added to the culture medium containing human epicorneal tissues from the two experimental groups to obtain medium concentrations of 0.001% or 0.01% (w/v), respectively. Epicorneal tissues from all four experimental groups were incubated for two days. Two days later, the culture medium was collected to measure mucin 1 secretion using a human mucin-1 (CA15-3) enzyme-linked immunosorbent assay (ELISA) kit (EHMUC1, ThermoFisher Scientific, Bridgewater, NJ) according to the manufacturer's protocol . To assess activity, colorimetric change was measured using a microplate photometer (SpectraMax M2E, Molecular Devices, Sunnyvale, CA, USA). This assay uses a standard enzyme-linked immunosorbent assay method and therefore there is a linear correlation between the concentration of mucin-1 in the sample and the colorimetric change. A standard curve was generated with mucin-1 concentration on the x-axis and absorbance on the y-axis indicating the corresponding mucin-1 concentration. The results are shown below in Fig. 2.

Example 3

Solutions can be prepared containing one or more compounds and/or extracts having retinol-like properties and/or beneficial effects of the present invention, as shown in Examples 3-7.

Table 1 shows the components of such formulations (as shown in formulations 3A-3D) that can be included in the formulation as described below using conventional mixing technology.

Table 1

3A
Used to relieve irritation caused by dry eyes 3B
Used to relieve irritation caused by dry eyes 3C
Used to relieve irritation caused by dry eyes (with or without contact lenses) 3D
Used to relieve irritation caused by dry eyes (with or without contact lenses) INGREDIENT % wt./
wt. Quantity per batch (grams) % wt./
wt. Quantity per batch (grams) % wt./
wt. Quantity per batch (grams) % wt./
wt. Quantity per batch (grams) Sodium hyaluronate 0.20 2.0 0.30 3.0 0.15 1.5 0.15 1.5 Lemon Aspen Extract 0.10 1.0 0.01 0.10 0.10 1.0 0.01 0.10 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 glycol 400 0.25 2.5 0.25 2.5 0 0 0 0 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 chloride 0.10 1.0 0.10 1.0 0.10 1.0 0.10 1.0 Calcium chloride dihydrate 0.006 0.06 0.006 0.06 0.006 0.06 0.006 0.06 Magnesium chloride 0.006 0.06 0.006 0.06 0.006 0.06 0.006 0.06 Sodium chlorite dihydrate 0.014 0.14 0.014 0.14 0.014 0.14 0.014 0.14 Polyquaternium-42 (33% aqueous solution) 0.0015 0.015 0.0015 0.015 0.0015 0.015 0.0015 0.015 Sodium chlorite dihydrate 0.014 0.14 0.014 0.14 0.014 0.14 0.014 0.14 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 280-290 mOsm/kg

**can be adjusted to pH 7.2

*** optionally in sufficient quantities up to 100% w/w.

For examples 3A-3D: Sodium hyaluronate can be supplied by CONTIPRO A.S. (DOLNI DOBRUCZ, CZECH REPUBLIC).

For Examples 3A-3D: Lemon Aspen Extract (Abacross™ Acronychia Fruit Extract) can be supplied by SOUTHERN CROBOTANICALS (KNOCKROW NSW, AUSTRALIA).

For Examples 3A-3D: Polysorbate 20 can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 3A-3D: Polysorbate 80 can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 5A-5B: Polyethylene glycol 400 can be supplied by Clariant Produkte (BURGKIRCHEN, GERMANY).

For Examples 3A-3D: Boric acid can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 3A-3D: Sodium borate can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 3A-3D: Sodium chloride can be supplied by Caldic (DUSSELDORF, GERMANY).

For Examples 3A-3D: Potassium chloride can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 3A-3D: Calcium chloride dihydrate can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 3A-3D: Magnesium chloride can be supplied by KGaA (DARMSTADT, GERMANY).

For Examples 3A-3D: Polyquaternium-42 (33% aqueous solution) can be supplied by DSM BIOMEDICAL (BERKELEY, CA, USA)

For Examples 3A-3D: Sodium chlorite dihydrate can be supplied by Oxychem (WICHITA, KANSAS, USA)

For Examples 3A-3D: 1N sodium hydroxide can be supplied by VWR (RADNER, PENNSYLVANIA, USA).

For Examples 3A-3D: 1N hydrochloric acid can be supplied by VWR (RADNER, PENNSYLVANIA, USA).

Solution 3A can be prepared as follows:

1. Add 800 grams of USP purified water to a 1500 ml beaker.

2. To the above solution add 10 g of polysorbate 80 and 50 g of polysorbate 20. The solution is stirred until both ingredients are completely mixed and dissolved.

3. Add 1.0 g of lemon aspen extract to the above solution. The solution is stirred until the lemon aspen extract dissolves.

4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.

5. Add 2.0 grams of sodium hyaluronate to the solution from step 4. The solution is stirred until the sodium hyaluronate is completely dissolved.

6. Then add the following ingredients sequentially, allowing each to dissolve completely before adding the next: 2.5 grams polyethylene glycol-400, 6.0 grams boric acid, 0.05 grams sodium borate, 1.0 grams sodium chloride, 0.06 grams chloride calcium, 0.06 grams of magnesium chloride and 0.0015 grams of polyquaternium-42 (aqueous).

7. While continuing to stir, add 0.14 grams of sodium chlorite dihydrate and stir until dissolved.

8. The tonicity of the composition is determined and adjusted to 280 mOsm/kg with sodium chloride.

9. The pH of the composition is adjusted to 7.2 using 1N sodium hydroxide and/or 1N hydrochloric acid.

10. The solution is brought to a mass of 1000.0 grams by adding purified water according to USP and stirring for 10 minutes until completely homogeneous.

11. Filter the solution through a 0.22 micron filter.

Solution 3B can be prepared as follows:

1. Add 800 grams of USP purified water to a 1500 ml beaker.

2. Add 2 g of polysorbate 80 and 10 g of polysorbate 20 to the above solution. Stir the solution until both ingredients are completely mixed and dissolved.

3. Add 0.1 g of lemon aspen extract to the above solution. The solution is stirred until the lemon aspen extract dissolves.

4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.

5. Add 3.0 grams of sodium hyaluronate to the solution from step 4. The solution is stirred until the sodium hyaluronate is completely dissolved.

6. Then add the following ingredients sequentially, allowing each to dissolve completely before adding the next: 2.5 grams polyethylene glycol-400, 6.0 grams boric acid, 0.05 grams sodium borate, 1.0 grams sodium chloride, 0.06 grams chloride calcium, 0.06 grams of magnesium chloride and 0.0015 grams of polyquaternium-42 (aqueous).

7. While continuing to stir, add 0.14 grams of sodium chlorite dihydrate and stir until dissolved.

8. The tonicity of the composition is determined and adjusted to 280 mOsm/kg with sodium chloride.

9. The pH of the composition is adjusted to 7.2 using 1N sodium hydroxide and/or 1N hydrochloric acid.

10. The solution is brought to a mass of 1000.0 grams by adding purified water according to USP and stirring for 10 minutes until completely homogeneous.

11. Filter the solution through a 0.22 micron filter.

The 3C solution can be prepared as follows:

1. Add 800 grams of USP purified water to a 1500 ml beaker.

2. Add 10 g of polysorbate 80 and 20 g of polysorbate 20 to the above solution. Stir the solution until both ingredients are completely mixed and dissolved.

3. Add 1.0 g of lemon aspen extract to the above solution. The solution is stirred until the lemon aspen extract dissolves.

4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.

5. Add 1.5 grams of sodium hyaluronate to the solution from step 4. The solution is stirred until the sodium hyaluronate is completely dissolved.

6. Then add the following ingredients in succession, allowing each to dissolve completely before adding the next: 6.0 grams boric acid, 0.05 grams sodium borate, 1.0 grams potassium chloride, 0.06 grams calcium chloride dihydrate, 0.06 grams chloride magnesium and 0.0015 grams of polyquaternium-42 (aqueous).

7. While continuing to stir, add 0.14 grams of sodium chlorite dihydrate and stir until dissolved.

8. The tonicity of the composition is determined and adjusted to 280 mOsm/kg with sodium chloride.

9. The pH of the composition is adjusted to 7.2 using 1N sodium hydroxide and/or 1N hydrochloric acid.

10. The solution is brought to a mass of 1000.0 grams by adding purified water according to USP and stirring for 10 minutes until completely homogeneous.

11. Filter the solution through a 0.22 micron filter.

The 3D solution can be obtained as follows:

1. Add 800 grams of USP purified water to a 1500 ml beaker.

2. To the above solution add 2 g of polysorbate 10 and 50 g of polysorbate 20. The solution is stirred until both ingredients are completely mixed and dissolved.

3. Add 0.1 g of lemon aspen extract to the above solution. The solution is stirred until the lemon aspen extract dissolves.

4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.

5. Add 1.5 grams of sodium hyaluronate to the solution from step 4. The solution is stirred until the sodium hyaluronate is completely dissolved.

6. Then add the following ingredients in succession, allowing each to dissolve completely before adding the next: 6.0 grams boric acid, 0.05 grams sodium borate, 1.0 grams potassium chloride, 0.06 grams calcium chloride dihydrate, 0.06 grams chloride magnesium and 0.0015 grams of polyquaternium-42 (aqueous).

7. While continuing to stir, add 0.14 grams of sodium chlorite dihydrate and stir until dissolved.

8. The tonicity of the composition is determined and adjusted to 280 mOsm/kg with sodium chloride.

9. The pH of the composition is adjusted to 7.2 using 1N sodium hydroxide and/or 1N hydrochloric acid.

10. The solution is brought to a mass of 1000.0 grams by adding purified water according to USP and stirring for 10 minutes until completely homogeneous.

11. Filter the solution through a 0.22 micron filter.

Example 4

Table 2 sets forth the components of the compositions of the present invention (as shown in Formulations 4A-4D) that can be formulated as described below using conventional mixing technology.

table 2

4A
Used to relieve irritation caused by dry eyes 4B
Used to relieve irritation caused by dry eyes (with or without contact lenses) 4C
Used to relieve irritation caused by dry eyes (with or without contact lenses) 4D
Used to relieve irritation caused by dry eyes INGREDIENT % wt./
wt. Quantity per batch (grams) % wt./
wt. Quantity per batch (grams) % w/w Quantity per batch (grams) % wt./
wt. Quantity per batch (grams) Sodium hyaluronate 0 0 0 0 0.120 1.20 0.120 1.20 Tamarind seed polysaccharide 0 0 0 0 0.200 2.00 0.200 2.00 Lemon Aspen Extract 0.10 1.0 0.10 1.0 0.01 0.10 0.01 0.10 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 glycol 400 0 0 0 0 0.25 2.5 0.25 2.5 Glycerol 0.25 2.5 0.25 2.5 0.25 2.5 0.25 2.5 Hypromellose E3 2910 0.198 1.98 0.198 1.98 0.198 1.98 0.198 1.98 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 Sodium hydrogen phosphate 0.027 0.27 0.027 0.27 0.027 0.27 0.027 0.27 Sodium citrate dihydrate 0.40 4.0 0.40 4.0 0.40 4.0 0.40 4.0 Sodium chloride* Potassium chloride 0.10 1.0 0.10 1.0 0.10 1.0 0.10 1.0 50% aqueous sodium lactate solution 0.057 0.57 0.057 0.57 0.057 0.57 0.057 0.57 Magnesium chloride 0.013 0.13 0.013 0.13 0.013 0.13 0.013 0.13 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 Edetate disodium 0.01 0.1 0.05 0.5 0.01 0.1 0.05 0.5 Polyquaternium-42 (33% aqueous solution) 0.0030 0.030 0.0015 0.015 0.0030 0.030 0.0015 0.015 Sodium chlorite dihydrate 0.014 0.14 0.014 0.14 0.014 0.14 0.014 0.14 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 280-290 mOsm/kg

**can be adjusted to pH 7.2

*** optionally in sufficient quantities up to 100% w/w.

For examples 4C-4D: Sodium hyaluronate can be supplied by CONTIPRO A.S. (DOLNI DOBRUCZ, CZECH REPUBLIC).

For Examples 4C-4D: Tamarind seed polysaccharide can be supplied by INDENA (MILAN, ITALY).

For Examples 4A-4D: Lemon Aspen Extract (Abacross™ Acronychia Fruit Extract) can be supplied by SOUTHERN CROBOTANICALS (KNOCKROW NSW, AUSTRALIA).

For Examples 4A-4D: Polysorbate 20 can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 4A-4D: Polysorbate 80 can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 6C-6D: Polyethylene glycol 400 can be supplied by Clariant Produkte (BURGKIRCHEN, GERMANY).

For Examples 4A-4D: Boric acid can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 4A-4D: Sodium borate can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 4A-4D: Sodium chloride can be supplied by Caldic (DUSSELDORF, GERMANY).

For Examples 4A-4D: Potassium chloride can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 4A-4D: Hypromellose E3 2910 can be supplied by DOW CHEMICAL (PLAQUEMINE, LOUISIANA, USA).

For Examples 4A-4D: Glycerin can be supplied by Emery Oleochemicals GmbH (DUSSELDORF, GERMANY).

For Examples 4A-4D: Disodium phosphate can be supplied by KGaA (DARMSTADT, GERMANY).

For Examples 4A-4D: Sodium citrate can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 4A-4D: Sodium lactate can be supplied as sodium lactate (50% aqueous solution) from Merck KGaA (DARMSTADT, GERMANY).

For Examples 4A-4D: Glucose can be supplied by Roquette Freres (LASTREME, FRANCE).

For Examples 4A-4D: Glycine can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 4A-4D: Ascorbic acid can be supplied by DSM NUTRITIONAL Products (DRAKEMERE, SCOTLAND, UK).

For Examples 4A-4D: Polyquaternium-42 can be supplied as Polyquaternium-42 (33% aqueous solution) from DSM BIOMEDICAL (BERKELEY, CA, USA).

For Examples 4A-4D: Edetate disodium can be supplied by Merck NV/SA (OVERYSE, BELGIUM).

For Examples 4A-4D: 1N sodium hydroxide can be supplied by VWR (RADNER, PENNSYLVANIA, USA).

For Examples 4A-4D: 1N hydrochloric acid can be supplied by VWR (RADNER, PENNSYLVANIA, USA).

For Examples 6A-6D: Sodium chlorite dihydrate can be supplied by Oxychem (WICHITA, KANSAS, USA)

Solution 4A can be prepared as follows:

1. Add 800 grams of USP purified water to a 1500 ml beaker.

2. To the above solution add 10 g of polysorbate 80 and 50 g of polysorbate 20. The solution is stirred until both ingredients are completely mixed and dissolved.

3. Add 1.0 g of lemon aspen extract to the above solution. The solution is stirred until the lemon aspen extract dissolves.

4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.

5. Add 1.98 grams of hypromellose E3 Premium to the above solution. The solution is stirred until the hypromellose E3 Premium dissolves.

6. Then add the following ingredients in succession, allowing each to dissolve completely before adding the next: 2.50 grams glycerin, 4.0 grams boric acid, 0.22 grams sodium borate, 0.27 grams sodium hydrogen phosphate, 4.00 grams sodium citrate dihydrate , 1 gram potassium chloride, 0.57 grams sodium lactate (50% aqueous solution), 0.13 grams magnesium chloride, 0.036 grams glucose, 0.0002 grams glycine, 0.0001 grams ascorbic acid, 0.10 grams edetate disodium, 0.030 grams of polyquaternium-42 (33% aqueous solution) and 0.14 grams of sodium chlorite.

7. The tonicity of the solution is determined and adjusted to 280 mOsm with sodium chloride.

8. Measure the pH of the solution and adjust it to 7.2 with 1N sodium hydroxide and/or 1N hydrochloric acid.

9. The solution is brought to a volume of 1000.00 grams with purified water and stirred for 10 minutes.

10. Filter the solution through a 0.22 micron filter.

Solution 4B can be prepared as follows:

1. Add 800 grams of USP purified water to a 1500 ml beaker.

2. To the above solution add 10 g of polysorbate 80 and 50 g of polysorbate 20. The solution is stirred until both ingredients are completely mixed and dissolved.

3. Add 1.0 g of lemon aspen extract to the above solution. The solution is stirred until the lemon aspen extract dissolves.

4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.

5. Add 1.98 grams of hypromellose E3 Premium to the above solution. The solution is stirred until the hypromellose E3 Premium dissolves.

6. Then add the following ingredients in succession, allowing each to dissolve completely before adding the next: 2.50 grams glycerin, 4.0 grams boric acid, 0.22 grams sodium borate, 0.27 grams sodium hydrogen phosphate, 4.00 grams sodium citrate dihydrate , 1 gram potassium chloride, 0.57 grams sodium lactate (50% aqueous solution), 0.13 grams magnesium chloride, 0.036 grams glucose, 0.0002 grams glycine, 0.0001 grams ascorbic acid, 0.05 grams edetate disodium, 0.015 grams of polyquaternium-42 (33% aqueous solution) and 0.14 grams of sodium chlorite.

7. The tonicity of the solution is determined and adjusted to 280 mOsm with sodium chloride.

8. Measure the pH of the solution and adjust it to 7.2 with 1N sodium hydroxide and/or 1N hydrochloric acid.

9. The solution is brought to a volume of 1000.00 grams with purified water and stirred for 10 minutes.

10. Filter the solution through a 0.22 micron filter.

The 4C solution can be prepared as follows:

1. Add 800 grams of USP purified water to a 1500 ml beaker.

2. Add 2 g of polysorbate 80 and 10 g of polysorbate 20 to the above solution. Stir the solution until both ingredients are completely mixed and dissolved.

3. Add 0.1 g of lemon aspen extract to the above solution. The solution is stirred until the lemon aspen extract dissolves.

4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.

5. Add 1.2 grams of sodium hyaluronate to the solution from step 4. The solution is stirred until the sodium hyaluronate is completely dissolved.

6. Add 2.0 grams of tamarind seed polysaccharide to the above mixture. The solution is stirred until the tamarind seed polysaccharide is completely dissolved.

7. Add 1.98 grams of hypromellose E3 Premium to the above solution. The solution is stirred until the hypromellose E3 Premium dissolves.

8. Then add the following ingredients sequentially, allowing each to dissolve completely before adding the next: 2.50 grams polyethylene glycol 400, 2.50 grams glycerin, 4.0 grams boric acid, 0.22 grams sodium borate, 0.27 grams sodium hydrogen phosphate, 4.00 grams sodium citrate dihydrate, 1 gram potassium chloride, 0.57 grams sodium lactate (50% aqueous solution), 0.13 grams magnesium chloride, 0.036 grams glucose, 0.0002 grams glycine, 0.0001 grams ascorbic acid acid, 0.10 grams of disodium edetate, 0.030 grams of polyquaternium-42 (33% aqueous solution) and 0.14 grams of sodium chlorite.

9. The tonicity of the solution is determined and adjusted to 280 mOsm with sodium chloride.

10. Measure the pH of the solution and adjust it to 7.2 with 1N sodium hydroxide and/or 1N hydrochloric acid.

11. The solution is brought to a volume of 1000.00 grams with purified water and stirred for 10 minutes.

12. Filter the solution through a 0.22 micron filter.

The 4D solution can be prepared as follows:

1. Add 800 grams of USP purified water to a 1500 ml beaker.

2. Add 2 g of polysorbate 80 and 10 g of polysorbate 20 to the above solution. Stir the solution until both ingredients are completely mixed and dissolved.

3. Add 0.1 g of lemon aspen extract to the above solution. The solution is stirred until the lemon aspen extract dissolves.

4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.

5. Add 1.2 grams of sodium hyaluronate to the solution from step 4. The solution is stirred until the sodium hyaluronate is completely dissolved.

6. Add 2.0 grams of tamarind seed polysaccharide to the above mixture. The solution is stirred until the tamarind seed polysaccharide is completely dissolved.

7. Add 1.98 grams of hypromellose E3 Premium to the above solution. The solution is stirred until the hypromellose E3 Premium dissolves.

8. Then add the following ingredients sequentially, allowing each to dissolve completely before adding the next: 2.50 grams polyethylene glycol 400, 2.50 grams glycerin, 4.0 grams boric acid, 0.22 grams sodium borate, 0.27 grams sodium hydrogen phosphate, 4.00 grams sodium citrate dihydrate, 1 gram potassium chloride, 0.57 grams sodium lactate (50% aqueous solution), 0.13 grams magnesium chloride, 0.036 grams glucose, 0.0002 grams glycine, 0.0001 grams ascorbic acid acid, 0.10 grams of disodium edetate, 0.015 grams of polyquaternium-42 (33% aqueous solution) and 0.14 grams of sodium chlorite.

9. The tonicity of the solution is determined and adjusted to 280 mOsm with sodium chloride.

10. Measure the pH of the solution and adjust it to 7.2 with 1N sodium hydroxide and/or 1N hydrochloric acid.

11. The solution is brought to a volume of 1000.00 grams with purified water and stirred for 10 minutes.

12. The solution is filtered through a 0.22 micron hydrophilic filter.

Example 5

Table 3 sets forth the components of the formulations of the present invention (as shown in Formulations 5A and 5B) that can be formulated as described below using conventional mixing technology.

Table 3

5A
Used to relieve irritation caused by dry eyes 5B
Used to relieve irritation caused by dry eyes INGREDIENT % w/w Quantity per batch (grams) % w/w Quantity per batch (grams) Sodium hyaluronate 0.20 2.0 0.10 1.0 Tamarind seed polysaccharide 0 0 0.20 2.0 Lemon Aspen Extract 0.01 0.1 0.10 1.0 Polysorbate 80 0.2 2.0 1.0 10.0 Polysorbate 20 1.0 10.0 5.0 50.0 Polyethylene glycol 400 0.25 2.5 0.25 2.5 Boric acid 0.60 6.0 0.60 6.0 Sodium borate 0.06 0.60 0.06 0.60 Sodium chloride* Specially refined castor oil 0.625 6.25 0.625 6.25 Lumuluse GRH-40 0.50 5.0 0.50 5.0 Ethyl linolenate 0.10 1.0 0 0 Retinyl palmitate 0.05 0.5 0 0 Polyquaternium 42
(33% aqueous solution) 0.0045 0.045 0.0045 0.045 1N sodium hydroxide solution** 1N hydrochloric acid solution** Purified water*** General 100.00% 1000.0 g 100.00% 1000.0 g

* can be adjusted to tonicity 280-290 mOsm/kg

**can be adjusted to pH 7.2

*** optionally in sufficient quantities up to 100% w/w.

For examples 5A-5B: Sodium hyaluronate can be supplied by CONTIPRO A.S. (DOLNI DOBRUCZ, CZECH REPUBLIC).

For Examples 5A-5B: Lemon Aspen Extract (Abacross™ Acronychia Fruit Extract) can be supplied by SOUTHERN CROBOTANICALS (KNOCKROW NSW, AUSTRALIA).

For Examples 5A-5B: Polysorbate 20 can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 5A-5B: Polysorbate 80 can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 5A-5B: Polyethylene glycol 400 can be supplied by Clariant Produkte (BURGKIRCHEN, GERMANY).

For Examples 5A-5B: Boric acid can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 5A-5B: Sodium borate can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 5A-5B: Sodium chloride can be supplied by Caldic (DUSSELDORF, GERMANY).

For Examples 5A-5B: 1N sodium hydroxide can be supplied by VWR (RADNER, PENNSYLVANIA, USA).

For Examples 5A-5B: 1N hydrochloric acid can be supplied by VWR (RADNER, PENNSYLVANIA, USA).

For Examples 5A-5B: Lumuluse GRH-40 can be supplied by VANTAGE (GURNEY, ILLINOIS, USA).

For Examples 5A-5B: Extra refined castor oil can be supplied by CRODA, EDISON, NJ, USA.

For Examples 5A-5B: Ethyl linolenate can be supplied by SIGMA-ALDRICH (ST. LOUIS, MISSOURI, USA).

For Examples 5A-5B: Retinyl palmitate can be supplied by SIGMA-ALDRICH (ST. LOUIS, MISSOURI, USA).

For Examples 5A-5B: Polyquaternium-42 (33% aqueous solution) can be supplied by DSM BIOMEDICAL (BERKELEY, CA, USA)

For Example 5B: Tamarind seed polysaccharide can be supplied by INDENA (MILAN, ITALY).

Solution 5A can be prepared as follows:

1. Add 5.0 grams of Lumuluse GRH-40 to a 50 ml beaker.

2. While stirring, add 6.25 grams of specially purified castor oil.

3. Next add 1 gram of ethyl inolenate and 0.5 grams

retinyl palmitate and stir until smooth.

4. Add 500 grams of purified water to a separate 1500 ml beaker.

5. To the above solution add 2 g of polysorbate 80 and 10 g of polysorbate 20. The solution is stirred until both ingredients are completely dissolved.

6. Add 0.1 grams of lemon aspen extract to the above solution. The solution is stirred until the lemon aspen extract dissolves.

7. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.

8. Add 2.0 grams of sodium hyaluronate to the solution in step 7. The solution is stirred until the sodium hyaluronate is completely dissolved.

9. Then add the following ingredients sequentially, allowing each to dissolve completely before adding the next: 2.5 grams polyethylene glycol 400, 6.0 grams boric acid, 0.06 grams sodium borate, and 0.045 grams polyquaternium-42 (33% aqueous solution) .

10. Add the mixture obtained in step 3 and mix until smooth using a homogenizer.

11. The tonicity of the composition is determined and adjusted to 280 mOsm/kg with sodium chloride.

12. The pH of the composition is adjusted to 7.2 using 1N sodium hydroxide and/or 1N hydrochloric acid.

13. The solution is brought to a mass of 1000.0 grams by adding purified water according to USP and stirring for 10 minutes until completely homogeneous.

14. Filter the solution through a 0.22 micron filter.

Solution 5B can be prepared as follows:

1. Add 5.0 grams of Lumuluse GRH-40 to a 50 ml beaker.

2. While stirring, add 6.25 grams of specially purified castor oil.

3. The resulting homogeneous solution is stored for later use.

4. Add 500 grams of purified water to a separate 1500 ml beaker.

5. To the above solution add 10 g of polysorbate 80 and 50 g of polysorbate 20. The solution is stirred until both ingredients are completely dissolved.

6. Add 1.0 grams of lemon aspen extract to the above solution. The solution is stirred until the lemon aspen extract dissolves.

7. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.

8. Add 1.0 grams of sodium hyaluronate to the solution in step 7. The solution is stirred until the sodium hyaluronate is completely dissolved.

9. Then add 2.0 grams of tamarind seed polysaccharide. The solution is stirred until the tamarind seed polysaccharide is completely dissolved.

10. Then add the following ingredients sequentially, allowing each to dissolve completely before adding the next: 2.5 grams polyethylene glycol 400, 6.0 grams boric acid, 0.06 grams sodium borate, and 0.045 grams polyquaternium-42 (33% aqueous solution) .

11. Add the mixture obtained in step 3 and mix until smooth using a homogenizer.

12. The tonicity of the composition is determined and adjusted to 280 mOsm/kg with sodium chloride.

13. The pH of the composition is adjusted to 7.2 using 1N sodium hydroxide and/or 1N hydrochloric acid.

14. The solution is brought to a mass of 1000.0 grams by adding purified water according to USP and stirring for 10 minutes until completely homogeneous.

15. Filter the solution through a 0.22 micron filter.

Example 6

Table 4 sets forth the components of the formulations of the present invention (as shown in Formulations 6A and 6B) that can be formulated as described below using conventional mixing technology.

Table 4

6A
Used to relieve irritation caused by dry eyes 6B
Used to relieve irritation caused by dry eyes (with or without contact lenses) INGREDIENT % w/w Quantity per batch (grams) % w/w Quantity per batch (grams) Sodium hyaluronate 0.30 3.0 0.15 1.5 Actinomyces extract 5.0 50.0 0 0 Connection 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 glycol 400 0.25 2.5 0 0 Boric acid 0.60 6.0 0.60 6.0 Sodium borate 0.05 0.50 0.05 0.50 Sodium chloride* Potassium chloride 0.10 1.0 0.10 1.0 Calcium chloride dihydrate 0.006 0.06 0.006 0.06 Magnesium chloride 0.006 0.06 0.006 0.06 Sodium chlorite dihydrate 0.014 0.14 0.014 0.14 Polyquaternium-42 (33% aqueous solution) 0.0015 0.015 0.0015 0.015 Sodium chlorite dihydrate 0.014 0.14 0.014 0.14 1N sodium hydroxide solution** 1N hydrochloric acid solution** Purified water*** General 100.00% 1000.0 g 100.00% 1000.00 g

* bringing to tonicity 280-290 mOsm/kg

** adjustment to pH 7.2

*** in sufficient quantity up 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: Sodium hyaluronate can be supplied by CONTIPRO A.S. (DOLNI DOBRUCZ, CZECH REPUBLIC).

For Example 6A: An extract of Actinomyces species A5640 (a bacterial extract in the IHVR collection designated collection nomenclature IHVR_39565_F7) can be supplied by the Baruch S. Blumberg Institute, Doylestown, Pennsylvania.

For Example 6B: Compound 1 can be supplied by Sigma-Aldrich.

For Examples 6A-6B: Polysorbate 20 can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 6A-6B: Polysorbate 80 can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 8A: Polyethylene glycol 400 can be supplied by Clariant Produkte (BURGKIRCHEN, GERMANY).

For Examples 6A-6B: Boric acid can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 6A-6B: Sodium borate can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 6A-6B: Sodium chloride can be supplied by Caldic (DUSSELDORF, GERMANY).

For Examples 6A-6B: Potassium chloride can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 6A-6B: Calcium chloride dihydrate can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 6A-6B: Magnesium chloride can be supplied by KGaA (DARMSTADT, GERMANY).

For Examples 6A-6B: Polyquaternium-42 (33% aqueous solution) can be supplied by DSM BIOMEDICAL (BERKELEY, CA, USA)

For Examples 6A-6B: Sodium chlorite dihydrate can be supplied by Oxychem (WICHITA, KANSAS, USA)

For Examples 6A-6B: 1N sodium hydroxide can be supplied by VWR (RADNER, PENNSYLVANIA, USA).

For Examples 6A-6B: 1N hydrochloric acid can be supplied by VWR (RADNER, PENNSYLVANIA, USA).

Solution 6A can be prepared as follows:

1. Add 800 grams of USP purified water to a 1500 ml beaker.

2. Add 10 g of polysorbate 80 and 100 g of polysorbate 20 to the above solution. Stir the solution until both ingredients are completely mixed and dissolved.

3. Add 50.0 g of Actinomyces extract to the above solution. The solution is stirred until the Actinomyces extract dissolves.

4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.

5. Add 3.0 grams of sodium hyaluronate to the solution from step 4. The solution is stirred until the sodium hyaluronate is completely dissolved.

6. Then add the following ingredients sequentially, allowing each to dissolve completely before adding the next: 2.5 grams polyethylene glycol-400, 6.0 grams boric acid, 0.05 grams sodium borate, 1.0 grams sodium chloride, 0.06 grams chloride calcium, 0.06 grams of magnesium chloride and 0.0015 grams of polyquaternium-42 (aqueous).

7. While continuing to stir, add 0.14 grams of sodium chlorite dihydrate and stir until dissolved.

8. The tonicity of the composition is determined and adjusted to 280 mOsm/kg with sodium chloride.

9. The pH of the composition is adjusted to 7.2 using 1N sodium hydroxide and/or 1N hydrochloric acid.

10. The solution is brought to a mass of 1000.0 grams by adding purified water according to USP and stirring for 10 minutes until completely homogeneous.

11. Filter the solution through a 0.22 micron filter.

Solution 6B can be prepared as follows:

1. Add 800 grams of USP purified water to a 1500 ml beaker.

2. To the above solution add 10 g of polysorbate 80 and 75 g of polysorbate 20. The solution is stirred until both ingredients are completely mixed and dissolved.

3. To the above, add 50.0 g of Compound I. The solution is stirred until Compound I dissolves.

4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.

5. Add 1.5 grams of sodium hyaluronate to the solution from step 4. The solution is stirred until the sodium hyaluronate is completely dissolved.

6. Then add the following ingredients in succession, allowing each to dissolve completely before adding the next: 6.0 grams boric acid, 0.05 grams sodium borate, 1.0 grams potassium chloride, 0.06 grams calcium chloride dihydrate, 0.06 grams chloride magnesium and 0.0015 grams of polyquaternium-42 (aqueous).

7. While continuing to stir, add 0.14 grams of sodium chlorite dihydrate and stir until dissolved.

8. The tonicity of the composition is determined and adjusted to 280 mOsm/kg with sodium chloride.

9. The pH of the composition is adjusted to 7.2 using 1N sodium hydroxide and/or 1N hydrochloric acid.

10. The solution is brought to a mass of 1000.0 grams by adding purified water according to USP and stirring for 10 minutes until completely homogeneous.

11. Filter the solution through a 0.22 micron filter.

Example 7

Table 5 sets forth the components of the formulations of the present invention (as shown in Formulations 7A and 7B) that can be formulated as described below using conventional mixing technology.

Table 5

7A
Used to relieve irritation caused by dry eyes (with or without contact lenses) 7B
Used to relieve irritation caused by dry eyes INGREDIENT % w/w Quantity per batch (grams) % w/w Quantity per batch (grams) Sodium hyaluronate 0.120 1.20 0.120 1.20 Tamarind seed polysaccharide 0.200 2.00 0.200 2.00 Actinomyces extract 5.0 50.0 0 0 Connection 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 glycol 400 0.25 2.5 0.25 2.5 Glycerol 0.25 2.5 0.25 2.5 Hypromellose E3 2910 0.198 1.98 0.198 1.98 Boric acid 0.40 4.0 0.40 4.0 Sodium borate 0.022 0.22 0.022 0.22 Sodium hydrogen phosphate 0.027 0.27 0.027 0.27 Sodium citrate dihydrate 0.40 4.0 0.40 4.0 Sodium chloride* Potassium chloride 0.10 1.0 0.10 1.0 50% aqueous sodium lactate solution 0.057 0.57 0.057 0.57 Magnesium chloride 0.013 0.13 0.013 0.13 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 Edetate disodium 0.01 0.1 0.05 0.5 Polyquaternium-42 (33% aqueous solution) 0.0030 0.030 0.0015 0.015 Sodium chlorite dihydrate 0.014 0.14 0.014 0.14 1N sodium hydroxide solution** 1N hydrochloric acid solution** Purified water*** General 100.00% 1000.00 g 100.00% 1000.00 G

* bringing to tonicity 280-290 mOsm/kg

** adjustment to pH 7.2

*** in sufficient quantity up 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: Sodium hyaluronate can be supplied by CONTIPRO A.S. (DOLNI DOBRUCZ, CZECH REPUBLIC).

For Examples 7A-7B: Tamarind seed polysaccharide can be supplied by INDENA (MILAN, ITALY).

For Example 7A: An extract of Actinomyces species A5640 (a bacterial extract in the IHVR collection designated collection nomenclature IHVR_39565_F7) can be supplied by the Baruch S. Blumberg Institute, Doylestown, Pennsylvania.

For Example 7B: Compound 2 can be supplied by Sigma-Aldrich.

For Examples 7A-7B: Polysorbate 20 can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 7A-7B: Polysorbate 80 can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 7A-7B: Polyethylene glycol 400 can be supplied by Clariant Produkte (BURGKIRCHEN, GERMANY).

For Examples 7A-7B: Boric acid can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 7A-7B: Sodium borate can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 7A-7B: Sodium chloride can be supplied by Caldic (DUSSELDORF, GERMANY).

For Examples 7A-7B: Potassium chloride can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 7A-7B: Hypromellose E3 2910 can be supplied by DOW CHEMICAL (PLAQUEMINE, LOUISIANA, USA).

For Examples 7A-7B: Glycerin can be supplied by Emery Oleochemicals GmbH (DUSSELDORF, GERMANY).

For Examples 7A-7B: Disodium phosphate can be supplied by KGaA (DARMSTADT, GERMANY).

For Examples 7A-7B: Sodium citrate can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 7A-7B: Sodium lactate can be supplied as sodium lactate (50% aqueous solution) from Merck KGaA (DARMSTADT, GERMANY).

For Examples 7A-7B: Glucose can be supplied by Roquette Freres (LASTREME, FRANCE).

For Examples 7A-7B: Glycine can be supplied by Merck KGaA (DARMSTADT, GERMANY).

For Examples 7A-7B: Ascorbic acid can be supplied by DSM NUTRITIONAL Products (DRAKEMERE, SCOTLAND, UK).

For Examples 7A-7B: Polyquaternium-42 can be supplied as Polyquaternium-42 (33% aqueous solution) from DSM BIOMEDICAL (BERKELEY, CA, USA).

For Examples 7A-7B: Edetate disodium can be supplied by Merck NV/SA (OVERYSE, BELGIUM).

For Examples 7A-7B: 1N sodium hydroxide can be supplied by VWR (RADNER, PENNSYLVANIA, USA).

For Examples 7A-7B: 1N hydrochloric acid can be supplied by VWR (RADNER, PENNSYLVANIA, USA).

For Examples 7A-7B: Sodium chlorite dihydrate can be supplied by Oxychem (WICHITA, KANSAS, USA)

Solution 7A can be prepared as follows:

1. Add 800 grams of USP purified water to a 1500 ml beaker.

2. Add 10 g of polysorbate 80 and 100 g of polysorbate 20 to the above solution. Stir the solution until both ingredients are completely mixed and dissolved.

3. Add 50 g of Actinomyces extract to the above solution. The solution is stirred until the Actinomyces extract dissolves.

4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.

5. Add 1.2 grams of sodium hyaluronate to the solution from step 4. The solution is stirred until the sodium hyaluronate is completely dissolved.

6. Add 2.0 grams of tamarind seed polysaccharide to the above mixture. The solution is stirred until the tamarind seed polysaccharide is completely dissolved.

7. Add 1.98 grams of hypromellose E3 Premium to the above solution. The solution is stirred until the hypromellose E3 Premium dissolves.

8. Then add the following ingredients sequentially, allowing each to dissolve completely before adding the next: 2.50 grams polyethylene glycol 400, 2.50 grams glycerin, 4.0 grams boric acid, 0.22 grams sodium borate, 0.27 grams sodium hydrogen phosphate, 4.00 grams sodium citrate dihydrate, 1 gram potassium chloride, 0.57 grams sodium lactate (50% aqueous solution), 0.13 grams magnesium chloride, 0.036 grams glucose, 0.0002 grams glycine, 0.0001 grams ascorbic acid acid, 0.10 grams of disodium edetate, 0.030 grams of polyquaternium-42 (33% aqueous solution) and 0.14 grams of sodium chlorite.

9. The tonicity of the solution is determined and adjusted to 280 mOsm with sodium chloride.

10. Measure the pH of the solution and adjust it to 7.2 with 1N sodium hydroxide and/or 1N hydrochloric acid.

11. The solution is brought to a volume of 1000.00 grams with purified water and stirred for 10 minutes.

12. Filter the solution through a 0.22 micron filter.

Solution 7B can be prepared as follows:

1. Add 800 grams of USP purified water to a 1500 ml beaker.

2. To the above solution add 10 g of polysorbate 80 and 30 g of polysorbate 20. The solution is stirred until both ingredients are completely mixed and dissolved.

3. To the above, add 5.0 g of Compound I. The solution is stirred until Compound I dissolves.

4. The solution is filtered through a 0.45 micron filter and returned to a 1500 ml beaker.

5. Add 1.2 grams of sodium hyaluronate to the solution from step 4. The solution is stirred until the sodium hyaluronate is completely dissolved.

6. Add 2.0 grams of tamarind seed polysaccharide to the above mixture. The solution is stirred until the tamarind seed polysaccharide is completely dissolved.

7. Add 1.98 grams of hypromellose E3 Premium to the above solution. The solution is stirred until the hypromellose E3 Premium dissolves.

8. Then add the following ingredients sequentially, allowing each to dissolve completely before adding the next: 2.50 grams polyethylene glycol 400, 2.50 grams glycerin, 4.0 grams boric acid, 0.22 grams sodium borate, 0.27 grams sodium hydrogen phosphate, 4.00 grams sodium citrate dihydrate, 1 gram potassium chloride, 0.57 grams sodium lactate (50% aqueous solution), 0.13 grams magnesium chloride, 0.036 grams glucose, 0.0002 grams glycine, 0.0001 grams ascorbic acid acid, 0.10 grams of disodium edetate, 0.015 grams of polyquaternium-42 (33% aqueous solution) and 0.14 grams of sodium chlorite.

9. The tonicity of the solution is determined and adjusted to 280 mOsm with sodium chloride.

10. Measure the pH of the solution and adjust it to 7.2 with 1N sodium hydroxide and/or 1N hydrochloric acid.

11. The solution is brought to a volume of 1000.00 grams with purified water and stirred for 10 minutes.

12. The solution is filtered through a 0.22 micron hydrophilic filter.

Embodiments of the Present Invention

1. A method for producing/releasing/delivering/releasing mucin from and/or into the cornea (optionally in a patient requiring such production/releasing/delivery/releasing 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 beneficial effects for use in the treatment of dry eye syndrome, selected from one or more of plant extracts or sources of plant extracts of the genus Acronychia, Licaria, Calendula and/or Trigonella ; bacterial extracts or sources of extracts of bacteria of the genus Actinomyces; and compounds of formula (I):

(I),

Where -

dotted lines indicate a single or double bond; optionally one of the dotted lines represents a double bond;

R1 represents H, a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms;

R2 represents a carbon chain, linear, cyclic ring or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; optionally a methyl (-CH3) or methylene (=CH2) functional group; a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; optionally from 1 to 10 carbon atoms; optionally 6 carbon atoms; optionally an aromatic functional group, optionally a phenyl functional group; optionally 2-methyl-prop-1,3-diene; And

ii) optionally, an ophthalmologically acceptable carrier.

2. The method of embodiment 1 (or any of the following embodiments), wherein the compound and/or extract having retinol-like properties and/or beneficial effects is a plant extract or a source of extracts of plants of the genus Acronychia and/or Licaria.

3. The method of embodiments 1 and/or 2 (or any of the following embodiments), wherein the compound and/or extract having retinol-like properties and/or beneficial effects is a plant extract or a source of plant extracts of the genus Acronychia.

4. The method according to any of embodiments 1-3 (or any of the following embodiments) or a combination thereof, wherein the plant extract or source of plant extracts of the genus Acronychia is selected from the group consisting of Acronychia aberrans, 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 spp. (Batavia Downs), Acronychia suberosa, Acronychia vestita, Acronychia wilcoxiana and combinations of two or more of them.

5. The method of any one of embodiments 1-4 (or any of the following embodiments) or a combination thereof, wherein the plant extract or source of plant extracts of the genus Acronychia is Acronychia acidula.

6. The method of any one of embodiments 1-5 (or any of the following embodiments) or a combination thereof, wherein the plant extract of Acronychia and/or Licaria contains from about 1% to about 20% of a compound of Formula II by weight of the extract.

wherein:

R1 is selected from the group consisting of C1 - C20 alkyl, C2 - C20 alkenyl, C2 - C20 alkynyl and C3 - C8 cycloalkyl or aryl;

R2 is selected from the group consisting of hydrogen, hydroxyl, C1 - C6 alkyl, C2 - C6 alkenyl, C2 - C6 alkynyl, C3 - C8 cycloalkyl or aryl, - OC1 - C6 alkyl, - OC2 - C6 alkenyl, - OC2 - C6 alkynyl , - OC3 - C8 cycloalkyl or aryl, thiol, - SC1 - C6 alkyl, - SC2 - C6 alkenyl, - SC2 - C6 alkynyl, - SC3 - C8 cycloalkyl or aryl, - NR4C1 - C6 alkyl, - NR4C2 - C6 alkenyl, - NR4C2 - C6 alkynyl and - NR4C3 - C8 cycloalkyl or aryl;

R3 is selected from -CO2H, -CO2R4 or the isosteric equivalent of a carboxyl group, where R4 is C1-C6 alkyl, C2-C6 alkenyl, C3-C8 cycloalkyl or aryl; And

Y represents -(CH2 - CH2)-, -(CH ═ H - or -(C ═ C)-.

7. The method of any one of embodiments 1-6 (or any of the following embodiments) or a combination thereof, wherein the plant extract of Acronychia and/or Licaria contains from about 1% to about 20% of a compound of Formula II by weight of the extract.

wherein:

R1 is selected from the group consisting of C5 - C16 alkyl, C5 - C16 alkenyl and C5 - C16 alkynyl, more preferably C5 - C16 alkenyl, including, for example, farnesyl;

R2 is selected from the group consisting of hydrogen, hydroxyl, - OC1 - C6 alkyl, - OC2 - C6 alkenyl, - OC2 - C6 alkynyl, - OC3 - C8 cycloalkyl, more preferably hydrogen, hydroxyl, - OC1 - C6 alkyl, even more preferably - hydrogen or - OC1 - C3 alkyl;

R3 is selected from - CO2H, - CO2R4, where R4 is a C1 - C6 alkyl or the isosteric equivalent of a carboxyl group; And

Y represents -(CH2 - CH2)- or -(CH ═ CH)-.

8. The method according to any of embodiments 1-7 (or any of the following embodiments) or a combination thereof, wherein the compound of formula (II) is in the form of an acid or an alkyl ester selected from 3-(4-farnesyloxyphenyl)propionic acid, 3-(4-farnesyloxy-3-hydroxyphenyl)-propionic acid, 3-(4-farnesyloxy-3-methoxyphenyl)-propionic acid, alkyl esters thereof and combinations of two or more of them.

9. The method according to any one of embodiments 1-8 (or any of the following embodiments) or a combination thereof, wherein the compound of formula II used in the present invention is 3-(4-farnesyloxyphenyl)-propionic acid and/or its ethyl ether.

10. The method of any one of embodiments 1-9 (or any of the following embodiments) or a combination thereof, wherein the compound and/or extract having retinol-like properties and/or beneficial effects is a plant extract or a source of extracts from plants of the genus Licaria .

11. The method of any one of embodiments 1-10 (or any of the following embodiments) or a combination thereof, wherein the plant extract or source of plant extracts 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 of them.

12. The method of any one of embodiments 1-11 (or any of the following embodiments) or a combination thereof, wherein the plant extract or source of plant extracts of the genus Licaria is Licaria vernicosa.

13. The method of any one of embodiments 1-12 (or any of the following embodiments) or a combination thereof, wherein the compound and/or extract having retinol-like properties and/or beneficial effects is an extract of bacteria or a source of extracts of the genus Actinomyces.

14. The method of any one of embodiments 1-13 (or any of the following embodiments) or a combination thereof, wherein the compound and/or extract having retinol-like properties and/or beneficial effects is a bacterial extract or a source of extracts of Actinomyces species A5640 .

15. The method according to any of embodiments 1-14 (or any of the following embodiments) or a combination thereof, wherein the compound and/or extract having retinol-like properties and/or beneficial effects contains a compound of formula (I):

(I),

Where -

dotted lines indicate a single or double bond; optionally one of the dotted lines represents a double bond;

R1 represents H, a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms;

R2 represents a carbon chain, linear, cyclic ring or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms;

16. The method of any one of embodiments 1-15 (or any of the following embodiments) or a combination thereof, 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 exhibiting retinoid-like activity, and mixtures thereof.

17. A method of maintaining a concentration of MU5AC in tear fluid in the range of 8 nanograms to 15 nanograms per milligram of protein or higher (optionally, in a patient requiring 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 beneficial effects for use in the treatment of dry eye syndrome, selected from one or more of plant extracts or sources of plant extracts of the genus Acronychia, Licaria, Calendula and/or Trigonella ; Bacterial extracts or sources of extracts of bacteria of the genus Actinomyces; and compounds of formula (I):

(I),

Where -

dotted lines indicate a single or double bond;

R1 represents H, a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms;

R2 represents a carbon chain, linear, cyclic ring or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; preferably a methyl (-CH3) or methylene (=CH2) functional group;

A represents a carbon chain, linear, ring or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; And

ii) optionally, an ophthalmologically acceptable carrier.

18. A method of treating a patient with reduced or low production/release/delivery/secretion of mucin from and/or into the cornea, comprising the step of locally administering to the patient's eye a composition containing:

i) a safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects for use in the treatment of dry eye syndrome, selected from one or more of plant extracts or sources of plant extracts of the genus Acronychia, Licaria, Calendula and/or Trigonella ; Bacterial extracts or sources of extracts of bacteria of the genus Actinomyces; and compounds of formula (I):

(I),

Where -

dotted lines indicate a single or double bond; preferably one of the dotted lines represents a double bond;

R1 represents H, a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms;

R2 represents H, a carbon chain, linear, cyclic ring or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; preferably a methyl (-CH3) or methylene (=CH2) functional group;

A represents a carbon chain, linear, ring or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; preferably from 1 to 10 carbon atoms; more preferably 6 carbon atoms; preferably an aromatic functional group, preferably a phenyl functional group; preferably 2-methylprop-1,3-diene.

ii) optionally, an ophthalmologically acceptable carrier.

19. A method of preventing or treating symptoms of dry eye syndrome, comprising the step of locally administering (optionally to a patient in need of such prevention or treatment) a composition containing:

i) a safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects for use in the treatment of dry eye syndrome, selected from one or more of plant extracts or sources of plant extracts of the genus Acronychia, Licaria, Calendula and/or Trigonella ; Bacterial extracts or sources of extracts of bacteria of the genus Actinomyces; and compounds of formula (I):

(I),

Where -

dotted lines indicate a single or double bond; preferably one of the dotted lines represents a double bond;

R1 represents H, a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms;

R2 represents a carbon chain, linear, cyclic ring or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; preferably a methyl (-CH3) or methylene (=CH2) functional group;

A represents a carbon chain, linear, ring or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; preferably from 1 to 10 carbon atoms; more preferably 6 carbon atoms; preferably an aromatic functional group, preferably a phenyl functional group; preferably 2-methylprop-1,3-diene;

ii) one or more emollients or sedatives; And

iii) optionally, an ophthalmologically acceptable carrier.

20. A method of stimulating healing or increasing the rate of healing of wounds in and/or on the surface of the eye (optionally, in a patient in need of such stimulated healing or increased rate of healing), comprising the step of administering compositions containing:

i) a safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects for use in the treatment of dry eye syndrome, selected from one or more of plant extracts or sources of plant extracts of the genus Acronychia, Licaria, Calendula and/or Trigonella ; Bacterial extracts or sources of extracts of bacteria of the genus Actinomyces; and compounds of formula (I):

(I),

Where -

dotted lines indicate a single or double bond; preferably one of the dotted lines represents a double bond;

R1 represents H, a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms;

R2 represents a carbon chain, linear, cyclic ring or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; preferably a methyl (-CH3) or methylene (=CH2) functional group;

A represents a carbon chain, linear, ring or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; preferably from 1 to 10 carbon atoms; more preferably 6 carbon atoms; preferably an aromatic functional group, preferably a phenyl functional group; preferably 2-methylprop-1,3-diene.

ii) optionally, an ophthalmologically acceptable carrier.

21. A method of improving antimicrobial properties in tear fluid (optionally, in a patient requiring such improved properties in tear fluid), comprising the step of administering compositions containing:

i) a safe and effective amount of a compound and/or extract having retinol-like properties and/or beneficial effects for use in the treatment of dry eye syndrome, selected from one or more of plant extracts or sources of plant extracts of the genus Acronychia, Licaria, Calendula and/or Trigonella ; Bacterial extracts or sources of extracts of bacteria of the genus Actinomyces; and compounds of formula (I):

(I),

Where -

dotted lines indicate a single or double bond; preferably one of the dotted lines represents a double bond;

R1 represents H, a carbon chain, linear, cyclic or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms;

R2 represents a carbon chain, linear, cyclic ring or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; preferably a methyl (-CH3) or methylene (=CH2) functional group;

A represents a carbon chain, linear, ring or branched, saturated or unsaturated, containing from 1 to 20 carbon atoms; preferably from 1 to 10 carbon atoms; more preferably 6 carbon atoms; preferably an aromatic functional group, preferably a phenyl functional group; preferably 2-methylprop-1,3-diene.

ii) optionally, an ophthalmologically acceptable carrier.

Claims (16)

1. A method for producing/releasing/delivering/secreting mucin from the cornea and/or into the cornea, including the step of administering a composition containing: i) a safe and effective amount of an extract having retinol-like properties and/or beneficial effects for use in the treatment of dry eye syndrome, selected from one or more of herbal extracts or extract sources containing Acronychia acidula; And ii) an ophthalmologically acceptable carrier. 2. A method of maintaining the concentration of MU5AC in tear fluid in the range from 8 to 15 ng per 1 milligram of protein or higher, comprising the step of administering a composition containing: i) a safe and effective amount of an extract having retinol-like properties and/or beneficial effects for use in the treatment of dry eye syndrome, selected from one or more of herbal extracts or extract sources containing Acronychia acidula; And ii) an ophthalmologically acceptable carrier. 3. A method of treating a patient with reduced or low production/release/delivery/secretion of mucin from and/or into the cornea, comprising the step of locally administering to the patient's eye a composition containing: i) a safe and effective amount of an extract having retinol-like properties and/or beneficial effects for use in the treatment of dry eye syndrome, selected from one or more of herbal extracts or extract sources containing Acronychia acidula; And ii) an ophthalmologically acceptable carrier. 4. A method for preventing or treating symptoms of dry eye syndrome, comprising the step of locally administering to a patient a composition containing: i) a safe and effective amount of an extract having retinol-like properties and/or beneficial effects for use in the treatment of dry eye syndrome, selected from one or more of herbal extracts or extract sources containing Acronychia acidula; ii) one or more emollients or sedatives; And iii) an ophthalmologically acceptable carrier. 5. A method for improving the antimicrobial properties of a patient’s tear fluid, including the stage of introducing compositions containing: i) a safe and effective amount of an extract having retinol-like properties and/or beneficial effects for use in the treatment of dry eye syndrome, selected from one or more of herbal extracts or extract sources containing Acronychia acidula; And ii) an ophthalmologically acceptable carrier.

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