MX2007005463A - Ophthalmic compositions and methods for treating eyes - Google Patents

Abstract

Ophthalmic compositions including compatible solute components and/or polyanionic components are useful in treating eyes, for example, to relieve dry eye syndrome, to protect the eyes against hypertonic insult and/or the adverse effects of cationic species on the ocular surfaces of eyes and/or to facilitate recovery from eye surgery.

Description

OPHTHALMIC COMPOSITIONS AND METHODS TO TREAT EYES BACKGROUND OF THE INVENTION The present invention relates to ophthalmic compositions and methods useful for treating the eyes. More particularly, the present invention relates to ophthalmic compositions which includes mixtures of components which are effective to provide desired protection to the ocular surfaces in the eyes of humans or animals and to methods for treating eyes of humans or animals using ophthalmic compositions. , for example the present ophthalmic compositions. The eyes of mammals, such as the eyes of humans and other mammals (animals) are advantageously lubricated adequately to provide comfort to the eye and to more effectively provide good and clear vision. Usually, said lubrication is obtained naturally from a tear film which is formed on the external exposed ocular surface of the eye. This tear film is a complete fluid that is normally continuously replenished by the lacrimal glands, meibomian glands and other glands and when they are intact it provides essential hydration and nutrients to the ocular surface. In addition to coating and protecting the delicate ocular surface, the limit of the tear-air film also serves as an initial refractive surface of the eye. However, in many cases, this tear film is not present in a sufficient amount and a condition known as "dry keratoconjunctivitis" can be generated. A relatively large amount of compositions for use in the treatment and administration of dry keratoconjunctivitis syndrome has been suggested. For example, artificial tears have been used, that is, materials that have chemical compositions that mimic or remind the functioning of natural tears. Such artificial tears often require very frequent use since they are quickly lost from the eye. In addition, although they wet the eye, their value to lubricate the eye is less than desired. Compositions have been suggested which include specific lubricants. For example, many compositions including carboxymethylcelluloses (CMC) have been used in the eyes. Under normal conditions, the ocular surface of a human or animal's eye is bathed by tears of a normal, eg, isotonic, osmotic force. If this osmotic force is increased, ocular surface cells are exposed to a hyperosmotic or hypertonic environment that results in an adverse reduction in cell volume due to loss of transepithelial water and other unwanted changes. In many aspects, the compensatory mechanisms are limited, which leads to deterioration of the ocular surface and discomfort. For example, cells may try to balance the osmotic pressure by increasing the level of electrolyte concentration. However, at high electrolyte concentrations, cellular metabolism is altered in many ways including reduction in enzyme activity and damage to the membranes. In addition, it has been shown that a hypertonic environment is proinflammatory for the ocular surface. The cells of many life forms can compensate the hypertonic conditions by means of the natural accumulation or the manufacture of the so-called "compatible solutes" that function as the electrolytes to balance the osmotic pressure but that do not interfere with the cellular metabolism like the electrolytes. Compatible solutes or compatible solute agents generally do not change, can be maintained within a living cell, for example an ocular cell, are relatively small molecular weight and are generally compatible with cell metabolism. Compatible solutes are also considered to be osmoprotectants since they allow cellular metabolism and / or an improvement in cell survival under hypertonic conditions that would otherwise be limiting.

For example, there is a class of organisms called halophiles that inhabit hypersaline environments such as salty lakes, marine pits and ponds artificially created by evaporation. These organisms can be eukaryotic or prokaryotic and have mechanisms for synthesizing and / or accumulating an adversity of compatible solute agents including polyols, sugars and amino acids and their derivatives such as glycine, betaine, proline, ectoine and the like. Glycerin (glycerol) is a widely used osmotic agent that has been identified as a compatible solute in a variety of cells for many different species. It is also considered as a humectant and an ophthalmic lubricant. In the United States, it is applied topically to the ocular surface to relieve irritation in concentrations of up to 1% and has been used in higher concentrations to impart osmotic strength in prescription medications. Given its small size and biological origin, it can easily cross cell membranes and transport channels have recently been identified in some types of cells to facilitate the displacement of glycerol. Although glycerol can serve as the only compatible solute, it can be excessively mobile, that is, to pass through the membranes too freely to provide a prolonged benefit in certain systems. An example is the film of human tears where the natural concentrations of glycerol are low. When a topical preparation is applied the displacement to the interior of the cells is probably carried out very quickly. However, at a concentration where tears are found, glycerol can eventually be lost from the cell to the tear film, which limits the duration of the benefit. Another major class of compounds with osmoprotective properties in a variety of tissues are certain amino acids. In particular it has been shown that betaine (trimethylglycine) is actively captured by renal cells in response to osmotic exposure and taurine accumulates in ocular cells under hypertonic conditions. The need continues to provide ophthalmic compositions, for example artificial tears, eye drops and the like which are compatible with ocular surfaces in the eyes of humans in animals and which are advantageously effective to allow said ocular surfaces to better tolerate hypertonic conditions . Hypotonic compositions have been used in the eyes as a method to counteract the effects of hypertonic conditions. These compositions effectively irrigate the ocular surface with water, which rapidly enters the cells when supplied as a hypotonic artificial tear. Due to the rapid mobility of water in and out of cells, however, any benefit of a hypotonic composition will be of extremely short duration. In addition, it has been shown that mobile cells from a hypertonic environment to an isotonic or hypotonic environment regulates by decreasing the transport mechanisms for cells to accumulate compatible solutes. In this way, the use of hypotonic artificial tears reduces the ability of cells to resist hypertonicity when they return shortly after instillation of the drops. The clinical observation is well established that agents such as sodium carboxymethylcellulose (CMC) and sodium hyaluronate (SH) are useful for treating signs and symptoms of the syndrome or dry keratoconjunctivitis disease. It has also been shown that these two polyanionic agents are particularly useful in conditions where there is induced deterioration in the cornea (surgical procedures CMC and LASIK) or an allergic attack to the cornea (SH and ulcers of the cover in allergy. of tears of the human eye or normal animal can probably have high (detectable) concentrations of the main basic protein (MBP, for its acronym in English), while it had been previously believed that this protein is expressed only under allergic conditions with eosinophilic involvement (allergy in late phase). It is now recognized that MBP is produced by mast cells (MCs) as well as eosinophils which are commonly known to reside within ocular surface tissues and are recognized to degranulate, releasing MBP and other cationic compounds under antigenic stimulation, mechanical trauma and other conditions. Another group of active cationic proteins on the ocular surface are one or more of the defensins, which are normally part of the antimicrobial defense system or the body. Defensins are found in increased concentrations in the tear film of patients with dry keratoconjunctivitis and can, either directly or through interaction with other substances, have adverse effects on ocular surface health. There are recognized treatments designed to reduce the probability of MC degranulation, most of which are used on the ocular surface together with the treatment of perennial seasonal or allergic conjunctivitis. However, once degranulation occurs, there are no recognized treatments for slurping, debugging or deactivating released cationic mediators that include MBP. Saline irrigation can dilute agents, but in most cases it is not practical. In addition, recent data indicate that detectable MBP exists on the ocular surface even in non-allergic eyes, which means that an overabundance of MBP and potential damage to the low-grade ocular surface may be present in individuals at any given time. It would be advantageous to provide ophthalmic compositions that are effective in mitigating against, or reducing the adverse effects of, cationic, eg, polycationic materials on ocular surfaces of the eyes of humans or animals.

SUMMARY OF THE INVENTION New ophthalmic compositions have been discovered to treat the eyes as well as methods of treating the eyes. The present compositions treat the eyes very effectively, for example eyes that are afflicted or susceptible to diseases / conditions such as, without limitation, dry keratoconjunctivitis syndrome, environments with low humidity and tension / trauma, for example due to surgical procedures and the like. In particular, these compositions may be useful in mitigating the damaging effects of a hypertonic tears film, regardless of the cause. The present compositions are relatively simple, can be manufactured easily and cost-effectively and can be administered, for example they can be administered topically on the ocular surface of each eye, conveniently. In a broad aspect of the present invention, ophthalmic compositions are provided which comprise a carrier component, advantageously a well-carrier component and an effective amount of a tonicity component that includes material that is selected from compatible solute components, for example one or more of certain compatible solute agents and mixtures thereof. In a very useful embodiment, the tonicity component comprises a material that is selected from the erythritol component and mixtures thereof. In a further embodiment, the tonicity component comprises a material that is selected from combinations of at least two different compatible solute agents. In another broad aspect of the invention ophthalmic compositions are provided which comprise a carrier component, for example, an aqueous carrier and an effective amount of a material that is selected from inositol components, xylitol components and mixtures thereof. The osmolality of said compositions is often higher or higher than isotonic, for example in a range of at least 310 to about 600 or about 1000 mOsmoles / kg.

In a further broad aspect of the invention ophthalmic compositions are provided which comprise a carrier component, for example an aqueous carrier and an effective amount of a tonicity component comprising a material that is selected from carnitine components and mixtures thereof. In a particularly useful embodiment, the compositions have a non-isotonic osmolality. In a further aspect of the invention ophthalmic compositions are provided which comprise a carrier component, for example an aqueous carrier and an effective amount of a tonicity component comprising a material that is selected from a mixture or combination of compatible solute agents, by example, selected from mixtures of one or more polyol components and / or one or more amino acid components. In each of the aspects of the invention indicated in the foregoing, the present compositions advantageously have chemical constitutions so that the material or mixture of the organic compatible solute included in the tonicity component is effective, when the composition is administered to an eye , to allow the ocular surface of the eye to better tolerate the hypertonic condition on the ocular surface in relation to an identical composition without the material or mixture of organic compatible solute agents.

A broad or additional aspect of the invention provides ophthalmic compositions comprising a carrier component, a tonicity component and a polyanionic component. The tonicity component is present in an amount effective to provide the composition with a desired osmolality and comprises a compatible solute component. The polyanionic component is present in an amount, when the composition is administered to the eye of a human or an animal, to reduce at least one adverse effect of a cationic material, for example a polycationic material on an ocular surface of a human eye or an animal in relation to an identical composition without the polyanionic component. This cationic material can be from any source, for example, it can be endogenous, an environmental contaminant or as an undesired consequence of applying an agent to the eye, for example a preserved solution or a contact lens care product. In a very useful modality, hyaluronic acid is not the only polyanionic component. Other polyanionic components are more suitable for use in the present compositions, for example they are more suitable than hyaluronic acid or its salts for topical administration to an ocular surface of an eye of a human or animal. In another embodiment of the present invention, the composition has an osmolality in a range of about 300 to about 600 or about 1000 mOsmoles / kg. A further broad aspect of the invention provides ophthalmic compositions comprising a carrier component and a polyanionic component that is selected from polyanionic peptides, polyanionic peptide analogs, polyanionic peptide analogue portions, carboxymethyl substituted sugar polymers that include but are not they limit glucose and similar sugars and mixtures thereof. Said polyanionic components are present in an effective amount, when the compositions are administered to the eye of a human or an animal, to reduce at least one adverse effect of a species and / or cationic substance, for example polycationic on the ocular surface of the eye in relation to an identical composition without the polyanionic component. Methods to treat the eyes of humans or animals are also provided. Said methods comprise administering a composition, for example a composition according to the present invention to the eye of humans or animals to provide at least one benefit to the eye. Any and all of the described features of the present and combinations of said features are included within the scope of the present invention insofar as the characteristics of any of said combinations are not mutually inconsistent. These and other aspects of the present invention will be apparent from the following detailed description, appended drawings, examples, and claims.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a graphic representation of the intensity with respect to the phosphorylated c-jun N-terminal kinases (p-JNK1 and p-JNK2) of certain ophthalmic compositions. Figure 2 is a graphical representation of the intensity with respect to p-JNK1 and p-JNK2 of some additional ophthalmic compositions. Figure 3 is a graphical presentation of the ratios of phosphorylated JNK: total for certain ophthalmic compositions used by the Beadlyte method. Figure 4 is a graphical presentation of phospho-total p38 MAP kinase for certain ophthalmic compositions obtained using the Beadlyte method. Figure 5 is a graphical presentation of phosphine: total MAP kinase ERK for certain ophthalmic compositions obtained using the Beadlyte method. Figure 6 is a graphical presentation of a summary of the effects dependent on the concentration of trans-epithelial electrical resistance (TEER) for various ophthalmic compositions. Figure 7 is a graphical presentation of the effects on TEER of various ophthalmic compositions including compositions that include combinations of compatible solute agents. Figure 8 is a graphical presentation of the effects on TEER of various additional ophthalmic compositions including compositions that include combinations of compatible solute agents.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to ophthalmic compositions useful for treating the eyes of humans or animals. As indicated above, in one aspect of the invention, compositions are provided which include a carrier component, for example a water or aqueous based carrier component and a tonicity component comprising a material that is selected from at least one compatible solute component, for example an organic compatible solute component. Advantageously, said compositions include an effective amount of the material such that, when the composition is administered to the eye, the material is effective to allow the ocular surface of an eye to better tolerate a hypertonic condition on the ocular surface relative to an identical composition. without the material. Although such compositions may have a suitable tonicity or osmolality, for example a hypotonic osmolality, a substantially isotonic osmolality or a hypertonic osmolality, highly useful compositions have osmolality different from isotonic osmolality, for example greater than isotonic osmolality. In one embodiment, the present compositions have osmolalities in a range of at least about 300 or about 310 to about 600 or about 1000 mOsmoles / kg. Polyols such as erythritol components, xylitol components, inositol components and the like and mixtures thereof are effective tonicity / osmotic agents and may be included alone or in combination with glycerol and / or other compatible solute agents in the present compositions Without wishing to limit the invention to any particular theory of operation, it is considered that due to their increased size in relation to glycerol, these polyol components when used topically in the eye accumulate in cells more slowly than glycerol but remain within of the cells for prolonged periods of time in relation to glycerol.

In a very useful embodiment it is advantageous to use mixtures of two or more different compatible solute components together, for example glycerol and / or one or more additional polyol components and / or one or more additional compatible solute components, for example, one or more components of switerionic amino acids and the like to provide one or more eye benefits that are not obtained using compositions that include only a single compatible solute component. As used herein, the term "component" as used herein with reference to a given compound refers to the compound itself, isomers and stereoisomers, if any, of the compound, suitable salts of the compound, derivatives of the compound and the like and mixtures thereof. As used herein, the term "derivative" as it relates to a given compound refers to a compound having a chemical structure or structure sufficiently similar to that of the given compound so that it functions substantially substantially similarly to substantially identical to the compound given in the present compositions and / or methods. Comfort and tolerability can be considered in formulating the present compositions. The amount of organic compatible solute component used in the present compositions may be effective to provide at least one benefit to a patient's eye without unduly harming the patient, for example without unduly inducing discomfort, crying reflex and similar adverse effects. For a formulator skilled in the art, it is possible to produce thick fluids and gels that are retained for longer periods of time on the ocular surface compared to the diluted fluids, where a compensatory relationship is often established between a transient blurred vision. Thick fluids and gels, however, have the advantage of less frequent dosing to supply a given amount of a substance. The xylitol or erythritol used alone may require prolonged contact time to allow them to function effectively as a compatible solute component, for example due to unnecessary time for cellular uptake. However, once in situ, for example, within ocular surface cells, the beneficial action of balancing hypertonic conditions is more time-consuming than with an equivalent amount of glycerol which moves more rapidly in and out of cells. This benefit of longer duration and less frequent dosing can be obtained without blurred vision.

In one embodiment, the present compositions include a combination or mixture of compatible solute agents wherein each agent advantageously is of a different chemical type and / or has a different molecular size and / or mobility. Small mobile agents offer a quick but short duration efficacy, for example protection from a hypertonic attack, while the larger mobile agents provide a delayed but longer lasting protection efficiency. Xylitol, erythritol and glycerol have all high hydroxyl group concentrations: one per carbon. Hydroxyl groups allow a greater binding to water and increase the solubility of the compound. In compositions for the treatment of dry keratoconjunctivitis syndrome, said high concentration of hydroxy groups can improve the performance of the composition by preventing loss of water from the tissues. Among the polyols, 5-carbon xylitol, 4-carbon erythritol and 3-carbon glycerol are preferred for ophthalmic use. The 2-carbon form (ethylene glycol) is a well-known toxin and is not suitable. The 6-carbon forms (mannitol, sorbitol and related deoxy compounds) may be useful in combination with smaller molecules. In one embodiment, combinations of polyols with 3 to 6 carbons and deoxy derivatives with 1 and 2 carbons including, without limitation, isomers, stereoisomers and the like, as appropriate, may be useful in the present invention. The unchanged or zwitterionic amino acids are useful as compatible organic solute components according to the present invention. The carnitine components, for example carnitine itself, the isomers / stereoisomers thereof, salts thereof, derivatives thereof and the like and mixtures thereof are compatible solute components very useful for use in the present ophthalmic compositions. Carnitine is well established as necessary for various parts of fatty acid metabolism, so that it has a significant role in the metabolism of liver and muscle cells. Carnitine can serve as a source of energy for many types of cells that include ocular cells. The carnitine components may have unique properties in multiple roles, for example as osmoprotectors, in the metabolism of fatty acid, as an antioxidant, to promote wound healing, as a protein chaperone and in neuroprotection. The organic compatible solute component can advantageously be provided in the present compositions by the use of a combination of said agents or materials of different size, mobility and mechanism of action. Small mobile agents such as smaller polyols can be predicted to provide rapid but short-term osmoprotection. Several of the amino acids and related compounds can function as compatible long-acting acellular solutes and protein stabilizers. In the present invention, carnitine components can be used alone or in combination with one or more compatible organic amino and / or polyol solute components, for example, as described herein. The organic compatible solute components based on amine and / or the components that may be used include, but are not limited to, betaine, taurine, carnitine, sarcosine, proline, trimethylamines in general, other, and the like, and mixtures thereof. Polyols which may be useful in combination with carnitine and / or one or more of the compatible organic solute components of amine-based organic include, but are not limited to glycerol, propylene glycol, erythritol, xylitol, myoisonitol, mannitol, sorbitol and the like and mixtures thereof. thereof . The amount of the compatible solute component included in the present compositions can be any suitable amount. However, said amount is advantageously effective to provide a benefit to the eye as a result of the administration of the composition containing the solute component compatible to the eye. Excessive amounts of compatible solute components should be avoided since the amounts may cause discomfort to the patient and / or potential damage to the eye being treated. Advantageously, the compatible solute component is present in an amount effective to provide the desired osmolality to the composition. The specific amount of compatible solute component used can vary over a broad range depending, for example, on the general chemical constitution and the proposed use of the composition, the desired osmolality of the composition, the specific compatible solute or the combination of said solutes that are used and similar factors. In one embodiment, the total amount of compatible solute component included in the present compositions may be in a range of about 0.01% (w / v) or about 0.05% (w / v) to about 1% (w / v) or about 2% (w / v) or about 3% (w / v) or more. Cells on the surface of the cornea respond to osmotic forces by regulating the transport of salt and water in an effort to main a constant cell volume. In conditions of chronic hypertonicity, for example, such as that which exists in the disease of dry keratoconjunctivitis, the transport mechanisms for the uptake of compatible solutes including various amino acids and polyols are regulated by increase. In one embodiment of the present invention ophthalmic compositions, for example artificial tears containing a compatible solute component, are formulated to have a greater or exceeding isotonicity tonicity, advantageously in a tonicity range of about 300 or about 310 to about 600. or approximately 1000 mOsmoles / kg. Without wishing to limit the invention to any particular theory of operation, it is considered that under such conditions both immediate and long-term mechanisms are stimulated to accumulate compatible solutes in the cells, allowing improved uptake and improved retention with cellular activity under isotonic or hypotonic conditions. Once the compatible solute component is accumulated by the cells, the cells have an improved protection from a hypertonic attack that is being carried out, for example caused by the dry keratoconic syndrome and / or one or more conditions / diseases. additional The results of this enhanced protection include improved cell metabolism and survival for a period of hours to days after the application of an ophthalmic composition of the present invention. In a normal tear system, the production of tears, the drainage of tears and the evaporation of tears are balanced in order to provide a moist and lubricated ocular surface. Typical values for tear osmolality derive from 290 to 310 mOsmoles / kg in normal individuals, and these may change during the day or response to changing environmental conditions. In a normal person, neural feedback from the ocular surface to the lacrimal glands controls the production of tears in order to maintain a stable ocular surface fluid. It has been proposed that the tonicity of the film of tears is one of the main stimuli for this regulatory feedback. In the disease of dry keratoconjunctivitis, the dysfunction of the production apparatus (the various glands), the drainage system, the neural signaling mechanism or another ocular surface by itself generates an inadequate film of tears, a deterioration of the ocular surface and subjective discomfort. At the cellular level, dry keratoconjunctivitis disease is usually characterized by an extracellular and chronically hypertonic environment (tear film). The reports published regarding the tonicity of the tear film of patients with dry keratoconjunctivitis provide a range of 300 to 500 mOsmoles / kg where most of the values are between 320 and 400 mOsmoles / kg. Under these conditions, cells will tend to lose water and / or gain salts and may experience changes in cell volume. It has been shown that hypertonicity alters cellular metabolic processes, reduces the functioning of enzymatic procedures and generates apoptosis and cell death. As a defense against hypertonic exposure, it has been shown that corneal cells up-regulate transport mechanisms for non-ionic solutes such as amino acids and polyols and accumulate these solutes intracellularly in order to maintain cell volume without changing the balance of electrolytes Under these conditions, cellular metabolism is less affected than with changes in volume and electrolyte, and these compounds are referred to as compatible solutes. Compatible solutes include but are not limited to the amino acids betaine (trimethylglycine), taurine, glycine and proline and the polyols glycerol, erythritol, xylitol, sorbitol and mannitol. Compatible solutes are also considered as osmoprotectants since they can allow cellular metabolism or improve cell survival under hypertonic conditions that might otherwise be limiting. The cells accumulate certain compatible solutes by biosynthesis within the cell and others by transmembrane transport increased from the extracellular fluid (in this case, the fluid from the tears). In both cases, specific synthesis proteins or transports are involved in this procedure. Experimental evidence indicates that these proteins are activated in the presence of hypertonic conditions and that the transcription and translation phenomena to produce these proteins are regulated by hypertonic conditions. Inversely, experimental tests indicate that cells of the cornea and other cells will expel compatible solutes when exposed to hypotonic conditions or when moving from a hypertonic environment to an isotonic one. In dry keratoconjunctivitis disease, cells on the cornea surface are exposed to a hypertonic environment and are stimulated to accumulate osmoprotective substances as they become available. The addition of isotonic or hypotonic artificial tears to the ocular surface provides relief of symptoms due to increased lubrication, but tends to down regulate the mechanisms in these cells for accumulation of osmoprotectors. This can result in additional vulnerability to osmotic damage in the minutes to hours after the use of the drops as the tear film returns to its hypertonic state in dry keratoconjunctivitis. The FDA's current guidance stipulates that "an ophthalmic solution must have an osmotic equivalence between 0.8 and 1.0 percent sodium chloride to meet the marked claims of" isotonic solution "." This is equivalent to a range of 274 to 342 mOsm / kg. In addition, FDA guidelines state that "two to five percent of ophthalmic sodium chloride preparations are hypertonic and are acceptable OTC products when marked as" hypertonic solutions. " This interval is equal to 684 to 1711 mOsm / kg. For purposes of the present invention, a "supratonic" solution is defined that which has an intermediate osmolality between these two ranges, or approximately 300 or 310 to approximately 600 or approximately 800, or approximately 1000 mOsmoles / kg, equivalent to approximately 0.9 to approximately 1.8 percent sodium chloride (1.8% is the FDA's top guideline for topical ophthalmic solutions not marked as hypertonic). The present invention takes these concepts into consideration when formulating an artificial tear at supratonic levels more compatible with the existing hypertonic state of the ocular surface of dry keratoconjunctivitis. In addition to being formulated in the supratonic range (about 300 to about 310 to about 600 or about 1000 mOsmoles / kg of total tonicity), the present compositions contain one or more compatible organic solute agents as described herein. The combination of supratonicity and inclusion of one or more compatible solutes in the present compositions serves to stimulate or maintain the uptake of these protective substances in the cells of the surface of the cornea and to provide abundant supplies of these materials or substances. In addition to sufficient amounts of compatible solutes in a supratonic medium, the present compositions may also contain appropriate demulcents and viscosity agents that provide comfort and lubrication and which are also advantageously also effective in maintaining the organic compatible solute composition on the ocular surface for a period of time. enough to improve the uptake by the cells of the surface of the cornea. It should be noted that the FDA guidelines clearly indicate that the final tonicity of the formulation must be terminated by non-ionic as well as ionic species. In this manner, the formula may contain significant amounts of glycerol and other compatible solutes and may not contain substantial amounts of any of the ionic tonicity agents such as sodium salts. In one embodiment, the present components are substantially free of ionic tonicity agents.

Advantageously, the present compositions include a combination of different organic compatible solute agents effective to provide uptake by corneal cells during the time of exposure to the drops during use, for example from about 5 to about 30 minutes, depending on the viscosity after administration and to provide intracellular retention during the period of hours between the applications of the drops. Due to the improved protection of the osmotic attack provided by the present composition, the duration of the clinical benefit resulting from each dosage or application is increased. With regular use of the present compositions, the health of the ocular surface is improved as the cells are less metabolically exposed and the survival of the cells is increased. Another aspect of the present invention provides compositions comprising a carrier component and a polyanionic component. Said compositions containing a polyanionic component advantageously, although in certain embodiments not necessarily include organic compatible solute components as described herein. In one embodiment, compositions are provided which comprise a carrier component and a polyanionic component in an amount effective to treat an ocular surface of an eye under a condition of an increased population of cationic species, for example and without limitation to major basic protein (MBP). , for its acronym in English) increased and / or polyanionic species decreased on the surface. In one embodiment, the present ophthalmic compositions include polyanionic components present in effective amounts, when the compositions are administered to the eyes of humans or animals, to reduce at least one adverse effect of a cationic material, for example polyanionics on a surface ocular in relation to an identical composition without the polyanionic component. In a useful embodiment, compositions comprising polyanionic components, for example with or without the compatible solute components can be effectively used before, during and / or after surgical procedures including, without limitation, surgical procedures in which the eye to laser energy, for example in the treatment of post-LASIK staining, dryness (keratoconjunctivitis) and other complications on the surface of the eyes. The etiology of the deteriorated post-LASIK surface can be multifactorial and includes, without limitation, surgically neurotrophic hypesthesia and keratitis, damage to the limbal cells from the strength of the suction ring, to altered position of the cap upon blinking due to altered corneal topography, chemical damage to the ocular surface by topical and conservative medications and the like. The administration of the compositions containing a polyanionic component according to the present invention to the ocular surface and the tear film can be effective to treat one or more, or even all of the mentioned causes before deterioration of the posterior ocular surface to LASIK. In a particularly useful embodiment, the present compositions include polyanionic components that mimic the activity, for example, the anionic and / or cytotoxic activity of the MBP propart, which has been shown to consist of a 89 residue polypeptide. Useful agents can include one or more polypeptide analogues of this sequence or portions of this sequence. As used herein, the term "mimic" means that the polyanionic component, for example the polypeptide analog, has an activity within (more or less) of about 5% or about 10% or about 15% or about 20% of the corresponding activity of the MBP pro-piece. The MBP pro-piece has an amino acid sequence as shown in the SEQUENCE OF IDENTIFICATION NUMBER: 1 below: lhlrsetstf etplgaktlp edeetpeqem eetpcrelee eeewgsgsed askkdgaves isvpdmvdkn Itcpeeedtv kvvgipgcq A polypeptide analogue of the sequence of ownersof the main basic protein or a portion of the sequence of the pro-piece of the main basic protein means a peptide comprising an amino acid sequence containing at least about 75% or about 80%, or about 85%, or about 90%, or about 95% or about 99% or more identity with the homologous continuous amino acid sequence comprised in the IDENTIFICATION SEQUENCE NUMBER: 1 or portions thereof. Carboxymethyl substituted sugar polymers for example and without limitation glucose and similar sugars, can be used as polyanionic components according to the present invention. In addition, additional useful polyanionic components include, without limitation, modified carbohydrates, other polyanionic polymers, for example without limitation those available in advance for pharmaceutical use and mixtures thereof. Mixtures of one or more of the polypeptide analogs indicated above and one or more of the additional polyanionic components indicated above can be used. The present compositions are advantageously ophthalmically acceptable and comprise an ophthalmically acceptable carrier component, a compatible solute component and / or a polyanionic component. A composition, a carrier component or other component or material is "ophthalmically acceptable" when it is compatible with ocular tissue, i.e., it does not cause significant or undue harmful effects when contacted with ocular tissue. Preferably, the ophthalmically acceptable component or material is also compatible with other components of the present compositions. As used herein, the term "polyanionic component" refers to a chemical entity, for example an ionically charged species such as an ionically charged polymeric material, which includes more than one separate anionic charge which are multiple separated anionic charges. Preferably, the polyanionic component is selected from the group consisting of polymeric materials having multiple anionic charges and mixtures thereof. The polyanionic component can have a substantially constant or uniform molecular weight, or it can be constituted by two or more portions of polyanionic components of different molecular weights. Ophthalmic compositions containing polyanionic components that include two or more portions of different molecular weights are described in the patent application of E.U.A. serial number 10 / 017,817 filed December 14, 2001, the disclosure of which is hereby incorporated by reference in its entirety. Preferably, the composition has an increased ability to adhere to the eye when the composition is administered to the eye, relative to a substantially identical composition without the polyanionic component. With respect to the increased ability to adhere to the eye, indicated in the foregoing, the present compositions are preferably effective to provide effective lubrication for a longer period of time before readministration is required in relation to a substantially identical composition without the polyanionic component. . Any suitable polyanionic component can be used in accordance with the present invention to the extent that it functions as described herein and does not have a substantial detrimental effect on the composition as a whole or on the eye to which the composition is administered. The polyanionic component is preferably ophthalmically acceptable at the concentrations used. The polyanionic component preferably includes three (3) or more anionic (or negative) charges. In the case where the polyanionic component is a polymeric material, it is preferred that many of the repeating units of the polymeric material include a separate anionic charge. Particularly useful anionic components are those which are water-soluble, for example, soluble at concentrations used in the present compositions at room temperature. Examples of suitable polyanionic components useful in the present compositions include, without limitation, anionic cellulose derivatives, polymers containing anionic acrylic acid, polymers containing anionic methacrylic acid, polymers containing anionic amino acids and mixtures thereof. Anionic cellulose derivatives are very useful in the present invention. One particularly useful class of polyanionic components are one or more polymeric materials that have multiple anionic charges. Examples include, but are not limited to: metal carboxymethylcelluloses, metal carboxymethylhydroxyethylcelluloses carboxymethylstarches metal carboxymethylhydroxyethylstarches metal carboxymethylpropilguar metal hydrolyzed polyacrylamides and polyacrylonitriles heparins, gucoaminoglycans hyaluronic acid chondroitin sulfate dermatan sulfate peptides and polypeptides alginic acid alginates metal homopolymers and copolymers of one or more of: acrylic and methacrylic acids metal acrylates and methacrylates vinyl sulphonic vinylsulfonate acid metal amino acids such as aspartic acid, glutamic acid and the like, metal salts of amino acids p-styrenesulfonic acid metal p-styrenesulfonate 2-methacryloyloxyethyl sulfonic acids Metal methacryloyloxyethyl sulfonates 3-methacryloyloxy-2-hydroxypropylsulfonic acids 3-methacryloyloxy-2-hydroxypropylsulfonates 2-acrylamido-2-methylated metal lpropanesulfonic acid 2-acrylamido-2-methylpropanesulfonates metal allylsulfonic acid allylsulfonate metal and the like. Excellent results are obtained by using polyanionic components which are selected from carboxymethylcellulose and mixtures thereof, for example alkali metal and / or alkaline earth metal carboxymethyl celluloses. The present compositions are preferably solutions, although other forms, such as ointments, gels and the like can be used. The carrier component is ophthalmically acceptable and may include one or more components which are effective in providing said ophthalmic acceptability and / or otherwise benefitting the composition and / or the eye to which the composition is administered and / or the patient whose eye is treated. Advantageously, the carrier component is based on water, for example, it comprises a larger amount which is at least about 50% by weight of water. Other components which may be included in the carrier components include, without limitation, buffering components, tonicity components, preservative components, pH adjusters, components commonly found in artificial tears and the like, and mixtures thereof. Preferably, the present compositions have viscosities that exceed the viscosity of the water. In one embodiment, the viscosity of the present compositions is at least about 10 cps (centipoise), more preferably it is in a range of about 10 cps to about 500 cps or about 1000 cps. Advantageously, the viscosity of the present composition is in a range of about 15 cps or about 30 cps or about 70 to about 150 cps or about 200 cps or about 300 cps or about 500 cps. The viscosity of the present composition can be measured in any suitable manner, for example in a conventional manner. A conventional Brookfield viscometer measures these viscosities. In a very useful embodiment, the polyanionic component is present in an amount in the range of from about 0.1% to about 5%, preferably from about 0.2% to about 2.5%, more preferably from about 0.2% to about 1.8% and from about even more preferably about 0.4% to about 1.3% (w / v) of the composition. Other components which may be included in the carrier components include, without limitation, shock-absorbing components, tonicity components, conservative components, pH adjusters, components commonly found in artificial tears, such as one or more electrolytes and the like, and mixtures thereof. In a very useful embodiment the carrier component includes at least one of the following: an effective amount of a buffer component; an effective amount of a tonicity component; an effective amount of a preservative and water component. These additional components are preferably ophthalmically acceptable and may be selected from materials which are conventionally used in ophthalmic compositions, for example compositions used to treat eyes afflicted with dry keratoconjunctivitis syndrome, artificial tears formulations and the like. The effective concentrations acceptable for these additional components in the compositions of the invention will be readily apparent to those skilled in the art. Preferably, the carrier component includes an effective amount of a tonicity adjusting component to provide the composition with the desired tonicity. The carrier component preferably includes a buffering component which is present in an amount effective to maintain the pH of the composition in the desired range. Among the suitable tonicity adjusting components that can be used are those conventionally used in ophthalmic compositions such as one or more of the various inorganic salts and the like. Sodium chloride, potassium chloride, mannitol, dextrose, glycerin, propylene glycol and the like and mixtures thereof are very useful tonicity adjusting components. Among the suitable shock absorber components or damping agents that can be used are those conventionally used in ophthalmic compositions. Buffer salts include alkali metal, alkaline earth metal and / or ammonium salts as well as citrate, phosphate, borate, lactate and similar salts and mixtures thereof. Conventional organic dampers such as Goode cushion and the like can also be used. Any suitable preservative component can be included in the present compositions with the proviso that said components are effective as a preservative in the presence of the polyanionic component. In this way, it is important that the preservative component is not substantially affected by the presence of the polyanionic component. Of course, the selected preservative component depends on various factors, for example the specific polyanionic component present, the other components present in the composition, etc. Examples of useful preservative components include, but are not limited to per-salts such as perborates, percarbonates and the like; peroxides such as those found in very low concentrations, for example from about 50 to about 200 ppm (w / v) hydrogen peroxide and the like; alcohols such as benzyl alcohol, chlorobutanol and the like; sorbic acid and ophthalmically acceptable salts thereof and mixtures thereof. The amount of the preservative component included in the present compositions containing said component varies over a relatively broad range depending, for example, on the specific preservative component used. The amount of said component preferably is in the range of about 0.000001% to about 0.05% or more (w / v) of the present composition. A particularly useful class of preservative components are precursors of chlorine dioxide. Specific examples of chlorine dioxide precursors include stabilized chlorine dioxide (SCD), metal chlorites such as alkali metal and alkaline earth metal chlorites and the like, and mixtures thereof. Technical grade sodium chlorite is a very useful precursor of chlorine dioxide. Complexes containing chlorine dioxide such as complexes of chlorine dioxide with carbonate, chlorine dioxide with bicarbonate and mixtures thereof are also included as precursors of chlorine dioxide. The exact chemical composition of many chlorine dioxide precursors, for example SDC and chlorine dioxide complexes, is not fully understood. The preparation or production of certain chlorine dioxide precursors is described in McNicholas, patent of E.U.A. 3,278,447, which is incorporated herein by reference in its entirety. Specific examples of useful SCD products include those sold under the trade name Purite7 by Allergan, Inc., sold under the trade name Dura Klor by Rio Linda, Chemical Company, Inc., and sold under the trade name Anthium Dioxide. by International Dioxide, Inc. The chlorine dioxide precursor is included in the present compositions to effectively preserve said compositions. Effective conservative concentrations are preferably in the range of about 0.0002 to about 0.002 to about 0.02% (w / v) or greater of the present compositions. In case chlorine dioxide precursors are used as preservative components, the compositions preferably have an osmolality of at least about 200 mOsmoles / kg and are buffered to maintain the pH within an acceptable physiological range, for example a range of about 6 to about 8 to about 10. The present compositions preferably include an effective amount of an electrolyte component that is one or more electrolytes, for example such as those found in natural tears and in artificial tears formulations. Examples of such electrolytes particularly useful for inclusion in the present compositions include, without limitation, alkaline earth metal salts, such as inorganic alkaline earth metal salts and mixtures thereof, for example calcium salts, magnesium salts and mixtures thereof. . Very good results are obtained by using an electrolyte component which is selected from calcium chloride, magnesium chloride and mixtures thereof. The amount or concentration of said electrolyte component in the present compositions can vary widely and depends on various factors, for example the specific electrolyte component that is used, the specific composition in which the electrolyte is to be included and similar factors. In a useful embodiment, the amount of electrolyte component is selected to at least partially recall or even to substantially recall the electrolyte concentration in natural human tears. Preferably, the concentration of electrolyte component is in the range of about 0.01 to about 0.5 or about 1% of the present composition.

The present compositions can be prepared using conventional methods and techniques. For example, the present compositions can be prepared by combining the components together such as in one volume. To illustrate, in one embodiment, the portions of polyanionic components are combined with purified water and caused to disperse in the purified water, for example by mixing and / or stirring. The other components such as the buffer component, tonicity component, electrolyte component, conservative component and the like are introduced as mixing continues. The final mixture is sterilized, for example steam sterilized, for example at temperatures of at least about 100 ° C, for example in a range of about 120 ° C to about 130 ° C for a time of at least about 15 minutes. minutes or at least about 30 minutes, for example in a range of about 45 to about 60 minutes. In one embodiment, the preservative component is preferably added to the mixture after sterilization. Preferably, the final product is filtered, for example through a sterilized 20 micron cartridge filter, for example a 20 micron clarity filter cartridge, for example sold by Pall under the trade name HDC II, to provide a solution uniform, clear which is supplied as aseptic filling in containers, for example containers of low density polyethylene sheet. Alternatively, each of the portions of the polyanionic component can be mixed with purified water to obtain individual polyanionic component portion solutions. By mixing the individual polyanionic component portion solutions together a combination is obtained which easily and effectively has the desired controlled ratio of the individual polyanionic component portions. The combined solution can then be combined with other components, sterilized and supplied as a filler in containers, as indicated above. In a particularly useful embodiment a solution of the polyanionic component and purified water portions is obtained, as indicated in the above. This solution is then sterilized, for example as indicated in the above. Separately, the other components to be included in the final composition are solubilized in purified water. This latter solution is sterilized by filtration, for example through a 0.2 micron sterilization filter such as that sold by Pall under the trade name Superflow, within a solution containing a polyanionic component to form the final solution. The final solution is filtered, for example, as indicated above to provide a uniform, clear solution, which is then aseptically supplied as a filler in containers, as indicated above. The present compositions can be used effectively, as needed, by methods which comprise administering an effective amount of the composition to an eye in need of lubrication, for example, an eye afflicted with the symbol of dry keratoconjunctivitis or having a propensity for the syndrome of dry keratoconjunctivitis. The administration step can be repeated as needed to provide effective lubrication to said eye. The mode of administration of the present composition depends on the form of the composition. For example, if the composition is a solution, drops of the composition can be applied to the eye, for example from a conventional eye dropper. In general, the present compositions can be applied to the surface of the eye in substantially the same manner as conventional ophthalmic compositions are applied. Said administration of the present compositions provides substantial and unexpected benefits as described elsewhere in that document. The following non-limiting examples illustrate certain aspects of the present invention.

EXAMPLE 1 In this experiment, epithelial cells are isolated from the rabbit eye cornea and grown under conditions so that they differentiate into a "high air" stratified culture that includes basal, aerial and squamous cells. As they grow and differentiate, these cultures develop tight junctions between cells that provide the basis for a trans-epithelial electrical resistance (TEER) through the cell layers between the apical and basal surfaces. The TEER value is a sensitive measure of the growth, differentiation and health of the cells. After 5 days in culture during which the stratified structure is formed, different culture wells are exposed to hypertonic fluid (400 mOsmoles / kg) with or without the addition of one of the 6 compatible candidate solutes at a low concentration (2 mM) . Then TEER is measured after 22 hours of exposure. The TEER value is expressed as the percentage of the TEER value obtained from a similar culture under isotonic conditions (300 mOsmoles). Table 1 shows the results of these tests.

Table 1. Test results These results show that all the candidates tested have some osmoprotective capacity, which increases the TEER in relation to hypertonic control. Surprisingly, of the agents tested, carnitine produces the greatest benefit. Without wishing to limit the invention to any particular observation theory, it is considered that the beneficial results obtained with carnitine can be related to the multiple roles of carnitine in the metabolism of energy and other cellular mechanisms as well as their osmoprotective effects. In addition, and inexplicably, erythritol provides the best results among the tested polyols. Xylitol and myo-inositol provide good results. These results indicate that each of the 6 candidate compounds, and preferably carnitine, erythritol, xylitol and myo-inositol can be useful in phthalic compositions, for example to mitigate against hypertonic conditions on ocular surfaces of human or animal eyes. Again, without wishing to limit the invention to any particular theory of operation, it is considered that, due to the variable roles that many of these compounds can play, combinations of two or more of these compounds, for example, include at least an amino acid, is likely to provide increased protection of corneal surfaces by protecting it from attacks, for example, due to desiccation and hyperosmolality as in the case of dry keratoconjunctivitis disease.

EXAMPLE 2 Phosphorylated JNK (the active form of stress-associated protein kinase, SAPK) plays a key role in the induction of inflammation and apoptosis in response to stress, including hyperosmolarity.

The human sclerotic cornea tissues of donors aged 16-59 years are obtained from the Lions Eye Bank of Texas (Houston TX). The epithelial cells of the cornea are grown from limbal explants. Briefly, after carefully removing the central cornea, excess conjunctiva and iris and endothelium of the cornea, the limbal border is cut into 12 equal pieces (each about 2 x 2 mm in size). Two of these cuts are placed with the epithelial lip facing up into each well of 6-well culture plates and each explant is covered with a drop of fetal bovine serum (FBS) overnight. The explants are then cultured in SHEM medium, which is a 1: 1 mixture of Dulbecco's modified Eagle's medium (DMEM) and Ham F-12 medium containing 5 ng / ml of EGF, 5 pg. / ml insulin, 5 pg / ml transferrin, 5 ng / ml sodium selenite, 0.5 pg / ml hydrocortisone, 30 ng / ml cholera toxin A, 0.5% DMSO, 50 pg / ml gentamicin, 1.25 pg / ml of amphotericin B and 5% FBS at 37 ° C under C02 5% and 95% humidity. The medium is renewed every 2-3 days. The epithelial phenotype of these cultures is confirmed by characteristic morphology and by immunofluorescent staining with antibodies to cytokeratin (AE-l / AE-3). Cell culture boxes, plates, centrifuge tubes and other plastic material is purchased from Becton Dickinson (Lincoln Park, NJ). Dulbecco's modified Eagle's medium (DMEM), Ham's F-12 medium, fugizona and gentamicin are from Invitrogen-Gibco BRL (Grand Island, NY). Fetal bovine serum (FBS) is from Hyclone (Logan, UT). A series of primary subconfluent corneal epithelial cultures (growing for 12 to 14 days, approximately 4-5 x 10 5 cells / well) are washed three times with preserved buffered saline (PBS) and changed to a balanced saline solution of Earle ( EBSS, for its acronym in English, 300 mOsmoles / kg) for 24 hours before treatment. The corneal epithelial cells are cultured for 1 hour in an equal volume (2.0 ml / well) of EBSS medium or 400 mOsmoles / kg of medium when adding 53 mM NaCl or sucrose, either with an internal salt of L-carnitine, hydrochloride of betaine, erythritol and xylitol (all at a concentration of 2 mM) that were previously added 60 minutes before adding NaCl or sucrose. Samples without these osmoprotectors are prepared and tested. Adherent cells are lysed in B Beadlyte ™ buffer (included in the Beadlyte ™ Cell Signaling buffer kit, Upstate Biotechnology, Lake Placid, NY) containing an EDTA-free protease inhibitor combination tablet (Roche Applied Science, Indianapolis, IN) during 15 minutes. The cell extracts are centrifuged at 12,000 x g for 15 minutes at room temperature and the supernatants are stored at -80 ° C until analyzed by Western blot analysis. The total protein concentrations of the cell extracts are determined using a Micro BCA protein assay kit (Pierce, Rockford, IL). The intensity of each of JNK1 and JNK2 is tested for each of these compositions using Western blot analysis with specific antibodies for each phosphorylated species. The Western blot analysis is carried out as follows. Protein samples (50 pg per lane) are mixed with reducing sample buffer 6 x SDS and boiled for 5 minutes before loading. Proteins are separated by polyacrylamide gel electrophoresis and SDS (4-15% Tris-HCl, gradient gels from Bio-Rad, Hercules, CA) and electronically transferred to polyvinylidene difluoride (PVDF) membranes. English) and (Millipore, Bedford, MA). The membranes are blocked with 5% non-fat milk in TTBS (50 mM Tris, pH 7.5, 0.9% NaCl and 0.1% Tween-20) for 1 hour at room temperature (RT), and then incubated for 2 hours at room temperature with a 1: 1000 dilution of rabbit antibody against phospho-p38 MAPK (cell signaling, Beverly, MA), 1: 100 dilution of rabbit antibody against phospho-JNK or 1: 500 dilution of monoclonal antibody against phospho-p44 / 42 ERK (Santa Cruz Biotechnology, Santa Cruz, CA) After three washes with TTBS, the membranes are incubated for 1 hour at room temperature with secondary goat antibody against rabbit IgG, conjugated with horseradish peroxidase (dilution 1: 2000, Cell Signaling, Beverly, MA) or goat antibody against mouse IgG (1: 5000 dilution, Pierce, Rockford, IL) After washing the membranes four times the signals are detected with a chemiluminescent reagent ECL advance (Amersham, Piscataway, New Jersey) and images are acquired by Kodak image station 2000R (Eastman Kodak, New Haven, CT). The membranes are purified in 62.5 mM Tris-HCl, pH 6.8 containing 2% SDS and 100 mM a-mercaptoethanol at 60 ° C for 30 minutes, then re-probed with 1: 100 dilution of rabbit antibody against JNK (Santa Cruz Biotechnmology) or 1: 1000 dilution of rabbit antibodies against ERK or p38 MAPK (Cell Signaling). These three antibodies detect the phosphorylated and non-phosphorylated forms which represent the total concentrations of these MAPK. The signals are detected and retained as described above. An intensity rating is determined from the image analysis of the resulting bands. The test results are shown in the figures 1 and 2. With reference now to Figure 1, there is no effect on the activation of JNK with either erythritol or xylitol. However, with reference to Figure 2, there is a definite decrease in the concentrations of JNK1 and JNK2 in L-carnitine and betaine cultures compared to the medium of 400 mOsmoles / kg alone. There is also a less robust effect on crops of 300 mOsmoles / kg.

EXAMPLE 3 In another series of experiments, the Beadlyte ™ cell signaling assay is used. This assay is an indirect immunoassay (sandwich type) based on fluorescent spheres. For example, each sample (10 μ? / 25 μ?) Can be pipetted into a well of a 96-well plate and incubated with 25 μ? of diluted 5X spheres coupled to protein-specific capture antibodies overnight. Said antibodies can specifically capture proteins, such as JNK, p38 and ERK. Incubation overnight can be used for the reaction of the capture spheres with the proteins of the cell lysates. The spheres can be washed and mixed with biotinylated specific indicator antibodies for the proteins of interest, followed by streptavidin-phycoerythrin. The amount of total protein or phosphoprotein can then be quantified by the Luminex 100MR system (Luminex, Austin, Texas). Fifty events per sphere can be read and the generated data obtained from the Bio-Plex Manager software can be transmitted to Microsoft ExcelMR for further analysis. The results can be presented as the ratio of phosphoprotein to total protein. The results of these tests are shown in Figures 3, 4 and 5. Figure 3 shows the ratio of phospho-JNK to total JNK. Figure 4 shows the ratio of phospho p38 to total p38. Figure 5 shows the ratio of phospho-ERK to total ERK. As shown in Figure 3, all of the candidate materials, i.e., the totality of erythritol, xylitol, L-carnitine and betaine, reduce the amount of phosphono-total JNK relative to the hypertonic control. With reference to Figure 4, all of the candidate materials, with the exception of betaine, reduce the amount of phospho-total p38 in relation to the hypertonic control. As shown in Figure 5, the candidate polyol materials, ie, erythritol and xylitol, reduce the amount of ERK relative to the hypertonic control. The amino acids betaine and carnitine no.

EXAMPLE 4 Example 1 is repeated, except that different concentrations of each of the candidate materials are used and TEER is measured at various times from 0 to 24 hours. The results of these tests are shown in Figure 6. As in Example 1, the TEER variable is represented as% of TEER in relation to isotonic control. These results demonstrate that the dose-related response is observed for L-carnitine, betaine and erythritol. A composition that includes betaine and stabilized chlorine dioxide is tested for component compatibility as a preservative. It was found that betaine is not completely compatible in said composition. In this way, betaine is not useful with certain preservatives, such as stabilized chlorine dioxide. However, betaine can be used advantageously as a compatible solute in ophthalmic compositions which use other preservative systems, or which are free of preservatives, for example in single or unit dose applications.

EXAMPLE 5 Example 4 is repeated, except that compositions including combinations of compatible solutes are used. Compositions that include only glycerol as a compatible solute are also tested. The test results are shown in figures 7 and 8.

These test results demonstrate that combinations of different compatible solutes can potentially provide added benefits.

EXAMPLE 6 The pro-piece of the main basic protein (MBP) has been shown to be a 90 residue polypeptide. Using established and well-known techniques, a polypeptide analogous to the sequence of this 90 residue polypeptide is produced. An ophthalmic composition is prepared by combining the following compounds: (1) Purite is a registered trademark of Allergan, Inc., for stabilized chlorine dioxide. This material is added to the mixture after heat sterilization.

EXAMPLE 7 The composition of Example 6, in the form of eye drops, is administered to the eye of a human patient who has undergone a surgical procedure in which the eye has been exposed to laser energy, in particular the LASIK surgical procedure. After the surgical procedure, the patient exhibits reduced pain and / or reduced discomfort and / or reduced irritation of the eye and / or faster recovery of the surgical procedure relative to that experienced with an identical surgical procedure that includes that the same composition be administered without the polypeptide analog.

EXAMPLE 8 The composition of Example 6, in the form of eye drops, is administered to the eye of a human patient who has undergone a surgical procedure in which the eye has been exposed to laser energy, in particular, a LASIK surgical procedure.

After the surgical procedure the patient presents reduced pain and / or reduced discomfort and / or reduced ocular irritation and / or a more rapid recovery of the surgical procedure in relation to that experienced by an identical surgical procedure that includes being administered the same composition without the polypeptide analog. .

EXAMPLE 9 The composition of Example 6, in the form of eye drops, is administered to the eye of a human patient substantially immediately after undergoing a surgical procedure in which the eye has been exposed to laser energy, in particular, a procedure surgical LASIK. The patient exhibits reduced pain and / or reduced discomfort and / or reduced ocular irritation and / or a more rapid recovery of the surgical procedure in relation to that experienced by an identical surgical procedure that includes administering the same composition without the polypeptide analogue.

EXAMPLE 10 A series of four ophthalmic formulations according to the present invention are prepared by combining the various components (shown in the following table) together. (1) Purite is a registered trademark of Allergan, Inc., for stabilized chlorine dioxide. This material is added to the mixture after heat sterilization.

EXAMPLE 11 The procedure of Example 10 is repeated to provide the following compositions: (1) Purite is a registered trademark of Allergan, Inc., for stabilized chlorine dioxide. This material is added to the mixture after heat sterilization.

EXAMPLE 12 The procedure of Example 10 is repeated to provide the following compositions: (1) Purite is a registered trademark of Allergan, Inc., for stabilized chlorine dioxide. This material is added to the mixture after heat sterilization.

EXAMPLE 13 repeats the procedure of example 10 to provide the following compositions: (1) Purite is a registered trademark of Allergan, Inc., for stabilized chlorine dioxide. This material is added to the mixture after heat sterilization.

EXAMPLE 14 The procedure of Example 10 is repeated to provide the following compositions: (1) Purite is a registered trademark of Allergan, Inc., for stabilized chlorine dioxide. This material is added to the mixture after heat sterilization.

EXAMPLE 15 repeats the procedure of Example 10 to provide the following compositions: (1) Purite is a registered trademark of Allergan, Inc., for stabilized chlorine dioxide. This material is added to the mixture after heat sterilization. (2) It is found that betaine is incompatible with the conservative Purite7. Therefore, no preservative was used. These compositions are useful as single-dose or unit-dose applications.

EXAMPLE 16 The procedure of Example 10 is repeated to provide the following compositions: (1) Purite is a registered trademark of Allergan, Inc., for stabilized chlorine dioxide. This material is added to the mixture after heat sterilization. (3) A mixture of 10% by weight of high molecular weight carboxymethylcellulose having an average molecular weight weight of about 700,000 and 90% by weight average molecular weight of carboxymethylcellulose having a molecular weight of about 250,000.

EXAMPLE 17 Each of the compositions produced in Examples 10 to 16, in the form of eye drops, is administered once a day or more frequently to the eyes of a patient who suffers from dry keratoconic syndrome. The administration may be in response to, or in anticipation of, exposure to adverse environmental conditions, for example, dry or high wind environments, low humidity, extensive computer use and the like. Such administration is substantially similar to that used with conventional artificial tears compositions. All patients, after one week of such administration, were found to receive substantial relief, for example in terms of reduced pain and / or reduced irritation and / or improved vision and / or improved appearance of the eyes, from the effects or symptoms of dry keratoconjunctivitis syndrome. In addition, those patients in whom compositions comprising carboxymethylcellulose (CMC) were administered were found to benefit from the anionic character of CMC and the relatively increased viscosities of such compositions. Such benefits include, without limitation, reduced irritation for longer periods of time after administration and / or improved ocular lubrication and / or improved protection against adverse effects of cationic species on the ocular surfaces of the patients' eyes.

EXAMPLE 18 Each of the compositions produced in Examples 10 to 16 including carboxymethylcellulose (CMC) in the form of eye drops is administered to an eye of a different human patient who has just undergone a LASIK surgical procedure. After the surgical procedure, each of the patients presents reduced pain and / or reduced discomfort and / or reduced ocular irritation and / or faster recovery of the surgical procedure in relation to that experienced by an identical surgical procedure that includes being administered the same composition without carboxymethylcellulose.

EXAMPLE 19 Each if the compositions are produced in Examples 10 to 16 which include carboxymethylcellulose in the form of eye drops is administered to the eye of a different human patient undergoing a LASIK surgical procedure. After the surgical procedure, each of the patients presents reduced pain and / or reduced discomfort and / or reduced ocular irritation and / or faster recovery of the surgical procedure in relation to that experienced in an identical surgical procedure that includes being administered the same composition without carboxymethylcellulose.

EXAMPLE 20 Each of the compositions produced in Examples 10 to 16 including carboxymethylcellulose in the form of eye drops is administered to the eye of a different human patient substantially immediately after undergoing a LASIK surgical procedure. Each patient has reduced pain and / or reduced discomfort and / or reduced ocular irritation and / or faster recovery of the surgical procedure in relation to undergoing an identical surgical procedure that includes being administered in the same composition without the carboxymethyl cellulose. Although this invention has been described with respect to various specific examples and embodiments, it should be understood that the invention is not limited thereto and that it may be practiced in a different manner but still within the scope of the following claims. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (84)

2. Having described the invention as above, the content of the following claims is claimed as property: 1. An ophthalmic composition, characterized in that it comprises: an aqueous carrier component; and an effective amount of a tonicity component comprising a material that is selected from the group consisting of erythritol components and mixtures thereof. The composition according to claim 1, characterized in that the material is effective, when the composition is administered to the eye, to allow the ocular surface of the eye to better tolerate a hypertonic condition on the ocular surface in relation to an identical composition without the material.
3. 3. The composition according to claim 1, characterized in that it has an osmolality in the range of about 300 to about 1000 mOsmoles / kg.
4. 4. The composition according to claim 1, characterized in that it has an osmolality in a range of about 300 to about 600 mOsmoles / kg.
5. 5. The composition according to claim 1, characterized in that it is substantially free of inorganic osmolytes.
6. 6. The composition according to claim 1, characterized in that the tonicity component includes at least one additional compatible solute component.
7. The composition according to claim 7, characterized in that at least one additional compatible solute component is selected from the group consisting of polyol components, components of the amino-acidic components and mixtures thereof.
8. The composition according to claim 1, characterized in that the material is present in an amount in a range from about 0.01% (weight / volume) to about 3% (weight / volume).
9. 9. Use of a composition according to claim 1, for making a medicament for treating an eye of a human or an animal.
10. 10. An ophthalmic composition, characterized in that it comprises: an aqueous carrier component; and an effective amount of a tonicity component comprising a material that is selected from the group consisting of inositol components, xylitol components and mixtures thereof, the osmolality of the composition is in a range of at least 310 to about 1000 mOsmoles / kg.
11. The composition according to claim 10, characterized in that the material is effective, when the composition is administered to the eye, to allow the ocular surface of the eye to better tolerate a hypertonic condition on the ocular surface in relation to an identical composition without the material.
12. 12. The composition according to claim 10, characterized in that the osmolality is in a range of at least 310 to about 600 mOsmoles / kg.
13. The composition according to claim 10, characterized in that the material is selected from the group consisting of xylitol components and mixtures thereof.
14. The composition according to claim 10, characterized in that the material is selected from the group consisting of inositol components and mixtures thereof.
15. 15. The composition according to claim 10, characterized in that the tonicity component includes at least one additional compatible solute component.
16. 16. The composition according to claim 15, characterized in that at least one additional compatible solute component is selected from the group consisting of polyol components, zwitterionic amino acid components and mixtures thereof.
17. The composition according to claim 10, characterized in that the material is present in an amount in a range from about 0.01% (weight / volume) to about 3% (weight / volume).
18. 18. Use of a composition according to claim 10, for preparing a medicament for treating the eye of a human or animal.
19. 19. An ophthalmic composition, characterized in that it comprises: an aqueous carrier component; and an effective amount of a tonicity component comprising a material that is selected from the group consisting of carnitine components and mixtures thereof, the composition having a non-isotonic osmolality.
20. The composition according to claim 19, characterized in that the material is effective, when the composition is administered to the eye, to allow the ocular surface of the eye to better tolerate a hypertonic condition on the ocular surface in relation to an identical composition without the material.
21. 21. The composition according to claim 19, characterized in that it has an osmolality in a range of about 300 to about 1000 mOsmoles / kg.
22. 22. The composition according to claim 19, characterized in that it has an osmolality in a range of about 300 to about 600 mOsmoles / kg.
23. 23. The composition according to claim 19, characterized in that the tonicity component includes at least one additional compatible solute component.
24. 24. The composition according to claim 23, characterized in that at least one additional compatible solute component is selected from the group consisting of polyol components, switerionic amino acid components and mixtures thereof.
25. 25. The composition according to claim 19, characterized in that the material is present in an amount in a range of about 0.01% (weight / volume) to about 3% (weight / volume).
26. 26. Use of a composition according to claim 19, for making a medicament for treating the eye of a human or an animal.
27. 27. An ophthalmic composition, characterized in that it comprises: an aqueous carrier component; and an effective amount of a tonicity component comprising a material that is selected from the group consisting of combinations of at least two different compatible solute agents.
28. The composition according to claim 27, characterized in that the material is effective, when the composition is administered to an eye, of allowing the ocular surface of the eye to better tolerate a hypertonic condition on the ocular surface in relation to an identical composition. without the material.
29. 29. The composition according to claim 27, characterized in that it has an osmolality in a range from about 300 to about 600 mOsmoles / kg.
30. 30. The composition according to claim 27, characterized in that it is substantially free of inorganic osmolytes.
31. 31. The composition according to claim 27, characterized in that the tonicity component includes at least one additional compatible solute component.
32. 32. The composition according to claim 27, characterized in that at least two different compatible solute agents are selected from the group consisting of polyol components, switerionic amino acid components and mixtures thereof.
33. The composition according to claim 27, characterized in that at least two different compatible solute agents include two polyols having different molecular weights.
34. 34. The composition according to claim 27, characterized in that at least two different compatible solute agents include a glycerol component and a different organic compatible solute component.
35. 35. The composition according to claim 27, characterized in that at least two compatible solute agents are selected from the group consisting of glycerol components, erythritol components, xylitol components, inositol components, mannitol components, sorbitol, taurine components, betaine components, carbitine components and mixtures thereof.
36. 36. The composition according to claim 27, characterized in that the material is present in an amount in a range of about 0.01% (weight / volume) to about 3% (weight / volume).
37. 37. Use of a composition according to claim 27, for preparing a medicament for treating the eye of a human or animal.
38. 38. An ophthalmic composition, characterized in that it comprises: an aqueous carrier component; a tonicity component in an amount effective to provide the composition with a desired osmolality, the tonicity component comprises a compatible solute component; and a polyanionic component in an effective amount, when the composition is administered to the eye of a human or animal, to reduce at least one adverse effect of a polycationic material on the eye surface of the human or animal eye relative to a composition identical without the polyanionic component, with the proviso that hyaluronic acid is not the only polyanionic component.
39. 39. The composition according to claim 38, characterized in that, when the composition is administered to the eye, the tonicity component is effective to allow the ocular surface of the eye to better tolerate a hypertonic condition on the ocular surface relative to a composition. identical without the compatible solute component.
40. 40. The composition according to claim 38, characterized in that it has an osmolality in a range of about 300 to about 1000 mOsmoles / kg.
41. 41. The composition according to claim 38, characterized in that it has an osmolality in a range of about 300 to about 600 mOsmoles / kg.
42. 42. The composition according to claim 38, characterized in that the compatible solute component is selected from the group consisting of polyol components, zwitterionic amino acid components and mixtures thereof.
43. 43. The composition according to claim 38, characterized in that the compatible solute component is present in an amount in a range of about 0.05% (w / v) to about 3% (w / v) of the composition.
44. 44. The composition according to claim 38, characterized in that the polyanionic component is a polymeric polyanionic component.
45. 45. The composition according to claim 38, characterized in that the polyanionic component is present in an amount in a range from about 0.1% (weight / volume) to about 10% (weight / volume) of the composition.
46. 46. The composition according to claim 38, characterized in that the polyanionic component is selected from the group consisting of anionic cellulose derivatives, hyaluronic acid, anionic starch derivatives, polymethacrylic acid, polymethacrylic acid derivatives, polyphosphazene derivatives, polyaspartic acid , derivatives of polyaspartic acid, gelatin,. alginic acid, alginic acid derivatives, polyacrylic acid, polyacrylic acid derivatives and mixtures thereof.
47. 47. The composition according to claim 38, characterized in that the polyanionic component is carboxymethylcellulose.
48. 48. The composition according to claim 38, characterized in that the polyanionic component is selected from the group consisting of polyanionic peptides, polyanionic peptide analogs, polyanionic peptide analogue portions, carboxymethyl substituted sugar polymers and mixtures thereof.
49. 49. The composition according to claim 38, characterized in that the polyanionic component comprises an agent having an activity which mimics the activity of a major basic protein pro-piece.
50. 50. The composition according to claim 38, characterized in that the polyanionic component comprises an agent that is selected from the group consisting of polypeptide analogs of a pro-piece sequence of major basic protein, polypeptide analogs in a portion of a sequence of Pro-piece of main basic protein and mixtures thereof.
51. 51. Use of a composition according to claim 38, for preparing a medicament for treating the eye of a human or animal.
52. 52. An ophthalmic composition, characterized in that it comprises: an aqueous carrier component; a tonicity component in an amount effective to provide the composition with an osmolality in a range of about 300 to about 1000 mOsmoles / kg, the tonicity component comprising a compatible solute component; and a polyanionic component in an effective amount, when the composition is administered to the eye of a human or animal, to reduce at least one adverse effect of the polycationic material on the ocular surface of the eye in relation to an identical composition without the polyanionic component .
53. 53. The composition according to claim 52, characterized in that the tonicity component is effective, when the composition is administered to the eye, allows an ocular surface of the eye to better tolerate a hypertonic condition on the ocular surface in relation to an identical composition. without the compatible solute component.
54. 54. The composition according to claim 52, characterized in that it has an osmolality in a range of about 300 to about 600 mOsmoles / kg.
55. 55. The composition according to claim 52, characterized in that the compatible solute component is selected from the group consisting of polyol components, components of switerionic amino acids and mixtures thereof.
56. 56. The composition according to claim 52, characterized in that the polyanionic component is a polymeric polyanionic component.
57. 57. The composition according to claim 52, characterized in that the compatible solute component is present in an amount in a range of about 0.05% (w / v) to about 3% (w / v) of the composition and the component. Polyanionic is present in an amount in a range of about 0.1% (weight / volume) to about 10% (weight / volume) of the composition.
58. 58. The composition according to claim 52, characterized in that the polyanionic component is carboxymethylcellulose.
59. 59. The composition according to claim 52, characterized in that the polyanionic component is selected from the group consisting of polyanionic peptides, polyanionic peptide analogs, polyanionic peptide analogue portions, sugar polymers substituted with carboxymethyl and mixtures thereof.
60. 60. The composition according to claim 52, characterized in that the polyanionic component comprises an agent having an activity which mimics the activity of a pro-piece of the main basic protein.
61. 61. Use of a composition comprising an aqueous carrier component, a tonicity component comprising a compatible solute component and present in an amount effective to provide the composition with the desired osmolality, and an effective amount of a polyanionic component , to prepare a medicament for treating a mammalian patient in the eye of a human or animal.
62. 62. The use according to claim 61, wherein the administration step is effective to perform at least one of: (1) allowing the ocular surface of the eye to better tolerate a hypertonic condition on the ocular surface in relation to a identical administration step without the compatible solute component, and (2) reducing at least one adverse effect of a polycationic material on the ocular surface of the eye in relation to an identical composition without the polyanionic component.
63. 63. The use according to claim 61, wherein the administration step is effective to carry out subsections (1) and (2).
64. 64. The use according to claim 61, wherein the composition has an osmolality in a range of about 300 to about 1000 mOsmoles / kg.
65. 65. The use according to claim 61, wherein the composition has an osmolality in a range of about 300 to about 600 mOsmoles / kg.
66. 66. The use according to claim 61, wherein the compatible solute component is selected from the group consisting of polyol components, components of switerionic amino acids and mixtures thereof.
67. 67. The use according to claim 61, wherein the polyanionic component is a polymeric polyanionic component.
68. 68. The use according to claim 61, wherein compatible solute component is present in an amount in a range of about 0.05% (w / v) to about 3% (w / v) of the composition and the polyanionic component is present in an amount in a range of about 0.1 (weight / volume) to about 10% (weight / volume) of the composition.
69. 69. The use according to claim 61, wherein the polyanionic component is carboxymethylcellulose.
70. 70. The use according to claim 61, wherein the polyanionic component is selected from the group consisting of polyanionic peptides, polyanionic peptide analogs, polyanionic peptide analogue portions, carboxymethyl substituted sugar polymers and mixtures thereof.
71. 71. The use according to claim 61, wherein the polyanionic component comprises an agent having an activity which mimics the activity of a major basic protein pro-piece.
72. 72. The use according to claim 61, wherein the step of administration is carried out at least once it is selected from the group consisting before surgery in the eye, during eye surgery or after surgery. surgery in the eye.
73. 73. The use according to claim 72, wherein the administration step is effective to promote recovery of the eye from surgery.
74. 74. The use according to claim 72, wherein the surgery comprises exposing the eye to laser energy.
75. 75. An ophthalmic composition, characterized in that it comprises: a carrier component; and a polyanionic component that is selected from the group consisting of polyanionic peptides, polyanionic peptide analogs, polyanionic peptide analogue portions, carboxymethyl substituted polymers of sugars and mixtures thereof, the polyanionic component is present in an effective amount, when the composition is administered to the eye of a human or an animal, to reduce at least one adverse effect of a polycationic material on an ocular surface of the human eye of the animal in relation to an identical composition without the polyanionic component.
76. 76. The composition according to claim 75, characterized in that the polyanionic component is present in an amount ranging from about 0.1% (weight / volume) to about 10% (weight / volume).
77. 77. The composition according to claim 75, characterized in that the polyanionic component comprises an agent having an activity which mimics the activity of a pro-piece of the main magic protein.
78. 78. The composition according to claim 75, characterized in that the polyanionic component comprises an agent that is selected from a group consisting of polypeptide analogues of a pro-piece sequence of major basic protein, polypeptide analogues of a portion of a sequence of pro-piece of main basic protein and mixtures thereof.
79. 79. Use of a composition comprising a carrier component and an effective amount of a polyanionic component that is selected from the group consisting of polyanionic peptides, polyanionic peptide analogs, polyanionic peptide analogue portions, carboxymethyl substituted sugar polymers and mixtures thereof, to make a medicament to treat the eye of a human or animal.
80. 80. The use according to claim 79, wherein the step of administration is effective to reduce at least one adverse effect of a polycationic material on an eye surface of a human or animal eye in relation to a step of administration. identical without the polyanionic component.
81. 81. The use according to claim 79, wherein the polyanionic component comprises an agent having activity which mimics the activity of a pro-piece of a major basic protein.
82. 82. The use in accordance with claim 79, wherein the polyanionic component comprises an agent that is selected from the group consisting of polypeptide analogues of a pro-piece sequence of major basic protein, polypeptide analogues of a portion of a pro-piece sequence of major basic protein and mixtures of the same.
83. 83. The use according to claim 79, wherein the step of administration is carried out in at least one moment that is selected from the group consisting of before the surgery in the eye, during surgery to the eye and after of a surgery on the eye.
84. 84. The use according to claim 83, wherein the surgery comprises exposing the eye to laser energy.