WO2013046059A2

WO2013046059A2 - Methods and compositions for tamarind-based ocular disease treatment in combination with trehalose

Info

Publication number: WO2013046059A2
Application number: PCT/IB2012/002608
Authority: WO
Inventors: Robert C SYKORA
Original assignee: Sykora Robert C
Priority date: 2011-09-27
Filing date: 2012-09-25
Publication date: 2013-04-04
Also published as: WO2013046059A3

Abstract

Disclosed is an ophthalmic preparation for topical application to the eye, the preparation consisting of, among other ingredients, (a) tamarind and (b) trehalose-in amounts sufficient to treat an ocular disease characterized by dry eye, eye surface inflammation, or eye surface damage.

Description

METHODS AND COMPOSITIONS FOR TAMARIND-BASED OCULAR DISEASE TREATMENT

IN COMBINATION WITH TREHALOSE

The instant uti lity application being filed as a PCT utility application with the USPTO as Receiving Office claims priority from provisional application 61 539582 filed in the USPTO on September 27, 201 1 . The contents of this provisional application are incorporated in their entirety by reference herein.

D ESCRI PTION

SOME RELEVANT DOCUMENTS

INTRODUCTION

0001 . The instant i nvention relates to an ophthalmic preparation for topical application to the eye, the preparation comprised of, among other ingredients, (a) tamarind and (b) trehalose-in amounts sufficient to treat an ocular disease characterized by dry eye, eye su rface inflammation, or eye surface damage.

FIELD OF THE INVENTION

0002. Th is invention relates to a composition for treating an ocular disease characterized by dry eye, eye su rface inflammation, or eye surface damage and a related method of use. In particular, the invention relates to a method of treating an ocular disease characterized by dry eye, eye surface inflammation, or eye su rface damage without an active pharmaceutical ingredient. More particularly, it relates to topical ophthalm ic preparations containing tamarind compounds and trehalose to suppress eye surface inflammation, heal eye su rface damage, or treat dry eye.

DETAILED DESCRIPTION THE OCCULAR TEAR FLUID

0003. The ocu lar tear fluid is an organized l iquid which coats the conjunctiva and the exposed surface of the eyebal l. In normal conditions, the tear fil m appears to be a complex three-layered structure that is comprised of: (a) a layer of mucus, consisting of a mixture of glycoproteins (mucin) produced by specialized cells (i.e. the conju nctival goblet cel ls) which are present in the conju nctival epitheliu m— said layer is adsorbed on the cornea, thus forming a hydrophilic su rface; (b) a thick intermediate aqueous layer, spread over said hydrophil ic su rface, consisti ng essentially of water, electrolytes, proteins, enzymes and mucin; (c) a thi n external l ipid layer, having the main function of control ling the water evaporation rate from the tear film. 0004. The eyelid movement squeezes the mucus out of the conjunctival cells and introduces it into the fornices. With blinki ng, the mucus is uniformly distributed on the whole corneal su rface. The three-layered structure descri bed above constitutes a complex physiological system , mainly directed to protect the eye su rface, to maintai n the hydration, the lu brication and the clearness of the corneal surface, and to cooperate in producing a correct vision. The perfect equil ibrium and continuous renovation of said physiological system is a necessary condition for it to be able to carry out said functions. For the said equilibrium and renovation to be realized, a steady rate of water evaporation from the tear flu id must take place, so as to keep the osmolarity matched to the physiological level of about 300 mOsm /liter. The tear film must be conti nuously redistributed on the corneal su rface as a result of blinki ng.

INTEGRITY OF THE TEAR FILM AND DRY EYE SYNDROME

0005. The i ntegrity of the internal mucin layer represents one of the essential elements of the maintenance of the tear film stability. Mucin enhances the wettability of the corneal su rface, allows the aqueous film to keep adhering to the exposed surface in a continuous and homogeneous way, thus safeguarding its stability, and i ncreases the viscosity of the lacrimal flu id, preventing it from flowing away too rapidly from the conjunctival sac. When mucin is absent or insufficient, the cornea becomes non-wettable and, as a consequence of the unbalance between electrolytes and glycoproteins present, the tear fi lm becomes unstable and subject to breaki ng, with subsequent formation of d ry areas.

0006. Various diseases or abnormal conditions of the eye manifest themselves with discontinu ities of the tear fluid, as a result, e.g., of an insufficient blink frequency, of the prolonged use of contact lenses, of the adm inistration of some systemic drugs or, more frequently, of a senile hyposecretion. In this connection, the term "dry eye" syndrome is commonly used to refer to the ophthal mic condition resulting from the reduction or the instability of the tear film while, more properly, the typical alterations of the corneal su rface occurring in this connection are referred to by the term "keratoconjunctivitis sicca", or dry eye. "Eye su rface dryness" includes any ocular disorder resu lting in loss of water from the tear film. Such disorders generally can be characte rized by i ncreased tear film osmolarity and decreased levels of corneal glycogen and conjunctival mucu s-containing goblet cells. Eye surface dryness can resu lt from a nu mber of different diseases including, for example, meibomian gland dysfunction and meibomian gland orifice stenosis or closu re. "Eye su rface inflammation" includes any inflam matory d isorder involvi ng the ocular surface. The eye su rface includes the eye lids, conjunctiva and cornea. Inflammation refers to white blood cell or leu kocytic infiltration associated with cellular injury. Eye su rface inflammatory disorders treatable by the ophthalmic preparation of the invention are typical ly manifested by signs and symptoms such as eye redness, or irritation. These diseases include, for example, meibom ianitis, blepharitis conjunctival hyperemia, eyelid hyperemia, keratitis and ocular rosacea. Eye surface inflammatory disorders are often associated with eye su rface dryness and irritation. "Eye Surface Damage" includes any injury involvi ng the ocular su rface. The ocular surface can be damaged by many cond itions including chemical /thermal injuries, conjunctival scarring conditions such as Stevens-Johnson syndrome and ocular cicatricial pemphigoid, chronic infections or inflammation of normal tissue growth on the conju nctiva such as pterygium or tu mors, damage to the sensory nerves of the cornea such as dysautonimia or Riley-Day syndrome, or rare hereditary conditions. These problems usually result in extensive damage to the ocular surface and lead to abnormal proliferation of the conjunctival cells on the corneal surface and abnormal blood vessel formation with scarring. Severe damage of the ocular surface may lead to profound loss of vision.

0007. The 2007 Report of the Dry Eye Workshop defined Dry eye as a multifactorial disease of the tears and ocu lar su rface that results in symptoms of discomfort, visual disturbance, 5-7 and tear fi lm i nstability with potential damage to the ocu lar su rface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular su rface. Although it appears that dry eye may result from a number of unrelated pathogenic causes, all presentations of the complication share a common effect, that is the breakdown of the pre-ocular tear fil m, which results in dehydration of the exposed outer su rface and many of the symptoms outlined above (Lemp, Report of the National Eye Institute/Industry Workshop on Clinical Trials in dry eyes, The CLAO Journal, volu me 21 , number 4, pages 221 -231 ( 1 995)). In such situation a degeneration of the conjunctival cells occu rs, resulting in increased desquamation, loss of the cell surface microfolds, breaking of the epithelial cells membrane and reduction of the num ber of mucin-producing goblet cells. This cellular degeneration, being responsible for the reduction of the density of goblet cells and of the lack of mucin, is held to be the origin of most clinical symptoms occurring in dry eye syndrome, such as dryness, irritation, photophobia and foreign body sensation.

0008. Another phenomenon wh ich is u nanimously considered to be a sign of an i rregularly structu red tear fluid is the reduction of the mucus ferning. In normal conditions, mucus is characterized by crystallizing i n a fern pattern when made to evaporate at room temperatu re from an aqueous solution. The ferning phenomenon, which is believed to result from the interaction of the electrolytes with the high molecu lar weight g lycoprotei ns of mucus, is evidenced after a short time from the collection of tear mucus from the lower fornix of the conjunctiva. It has been ascertained that the various different ferning patterns (i.e., Type I, u niform ferning; Type II, good amount of ferning with ferns of reduced size and empty spaces; Type III; ferning only partially present, Type IV, ferning absent) are connected with the normal or pathological condition of the tear fluid. A dense ferni ng, for instance, is considered to be the expression of a perfect equ ilibrium between muci n and electrolytes, while the partial presence or the absence of tear ferning, which is detected in eyes affected by keratoconju nctivitis sicca, denotes a quantitative lack of tear mucus or a qualitative alteration of the glycoproteins or of their envi ronment (i.e., pH, hydration, electrolytic equilibriu m).

0009. From a diagnostic poi nt of view, dry eye syndrome may be detected and monitored not only by means of the evaluation of the typical symptoms thereof, but also by means of well established procedures, i ncluding, as the most common, the evaluation of lacrimal secretion (Schirmer test), the evaluation of the ti me needed for the tear film to break after a compete bl ink (break-up time. BUT), and the evaluation of the color of the corneal and/or conjunctival surface u pon staining with rose Bengal, fluorescein, or lissamine green.

CURRENT APPROACHES TO TREA T DRY EYE

001 0. Practitioners have taken several approaches to the treatment of dry eye. Keratoconju nctivitis sicca is normally treated with liquid ophthalmic preparations generally known as "artificial tears", to be instilled in d rops in order to replace or su pplement the natural tear production. In the simplest case said preparations have only a moistening effect, as they consist of physiological saline solutions, neutral and isotonic with the lacrimal flu id, based on sodiu m chloride only or on balanced mixtu res of various electrolytes. An example of such a preparation, comprising at least four different ionic species (i.e. potassiu m, sodiu m, chloride and bicarbonate) in concentrations su itable to reproduce as faithfully as possible the electrolyte composition of the tear fluid, is disclosed i n EP-A-0 205 279. Such preparations, as do the simpler physiological solutions, reach the objects of increasing the tear volu me, moisteni ng the ocu lar su rface, diluting the mucus deposits and washing away any debris and foreign bodies. However, as the physiological solutions, said preparations have an extremely short duration of action (of the order of a few m inutes), since the solution readily drains into the conjunctival sac. As a consequence, the instillation must be repeated every 1 0- 1 5 minutes, and this brings about the patients' "non-compliance". In addition, a toxic action on the ocular tissues (conjunctiva and cornea) is exerted by the preservatives normally present in the composition. In order to overcome the drawback mentioned above, artificial tear preparations have been i ntroduced, which are made viscous by the add ition of high molecular weight agents, such as, usually, water-soluble polymers of a synthetic, semi-synthetic or natu ral origin. For i nstance, U .S. Pat. No. 4,409,205 discloses a composition for ophthalmic use, which can serve both as an artificial tear substance and as a carrier for therapeutical ly active agents, wherein the viscosity enhancing agent is a non-ionic synthetic polymer, selected between polyvinyl alcohol , polyethylene glycol and mixtures thereof. However, it has been found that, for said viscosity enhancers to confer advantageous featu res to a composition for use as artificial tear, is not sufficient that these viscosity enhancers generically increase the viscosity of the product, but it is also necessary that the dispersions thus formed have properties as close as possible to those of mucin dispersions. Namely, these dispersions must behave as much as possible as mucom imetic substances. This requires, first of al l, a particular rheological behaviou r, i.e. non-newtonian, simi lar to the rheological behaviour of natural tears (see, e.g., Bothner et al., Drug Dev. Ind. Pharm . , 1 6, 755-768, 1 990). As a matter of fact, it has been shown experimentally that an artificial tear, in order to have a prolonged residence time on the corneal su rface whi le being, at the same time, well tolerated by the patient, must not have a constant viscosity, as newtonian fluids do, but must behave as a non-newtonian pseudoplastic fluid (shear-thinning fluid), i.e. it must show a decrease of viscosity with increasing shear rate. Only such type of rheology may offer a high viscosity in the precorneal tear film at rest, so that i n the absence of any stress the film adheres on the corneal surface without dropping, and, at the same time, may provide a low viscosity in the tear film du ring a blinking movement, when the film is su bjected to a shear stress, so that the ophthalmic solution is well tolerated, and is distributed by blinking on the whole corneal su rface without being massively displaced, due to friction, towards the lower eyelid rim. Examples of compositions for use as artificial tears having non-newtonian rheologic behaviou r are disclosed in WO-A-8404681 and in U.S. Pat. No. 5 , 1 06,61 5. The first document proposes the use of carboxyvinyl polymers such as Carbopol.RTM. , to be i ncluded in the formulation in amounts from 0.05 to 0.25% by weight, as viscosity enhancing agents for ophthalm ic solutions. The resulting solutions show, according to this document, a non-newtonian behavior wh ich is currently defined as "plastic", characterized by a yield value for the shear stress, below which value no flow occurs. U.S. Pat. No. 5, 1 06,61 5 discloses compositions useful both as artificial tears and as carriers for ophthalmic medicaments, which are viscosified with anionic polymers of high molecular weight (comprised between 500,000 and 4,000,000). Among the latter, the carboxyvinyl polymers mentioned above and hyaluronic acid are mentioned as preferred. Hyaluronic acid is a polysaccharide of natu ral origin present i n many tissues and fluids, both human and animal, and largely employed in ophthalmic preparations, owing to the marked pseudoplastic behaviour of its aqueous solutions. Equally diffused as thickening agents and viscosity enhancers capable of imparting to the resu lting composition the desired non-newtonian rheology are the cellulose esters, such as methylcellu lose and the alcoholic derivatives thereof, e.g. hydroxypropylcellu lose and hydroxypropyl methylcellulose. 001 1 . As poi nted out in the foregoing, in order to suitably replace and mimic the mucin component of the tear fluid, a product for use as an ophthalmic solution must not only show a pseudoplastic rheological behavior, but also it must show other properties similar to those of muci n. Among such properties there are the ability of wetting the corneal surface, which is intrinsically hyd rophobic, thus increasing the u niform spreading of the tear fluid, and the ability of maintaining the integrity of the layer of tear fluid which covers the ocular su rface. All that taking into account that the eye receiving the administration of an artificial tear is normally an eye with poor tear secretion, whose tear flu id contai ns a scarce amount of mucin. Although the products referred to above are endowed with valuable mucomimetic properties, still a significant amount of product is to be ad mi nistered with relatively high frequency (from 6 to 1 2 times a day). As a consequence, the patient is still exposed to the risk of damages deriving from the preservatives which are normally present, often in combination with each other, in multiple-dose bottles.

001 2. For the above reasons there have been proposed, for the treatme nt of keratoconjunctivits sicca, erodible ocular inserts to be placed in the conju nctival sac. Said inserts consist, e.g. , of smal l cyl inders made of hydroxypropylcellulose which, d issolving in the conjunctival sac, continuously provide the viscosifying and lu bricating mucomimetic su bstance. Although such inserts have the advantage of being totally free of preservatives, they can be d ifficult to insert, and their presence in the conjunctival sac adds to the foreign body sensation, which is always present in cases of dry eye syndrome. Furthermore, the erodible conju nctival inserts cause temporary vision disturbance, owing to the excess of polymer on the corneal su rface.

001 3. In order to obtain an enhanced and prolonged lubricating action, the use of products in gel form has also been proposed (e.g., hyaluronic acid or carboxymethylcellulose gel products). However, these preparations have the drawback of blurring the vision and , therefore, they cannot be used when awake, but only while sleeping.

001 4. Phospholipid compositions have been shown to be usefu l in treating dry eye; see, e.g., McCulley and Shine, Tear film structure and Dry eye, Contactologia , volume 20(4), pages 1 45-49 (1 998); and Shine and McCu lley, Keratoconjunctivitis sicca associated with meibomian secretion polar lipid abnormality, Archives of Ophthalmology , volu me 1 1 6(7), pages 849-52 (1 998). Examples of phospholipid compositions for the treatment of Dry eye are disclosed in U.S. Pat. No. 4, 1 31 ,651 (Shah et al.), U.S. Pat. No. 4,370,325 (Packman), U.S. Pat. No. 4,409,205 (Shively), U.S. Pat. Nos. 4,744,980 and 4,883,658 (Holly), U.S. Pat. No. 4,91 4,088 (Glonek), U.S. Pat. No. 5,075 , 1 04 (Gressel et al.), U.S. Pat. No. 5,278, 1 51 (Korb et al .), U.S. Pat. No. 5,294,607 (Glonek et al.), U.S. Pat. No. 5 , 371 , 1 08 (Korb et al.) and U.S. Pat. No. 5,578, 586 (Glonek et al.). U.S. Pat. No. 5, 1 74,988 (Mautone et al .) discloses phospholipid drug delivery systems involving phospholipids, propellants and an active su bstance.

001 5. Another approach involves the provision of lubricating su bstances in lieu of artificial tears. For example, U.S. Pat. No. 4,81 8, 537 (Guo) discloses the use of a lu bricating, liposome-based composition, and U.S. Pat. No. 5 ,800,807 (Hu et al.) discloses compositions containi ng glycerin and propylene glycol for treating Dry eye.

001 6. Although these approaches have met with some success, problems in the treatment of dry eye nevertheless remai n. The use of tear substitutes, while temporarily effective, generally requires repeated application over the course of a patient's waking hours. It is not uncommon for a patient to have to apply artificial tear solution ten to twenty ti mes over the course of the day. Such an u ndertaking is not only cu mbersome and time consu mi ng, but is also potential ly very expensive. Transient symptoms of dry eye associated with refractive su rgery have been reported to last in some cases from six weeks to six months or more following su rgery.

001 7. Aside from efforts directed primarily to the alleviation of symptoms associated with dry eye, methods and compositions directed to treatment of the dry eye condition have also been pu rsued. For exam ple, U.S. Pat. No. 5 ,041 ,434 (Lubkin) discloses the use of sex steroids, such as conjugated estrogens, to treat dry eye conditions in post-menopausal women; U.S. Pat. No. 5,290,572 (MacKeen) discloses the use of finely divided calcium ion compositions to stimulate pre-ocular tear film production; and U.S. Pat. No. 4,966,773 (Cressel et al.) discloses the use of microfine particles of one or more reti noids for ocular tissue normalization.

001 8. Some recent literature reports suggest that patients suffering from dry eye syndrome disproportionately exhibit the hallmarks of excessive inflammation in relevant ocular tissues, such as the lacrimal and meibomian glands. The use of steroids and cytokine release inhi bitors to treat dry eye patients has been disclosed: U.S. Pat. No. 5,958,91 2 ; Pflugfelder, et. al. U.S. Pat. No. 6, 1 53 ,607; and Yanni, J. M . ; et. al. WO 0003705 Al . Additionally, cyclosporine A [Tauber, J. Adv. Exp. Med. Biol. 1 998, 438 (Lacrimal Gland, Tear Film, and Dry eye Syndromes 2), 969] has been disclosed for treati ng dry eye.

001 9. Corticosteroids, such as prednisolone and loteprednol, reduce inflammation but cannot be used for prolonged therapy i n dry eye patients due to the propensity of steroids to elicit ocular side effects. Steroid-related complications i ncluding increased intraocular pressure and cataract formation have been observed in dry eye patients treated with corticosteroids after several months of therapy. See Marsh, et al., Ophthalmologv, 1 06(4): 81 1 -81 6 ( 1 999). Marsh, et al. conclude: "Because of the chronic nature of [dry eye] disease and the likelihood of patients developing steroid-related complications with their long-term use, topical nonpreserved methylprednisolone therapy appears to be most appropriate for short-term 'pulse' treatment of exacerbations of ke ratoconju nctivits sicca." Id . at 81 1 .

0020. Agents clai med for increasi ng ocular mucin and/or tear production include vasoactive intesti nal polypeptide (Dartt et. al., Vasoactive intestinal peptide - stimulated glycocongjugate secretion from conjunctival goblet cells. Experimental Eve Research , volume 63 , pages 27-34, ( 1 996)), gefarnate (Nakmu ra et. al., Gefamate stimulates secretion of mucin - like glycoproteins by corneal epithelium in vitro and protects corneal epithelium from dessication in vivo, Experimental Eve Research , volu me 65 , pages 569-574 (1 997)), liposomes (U.S. Pat. No. 4,81 8, 537), androgens (U.S. Pat. No. 5,620,92 1 ), melanocycte sti mulating hormones (U.S. Pat. No. 4,868, 1 54), phosphodiesterase inhibitors (U.S. Pat. No. 4,753 ,945), and retinoids (U.S. Pat. No. 5,455,265).

0021 . U.S. Pat. No. 5,696,1 66 discloses the use of certain HETE derivatives, including 1 5- H ETE, for treating dry eye and other disorders requiring the wetting of the eye. According to the Ί 66 patent, the HETE derivatives stimu late mucin production and /or secretion in the conjunctival epithelium and goblet cells. Preferably, the HETE derivatives are topically ad ministered to the eye. 1 5-HETE has been shown to increase the secretion of mucin-1 (MUC- 1 ) from hu man conjunctival epithelial cells.

SUMMARY OF THE INVENTION

0022. The present invention is a therapeutic preparation for ophthalmic use that provides the advantage of drug delivery and treatment or prevention of dry eye disease, eye su rface inflammation, or healing of eye surface damage. The composition comprises an aqueous preparation of the mucomimetic ingredients tamari nd seed polysaccharide (TSP) and trehalose disaccharide, the demulcents polyvi nyl alcohol and polyethylene glycol 400, a preservative such as polyhexamethylene biguanide (PHMB) , in an electrolye-based solution that may include a combination of the followi ng: sod ium chloride, potassium chloride, magnesiu m hydroxyhexahydrate, sodium phosphate monbasic monohyd rate, and calcium ch loride dehydrate, which may be applied topically to the eye, permitting the maintenance or restoration of essentially normal levels of conju nctival mucus and corneal glycogen.

BRIEF DESCRIPTION OF THE FIGURES

FIGURE 1 - TREHALOSE DISACCHARIDE CHEM ICAL STRUCTURE

FIGURE 2 - TAMARIND POLYSACCHARIDE CHEM ICAL STRUCTURE

DETAILED DESCRIPTION OF THE INVENTION

0023. The present invention is directed to a dry eye composition comprising an aqueous solution of fou r polyols: two polysaccharides and two demu lcents. The composition has been shown to moisturize the eye for a relatively long duration. The efficacy of the dry eye medication described herein depends upon the novel combination of two polysaccharides: tamarind seed extract and trehalose disaccharide. As is known by those normally skilled in the art, the mucoadhesive polymer extracted from tamari nd seeds (xyloglucan, or tamarind seed polysaccharide [TSP]) has been described as a viscosity enhancer showing mucomimetic, mucoadhesive, and bioadhesive activities [ref] . Several features make TSP an attractive candidate as a vehicle for ophthalmic medicaments, since it (i) is completely devoid of ocu lar toxicity; (ii) has been put on the market as a tear fluid substitute because of its activity in preventing alterations of the corneal surface known as keratoconjunctivitis sicca; and (ii i) increases the corneal-wou nd healing rate when used in concentrations between 0.25% and 1 %. The other active ingredient, trehalose disaccharide, present in a concentration range of approximately 3.5% to 4%, is implicated in anhydrobiosis — the ability of plants and animals to withstand prolonged periods of desiccation. It has high water retention capabilities, and is used in food and cosmetics. The sugar is thought to form a gel phase as cells dehydrate, which prevents disruption of internal cell organelles, by effectively splinti ng them in position. Rehydration then allows normal cellular activity to be resumed without the major, lethal damage that wou ld normally follow a dehydration / rehydration cycle. Trehalose has the added advantage of being an antioxidant, further protecting the ocular and periocular tissues. These components, when combined into one medication, act synergistically to yield a longer acting, more effective dry eye medication than either substance acting alone.

0024. The polyols of the present invention are selected from the grou p consisting of glycerin, ethylene glycol, poly (ethylene glycol), propylene glycol, polyvi nyl alcohol, sorbitol , manitol and monosaccharides, disaccharides and oligosaccharides.

0025. As noted in the published application US20060222623 the present com position may also contain a disinfecting amount or a preservative of an anti microbial agent. Antimicrobial agents are defi ned as organic chemicals that derive their anti microbial activity through a chemical or physiochemical interaction with the microbial organisms. These include sorbic acid , quarternary ammonium polymers and low and high molecular weight biguanides. For example, biguanides include the free bases or salts of alexidine, chlorhexidine, hexamethylene biguanides and their polymers, and combi nations of the foregoi ng. The salts of alexid ine and chlorhexidine can be either organic or inorganic and are typically gluconates, nitrates, acetates, phosphates, sulfates, halides and the like. A preferred polymeric biguanide is poly(hexamethylene biguanide) commercially available from Zeneca, Wilmington, Del. under the trademark Cosmocil™ CQ. Generally, the hexamethylene biguanide polymers, also referred to as poly(aminopropyl biguanide) (PAPB), have molecular weights of up to about 1 00 kDa. A particularily preferred preservative is alexid ine. If used in the subject solution, the antimicrobial agent should be used in an amou nt which will preserve or prevent the growth of the microorganism popu lation in the formulations employed. Typically, such agents are present in a minimum concentration of about 0.0001 wt. %, 0.0003 wt. % or 0.0005 wt. % and a maxi mum concentration of about 0.0005 wt. % or 0.001 wt. % or about 0.005 wt. % or about 0.01 wt. % or 0.02 wt. % based upon the total weight of the composition.

0026. The aqueous solutions employed in this invention may contain additional ingredients described above, one or more other components that are commonly present in ophthalmic solutions, for example, sodium chloride, potassium chloride, magnesiu m chloride hexahydrate, sodiu m phosphate monobasic monohydrate, and calcium chloride d ihydrate. The aqueous solutions of the present invention are typically adjusted with tonicity agents to create a hypotonic preparation to yield an osmolarity range of 1 50- 1 80 Osm that stabilizes the hypertonic tears of dry eye to approximate the tonicity of normal lacrimal fluids which is equivalent to a 0.9 wt. % solution of sodium chloride or approximately 31 6 Osm.

0027. Once again per US20060222623, the pH of solutions used to treat dry eye should be maintained at a minimum of about 4, about 5, about 5.5 , about 6, about 6.5 and/or a maximum of about 7.5 , about 7.8, about 8, about 8.5. Suitable buffers may be added, such as borate, citrate, bicarbonate, aminoalcohol buffers, MOPS buffer, bicine, tricine, TRIS, BIS/TRIS and various mixed phosphate buffers (including combinations of Na 2 H PO 4 , NaH 2 PO 4 and KH 2 P0₄) and mixtu res thereof. Borate buffers are preferred, particularly for enhancing the efficacy of PAPB. Preferred combination buffers include borate/ phosphate and borate/citrate combi nation buffers. General ly, buffers will be used in amounts having a minimum of about 0.05 wt. % or about 0.1 wt. % and/or a maximum of about 1 .5 wt. % or about 2.5 wt. %.

DOSAGE FORMS

0028. The dry eye treatment can be formu lated as instant release and modified release dosage forms, including delayed-, extended-, prolonged-, sustai ned-, pulsatile-, control led-, accelerated-, fast-, targeted-, and program med-release dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Rathbone et ai, eds., 2008, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2 nd ed., New York, NY: Marcel Dekker, I nc.). The treatments can be administered by a health care practitioner or by the subject. I n some embodiments, the subject adm inisters the dry eye medication to hi m or herself.

0029. In one embod iment, the eye-drop treatment containing tamarind and trehalose will be thermo-reversible viscosity effects. By "thermoreversible" is meant an increase in viscosity with an increase in tem peratu re. A dry-eye formu lation that is administered as a low viscosity l iqu id at room tem perature and which "gels" on the ocu lar su rface will increase the residence ti me of the ingredients, thus prolonging the effect.

0030. In one embodiment, the eye-drop treatment will be applied cold, to provide a soothing "feel ing" to the eye.

0031 . In another embodiment, the eye-drop treatment will be applied via a precise dose eye-drop applicator to prevent "run-off". In another embodi ment, it is envisioned that the medicament will be applied i n the form of a mist-delivering applicator.

0032. The dry eye medicament can also comprise liposomes, micelles, m icrospheres, microparticles, nanosystems, e.g., nanoparticles, nano-coacervates and mixtu res thereof. In one embod iment, the nano-sized delivery matrix is fabricated through a well-defined process, such as a process to produce tamarind and /or trehalose encapsulated in a polymer. I n another em bodiment, the tamarind and trehalose combination spontaneously assembled in aqueous solutions, such as in liposomes and micelles.

0033. In some embodiments, the formulation for topical administration will be lipid-based. In one embod iment, a formulation in ointment form comprises one or more of the following ingredients: wool alcohol (acetylated lanolin alcohol), hard paraffin, white soft paraffin, liquid paraffin, and water. See, e.g., Langtry et a/., supra. In some embodiments, the selected formulation is inconspicuous when applied to the ocu lar surface, for example, is colorless, odorless, quickly-absorbing, etc.

0034. In some embodiments, the selected formu lation is applied on the ocu lar surface as a solution, wh ich can crosslink into a hydrogel within a few minutes, thus creating a biocompatible dressing. In one application, the hydrogel may be biodegradable. In another embodiment, the solution wi ll absorb into the ski n and crossl ink i nto depots releasing drug.

0035. Pharmaceutically acceptable carriers and excipients suitable for use in ocular formulations include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, anti-microbial agents or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isoton ic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or e mulsifying agents, com plexi ng agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.

0036. Forms for ocular admi nistration can also be in the form of oi ntments, creams, emulsions, sprays, eye baths, and gels. Su itable ointment vehicles include oleaginous or hydrocarbon vehicles, olive oil, cottonseed oil, mineral oil and other oils, white petrolatum , paraffins; emu lsifiable or absorption vehicles, such as hydrophilic petrolatum , hydroxysteari n sulfate, and anhydrous lanolin; water- re movable vehicles, such as hydrophil ic ointment; water-soluble ointment vehicles, including polyethylene glycols of varying molecular weight; emu lsion vehicles, either water-i n-oi l (W/O) emulsions or oil— in— water (O/W) emu lsions, includ ing cetyl alcohol , glyceryl monostearate, lanolin, wool alcohol (acetylated lanoli n alcohol), and stearic acid {see, Remington: The Science and Practice of Pharmacy, supra).

0037. Suitable cream base can be oil-in-water or water-in-oil . Suitable cream vehicles may be water-washable, and contai n an oil phase, an emulsifier, and an aqueous phase. The oil phase is also called the "internal" phase, which is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol . The aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a hu mectant. The emulsifier in a cream formu lation may be a nonionic, anionic, cationic, or amphoteric su rfactant.

0038. Gels are semisolid, suspension-type systems. Single- phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include, but are not limited to, crosslinked acrylic acid polymers, such as carbomers, carboxypolyalkylenes, and CARBOPOL^®; hydrophilic polymers, such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellu lose; gums, such as tragacanth and xanthan gum; sodiu m alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or g lycerin can be added, or the gelling agent can be d ispersed by tritu ration, mechanical mixing, and/or stirring.

0039. Compositions intended for ocular administration can include one or more pharmaceutically acceptable carriers and excipients, includi ng, but not limited to, aqueous vehicles, water-misci ble vehicles, non-aqueous vehicles, anti-microbial agents or preservatives agai nst the growth of microorganisms, stabil izers, solubi lity enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases. All such com positions must be ste rile, as known in the art. The compositions for ocular adm inistration can be formu lated as a suspension, sol id, semisolid, or thixotropic liquid, for administration as an implanted depot.

Claims

What is claimed is:

[Claim 1] . An ophthalmic preparation for topical application to the eye, the preparation comprising an aqueous solution containing (a) a tamarind extract in an amount sufficient to treat an ocular disease characterized by dry eye, eye surface inflammation, or eye surface damage; and (b) trehalose in an amount sufficient to treat an ocular disease characterized by dry eye, eye surface inflammation, or eye surface damage.

[Claim 2] The ophthalmic preparation of claim 1 further comprising a balance of electrolytes selected from the group comprising potassium, chloride, bicarbonate and sodium, wherein said potassium is present at a concentration of about 22.0 to 43.0 mM/l, said bicarbonate is present at a concentration of about 29.0 to 50.0 mM/l, said sodium is present at a concentration of about 130.0 to 140.0 mM/l, and said chloride is present at a concentration of about 118.0 to 136.5 mM/l, or a therapeutically effective dilution or concentration of said solution.

[Claim 3] The ophthalmic preparation of claim 1 wherein the solution has an osmolarity of about 150-180 mOsm/Kg.

[Claim 4] The ophthalmic preparation of claim 1 , wherein the solution further comprises a balance of electrolytes selected from the group consisting of calcium, magnesium and phosphate, wherein said calcium is present at a concentration of about 0.5 to 2.0 mM/l, said magnesium is present at a concentration of about 0.3 to 1.1 mM/l, and said phosphate is present at a concentration of about 0.8 to 2.2 mM/l.

[Claim 5] The ophthalmic preparation of claim 4 wherein the solution has an osmolarity of about 150-180 mOsm/Kg.

[Claim 6] The ophthalmic preparation of claim 1 further comprising one or more demulcents such as polyvinyl alcohol or polyethylene glycol 400.

[Claim 7] The ophthalmic preparation of claim 6 further comprising polyvinyl alcohol at a concentration of 0.1% to 4%, preferably 1%.

[Claim 8] The ophthalmic preparation of claim 6 further comprising polyethylene glycol at a concentration of 0.2-1%, preferably 1%.

[Claim 9] The ophthalmic preparation of claim 1 optionally comprising one or more preservatives such as polyhexamethylene biguanide (PHMB).

[Claim 10] The ophthalmic preparation of claim 9 further comprising polyhexamethylene biguanide at a concentration of 0.01 % to 0.1 %, preferably 0.02%.

[Claim 11] The ophthalmic preparation of claim 1 wherein the tamarind extract is tamarind seed polysaccharide.

[Claim 12] The ophthalmic preparation of claim 1 wherein the tamarind extract is tamarind seed polysaccharide present at a concentration of about 0.1% to 5%.

[Claim 13] The ophthalmic preparation of claim 1 wherein the tamarind seed extract is tamarind seed polysaccharide present at a concentration of 0.1 to 2%, preferably 0.25% to 2%, most preferably 0.25% to 1%.

[Claim 14] The ophthalmic preparation of claim 1 wherein the trehalose is present at a concentration of 0.01% to 20%.

[Claim 15] The ophthalmic preparation of claim 1 wherein the trehalose is present at a concentration of between 0.01% - 10%, preferably 0.1% - 5%, more preferably 0.5% - 5%, most preferably 3% to 4%.

[Claim 16] An aqueous ophthalmic solution comprising: (a) a tamarind extract at a concentration of about 0.25% to 1 %; and (b) trehalose at a concentration of about 3% to 4%.

[Claim 17] The ophthalmic solution of claim 16 wherein the solution has an osmolarity of about 150-180 mOsm/Kg.

[C lai m 1 8] The ophthal mic solution of clai m 1 1 wherei n the (a) tamarind extract is tamarind seed polysaccharide at a concentration of about 0.25% to 1 % and; (b) trehalose at a concentration of about 3% to 4%.

[C lai m 1 9] A method of treating eye su rface inflammation or dryness or damage comprising topically applying to the surface of an eye of a subject suffering from said disorder an aqueous ophthalmic solution comprising: (a) a tamarind extract in an amount sufficient to treat an ocular d isease characterized by eye su rface inflammation or dryness or damage; and (b) trehalose in an amou nt sufficient to treat an ocu lar disease characterized by eye surface dryness, inflam mation, or damage.

[C lai m 20] A method of simultaneously reducing inflammation, dryness, or damage of an ocular surface, comprising topically applying to said ocular su rface an aqueous ophthalmic solution com prising: (a) a tamarind extract in an amount sufficient to treat an ocular disease characterized by eye surface inflammation, dryness, or damage; and (b) trehalose in an amou nt sufficient to treat an ocu lar disease characterized by eye surface inflammation, dryness, or damage.