WO2008074853A1

WO2008074853A1 - Ophthalmic rebamipide solution

Info

Publication number: WO2008074853A1
Application number: PCT/EP2007/064276
Authority: WO
Inventors: Karine Corcelle; Andreas Fritze
Original assignee: Novartis Ag
Priority date: 2006-12-21
Filing date: 2007-12-19
Publication date: 2008-06-26

Abstract

This invention relates to a homogeneous ophthalmic composition, in particular an aqueous solution, comprising (1) rebamipide; (2) a viscosity enhancer; (3) an isotonic agent; and (4) a buffer, which solution has a pH of between about 7 and about 9. The invention further relates to rebamipide solutions which have a chloride concentration of less than about 0.5 mM.

Description

OPHTHALMIC REBAMIPIDE SOLUTION

This invention relates to stable homogeneous aqueous compositions comprising an ophthalmic drug, in particular to stable homogeneous solutions comprising a carbostyril derivative, e.g., Rebamipide (2-(4-chlorobenzamido)-3-(2-oxo-1 ,2-dihydroquinolin-4-yl)propanoic acid).

Previous attempts to prepare pharmaceutically or ophthamologically stable homogeneous rebamipide solution at neutral pH have been unsuccessful. Currently, pharmaceutically and/or ophthamologically acceptable formulations of rebamipide are aqueous suspensions which require pre-sterilization of the ingredients and mixing and packaging of the formulation under aseptic conditions.

Thus, it would be desirable to provide stable homogeneous rebamipide solutions which are suitable for use in pharmaceutical and/or ophthalmic applications. In particular, it would be desirable to provide new ophthalmic solutions of rebamipide which are stable during terminal sterilization and storage.

It has now been found that rebamipide (2-(4-chlorobenzamido)-3-(2-oxo-1 ,2-dihydroquinolin-4- yl)propanoic acid) can be formulated in a pharmaceutically acceptable and/or ophthamologically acceptable solution without precipitation or gelation during storage or sterilization. In particular, aqueous solutions of rebamipide with a polymeric viscosity agent, a tonicity agent, and a buffer are provided which are stable at a pH of between about 7.5 and about 9 and/or have a chloride concentration of less than 0.5 mM. The solutions of the invention are stable during terminal sterilization and storage. The solutions of the invention are suitable for use in topical and oral administration and are well tolerated by the skin and by ocular tissue during topical administration.

It has furthermore surprisingly been found that rebamipide solutions according to the invention are effective in the treatment of ocular inflammation disorder, including but not limited to dry eye, and are well tolerated by the ocular tissue of the patient. A first embodiment of the instant invention is therefore a pharmaceutically acceptable solution comprising: (1) rebamipide; (2) a viscosity enhancer; (3) an isotonic agent; and (4) a buffer, wherein the solution has a pH of between about 7.5 and about 9.

A second embodiment of the instant invention is a pharmaceutically acceptable solution comprising (1) rebamipide; (2) a viscosity enhancer; (3) an isotonic agent; and (4) a buffer, wherein the solution has a chloride concentration of less than 0.5 mM.

A third embodiment of the instant invention is a pharmaceutically acceptable solution, comprising (1) rebamipide; (2) a viscosity enhancer selected from hydroxypropylmethylcellulose, polyvinylpyrrolidone, sodium hyaluronate, hyaluronic acid, polyethylene glycol, or a mixture thereof; (3) propylene glycol; and (4) a buffer selected from sodium borate or disodium phosphate, wherein the solution has a pH of between about 7.7 and about 8.3.

A fourth embodiment of the instant invention is a pharmaceutically acceptable solution, comprising (1) rebamipide; (2) hydroxypropylmethylcellulose, polyvinylpyrrolidone, sodium hyaluronate, hyaluronic acid, propylene glycol, or a mixture thereof; (3) polyethylene glycol; and (4) a buffer selected from sodium borate or disodium phosphate, wherein the solution has a chloride concentration of less than about 0.5 mM. In certain embodiments, the chloride concentrationis preferably less than about 0.1 mM, less than about 50 μM or less than about 10 μM.

In certain embodiments the rebamipide concentration in the pharmaceutical solution of the invention is between about 0.01% w/v and about 2.5% w/v. In certain other solutions, the concentration of rebamipide is between about 0.5% w/v and about 1.5% w/v. In yet other solutions of the invention the rebamipide concentration is about 0.1% w/v, about 0.2% w/v, about 0.3% w/v, about 0.4% w/v, about 0.5% w/v, about 0.6% w/v, about 0.7% w/v, about 0.8%w/v, about 0.9% w/v, about 1.0% w/v, about 1.1% w/v, about 1.2% w/v, about 1.3% w/v, about 1.4% w/v, or about 1.5% w/v. In certain particularly preferred solutions the rebamipide concentration is about 0.1% w/v or about 1.0% w/v. In certain embodiments the viscosity enhancer in the pharmaceutical solution of the invention is between about 0.01% w/v and about 5% w/v. In certain other solutions, the concentration of viscosity enhancer is between about 0.5% w/v and about 4% w/v. In yet other solutions of the invention the viscosity enhancer concentration is about 0.1% w/v, about 0.2% w/v, about 0.3% w/v, about 0.4% w/v, about 0.5% w/v, about 0.6% w/v, about 0.7% w/v, about 0.8%w/v, about 0.9% w/v, 1.0% w/v, about 1.1% w/v, about 1.2% w/v, about 1.3% w/v, about 1.4% w/v, about 1.5% w/v, about 1.6% w/v, about 1.7% w/v, about 1.8% w/v, about 1.9% w/v, about 2.0% w/v, about 2.1% w/v, about 2.2% w/v, about 2.3% w/v, about 2.4% w/v, or about 2.5% w/v.

The viscosity enhancer is selected from hydrophilic polymers, monosaccharides, polysaccharides (including functionalized polysaccharides), cyclic saccharides (including Dextrans), polyols, celluloses (including cellulose, methylcelluloses, sodium carboxymethyl cellulose, hydroxyalkylmethylcellulose, and derivatized celluloses), cremophor EL, gums (e.g., xanthan gum and the like), polyvinyl alcohols, polyvinylpyrrolidone, polymethacrylates, polyvinyl acetates, pectins and mixtures thereof. In certain embodiments, the viscosity enhancer is preferably selected from among a methylcellulose, an hydroxy-Ci-Cs alkylmethylcellulose, Carbomer 940, polyethylene glycol, and polyvinyl alcohol, and is more preferably methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, or polyvinylpyrrolidone.

Preferred celluloses include methylcelluloses, sodium carboxymethyl celluloses (e.g., Na-CMC), hydroxypropylmethyl celluloses (HPMC), polyethylene glycols, Carbomer 940 and mixtures thereof. Suitable hydroxypropylmethyl celluloses include HPMCs having a weight average molecular width (M_w) of between about 5,000 and about 250,000 or more preferably a weight average molecular width (M_w) of between about 10000 and about 150000 and/or having a viscosity (measured as a 2% aqueous solution at 20⁰C measured by Ubbelhode method, e.g., a U-tube capillary viscometer) of between about 1 and about 250,000 mPa^*s or more preferably between about: 2 to 120,000 mPa^*s. Certain preferred HPMCs are commercially available. Examples of suitable HPMCs include, but are not limited to: HPMC E4M (HPMC2910), F4M (HPMC2906) and K4M (HPMC2208)

Preferred polyvinylpyrrolidones include polymers having a weight average molecular width (M_w) of between about 5,000 and about 1 ,500,000 or more preferably a molecular weight of between about 10,000 and about 700,000. Certain preferred polyvinylpyrrolidones are commercially available. Examples of suitable polyvinylpyrrolidones include, but are not limited to Povidone K17, K25, K30, K64 VA and K90.

In certain embodiments, it may be desirable to use a low molecular weight viscosity enhancer. Preferred low molecular weight viscosity enhancers are well tolerated by the eye. Certain, non limiting, low molecular weight viscosity enhancers are selected from hyaluronic acid, sodium hyaluronate, and Dextran 70.

Furthermore, the compositions of the present invention comprise an isotonic agent. Suitable isotonic agents include, but are not limited to, non-chlorinated ionic compounds, such as alkali metal halides, such as KBr, LiBr, NaI, or NaBr, or boric acid, and/or non-ionic compounds such as urea, glycerol, sorbitol, mannitol, propylene glycol, polyethylene glycol, or dextrose. Propylene glycol, polyethylene glycol and glycerol is a preferred isotonic agent in certain pharmaceutical compositions of the invention.

In certain embodiments the isotonic agent in the pharmaceutical solution of the invention is between about 0.01% w/v and about 5% w/v. In certain other solutions, the concentration of isotonic agent is between about 0.5% w/v and about 4% w/v. In yet other solutions of the invention the isotonic agent concentration is about 0.1% w/v, about 0.2% w/v, about 0.3% w/v, about 0.4% w/v, about 0.5% w/v, about 0.6% w/v, about 0.7% w/v, about 0.8%w/v, about 0.9% w/v, 1.0% w/v, about 1.1% w/v, about 1.2% w/v, about 1.3% w/v, about 1.4% w/v, about 1.5% w/v, about 1.6% w/v, about 1.7% w/v, about 1.8% w/v, about 1.9% w/v, about 2.0% w/v, about 2.1% w/v, about 2.2% w/v, about 2.3% w/v, about 2.4% w/v, or about 2.5% w/v.

In certain embodiments, a sufficient quantity of at least one isotonic agent is added to impart to the ready-for-use pharmaceutical composition an osmolality of approximately from 50 to 1000 mOsm/kg, preferred from 100 to 400 mOsm/kg, more preferred from 200 to 400 mOsm/kg and even more preferred from 280 to 350 mOsm/kg.

Suitable polyethylene glycols are typically mixtures of polymeric compounds of the general formula H-(OCH₂-CH₂)nOH, wherein the index n may typically range from 4 to 230 and the mean molecular weight from about 200 to about 10000. Preferably n is a number from about 6 to about 22 and the mean molecular weight between about 300 and about 1000, more preferably n ranges from about 6 to about 13 and the mean molecular weight from about 300 to about 600, most preferably n has a value of about 8.5 to about 9 and the relative molecular weight is about 400. Suitable polyethylene glycols are readily available commercially, for example polyethylene glycols having a mean molecular weight of about 200, 300, 400, 600,1000, 1500, 2000, 3000, 4000, 6000, 8000 and 10000.

In certain embodiments the buffer in the pharmaceutical solution of the invention is between about 1% w/v and about 15% w/v. In certain other solutions, the concentration of buffer is between about 2.5% w/v and about 10% w/v. In yet other solutions of the invention the buffer concentration is about 2.5% w/v, about 3% w/v, about 3.5% w/v, about 4% w/v, about 4.5% w/v, about 5% w/v, about 5.5% w/v, about 6%w/v, about 6.5% w/v, 7% w/v, about 7.5% w/v, about 8% w/v, about 8.5% w/v, about 9% w/v, about 9.5% w/v, about 10% w/v, about 11% w/v, about 12% w/v, about 13% w/v, about 14% w/v, or about 15% w/v.

The compositions of the present invention also comprise a buffer such as acetate, ascorbate, borate, hydrogen carbonate / carbonate, citrate, gluconate, lactate, phosphate, propionate and TRIS (trimethamine) buffers. Trimethamine and borate buffers are preferred buffers. The amount of a buffer added is, for example, that necessary to ensure and maintain a physiologically tolerable pH range. The pH range is typically in the range of from 7.5 to 9, preferably from 7.7 to 8.5 and more preferably from 7.7to 8.3. Certain preferred compositions have a pH of about 7.8.

The compositions of the present invention may, in certain embodiments, further comprise a preservative. Suitable preservatives include

• a quaternary ammonium compound such as e.g. benzalkonium chloride (N-benzyl-N-(C₈- C₁₈-alkyl)-N,N-dirnethylarnrnonium chloride), benzoxonium chloride, benzethonium chloride, cetrimide (hexadecyl-trimethylammonium bromide), sepazonium chloride, cetylpyridinium chloride, domiphen bromide (Bradosol^®) or the like,

• quaternized ammonium cyclodextrin compounds (QACD compounds) such as those having the following formula:

, wherein

r cyclodextrin-

represents a n-valent residue derived from a cyclodextrin compound by removing n of its hydroxyl groups; n is a number greater than 0 and represents the average number of substituents of formula

per molecule of said compound; h is 0 or 1 ;

R₁ is a divalent group selected from alkylene, hydroxy alkylene, halogeno alkylene, monocyclic aralkylene, cycloalkylene and phenylene;

R₂, R₃ and R₄ are each independently of one another a group selected from alkyl, cycloalkyl, aryl, aralkyl, and cycloheteryl;

X^m" is a m-fold negatively charged anion; m is an integer being equal or greater than 1 ; and k is n/m, as described, for instance, in U. S. -Patent No. 3,453,257 (index h = 1) or U.S.-Patent

5,241 ,059 (index h = 0),

• alkyl-mercury salts of thiosalicylic acid, such as e.g. thiomersal, phenylmercuric nitrate, phenylmercuric acetate or phenylmercuric borate,

• parabens, such as e.g. methylparaben or propylparaben,

• alcohols, such as e.g. chlorobutanol, benzyl alcohol or phenyl ethyl alcohol,

• biguanide derivatives, such as e.g. chlorohexidine or polyhexamethylene biguanide,

• sodium perborate,

• imidazolidinyl urea as known and commercially available under the trade name Germal®ll,

• sorbic acid,

• stabilized oxychloro complexes such as known and commercially available under the trade name Purite®,

• polyglycol-polyamine condensation resins, such as known and commercially available e.g. under the trade name Polyquart® from Henkel KGaA,

• stabilized hydrogen peroxide generated from a source of hydrogen peroxide for providing an effective trace amount of resultant hydrogen peroxide, e.g. sodium perborate tetrahydrate, and/or

• a mixture of two or more members of such components. Preferred preservatives are quaternary ammonium compounds, in particular benzalkonium chloride, cetrimide and phenyl ethyl alcohol, a particularly preferred preservative for the purposes of the instant invention. Where appropriate, a sufficient amount of preservative is added to the ophthalmic composition to ensure protection against secondary contaminations during use caused by bacteria and fungi, e.g. benzalkonium chloride and/or cetrimide are present in an amount of about 0.001-0.02%, or phenyl ethyl alcohol is present in an amount of about 0.05 to 5 percent by weight, preferably 0.1 to 2, e. g. 0.1 to about 1 percent by weight.

The compositions of the present invention may further comprise complexing agents such as

• disodium-ethylenediamine tetraacetate, ethylenediamine tetraacetic acid (EDTA),

• chelating agents having phosphonic acid or phosphonate groups, preferably organophosphonates, particularly amino tri(lower alkylene phosphonic acids) such as those known and commercially available from Monsanto Company, St. Louis, under the trade name Dequest®, or the like,

• cyclodextrins, e.g. alpha, beta, or gamma-cyclodextrin, e.g. alkylated, hydroxyalkylated, carboxyalkylated or alkyloxycarbonyl-alkylated derivatives, or alkylthioether derivates (e.g. butylthioether derivatives and the like) or mono- or diglycosyl-alpha, beta, or gamma- cyclodextrin, mono- or dimaltosyl- alpha, beta, or gamma- cyclodextrin or panosyl- cyclodextrin, e.g. such as known and commercially available under the trade name Cavamax® or Cavasol® from Wacker Chemie, or

• a mixture of two or more of such components.

The compositions of the present invention may further comprise antioxidants such as ascorbic acid, acetylcysteine, cysteine, sodium hydrogen sulfite, butylated hydroxyanisole, butylated hydroxytoluene or natural or synthetic Vitamin E derivatives, such as alpha-tocopherol or alpha- tocopherol acetate.

The compositions of the present invention may further comprise stabilizers such thiourea, thiosorbitol, sodium dioctyl sulfosuccinate or monothioglycerol.

It will be appreciated that although the excipients have been described above by reference to a particular function any particular excipient may have alternative or multiple functions, e.g. cyclodextrin or a mixture of cyclodextrins may act as e.g. stabilizer, complexing agent and/or solubilizer.

Information on the properties, specifications and characteristics of the excipients are described e.g. in standard texts such as Fiedler, H. P.; 1996; Lexikon der Hilfsstoffe fϋr Pharmazie. Kosmetik und anqrenzende Gebiete; Editio Cantor Verlag Aulendorf (Germany), and Kibbe, A.H.; 2000; Handbook of Pharmaceutical Excipients. a joint publication of Pharmaceutical Press, London (UK), and American Pharmaceutical Association, Washington (US) as well as manufacturers' brochures, the contents of which are incorporated herein by reference.

Preferably, the compositions of the present invention are free of components such as perfumes or colorants.

In certain embodiments, pharmaceutical formulations comprising a rebamipide solution comprise, or consist essentially of: water, rebamipide, glycerol, and hydroxypropylmethylcellulose. In certain embodiments, citric acid or sodium hydroxide is added to adjust the final pH of the pharmaceutical composition such that the pharmaceutical compositions comprises a rebamipide solution comprise, or consist essentially of: water, rebamipide, glycerol, and hydroxypropylmethylcellulose, and at least one of sodium hydroxide and citric acid.

Especially preferred is a composition according to this invention comprising or, more preferably, essentially consisting of

(1) Rebamipide 0.01-3% (or more preferably 0.1-2%);

(2) Glycerol 0.1 %-5% (or more preferably 0.5%- 4%);

(3) HPMC 0.05%-1% (or more preferably 0.1% to 0.8%);

(4) Potassium Borate 0.01 %- 1 % (or more preferably 0.05-0.2%)

(5) NaOH and/or citric acid as necessary to adjust pH (preferably less than 0.5% each);

(6) Water up to 100% wherein all percentages relate to the total weight of the components (1) to (5) and only combinations of percentages are permitted which add up to 100. Especially preferred is a composition according to this invention comprising or, more preferably, essentially consisting of

(1) Rebamipide 1%;

(2) Glycerol 2%;

(3) HPMC 0.5%;

(4) Potassium Borate 0.05-0.2% (e.g., an amount sufficient to establish a pH of about 7.8-8.0)

(5) NaOH 0.1%;

(6) Water 96.4%; wherein all percentages relate to the total weight of the components (1) to (5) and only combinations of percentages are permitted which add up to 100.

The compositions of the present invention are stable, as indicated by conventional tests, e.g. under stressed conditions, such as a temperature cycling test at 5 to 30⁰C, for several months, e.g. 1 to 12 months, at 30⁰C. The compositions of the present invention are also stable under the conditions of the Roger test, e.g., the solutions remain clear and precipitate free or exhibit minor flake precipitation. Preferred formulations remain homogeneous solutions after the Roger test.

The ophthalmic compositions of the present invention may be prepared in conventional manner e.g. by mixing the preferably gamma-irradiated ophthalmic drug, e.g. the rebamipide, if necessary under heating and/or sonication, e. g. for 0.5 to 6 hours, optionally adding further excipients, such as e. g. a preservative and/or an antioxidant, and mixing the resulting rebamipide solution, sterilizing the solution, for instance by filtration through a 0.2 micron meter filter, thermal sterilization or gamma irradiation, and packaging the rebamipide solution in a container. In the alternative, thermal sterilization can be performed after the solution is loaded into a container.

The homogeneous rebamipide solutions, according to the present invention are particularly useful for topical administration of rebamipide to the skin, e. g. the skin of the eyelid, or in the cul du sac of the eye or to the surface of the eye, in particular in particular to the cornea, sclera and/or conjunctiva. The homogeneous rebamipide solutions, according to the present invention are particularly useful for oral administration of rebamipide as a intestinal infusion or drink solution for the treatment of ulcus ventriculi or ulcus duodeni, or ulcus pepticum. In certain embodiments, the homogeneous rebamipide solutions are also suitable for intravenous or subcutaneous administration.

The pharmaceutical compositions comprising a rebamipide solution are suitable for use in the treatment of inflammatory diseases, especially dry eye or blepharitis e.g. chronic blepharitis, e.g. seborrhoeic blepharitis or allergic blepharitis.

In another aspect the present invention provides a method for treating inflammatory diseases, especially dry eye or blepharitis, e.g. chronic blepharitis, e.g. seborrhoeic blepharitis or allergic blepharitis, comprising topically administering a composition as defined above and comprising rebamipide to the skin of a patient in need thereof.

In another aspect the present invention provides the use of the ophthamologically acceptable rebamipide solutions in the preparation of a medicament for topically administering to the eye, e.g. on the skin of the eyelid or in the cul de sac of the eye or upon the ocular surfaces of the eye, of a patient in need thereof.

In yet another aspect, the present invention provides the use of the ophthamologically acceptable rebamipide solutions in the preparation of a medicament for the treatment of inflammatory diseases, especially blepharitis e.g. chronic blepharitis, e.g. seborrhoeic blepharitis or allergic blepharitis.

The utility of the compositions according to the invention can be observed in standard clinical tests such as the test set out below.

The exact amount of the pharmaceutical rebamipide solutions to be administered depends on several factors, for example the targeted disease, mode of administration, the species, age, weight and physical condition of the subject, desired duration of treatment and pharmacological data, e. g. the rate of release of the drug. For ophthalmic diseases and disorders, satisfactory results are obtained in larger mammals, e.g. humans, with the local application upon the ocular tissue to be treated or upon the ocular surfaces of the eye of a 0.01 to 2.5% by weight concentration of rebamipide once or several times a day. For gastrointestinal diseases and disorders, satisfactory results are obtained by administration of the pharmaceutical rebamipide solutions of the invention using current dosing schedule and administration route.

The following Examples illustrate the invention.

Example 1

A 1% rebamipide solution having the ingredients of Table 1 is prepared by the procedure as follows.

Hydroxypropylmethyl cellulose (Fluka; Mat. No. 56340) is dissolved in nanopure water (20 g) with stirring using a magnetic stirrer at 800 rpm until a clear solution is generated. Subsequently, Rebamipide, potassium borate buffer (20 mM) and glycerol are added and stirring maintained at 800 rpm until homogenation is obtained. The pH of the solution is adjusted to 7.8 by addition of citric acid (1 M) and NaOH. After pH adjustment, the volume is adjusted with additional nanopure water to 100%. The product is a clear solution having a pH of 7.80 and an osmolality of 307 mθsm/kg.

Table 1

Example 2 A 0.1 % rebamipide solution having the ingredients of Table 2 is prepared by the procedure recited in Example 1. The product is a clear solution having a pH of 7.80 and an osmolality of 281 mθsm/kg.

Table 2

Example 3.

A placebo solution having the ingredients of Table 3 is prepared by the procedure recited in Example 1 except for the omission of rebamipide from the formulation process. The product is a clear solution having a pH of 7.80 and an osmolality of 285 mθsm/kg.

Table 3

Example 4

Solution sterilization by moisture heat:

A rebamipide solution, e.g., a solution such as those recited in Examples 1 and 2 or the placebo of Example 3, is filled into glass vials. The vials are sealed and subsequently sterilized by autoclaving at 121⁰C and 2 bar for 15 minutes.

Example 5

Solution sterilization by filtration: A rebamipide solution is filtered through either a Pall Acrodisc 32 mm filter with a poresize of 0.2 micrometers or a Millix GP Millipore Express PES membrane with also a poresize of 0.22 micrometer. The sterilization is conducted under aseptic conditions and under laminar flow.

Sterilization of solutions by the method of Example 4 and Example 5 provide sterile solutions which exhibit no difference regarding rebamipide concentration, formation of degradation products or gross appearance.

Certain preferred embodiments of the pharmaceutically acceptable solutions according to the present invention comprise or, preferably, consist essentially of the formulations of Table A. The pH of each formulation of Table A is adjusted with sodium hydroxide and citric acid and the pH for each formulation is tabulated in Table A. Each of the compositions of Table A remain clear for several days to weeks at room temperature after which minor flaking is observed. Compositions 3 and 4 of the Table A remain as clear solutions indefinitely at room temperature.

Tris is ThS(HYDROXYMETHYL)AMINOMETHANE

Example 6: Animal Model for ocular tolerability of formulation of Examples 1 and 2.

One animal test comprises a modified Draize test on three female New-Zealand albino rabbits wherein the ocular tolerability after a single dose instillation of 50 microlitres of compositions of the present invention on the outer superior part of the bulbar conjunctiva. The contralateral eye is used as non treated control. After installation of the formulation the eyelid is gently closed. Before the instillation, for the 15 first minutes, 1, 2 and 7 days after the instillation, ocular examinations are carried out. The tolerability is based on visual examination considering the following parameters: discomfort as judged by blinking or partial/complete closure of the eye, duration of discomfort, discharge, redness of conjunctiva (palpebral and bulbar conjunctiva), chemosis of conjunctiva (swelling), degree of opacity of cornea and area of cornea involved, and pathological influence upon iris.

The compositions of the invention (Examples 1 and 2) are found to be effective and well tolerated. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments and methods described herein. Such equivalents are intended to be encompassed by the scope of the following claims.

The entire contents of all patents, published patent applications and other references cited herein are hereby expressly incorporated herein in their entireties by reference.

Claims

1. A pharmaceutically acceptable solution comprising

(1) rebamipide;

(2) a viscosity enhancer;

(3) an isotonic agent; and

(4) a buffer, wherein the solution has a pH of between about 7.5 and about 9.

2. A pharmaceutically acceptable solution comprising

(1) rebamipide;

(2) a viscosity enhancer;

(3) an isotonic agent; and

(4) a buffer, wherein the solution has a chloride concentration of less than 0.5 mM.

3. The pharmaceutically acceptable solution of claim 1 or claim 2, wherein the concentration of rebamipide is between about 0.01% w/v and about 2.5 w/v.

4. The pharmaceutically acceptable solution of claim 1 or claim 2, wherein the concentration of rebamipide is between about 0.5% w/v and about 1.5 w/v.

5. The pharmaceutically acceptable solution of claim 1 or claim 2, wherein the concentration of rebamipide is about 1.0% w/v.

6. The pharmaceutically acceptable solution of claim 1 or claim 2, wherein the isotonic agent is a polyol.

7. The pharmaceutically acceptable solution of claim 1 or claim 2, wherein the isotonic agent is polyethylene glycol, glycerol, or propylene glycol.

8. The pharmaceutically acceptable solution of claim 1 or claim 2, wherein the buffer is selected from sodium borate, potassium borate, lithium borate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, dilithium hydrogen phosphate, calcium hydrogen phosphate, and mixtures thereof

9. The pharmaceutically acceptable solution of claim 8, wherein the buffer is selected from sodium borate and disodium hydrogen phosphate.

10. The pharmaceutically acceptable solution of claim 1 or claim 2, wherein the viscosity enhancer is a polymeric viscosity enhancer.

11. The pharmaceutically acceptable solution of claim 10, wherein the polymeric viscosity enhancer is selected from hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose (Na-CMC), polyvinylpyrrolidone, dextran 70, polyvinyl alcohols, polaxamers, and mixtures thereof.

12. The pharmaceutically acceptable solution of claim 11 , wherein the polymeric viscosity enhancer is selected from hydroxypropylmethylcellulose, PVA40-88, Polaxamer 407, and Povidone K17, K25, K29, K30, K32, K64 VA or K90.

13. The pharmaceutically acceptable solution of claim 11 , wherein the polymeric viscosity enhancer is a hydroxypropylmethylcellulose.

14. The pharmaceutically acceptable solution of claim 1 or claim 2, wherein the viscosity enhancer is a low molecular weight viscosity enhancer.

15. The pharmaceutically acceptable solution of claim 16, wherein the low molecular weight viscosity enhancer is selected from glycerol and sodium hyaluronate and mixtures thereof.

16. The pharmaceutically acceptable solution of claim 1 or claim 2, wherein the solution has a pH of between about 7.7 and about 8.3.

17. The pharmaceutically acceptable solution of claim 1 or claim 2, wherein the solution has a pH of between about 7.7 and about 8.

18. The pharmaceutically acceptable solution of claim 1 or claim 2, wherein the solution has a pH of about 7.8.

19. A pharmaceutically acceptable solution, comprising

(1) rebamipide;

(2) viscosity enhancer selected from hydroxypropylmethylcellulose, polyvinylpyrrolidone, sodium hyaluronate, hyaluronic acid, or a mixture thereof;

(3) glycerol; and

(4) a buffer selected from sodium borate or disodium phosphate, wherein the solution has a pH of between about 7.7 and about 8.3.

20. The pharmaceutically acceptable solution of claim 19, wherein the solution has a chloride concentration of less than about 0.5 mM.

21. A pharmaceutically acceptable solution, comprising

(1) rebamipide;

(3) glycerol; and

(4) a buffer selected from sodium borate or disodium phosphate, wherein the solution has a chloride concentration of less than about 0.5 mM.

22. The pharmaceutically acceptable solution of claim 21 , wherein the solution has a pH of between about 7.7 and about 8.3.

23. The pharmaceutically acceptable solution according to claim 1 or claim 2, further comprising a preservative.

24. The pharmaceutically acceptable solution of claim 23, wherein the preservative is selected from quaternary ammonium compounds, cetrimide and phenyl ethyl alcohol.

25. The pharmaceutically acceptable solution according to claim 1 or claim 2, further comprising an antioxidant.

26. The pharmaceutically acceptable solution of claim 25, wherein the preservative is selected from a natural or synthetic Vitamin E derivative.

27. The pharmaceutically acceptable solution of any one of claims 1-26, for topical application to the eye.

28. The pharmaceutically acceptable solution of claim 27, for use in treatment of patients suffering from or susceptible to inflammation of the eye and/or dry eye.

29. The pharmaceutically acceptable solution of any one of claims 1-26, for oral administration to a patient.

30. The pharmaceutically acceptable solution of claim 29, for use as an oral solution in the treatment of patients suffering from or susceptible to peptic ulcus.

31. Use of a composition according to any one of claims 1-26, in the preparation of a medicament for the treatment and/or prevention of human ocular diseases or disorders.

32. Use according to claim 31 , wherein the medicament is adapted to topical administration to the ocular surfaces of the eye of the patient for the treatment of dry eye.

33. Use according to claim 31 , wherein the medicament is adapted to topical administration to the ocular surfaces of the eye of the patient for the treatment of inflammatory diseases.

34. Use according to claim 33, wherein the inflammatory disease is selected from blepharitis, chronic blepharitis, seborrhoeic blepharitis or allergic blepharitis.