WO2016196989A1

WO2016196989A1 - Topical composition

Info

Publication number: WO2016196989A1
Application number: PCT/US2016/035813
Authority: WO
Inventors: Jun Inoue; Takahiro Ogawa
Original assignee: Senju USA Inc
Current assignee: Senju USA Inc
Priority date: 2015-06-03
Filing date: 2016-06-03
Publication date: 2016-12-08
Anticipated expiration: 2017-12-03

Abstract

A topical composition comprising Vancomycin or a salt thereof, and squalane, wherein the composition has improved stability of Vancomycin or a salt thereof. A method of treating an infection of the eye, nose, ear or skin, by administration of a therapeutically effective amount of the topical composition to a patient in need thereof, wherein the administration provides improved comfort for the patient

Description

TOPICAL COMPOSITION

FIELD OF THE INVENTION

The present invention relates to a topical composition comprising Vancomycin or a salt thereof and squalane, a method of stabilizing Vancomycin or a salt thereof in a topical composition, and a method of treating an infection of the eye, nose, ear or skin by administration of the topical composition to a patient in need thereof.

BACKGROUND OF THE INVENTION

Squalane (Formula 1) is a structurally unique triterpene compound that is derived by hydrogenation of squalene. Squalane was so named because it was first isolated from shark (Squalus spp.) liver oil, which contains large quantities of squalane and is considered its richest source. Squalane is one of the main components (about 13%) of skin surface lipids, and is transported in serum, generally in association with very low density lipoproteins and is distributed ubiquitously in human tissues, with the greatest concentration in the skin. (See Document 1)

Formula 1. Chemical structure of Squalane

Vancomycin is an antibiotic classified as a glycopeptide antibiotic, and is primarily used for the treatment of serious infections caused by Gram-positive bacteria, such as Methicillin- resistant Staphylococcus aureus (MRSA) or multi -resistant Staphylococcus epidermidis (MRSE). Vancomycin has a water solubility of more than 5 mg/mL.

A Vancomycin topical solution is not commercially available because of its instability in aqueous solution. (See Document 2) A composition comprising Vancomycin or a salt thereof, in combination with squalane, is not known. Further, a method of treating an infection of the eye, nose, ear or skin by the administration of a composition comprising Vancomycin or a salt thereof and squalane to a patient in need thereof is not known.

Document 3 discloses an ophthalmic ointment for treating infective eye diseases, containing as an active ingredient from 0.01% to 5.0% of Vancomycin hydrochloride. However, the disclosure relates only to an ophthalmic ointment, with no teaching of a topical solution. Problems associated with ophthalmic ointments include difficulty in application to the eye by patients, and the lack of comfort for patients after dosing for several hours.

Ophthalmic ointments have limited use in the day-time treatment of keratoconjunctivitis sicca, since the diminished visual activity experienced after administration of an ointment limits its use to night-time administration. (See Document 4) The use of eye ointment is often accompanied by visual impairment for 10-15 minutes, and bulk application can cause lengthy blurred vision for up to several hours, resulting in decreased patient satisfaction and restriction of daily activities. (See Document 5)

Document 6 discloses Vancomycin hydrochloride as an active ingredient in peroral oil suspensions or in soft gelatin capsules. However, no disclosure is provided regarding a topical solution, a use thereof, or any specific composition comprising squalane and Vancomycin or a salt thereof. Document 7 discloses a topical, bactericidal composition comprising Vancomycin or Vancomycin HC1, and a method of using the composition for the treatment of MRSA in wounds. The composition comprises potassium sorbate at a concentration of about 0.2% wt/wt; dimethylol dimethylhydantoin (DMDM hydantoin) at a concentration of about 0.1% wt/wt; boric acid at a concentration of about 0.5% wt/wt; carboxymethylcellulose (CMC) at a concentration of about 0.1%) wt/wt; sodium/calcium alginate mixture at a concentration of about 0.5% wt/wt; a cross-linked polyacrylate polymer, such as Carbopol 940, at a concentration of about 0.5% wt/wt; propylene glycol at a concentration of about 10.0% wt/wt; triethanolamine at a concentration of about 0.5% wt/wt; a sufficient quantity of deionized water; and an antibiotic at an effective concentration to reduce the amount of microbial organisms which result in MRSA infection. However, no disclosure is provided regarding a topical solution, a use thereof, or any specific composition comprising squalane and Vancomycin or a salt thereof.

Document 8 describes anhydrous, stable pharmaceutical compositions of Vancomycin for topical use for the treatment of dermal infections. The composition comprises Vancomycin, in the form of the free base or a pharmaceutically acceptable salt, together with one or more glycols and/or ethers, such as diethylene glycol monomethyl ether, one or more fatty acid triglycerides and/or the polyoxyethylene derivatives, such as propylene glycol, and a gelling agent, such as carbopol. However, no disclosure is provided regarding a topical solution, a use thereof, or any specific compositions comprising squalane and Vancomycin or a salt thereof.

Document 9 describes a pharmaceutical anhydrous formulation for topical use comprising Vancomycin, Vancomycin Hydrochloride, or Teicoplanin, dimethyl sulfoxide, one or more glycols and/or ethers, such as propylene glycol, optionally one or more fatty acids triglycerides and/or the polyoxyethylene derivatives, such as diethylene glycol monoethyl ether. However, no disclosure is provided regarding a topical solution comprising squalane and Vancomycin or a salt thereof, or a use thereof.

Documents 10 and 11 disclose a topical ointment comprising Vancomycin for treating skin conditions caused by bacterial infections. The ointments include traditionally known ointment bases, such as liquid paraffin and white petrolatum. However, the disclosure relates only to an ointment, with no specific disclosure of a topical solution comprising Vancomycin or a salt thereof. In fact, the documents recognize the lack of topical formulations of Vancomycin, due to the instability thereof. Additionally, no disclosure is provided regarding a topical solution comprising Vancomycin or a salt thereof and squalane, or a use thereof.

Document 12 describes a topical spray preparation for burn treatment and microbial infections on humans or animals. The non-aerosol preparation contains an antimicrobial drug, i.e., silver sulfadiazine, dispersed or solubilized in a cream or lotion base matrix which can be sprayed directly from a common trigger spray device. However, no disclosure is provided regarding a composition comprising squalane and Vancomycin or a salt thereof.

Document 13 describes an ophthalmic solution comprising squalane, as a two-layer separation-type eye drop. However, no disclosure is provided regarding Vancomycin or a salt thereof, or a specific composition comprising squalane and Vancomycin or a salt thereof.

None of the compositions in the art, exemplified by the above disclosures, comprise Vancomycin or a salt thereof in combination with squalane. A solution comprising Vancomycin or a salt thereof, in combination with squalane, and optionally in the absence of water, is not known. A composition comprising Vancomycin or a salt thereof, in combination with squalane as the only solvent, is not known. A method of treating an ocular, nose, ear or skin infection by the administration of a topical composition comprising a therapeutically effective amount of Vancomycin or a salt thereof and squalane is not known.

Document 1 : Huang et al., Molecules, 2009, 14, 540-554

Document 2: Fuhrman et al., Am J Health Syst Pharm., 1998, 55(13), 1386-8

Document 3 : WO 01/000226

Document 4: Greaves et al., Br. J. Clin. Pharmac, 1993, 35, 188-192

Document 5: Hiraoka et al., Eye, 2012, 26, 1310-1317

Document 6: WO 96/006631

Document 7: US 2012/0128622

Document 8: WO 02/04012

Document 9: WO 2009/056547

Document 10: US 9,241,971

Document 1 1 : WO 2016/01 1424

Document 12: WO 98/51273

Document 13 : WO 2014/148450

OBJECT OF THE INVENTION

An object of the invention is to provide a topical composition comprising Vancomycin or a salt thereof, and squalane, wherein the composition has improved stability of Vancomycin or a salt thereof. Another object of the invention is to provide a topical composition comprising Vancomycin or a salt thereof, and squalane, wherein the composition has improved comfort for the patient. Another object of the invention is to provide a method of using the topical composition described above for treatment of an infection of the eye, nose, ear or skin in a patient in need thereof.

DISCLOSURE OF THE INVENTION

The present inventors have studied topical compositions comprising Vancomycin or a salt thereof and squalane. The present inventors have discovered that the stability of Vancomycin or a salt thereof is improved in a solution comprising squalane. The present inventors have further discovered methods of using the topical compositions comprising Vancomycin or a salt thereof and squalane to treat an infection of the eye, nose, ear or skin, wherein the patient has improved comfort.

The present invention provides:

(1) A topical composition comprising Vancomycin or a salt thereof and a solvent.

(2) The topical composition according to the above (1), wherein the

concentration of Vancomycin or a salt thereof may be about 0.01 to 10 (w/v) %, about 0.1 to 8 (w/v) %, about 0.5 to 5 (w/v) %, or about 1 to 3 (w/v) %, wherein (w/v) % represents the fraction of the weight of Vancomycin or a salt thereof (g) to the volume of the solvent (mL).

(3) The topical composition according to the above (1) or (2), wherein the

solvent is squalane.

(4) The topical composition according to any of the above (1) to (3), which is

free of water.

(5) The topical composition according to any of the above (1) to (4), which is free of preservatives.

(6) The topical composition according to any of the above (1) to (5), further comprising mineral oil.

(7) The topical composition according to any of the above (1) to (6), further comprising carboxy vinyl polymer.

(8) The topical composition according to any of the above (1) to (7), which is an ophthalmic solution.

(9) The topical composition according to any of the above (1) to (7), which is an ear drop solution.

(10) The topical composition according to any of the above (1) to (7), which is a collunarium.

(11) The topical composition according to the above (10), wherein the collunarium is a nasal spray.

(12) The topical composition according to any of the above (1) to (7), which is a liquid or solution for cutaneous application.

(13) The topical composition according to the above (12), which is packaged in a spray-type device.

(14) The topical composition according to the above (13), wherein the spray-type device is a finger sprayer.

(15) The topical composition according to any of the above (1) to (14), further comprising one or more additional antibiotics.

(16) The topical composition according to the above (15), wherein the one or more additional antibiotic is at least one selected from beta-Lactams (penicillin, cefem, carbapenem, cephalosporin), aminoglycosides, tetracyclines, macrolides, ketolides, polyene macrolides, new quinolones, Oxazolidinone, and chloramphenicol.

(17) The topical composition according to the above (16), wherein the one or more additional antibiotic is at least one selected from aminoglycosides and new quinolones.

(18) The topical composition according to the above (17), wherein the one or more additional antibiotics is at least one selected from gentamycin, tobramycin, gatifloxacin, moxifloxacin, levofloxacin ofloxacin, norfloxacin, lomefloxacin, ciprofloxacin, cinoxacin, sparfloxacin, tosufloxacin, nalidixic acid, fleroxacin, and salts thereof.

(19) A method of treating an infection of the eye, nose, ear or skin comprising topically administering a therapeutically effective amount of the topical composition according to any of the above (1) to (18) to the eye, nose, ear or skin of a patient in need thereof.

(20) A method of improving the stability of Vancomycin or a salt thereof in solution, comprising adding squalane to Vancomycin or the salt thereof.

(21) A method of forming a stable solution of Vancomycin or a salt thereof, by combining Vancomycin or a salt thereof with squalane.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the stability of Vancomycin in squalane at room temperature. Figure 2 shows the stability of Vancomycin in squalane at 60°C. Figure 3 shows the in vivo efficacy of a formulation comprising Vancomycin in squalane.

Figure 4 shows the effect on the degree of corneal opacity by a formulation comprising Vancomycin in squalane.

Figure 5 shows the effect on the area of corneal opacity by a formulation comprising Vancomycin in squalane.

Figure 6 shows the effect on the chemosis by a formulation comprising Vancomycin in squalane.

Figure 7 shows the effect on the conjunctival injection by a formulation comprising Vancomycin in squalane.

Figure 8 shows the effect on discharge by a formulation comprising Vancomycin in squalane.

DETAILED DESCRIPTION OF THE INVENTION

The topical compositions comprise Vancomycin or a salt thereof and a solvent, wherein the solvent may be squalane. The compositions are topically administrable therapeutic compositions for treatment of infections of the eye, nose, ear or skin. Further, the compositions have improved stability and provide improved comfort.

Vancomycin or a salt thereof includes Vancomycin in free base form, or any pharmaceutically acceptable salt thereof. Examples of the pharmaceutically acceptable salt include, but are not limited to, inorganic acid salts including hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and borate; sulfonates including methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and camphorsulfonate; organic carboxylates including formate, acetate, propionate, oxalate, hydroxyacetate, citrate, tartrate, succinate, maleate, benzoate, salicylate, fumarate, and phthalate. In certain aspects, the pharmaceutically acceptable salt may be hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, oxalate, or tartrate. In specific aspects, the pharmaceutically acceptable salt may be hydrochloride, hydrobromide, sulfate, methanesulfonate, or p-toluenesulfonate. In a selected aspect, the pharmaceutically acceptable salt may be hydrochloride.

The topical composition comprises Vancomycin or a salt thereof, and a solvent. The Vancomycin or a salt thereof may be present in the topical composition in a concentration of about 0.01 to 10 (w/v) %. In certain aspects, the concentration of Vancomycin or a salt thereof may be about 0.1 to 8 (w/v) %, about 0.5 to 5 (w/v) %, or about 1 to 3 (w/v) %. In specific aspects, the concentration of Vancomycin or a salt thereof may be about 0.01, 0.05, 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5 or 10 (w/v) %. In a selected aspect, the concentration of Vancomycin or a salt thereof may be about 0.5 to 3 (w/v) %. (W/v) % represents the fraction of the weight of Vancomycin or a salt thereof (g) to the volume of the solvent (mL).

The solvent comprises squalane, which may be present in a concentration of about 50 to 100 (v/v) %. In certain aspects, the concentration of squalane may be about 60 to 90 (v/v) %, about 70 to 80 (v/v) %, or about 75 to 85 (v/v) %, of the solvent. In specific aspects, the concentration of squalane may be about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100 (v/v) %, of the solvent.

The solvent optionally includes mineral oil, which may be present in a concentration of about 0 to about 50 (v/v) %. In certain aspects, the concentration of mineral oil may be about 10 to 40 (v/v) %, about 20 to 30 (v/v) %, or about 15 to 25 (v/v) %, of the solvent. In specific aspects, the concentration of mineral oil may be about 50, 45, 40, 35, 30, 25, 20, 15, 10, 5, or 0 (v/v) %, of the solvent.

The topical composition may further comprise one or more known pharmaceutically acceptable additives, thickening agents including but not limited to carboxy vinyl polymer, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, and salts thereof, carriers, excipients or diluents, unless the incorporation thereof would adversely affect the intended purpose of the present invention.

The topical composition may be free of water. The topical composition may be free of preservatives, such as surfactants. The topical composition may also be free of dimethylsulfoxide.

A non-limiting embodiment of the invention is a composition consisting of Vancomycin or a salt thereof, squalane, and optionally mineral oil.

The topical composition may be provided in any pharmaceutical dosage form that is conventionally used as a topical preparation, including but not limited to an ophthalmic solution, an ear drop solution, a collunarium, a nasal spray, and a solution for cutaneous application. The topical composition may be formulated in accordance with methods known in the art, including, but not limited to, those described in the United States Pharmacopeia.

The term solution, as used herein, encompasses solutions, suspensions and emulsions.

The topical composition may comprise one or more additional antibiotics, in addition to Vancomycin or a salt thereof. The one or more additional antibiotic is at least one selected from beta-Lactams, including penicillin, cefem, carbapenem, and cephalosporin, aminoglycosides, tetracyclines, macrolides, ketolides, polyene macrolides, new quinolones, and chloramphenicol, including gentamycin, tobramycin, gatifloxacin, moxifloxacin, levofloxacin ofloxacin, norfloxacin, lomefloxacin, ciprofloxacin, cinoxacin, sparfloxacin, tosufloxacin, nalidixic acid, fleroxacin, and salts thereof.

Unless the intended purpose of use is adversely affected, the topical composition may contain or may be used together with other appropriate pharmacologically effective substances, for example, steroidal anti-inflammatory agents (dexamethasone, prednisolone and the like), non-steroidal anti-inflammatory agents (diclofenac sodium, pranoprofen and the like), antiallergic agents (tranilast, ketotifen fumarate, sodium cromoglicate and the like), antihistamic agents (diphenhydramine hydrochloride and the like), glaucoma-treating agents (pilocarpine hydrochloride, physostigmine salicylate, timolol, isopropylunoprostone and the like), antibiotics (gentamycin sulfate, fradiomycin sulfate, tobramycin, sulbenicillin, cefmenoxime, erythromycin, colistin, oxytetracycline, polymyxin B, chloramphenicol, micronomicin, arbecacin, dibekacin, sisomicin and the like), antibacterial agents (sulfamethizole, sulfamethoxazole, ofloxacin, norfloxacin, lomefloxacin hydrochloride, enoxacin, ciprofloxacin hydrochloride, cinoxacin, sparfloxacin, tosufloxacin tosylate, nalidixic acid, pipemidic acid trihydrate, pipemidic acid, fleroxacin, levofloxacin and the like), antiviral agents (idoxuridine, acyclovir and the like), antimycotic agents (pimaricin, fluconazole, miconazole, amphotericin B, flucytosine, itraconazole and the like), and anti VEGF antibodies (Pegaptanib and the like).

The present invention encompasses a method of treating an infection of the eye, nose, ear or skin, comprising topically administering a therapeutically effective amount of the topical composition of the present invention, to the eye, nose, ear or skin of a patient in need thereof. The present invention also encompasses a method of improving the stability of Vancomycin or a salt thereof in solution, or of forming a stable solution of Vancomycin or a salt thereof, comprising adding squalane to the Vancomycin or the salt thereof.

The topical composition may be administered to a mammal, including a human, rabbit, dog, cat, cattle, horse or monkey, which is or may be suffering from an infectious disease. Examples of the infectious disease include but are not limited to ear infections including otitis externa and otitis media, eye infections including conjunctivitis, bacterial keratitis, corneal ulcers and blepharitis, nose infections, skin infections including impetigo, ecthyma, Staphyl involvcoccal scalded skin syndrome (SSSS), erysipelas, cellulitis, abscess, necrotizing fasciitis, folliculitis, furunculosis„ carbunculosis and secondary skin infections, sinusitis, as well as symptoms resulting from infection, including but not limited to phlegmon.

The administration route and the dose may vary depending on a symptom, age and body weight of a subject. The Vancomycin or a salt thereof, provided in a concentration as previously disclosed, is contained in a formulation for administration to the subject in need thereof. The formulation may be topically administered to the eye, nose, ear or skin, 1, 2, 3, 4, 5, 6, 7 or 8 times per day, in a single dose which comprises 1 2, 3, 4 or 5 drops, or as necessary.

The present invention is further illustrated in detail by the following Experimental Examples. The Experimental Examples are merely illustrative, and are not intended to limit the scope of the present invention.

EXPERIMENTAL EXAMPLE 1

A Study of Vancomycin Stability Method

Suspensions of Vancomycin hydrochloride in squalane were prepared in the following manner. 5 mg of Vancomycin hydrochloride was added to 5 mL of squalane (Vancomycin Ophthalmic Suspension 2% in Squalane) (SQ) or 5 mM KH₂P0₄ buffer (pH 3.2) (Control), and stored at room temperature or 60°C. The contents of Vancomycin hydrochloride were analyzed by UPLC (using: a gradient 5% acetonitrile in 5 mM KH₂P0₄ (pH 3.2) to 20% acetonitrile in 5 mM KH₂P0₄ (pH 3.2) for 6 min, performed at 35 °C, with the flow rate of 0.6 mL/min, at 230 nm wavelength and 5 μΙ_, injection volume, on Supelco Titan CI 8 1.9 μτη, 2.1 X 10 cm column.)

Results and Discussion

As shown in Figure 1, Vancomycin hydrochloride was stable in squalane for 8 weeks at room temperature. The remaining % of Vancomycin hydrochloride in the pH 3.2 buffer was lower, at about 90%.

As shown in Figure 2, about 80% of Vancomycin hydrochloride was remaining after 8 weeks at 60 °C in squalane, but 50% of Vancomycin hydrochloride was decomposed in pH 3.2 buffer after 2 weeks.

These results demonstrate that the compositions comprising Vancomycin hydrochloride and squalane had unexpectedly superior stability at room temperature and at 60 °C, when compared to the control buffer solution.

EXPERFMENTAL EXAMPLE 2

In vivo efficacy on rabbit cornea infection model Method

Inoculation of MRS A on the rabbit cornea

The eyes of eighteen Japanese white rabbits (weighing between 1.5 and 2.0 kg) were anesthetized by administration of Oxybuprocaine hydrochloride (0.4 w/v %, Nitto Medic Co., Ltd, Toyama, Japan) eye drops. Each eye was held steady with clamping forceps, 30 μΐ_^ of MRS A (5 X 10⁷ CFU/mL) was instilled, and the cornea surface was punctured with the edge of 24G needle at 16 points along cornea limbus. Upon removal of the clamping forceps, and again 5 minutes after removal of the clamping forceps, 30 μΐ_^ of MRSA was instilled and the eyelid was forced closed two times.

Treatment schedule

30 minutes after the final application of MRSA solution, one eye of each rabbit was topically treated with three single drops of either Vancomycin Ophthalmic Ointment 1% (Toa Pharmaceutical Co., Ltd, Toyama, Japan) (Ointment) or Vancomycin Ophthalmic Suspension 2% in Squalane (same formulation as in Experimental Example 1) (SQ). The topical treatment was thereafter performed at 4 hour intervals for 2 days. The contralateral eyes were treated with phosphate-buffered Saline (PBS), to serve as the control.

Examination and scoring of the eyes

The eyes of the test rabbits were examined by slit-lamp biomicroscopy at 0 hours (before infection) and 8, 24, 32, 48 hours post infection. Five parameters which are symptoms of infection of the eye (degree of corneal opacity, area of corneal opacity, chemosis, conjunctival injection, and discharge) were assessed to determine the severity of infection. Each parameter was scored from 0 (normal) to 4 (maximal severity) for each eye of the rabbit, based upon the scale provided below.

Degree of Corneal Opacity

0=Normal cornea. Cornea appears with a slit lamp as having a bright grey line on the epithelial surface and a bright grey line on the endothelial surface, with a marble-like grey appearance of the stroma.

1 = Some loss of transparency. Only the anterior half of the stroma is involved as observed with an optical section of a slit lamp. The underlying structures are clearly visible with diffuse illumination, although some cloudiness is apparent with diffuse illumination.

2=Moderate loss of transparency. In addition to involving the anterior stroma, the cloudiness extends to the endothelium. The stroma does not have a marble-like appearance and is homogeneously white. With diffuse illumination, underlying structures are clearly visible.

3 = Involvement of the entire thickness of the stroma. With optical section, the endothelial surface is still visible. However, with diffuse illumination, the underlying structures are barely visible (to the extent the observer is still able to grade flare, iritis, and note lenticular changes).

4 = Involvement on the entire thickness of the stroma. With the optical section, the endothelium cannot be clearly visualized. With diffuse illumination, the underlying structures cannot be seen. Cloudiness removes the capability for judging and grading aqueous flare, iritis, and lenticular changes. The posterior margin of the cornea can be seen, but cannot score by slit lamp examination. Area of corneal opacity

0 =Normal cornea with no area of cloudiness

1 = 1% to 25% area of stromal cloudiness

2 =26%) to 50% area of stromal cloudiness

3 = 51%) to 75%) area of stromal cloudiness

4 = 76%o to 100%) area of stromal cloudiness

Chemosis

0 =Normal or no swelling of the conjunctival tissue

0.5 = Tendency of slight edema

1 = Swelling above normal without eversion of the lids (ascertainable by noting that the upper and lower eyelids are positioned as in the normal eye). Swelling generally starts in the lower cul-de-sac near the inner canthus.

2 = Swelling with misalignment of the normal approximation of the upper and lower eyelids; primarily confined to the upper eyelid so in the initial stages the misapproximation of the eyelids begins by partial eversion of the upper eyelid. In this stage, swelling is confined generally to the upper eyelid, although it exists in the lower cul-de-sac (observed best with a slit lamp).

3 = Swelling definite with partial eversion of the upper and lower eyelids which is essentially equivalent. This can be ascertained by looking at the patient head-on and noticing the positioning of the eyelids; if the eye margins do not meet, eversion has occurred.

4 = Eversion of the upper eyelid is pronounced with less pronounced eversion of the lower eyelid. It is difficult to retract the lids and observe the perilimbal region. Conjunctival Injection

0=Normal. May appear blanched to reddish pink without perilimbal injection (except at 12 and 6 o'clock positions) with vessels of the palpebral and bulbar conjunctiva easily observed.

1 = A flushed reddish color predominantly confined to the palpebral conjunctiva with some perilimbal injection but primarily confined to the lower and upper parts of the eye from the 4 and 7 and 11 and 1 o'clock positions.

2 = Bright red color of the palpebral conjunctiva with accompanying perilimbal injection covering at least 75% of the circumference of the perilimbal region.

3 =More diffuse, deeper crimson red, individual vessels not easily discernible.

4=Dark, beefy red color with congestion of both the bulbar and the palpebral conjunctiva along with pronounced perilimbal injection and the presence of petechia on the conjunctiva. The petechiae generally predominate along the nictitating membrane and the upper palpebral conjunctiva.

Discharge

0=Normal. No discharge present.

1 =Discharge is above normal and present on the inner portion of the eye but not on the lids or hairs of the eyelids. One can ignore the small amount that is in the inner canthus if it has not been removed before the study began.

2=Discharge is abundant, easily observed, and has collected on the lids and around the hairs of the eyelids.

3 =Discharge has been flowing over the eyelids and has wet the hairs substantially on the skin around the eyes.

The results of the five parameters are shown in Figures 4 - 8.

Figure 4 demonstrates the results of the degree of corneal opacity.

Figure 5 demonstrates the results of the area of corneal opacity.

Figure 6 demonstrates the results of the chemosis, which assesses the edema of the conjunctiva of the eye.

Figure 7 demonstrates the results of the conjunctival injection, which assesses the redness of the eyes due to dilation of the conjunctival vessels overlying the sclera.

Figure 8 demonstrates the results of the discharge.

The 5 scores for each eye were added to give a total score, the results of which are shown in Figure 3.

Results and Discussion

As shown in Figure 3, the clinical score of PBS increased post infection and reached maximum at 24 hours post infection and maintained for 48 hours. Both the Vancomycin suspension 2% and the Vancomycin ointment 1% suppressed infectious symptom of eye significantly when compared to the control. There was no significant difference between the ointment and the suspension.

These results demonstrate that the Vancomycin suspension is as effective as the Vancomycin ointment. This is unexpected, and advantageous, in view of the problems associated with ophthalmic ointments, including difficulty in application, lack of comfort, limited day-time use, visual impairment, blurred vision, and decreased patient satisfaction.

Claims

1. A topical composition comprising Vancomycin or a salt thereof and a solvent.

2. The topical composition according to claim 1, wherein the concentration of Vancomycin or a salt thereof is about 0.01 to 10 w/v %.

3. The topical composition according to claim 1 or 2, wherein the concentration of Vancomycin or a salt thereof is about 0.5 to 3 (w/v) %.

4. The topical composition according to any of claims 1 to 3, wherein the solvent is squalane.

5. The topical composition according to any of claims 1 to 4, which is free of water.

6. The topical composition according to any of claims 1 to 5, which is free of preservatives.

7. The topical composition according to any of claims 1 to 6, further comprising mineral oil.

8. The topical composition according to any of claims 1 to 7, further comprising carboxy vinyl polymer.

9. The topical composition according to any of claims 1 to 8, which is an ophthalmic solution.

10. The topical composition according to any of claims 1 to 8, which is an ear drop solution.

11. The topical composition according to any of claims 1 to 8, which is a collunarium.

12. The topical composition according to claim 11, wherein the collunarium is a nasal spray.

13. The topical composition according to any of claims 1 to 8, which is a liquid or solution for cutaneous application.

14. The topical composition according to claim 13, which is packaged in a spray-type device.

15. The topical composition according to claim 14, wherein the spray-type device is a finger sprayer.

16. The topical composition according to any of claims 1 to 15, further comprising one or more additional antibiotics.

17. The topical composition according to claim 16, wherein the one or more additional antibiotic is at least one selected from beta-Lactams (penicillin, cefem, carbapenem, cephalosporin), aminoglycosides, tetracyclines, macrolides, ketolides, polyene macrolides, new quinolones, and chloramphenicol.

18. The topical composition according to claim 17, wherein the one or more additional antibiotic is at least one selected from aminoglycosides and new quinolones.

19. The topical composition according to claim 18, wherein the one or more additional antibiotics is at least one selected from gentamycin, tobramycin, gatifloxacin, moxifloxacin, levofloxacin ofloxacin, norfloxacin, lomefloxacin, ciprofloxacin, cinoxacin, sparfloxacin, tosufloxacin, nalidixic acid, fleroxacin, and salts thereof.

20. A method of treating an infection of the eye, comprising topically administering a therapeutically effective amount of the topical composition according to any of claims 1-9 and 16-19 to the eye of a patient in need thereof.

21. A method of treating an infection of the nose, comprising topically administering a therapeutically effective amount of the topical composition according to any of claims 1-8, 11, 12 and 16-19 to the nose of a patient in need thereof.

22. A method of treating an infection of the ear comprising topically administering a therapeutically effective amount of the topical composition according to any of claims 1-8, 10 and 16-19 to the ear of a patient in need thereof.

23. A method of treating an infection of the skin comprising topically administering a therapeutically effective amount of the topical composition according to any of claims 1-8 and 13-19 to the skin of a patient in need thereof.

24. A method of improving the stability of Vancomycin or a salt thereof in solution, comprising adding squalane to Vancomycin or the salt thereof.

25. A method of forming a stable solution of Vancomycin or a salt thereof, comprising combining Vancomycin or a salt thereof with squalane.