The present invention is directed to the use of substituted glycosides, particularly alkyl glucamides, to potentiate the efficacy of antimicrobial agents in ophthalmic formulations. Some of the alkyl glucamides are effective antimicrobial agents themselves.

Background of the Invention

U.S. Patent No. 5,369,095 discloses the use of the compounds of the present invention as mucous membrane penetration enhancers. An abstract for J 55102507-A discloses a fish preservative containing iodine, ethanol, and sucrose monolaurate. An abstract for J 49054524-A discloses a food preservative containing a sucrose-fatty acid ester and /or polyoxyethylenesorbitol-fatty acid ester and a monoglyceride of six to eight carbon atoms. EP 0422508 A2 discloses a liquid detergent useful for the skin and hair containing a nonionic saccharide surfactant, including a saccharide amide surfactant, and an antibacterial. A translation of Japanese Patent Application No. 2-409899 describes a cleanser composition containing a sugar based nonionic surfactant, including a sugar amide based surfactant, and an antiinflammatory. The composition is useful for the skin and hair. A translation of Japanese Patent Application No. 3-282925 describes a prophylactic for microbial infection. The active component is a phosphate substituted alkyl glucamide.

None of the above references disclose the use of alkyl glucamides to potentiate the antimicrobial activity of antimicrobial agents in ophthalmic formulations, nor do they disclose them as useful as antimicrobial agents.

Benzalkonium chloride (BAC), although commonly used and quite effective, has been found to be toxic to the cornea at high concentrations (>.05%); chlorobutanol cannot be formulated above pH 6, and chlorhexidine readily precipitates with anions commonly used in ophthalmic formulations. The

compounds of the present invention potentiate the efficacy of known antimicrobials allowing for their use at lower, less potentially toxic levels. The alkyl glucamides also produce significantly less corneal irritation than BAC; and they can be readily formulated in ophthalmic solutions at physiological pH.

Summary of the Invention

The alkyl glucamides are useful to potentiate the efficacy of antimicrobial agents used as preservatives or disinfectants in ophthalmic formulations, such as contact lens care solutions, ophthalmic pharmaceutical compositions, and comfort or rehydrating eye drop formulations. The invention is also directed to methods for preserving ophthalmic formulations and disinfecting contact lenses.

Detailed Description of the Preferred Embodiments

The substituted glycosides used in the present invention have the following structure:

(R ₂ ) _x -Z-R,

wherein R _x is a hydrophobic group including saturated and unsaturated aliphatic hydrocarbon groups which range from 8 to 28 carbons in length with 1 to 5 double bonds. The aliphatic hydrocarbon group can be a straight or branched chain and may be substituted by one or more aromatic, cycloaliphatic or hydrophilic (e.g. hydroxyl, thiol, ester or amino) groups.

1^ is a group derived from any cyclic or acyclic saccharide containing 4 - 7 carbons and their isomers;

X is an integer from 1-10; and

O O

II II

Z is an oxy (-0-), carbonyloxy (-0-C-), phosphoryl (-0-P-0-), thio (-S-), or O I

II o- carboxamido (-N-C-) where R ₂ is covalently bound to such group.

More specifically R, can be a straight 8-18 carbon alkyl chain in hemiacetal linkage (glycoside) to the saccharide; and

Ra a group derived from any of a variety of isomeric saccharides containing 5 or 6 carbons. The saccharide can be, for example, an aldehyde-containing saccharide (glucose, mannose, arabinose, galactose, xylose); a ketone-contair ng saccharide (fructose, xylulose, sorbose); a saccharide alcohol (sorbitol, inositol, xylitol, mannitol); a saccharide acid (glucuronic acid, neuramic acid, mannuronic acid); a deoxysaccharide (deoxy-ribose, rhamnose,); an aminosaccharide (glucosamine, galactosamine). Higher order saccharides being covalently linked in any of a number of ways to form different isomeric structures including for example, disaccharides such as maltose, cellobiose, sucrose, and lactose and trisaccharides, such as raffinose.

Preferred substituted glycosides are alkyl glucamides which have the following structure:

R ₃ -N(R ₂ )-C(=0)-R ₁

wherein R _t and Rj are as above defined and

R ₃ is hydrogen, thiol, hydroxyl, amino, amine, C _w alkyl, C]. ₆ alkoxy or alkyl sulfide.

The substituted glycosides are useful as disinfectants or preservatives in all types of ophthalmic formulations, such as contact lens care solutions and pharmaceutical formulations. The compounds are present in contact lens care formulations to potentiate the antimicrobial activity of a disinfectant or preservative at concentrations at or above about 0.01 weight/ volume percent (w/v%) to 10.0 w/v%; preferably 0.01-2 w/v%; most preferably 0.1-0.5 w/v%. The compounds are useful in other ophthalmic formulations to potentiate the preservative efficacy of, for example, benzalkonium chloride (BAC), at concentrations at or above about 0.01 w/v%; preferably 0.01-2 w/v%; most preferably 0.1-0.5 w/v%. When used to potentiate the efficacy of BAC, the BAC

concentration can be reduced to about 75% of its usual concentration in ophthalmic formulations.

The preferred alkyl glucamides include compounds wherein Rj is C ₁₀ , Rj is glucose, and R ₃ is methyl (Glucamide C-10) and wherein Rj is , Rj is glucose, and R ₃ is methyl (Glucamide C-9). Most preferred is Glucamide C-10. Glucamide C-10 is not only effective in potentiating the efficacy of BAC, but is useful alone as an ophthalmic preservative at concentrations of above 0.01 w/v%; preferably 0.05- 0.5 w/v%; most preferably 0.1-0.3 w/v%.

The compositions can include other components known to those skilled in the art of formulating ophthalmic products. The compounds of Structure I can be incorporated into various types of ophthalmic formulations for delivery to the eye. The compounds may be combined with ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, buffers, sodium chloride and water to form aqueous, sterile ophthalmic suspensions or solutions. In order to prepare sterile ophthalmic ointment formulations, the compounds are combined with the active ingredient and a preservative in an appropriate vehicle, such as, mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations may be prepared by suspending the active ingredient in a hydrophilic base prepared from the combination of, for example, carbopol-940 or the like according to the published formulations for analogous ophthalmic preparations; alkyl glucamides, preservatives, and tonicity agents can be incorporated. Ophthalmic solution formulations may be prepared by dissolving the active ingredient in a physiologically acceptable isotonic aqueous buffer. Further, the ophthalmic solution may include an ophthalmologically acceptable surfactant to assist in dissolving the active ingredient and preservatives to preserve the solution. Furthermore, the ophthalmic solution may contain a viscosity enhancing agent, such as, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethyl-cellulose, methylcellulose, polyvinylpyrrolidone, or the like to improve the retention of the medicament in the conjunctival sac or the comfort of a contact lens.

The following examples are representative of the type of ophthalmic formulations in which the substituted glycosides are useful. They are not meant to be limiting.

Active ingredients can be added to the following formulations to provide preserved ophthalmic solutions. Active ingredients can include any medicament useful for treating the eye included at concentrations and made according to techniques known to those skilled in the art of making ophthalmic formulations. Examples 2-4 can also be used without the addition of a medicament as contact lens care solutions for disinfecting, rinsing, and storage of contact lenses. Examples 4-7 can be used without a medicament as ophthalmic comfort drop formulations.

EXAMPLE 1

Component Concentration (w/v%)

Na ₂ HP0 ₄ 0.12

NaH ₂ P0 ₄ 0.18

NaCl 0.60

BAC 0.01

EDTA 0.01

Substituted Glycoside 0.20

Water qs

EXAMPLE 2

Component Concentration (w/v%)

Na ₂ HP0 ₄ 0.12

NaH ₂ P0 ₄ 0.18

Mannitol 3.31

Polyquad* 0.01

EDTA 0.01

Substituted Glycoside 0.05

Water qs

EXAMPLE 3

Component Concentration w/γ%

Na ₂ HP0 ₄ 0.12

NaH ₂ P0 ₄ 0.18

NaCl 0.60

Polyquad* 0.01

EDTA 0.01

Glucamide C-10 0.20

Water qs

EXAMPLE 4

Component Concentration w/v%

Na ₂ HP0 ₄ 0.12

KH ₂ P0 ₄ 0.18

Mannitol 3.31

Polyquad ^® 0.001

EDTA 0.01

Substituted Glycoside 0.20

Water qs

EXAMPLE 5

Component Concentration w/v%

Na ₂ HP0 ₄ 0.12

NaH ₂ P0 ₄ 0.18

Mannitol 3.31

BAC 0.01

EDTA 0.01

Glucamide C-10 0.20

Water qs

EXAMPLE 6

Component Concentration w/v%

Na ₂ HP0 ₄ 0.12

NaH ₂ P0 ₄ 0.18

Mannitol 3.31

BAC 0.0025

EDTA 0.01

Glucamide-9 0.20

Water qs

EXAMPLE 7

Component Concentration w/v%

NajHPO, 0.12

KH ₂ P0 ₄ 0.18

Mannitol 3.31

EDTA 0.01

Glucamide C-10 0.20

Water qs