Ophthalmic and contact lens solutions containing simple saccharides as preservative enhancers

Abstract

The present invention relates to an ophthalmic solution comprising 0.00001 to 10.0 weight percent of a simple saccharide, at least 0.00001 weight percent of a preservative, and not more than about 0.2 percent by weight chloride. The simple saccharide is chosen from the group consisting of: inositol; mannitol; sorbitol; sucrose; dextrose; glycerin; propylene glycol; ribose; triose; tetrose; erythrose; threose; pentose; arabinose; ribulose; xylose; xylulose; lyxose; hexose; allose; altrose; fructose; galactose; glucose; gulose; idose; mannose; sorbose; talose; tagatose; adlose; ketose; heptose; sedoheptulose; monosaccharides; disaccharides; sugar alcohols; xylitol; and polyol.

Claims

1. A method for providing an ophthalmic solution comprising: contacting an eye with a single-part solution comprising 0.00001 to 10.0 weight percent of a simple saccharide that is a tetrose; at least 0.00001 weight percent of a preservative with a structure given by: ##STR00004## wherein n is a number between 1 and 500 and Z is a divalent bridging group; and wherein the concentration of chloride in said solution is not more than 0.2 percent by weight.

2. The method as recited in claim 1, wherein the concentration of the preservative is between 0.1 and 100 parts per million.

3. The method as recited in claim 2, wherein the preservative is polyhexamethylene biguanide.

4. The method as recited in claim 1, wherein the single-part solution further comprises a physiologically compatible buffer.

5. The method as recited in claim 4, wherein the physiologically compatible buffer is selected from a group consisting of: phosphate, bicarbonate, citrate, borate, ACES, acetate, BES, BICINE, BIS, BIS-Iris, BIS-Iris Propane, bicarbonate, histidine, HEPES, Iris, HEPPS, imidazole, MES, MOPS, PIPES, TAPS, TES, glycine, tromethamine, and Tricine.

6. The method as recited in claim 1, wherein the single-part solution further comprises a wetting agent.

7. The method as recited in claim 6, wherein the wetting agent is selected from a group consisting of: polysorbate surfactants, polyoxyethylene surfactants, polyethoxylated glycerides, phosphonates, saponins and polyethoxylated castor oils.

8. The method as recited in claim 1, wherein the single-part solution further comprises a sequestering agent.

9. The method as recited in claim 8, wherein the sequestering agent selected from a group consisting of: ethylenediaminetetraacetic acid, phosphonates, citrate, gluconate, nitrilotriacetic acid, diethylenetriamine pentaacetic acid, hydroxyethylethylenediaminetiacetic acid, 1,2-diaminocyclohexanetetraacetic acid, ethylene glycol bis (beta-aminoethyl ether), tetraacetic acid (EGTA), aminodiacetic acid, hydroxyethylamino diacetic acid, tartarate, and water-soluble salts thereof.

10. The method as recited in claim 1, wherein the simple saccharide is a tetrose.

11. The method as recited in claim 1, wherein the simple saccharide is erythrose or threose.

12. A method for providing an ophthalmic solution comprising: contacting an eye with a single-part solution comprising 0.00001 to 10.0 weight percent of a simple saccharide that is a pentose; at least 0.00001 weight percent of a preservative with a structure given by: ##STR00005## wherein n is a number between 1 and 500 and Z is a divalent bridging group; and wherein the concentration of chloride in said solution is not more than 0.2 percent by weight.

13. The method as recited in claim 12, wherein the simple saccharide is a pentose.

14. The method as recited in claim 12, wherein the simple saccharide is arabinose, ribulose, xylose, xylulose, lyxose or xylitol.

15. A method for providing an ophthalmic solution comprising: contacting an eye with a single-part solution comprising 0.00001 to 10.0 weight percent of a simple saccharide that is a hextose; at least 0.00001 weight percent of a preservative with a structure given by: ##STR00006## wherein n is a number between 1 and 500 and Z is a divalent bridging group; and wherein the concentration of chloride in said solution is not more than 0.2 percent by weight.

16. The method as recited in claim 15, wherein the simple saccharide is a ketose.

17. The method as recited in claim 15, wherein the simple saccharide is a hextose.

18. The method as recited in claim 15, wherein the simple saccharide is inositol, ribose, allose, altrose, fructose, galactose, glucose, gulose, idose, mannose, sorbose, talose or tagatose.

Description

EXAMPLE 1

(1) An example of a formulation containing low salt, a buffer and cationic preservative follows:

(2) TABLE-US-00001 Preservative Log Reduction Buffer Preservative Enhancer Wetting Agent 2.27 none PHMB None None 0.0001% 3.85 Bis-Tris PRMB None CREMOPHORRH 40 Propane 0.2% 0.0001% 4.00 Bis-Tris PHMB propylene CREMOPHORRH 40 Propane 0.2% 0.0001% glycol 3% 4.40 Bis-Tris PHMB sorbitol 5% CREMOPHORRH 40 Propane 0.2% 0.0001% 4.40 Bis-Tris PHMB inositol 5% CREMOPHORRH 40 Propane 0.2% 0.0001% 2.98 OPTI-FREE Express 0.68 Ciba SOLO- CARE 2.99 B&L RENU MULTIPLUS MPS

(3) Column 1 shows the reduction of C. albicans at 2 hours using a typical antibacterial test. The data shows improved activity over the preservative alone; improved activity over the buffer control without sugar additive and improved activity over commercially available products

EXAMPLE 2

(4) Data Table

(5) TABLE-US-00002 Log Reduction Buffer Preservative Additive 2.53 None PHMB 0.0001% none 1.34 Bis-Tris Propane 0.2% PHMB 0.0001% sodium chloride 0.5% 3.42 Bis-Tris Propane 0.2% PHMB 0.0001% glycerin 0.5% 2.73 Bis-Tris Propane 0.2% PHMB 0.0001% propylene glycol 05% 1.13 Bis-Tris Propane 0.2% PHMB 0.0001% potassium chloride 0.5% 3.92 Bis-Tris Propane 0.2% PHMB 0.0001% sorbitol 0.5% 3.23 Bis-Tris Propane 0.2% PHMB 0.0001% mannitol 0.5% 3.06 Bis-Tris Propane 0.2% PHMB 0.0001% inositol 0.5% 3.72 Bis-Tris Propane 0.2% PHMB 0.0001% dextrose 0.5%

(6) This data shows that the antimicrobial activity of buffer with the sugar or glycol is greater than the preservative alone and that decreased activity at 0.5% sodium chloride or 0.5% potassium chloride solutions occurs as well. Thus the surprising effect of the sugar derived preservative enhancers is displayed and the effects relationship to chloride concentration is demonstrated.

EXAMPLE 3

(7) Solutions with a cationic polymeric preservative (PHMB) sodium chloride and glycerin and a buffer were made as shown in the following table and the preservative efficacy was measured.

(8) TABLE-US-00003 Log Re- Sodium Glyc- duction Buffer Preservative Chloride erin 1.69 none PHMB 0.0001% none none 1.74 none PHMB 0.0001% 0.1% none 1.46 none PHMB 0.0001% 0.2% none 0.86 none PHMB 0.0001% 0.4% none 0.49 none PHMB 0.0001% 0.5% none 2.44 Bis-Tris Propane 0.2% PHMB 0.0001% none none 1.89 Bis-Tris Propane 0.2% PHMB 0.0001% 0.1% none 1.54 Bis-Tris Propane 0.2% PHMB 0.0001% 0.2% none 0.98 Bis-Tris Propane 0.2% PHMB 0.0001% 0.4% none 0.89 Bis-Tris Propane 0.2% PHMB 0.0001% 0.5% none 2.46 Bis-Tris Propane 0.2% PHMB 0.0001% none 0.20% 2.41 Bis-Tris Propane 0.2% PHMB 0.0001% none 0.50%

(9) The above date illustrates the effect of sodium chloride on preservative efficacy and the effect of glycerin in improving preservative efficacy in low salt solutions.

EXAMPLE 4

(10) Solutions were made according to methods described supra with sodium phosphate as the buffer.

(11) TABLE-US-00004 Log Reduction Buffer Preservative Tonicity Agent 0.79 Sodium Phosphate 0.2% PHMB 0.0001% none 0.33 Sodium Phosphate 0.2% PHMB 0.0001% Sodium Chloride 0.7%

(12) This data illustrates the problem with sodium chloride is independent of buffer type.

EXAMPLE 5

(13) Solutions were formulated with sodium chloride, sorbitol and sucrose and then lenses were immersed in the resultant solutions and chlorohexidine gluconate was added. The lenses were exposed for 3 hours and the amount of the chlorohexidine deposited on the lens was measured.

(14) Method: HPLC analysis for chlorhexidine gluconate

(15) 3.0 mL solution exposed to lens
Matrix: 1 ppm CHG/0.2% Bi-Tris Propane/0.1% CREMOPHOR RH 40
Lens: Freshlook ColorBlends (45% phemfilcon A, 55% water) Wesley Jess

(16) TABLE-US-00005 Additive g CHG per lens % Decrease None 4.0 67.3% Sodium Chloride 3.6 59.3% Sorbitol 3.0 50.7% Sucrose 1.3 21.4%

(17) This test shows that the sugars used in the test have an ability to decrease the extent of preservative binding for of cationic preservatives when properly formulated. Both sorbitol and sucrose solutions demonstrated efficacy in reducing preservative deposition.

EXAMPLE 6

(18) The following experiment demonstrates the effect of chloride concentration on the antimicrobial effectiveness of PHMB preservative solutions.

(19) TABLE-US-00006 Log Ad- Reduction Buffer Preservative NaCI ditive Effect 1.05 Bis-Tris 0.2% PHMB 0.0001% None none 54% 1.47 Bis-Tris 0.2% PHMB 0.0001% None None 75% 0.77 Bis-Tris 0.2% PHMB 0.0001% 0.70% None 39% 2.36 Bis-Tris PHMB 0.0001% None None 123% Propane 0.2% 2.32 Bis-Tris PHMB 0.0001% None None 119% Propane 0.2% 0.91 Bis-Tris PHMB 0.0001% 0.70% None 47% Propane 0.2% 1.27 Tricine 0.2% PHMB 0.0001% None None 65% 1.31 Tricine 0.2% PHMB 0.0001% None None 67% 0.62 Tricine 0.2% PHMB 0.0001% 0.70% none 32%

EXAMPLE 7

(20) Formulations containing inositol (Spectrum) were prepared in a 0.2% phosphate buffer. The solutions were made isotonic with sodium chloride and preserved with polyhexamethylene biquanide at 0.0001%. The pH was adjusted to 7.2 with either 1 N sodium hydroxide or 1 N hydrochloric acid. The in vitro microbicidal activity of the solutions was determined by exposing C. albicans to 10 ml of each solution at room temperature for 4 hours. Subsequently, an aliquot of each solution was serial diluted onto agar plates and incubated for 48 hours at elevated temperatures. At the conclusion of the incubation period the plates are examined for the development of colonies. The log reduction was determined based on a comparison to the inoculum control. The following table provides the results of the in vitro studies.

(21) TABLE-US-00007 Additive 4 hour log reduction Inositol (0.5%) 1.1 Buffer control 0.8

(22) The solution containing inositol showed an improvement in the activity against C. albicans as compared to the buffer control.

EXAMPLE 8

(23) Formulation Preserved Solution for rinsing, storage, reconstituting enzyme tablets. A formulation was prepared by dissolving Tricine, Allantoin, Inositol, Disodium edetate, and Polyoxyl 40 Hydrogenated Castor Oil in 80% of the water volume. The pH of the solution was adjusted to 7.3 with 1 N sodium hydroxide. The tonicity of the solution was adjusted with sodium chloride and polyhexamethylene biguanide was added. The solution was diluted to volume with water.

(24) TABLE-US-00008 Constituent Supplier % Weight/Volume Amount Purified water to 80% 40 mL Tricine Spectrum 1.0% 0.500 g Allantoin Spectrum 0.25% 0.125 g Inositol Spectrum 0.1% 0.050 g Edetate Disodium Spectrum 0.055% 0.0275 g Polyoxyl 40 CREMOPHOR RH 0.1% 0.5 mL of 10% Hydrogenated Castor 40 from BASF Co. Oil Sodium Hydroxide, as required for pH as required for pH 1N adjustment to 7.3 adjustment to 7.3 Purified Water to 98% Dilute to 49 mL Sodium Chloride Fisher As required for As required for tonicity adjustment tonicity adjustment 285 mOsm 285 mOsm Polyhexamethylene- 20% w/w solution 0.0001% 50 L of 0.1% biguanide HCl available under the mark COSMOCIL CQ from Avecia Purified Water Balance to 100% Dilute to 50 mL

(25) This provides an example of a specific formulation of the present invention but does not fully illustrate the bounds or limits of the invention.