GB2205175A

GB2205175A - Chlorhexidine cleaning compositions for contact lenses

Info

Publication number: GB2205175A
Application number: GB08809536A
Authority: GB
Inventors: David James Geler Davies; Brian John Meakin; John Nicholas Staniforth
Original assignee: University of Bath
Current assignee: University of Bath
Priority date: 1987-04-24
Filing date: 1988-04-22
Publication date: 1988-11-30
Also published as: AU1628488A; GB8709765D0; GB8809536D0; WO1988008309A1

Abstract

Contact lens treating solutions are obtained by dissolving in bulk in purified water a solid, preferably powdered, composition comprising chlorhexidine or a salt thereof, an alkali metal or ammonium salt of a hydroxyalkanic carboxylic acid and a vehicle. The alkali metal or ammonium salt does not hinder the dissolution of chlorhexidine or salt thereof, which usually is hindered when using an inorganic electrolyte salt as the buffering agent. Preferably chlorhexidine gluconate, sodium gluconate and sorbitol are used with the sodium gluconate and sorbitol substantially constituting the composition in a ratio by weight of about 2:1.

Description

COMPOSITIONS FORx TREATING CONTACT LENSES The present invention relates to the cleaning and/or disinfection of contact lenses and has pa%-ict:'ar but not exclusive, application to the cleaning and disinfection of hydrophilic soft contact lenses and to the cleaning, wetting and disinfection of hard contact lenses. It provides solid cornposition for addition to water to produce contact lens treating solutions and the method of sc pr,dllcin9 said solutions.

Contact lenses are thin convex lenses placed directly on the eye surface to correct sight defects.

There are two general categories of contact lenses, namely hard lenses and soft lenses. Hard lenses usually are made of cross-linked polymethyl-meth- acrylate or, in the so-called gas permeable lenses polymethyl methyacrylate-silicone copolymers. Soft lenses usually are made of polyhydroxyethyl meth- acrylate cross-linked with ethylene glycol dimeth- acrylate.

Chlorhexidine salts, especially the gluconate are widely used as antimicrobial agents to disinfect contact lenses, especially soft contact lenses. In particular, soft lenses are soaked in a dilute aqueous solution of the chlorhexidine salt. Usually, the solution is made isotonic and buffered by the presence of one or more tonicity adjusting and/or buffering agents. Solutions can be made up by the wearer of the lens by adding a tablet, or other solid composition, to a measured quantity of water. Until recently, the art taught that deionized, or otherwise specially purified, water had to be used but International Patent Publication No. t 85/01209 discloses a solid composition intended to be dissolved in tap water.

However, it is more usual or the sterilizing solution to be made up by a manufacturer and supplied to the lens wearer in bottles.

The practice of manufacturers supplying ready made sterilizing solutions results in substantial storage and transportation costs when supplying markets remote from the manufacturing plant. Although these costs can be reduced by local manufacture, the expertise and plant often is not available to reproduce the relatively sophisticated manufacturing techniques employed by the original manufacturer. This problem could be circumvented by the provision of a solid composition to be bulk dissolved in water locally.

;water purified by ion exchange; reverse osmosis or other suitable means is almost universally available.

The tablets and other solid compositions previously proposed are not suitable for the bulk manufacture of disinfecting solutions because they are intended to make up only sufficient solution to treat one pair of contact lenses. If these single-use compositions are scaled up for bulk manufacture, the dissolution is too slow and/or insufficiently complete. In particular, the dissolution of chlorhexidine salts such as the gluconate, acetate, and hydrochloride is hindered by the presence of inorganic electrolyte salts used as buffering and/or tonicity adjusting agents.

It has now been found that the dissolution of chlorhexidine salts is not hindered if an alkali metal or ammonium salt of a hydroxy alkane carboxylic acid is employed as the buffering agent. Further, it has been found that it is particularly suitable for the chlorhexidine salt and said alkali metal or ammonium salt to be provided in a hydrophilic, highly watersoluble, non-ionic tonicity adjusting agent as a vehicle to provide a powdered composition readily soluble in purified water.

U.K. Patent No. 2090013 discloses that the sterilizing effect of low concentration solutions of chlorhexidine salts is increased by making the solutions isotonic with non-ionic tonicity adjusting agents instead of sodium chloride or other ionic tonicity adjusting agents. Polyhydric alcohols are specified to be suitable non-ionic tonicity adjusting agents.

Hydrophilic, highly water-soluble, non-ionic tonicity adjusting agents such as sugars, sugar alcohols and hydrophilic glycols are well known as diluents or carriers in solid pharmaceutical compositions. Some have been proposed for use in solid chlorhexidine-containing compositions for dissolution in purified water to make up contact lens disinfecting solutions (see US 3888782).

U.K. 2040492 discloses the use of sodium gluconate as a sequestering agent in an aqueous saline solution for removing, or preventing, inorganic deposits on contact lenses. There is a general reference to the solutions containing a sterilizing agent but the only exemplified agent is thimerosal (thiomersal). There is a reference to incorporation of the sequesting agents into "cold disinfecting systems containing lens preservatives and disinfectants" but this aspect is not exemplified. Only treatment of the contact lenses by heating in the solution is exemplified.

According to a first aspect of the present invention, there is provided a solid composition for addition to water to form a contact lens treating solution, said composition comprising an antimicrobial effective amount of chlorhexidine or an ophthalmically acceptable salt thereof and a solid ophthalmically acceptable buffering agent, characterized in that said buffering agent is an alkali metal or ammonium salt of a hydroxyalkane carboxylic acid.

In a second aspect, the invention provides a powder composition for addition to water to form, a contact lens treating solution, said composition comprising an antimicrobial effective amount of chlorhexidine or an ophthalmically acceptable chlorhexidine salt thereof and a buffering amount of a solid ophthalmicslly acceptable alkali metal or ammonium salt of a hydroxyalkane carboxylic acid, in an ophthalmically acceptable hydrophilic, highly water-soluble, non-ionic, tonicity adjusting agent as a vehicle.

According to a third aspect of the invention, there is provided a method of preparing a contact lens treating solution which comprises adding to purified water a conposition in accordance with the first or second aspects of the invention.

Depending upon the composition of the solid composition of the invention, the resulting solution can be used for cleaning, disinfecting, soaking and/or wetting hard or soft contact lenses.

In order to facilitate dissolution, it is preferred that the composition of the invention is in the form of a powder. It is particularly preferred that the powder is free-flowing to facilitate both dissolution and also weighing of the required quantity of composition to be added to a measured quantity of water.

The chlorhcxidine base or sa't usually will be present in an amount of 0.01 to 0.1%, preferably 0.04 to 0.09%, by weight (calculated as gluconate).

Although chlorhexidine base or any ophthalmically acceptable chlorhexidine salt, eg. the acecate or hydrochloride, can be used, the gluconate presently is preferred because it is available as an aqueous solution which is readily dispersed in the solid mix.

The buffering agent employed in the invention is L an alkali metal or ammonium salt or a hydroxyalkane carboxylic acid, especially a polyhydroxycarboxylic acid. Preferably, the acid is a monocarboxylic acid but dicarboxylic or polycarboxylic, especially tricarboxylic, acids can be used when lower water-solubility rates are acceptable. when the acid is a monocarboxylic acid, preferably it is an alpha-omega polyhydroxyalkane monocarboxylic acid.

Particularly preferred nonocarboxylic acids are those of the following Formula (I) whose alkali metal or ammonium salts are solid at ambient temperature: HOCH2(CHR)nCO2H (I) wherein n is 1 to 5 and R represents hydroxyl or hydrogen with each R being the same or different when n is greater than 1. Examples of monocarboxylic acids of Formula I are glycolic acid; glyceric acid (ie.

dihydroxypropionic acid); the various isomers of 2-6 pentahydroxy-hexane-l-carboxylic acid, especially gulonic acid (ie. xylose carboxylic acid) and, particularly, gluconic acid; and the various isomers of 2-7 hexahydroxy-heptane-l-carboxylic acid, especially glucoheptanoic acid. Other suitable monocarboxylic acids include pentose and hexose carboxylic acids, especially glucuronic acid and galacturonic acid, and keto-polyhydroxy acids, especially 2-keto-gulonic acid The most preferred salt is an alkali metal or ammonium gluconate, especially sodium gluconate.

The salt contributes to the tonicity of the resultant solution and suitably is present in an amount to contribute 110 to 180 milliosmolal units to the resultant solution. The remaining tonicity, i.e. up to 250-350 milliosmolal units, especially up to about 300 osmolal units, can be contributed by the vehicle.

Usually, the salt is present in an amount which will provide the solution with a pH in the range 5 to 8.5, preferably 6 to 7.5. Suitably, the composition will contain 20 to 40E, preferably 30 to 40%, by weight of the salt, based upon the combined weights of salt and vehicle present.

The vehicle for the composition preferably is a powdered hydrophilic, highly water-soluble, non-ionic tonicity adjusting agent.

Suitable vehicles include sugar alcohols including hexitols, for example, galactitol, mannitol and, especially, sorbitol, and pentitols, for example adonitol (ie. ribitol), arabitol (ie. lyxitol), and, especially, xylitol; sugars, incliiding hexoses, for example, glucose, galactose, gulose and mannose, pentoses, for example ribose and xylose, inositois, disaccharides, for example lactose, maltose and sucrose, ketopentoses, for example ribulose, and ketohexoses, for example sorbose; and solid hydrophilic glycols, for example polyethylene glycol having at least 20 oxyethylene groups in the chain. Sugar alcohols are preferred to sugars because the latter provide ready nutrients for micro-organisms. The presently preferred vehicles are xylitol and, especially, sorbitol.

The vehicle usually will be present in an amount sufficient to render the resultant solution substantially isotonic, ie. 250-350 milliosmolal units, especially about 300 milliosmolal units. Having regard to the organic salt contribution to tonicity discussed above, the vehicle usually will contribute 100 to 200 milliosmolal units.

Suitably, the vehicle will constitute 60 to 80%, preferably 60 to 70%, by weight of the combined weight of salt and vehicle.

Contact lens disinfecting solutions are made up in bulk by dissolving a solid composition of the invention in purified water. Conveniently, the water is purified by reverse osmosis, although other techniques such as ion exchange can be used. As mentioned previously, the intention is that the solid composition would be formulated in a main manufacturing plant in, for example, a major industrial country and shipped, or otherwise transported, to a local plant in, for example, a third world country. At the local plant, the composition would be dissolved in water which had been purified by reverse osmosis or otherwise at the plant or supplied locals". Tne resultant solution would then be sterilized by, for example, passage through a bacteria-proof grade filter.

Usually, the composition will be dissolved in a sufficient quantity of water to provide a chlorhexidine concentration in the range 0.001 to 0.005, especially 0.002 to 0.003%, by weight (calculated as gluconate).

Conveniently the alkali metal or ammonium salt and vehicle concentrations in the solution would be 1 to 2%, preferably 1.5%, by weight and 2.5 to 3.5, preferably 3%, by weight respectively.

In addition to the chlorhexidine or salt thereof, the alkali metal or ammonium salt and the vehicle, the composition may also contain other components, especially a non-ionic surfactant and, when intended for cleaning of soft lenses or cleaning and wetting hard contact lenses, a viscolysing agent.

The presence of a non-ionic surfactant usually is required in a composition intended for the cleaning of soft contact lenses and the cleaning and wetting of hard contact lenses in order to facilitate both the cleaning and wetting functions. However, the presence of certain non-ionic surfactants also is preferred in other compositions. Suitable surfactants include Poloxamers (ie. polyoxyethylene-polyoxy- propylene co-polymers) for example Poloxamer 184 or Poloxamer 188; tzacrogol esters (ie. polyoxyethylene alkyl esters) for example Polyoxyl-8-stearate; Macrogol ethers (ie.

polyoxyethylene alkyl o alkyl phenol ethers) for example Cetomacrogols, Nonoxinols and Octoxinols; and sugar esters for example sucrose monolaurate. Usually, the surfactant will be present in an amount providing up to 1% by weight of the resultant solution obtained on dissolving the solid composition of the invention in water. In the case of disinfecting soaking solutions for hard and soft lenses, the surfactant concentration conveniently is up to 0.2%, especially about 0.1%, by weight. In cleaning/wetting solutions for hard and soft lenses, the surfactant concentration conveniently is 0.3 to 0.7%, especially about 0.5%, by weight.

Thus, in the solid composition of the invention, the surfactant usually will be present in an amount of up to about 20%, preferably 2 to 10%, by weight of the total composition. The presently preferred surfactants are the Poloxamers.

The presence of a viscolysing agent usually is required in a composition intended for the cleaning and wetting of hard lenses and in compositions intended for the cleaning of soft lenses. Suitable viscolysing agents include celluloses, for example, methylcellulose, hydroxpropyl cellulose, hypomellose (ie.

hydroxy propylmethyl cellulose) and especially hydroxyethyl cellulose; polyvinyl alcohols, polyvinylpyrrolidones, and polyacrylamides. Presently, hydroxyethyl cellulose is the preferred viscolysing agent. The amount of viscolysing agent present will be detrermined by the viscosity required in the resultant solution. Conveniently, an amount providing a concentration in ths resultant solution of up to 5% especially 0.1 to 0.5%, by weight is employed. Thus, in the solid composition of the invention, the viscolysing agent usually will be present in an amount up to about 30%, preferably 2 to 20%, by weight of the total composition. The invention is illustrated in the following non-limiting examples. All percentages are by weight and the abbreviation 'CX' is used for chlorhexidine.

Example 1 The following components are mixed together in the specified proportions to provide a free-flowing powder: - CX gluconate 0.044 % Sorbitol 65.19 % Sodium gluconate 32.60 % Poloxamer 184 2.17 % The powder is dissolved in sufficient water purified by reverse osmosis to provide a disinfecting and soaking solution for hard or soft contact lenses having the following formulation: CX gluconate 0.002 % Sorbitol 3.00 % Sodium gluconate 1.50 % Poloxamer 184 0.10 só Water to 100 90 Examp'.e 2 The following components are mixed together in the specified proportions to provide a free-flowing powder: - CX gluconate 0.057 % Sorbitol *57.33 % Sodium gluconate 28.66 % Poloxamer 188 9.55 % Hydroxyethyl cellulose (250eel) 4.40 % The powder is dissolved in sufficient water purified by reverse osmosis to provide a cleaning and wetting solution for hard contact lenses or a cleaning solution for soft contact lenses having the following formulation: CX gluconate 0.003 % Sorbitol 3.00 % Sodium gluconate 1.50 % Poloxamer 188 0.50 % Hydroxyethyl cellulose (250H) 0.23 % Water to 100 % Example 3 The procedure of Example 1 was repeated to provide a powder of the following formulation: CX gluconate 0.067 % Sorbitol 66.62 % Sodium gluconate 33.31 % which provided a solution of the formulation: CX gluconate 0.003 % Sorbitol 3.00 % Sodium gluconate 1.50 % later to 100 % Example 4 The procedure of Example 1 was repeated to provide a powder of the following formulation CX gluconate 0.048 % Xylitol 59.35 % Potassium gluconate 38.22 % Poloxamer 184 2.37 % which provided a solution of the formulation:: CX gluconate 0.002 % Xylitol 2.50 % Potassium Gluconate 1.61 % Poloxamer 184 0.10 % later to 100 % Example 5 The procedure of Example 1 was repeated to provide a powder of the following formulation: CX acetate 0.041 % Gulose 61.07 96 Sodium gluco-heptanoate 34.81 9s Cetomacrogol 4.07 % which provided a solution of the formulation: CX acetate 0.002 % Gulose 3.00 % Sodium gluco-heptanoate 1.71 96 Cetomacrogol 1000 0.20 96 Water to 100 % Example 6 The procedure of Example 1 was repeated to provide a powder of the following formulation: CX gluconate 0.070 % Sorbose 58.10 % Sodium gluconate 34.86 % Poloxamer 188 6.97 % which provided a solution of the formulation:: CX gluconate 0.003 9s Sorbose 2.50 % Sodium gluconate 1.50 % Poloxamer 188 0.30 % Water to 100 9s Example 7 The procedure of Example 2 was repeated to provide a powder of the following formulation: CX gluconate 0.072 % Sorbitol 47.62 % Sodium gluconate 32.47 % Poloxamer 188 18.04 % Hycroxyethyl cellulose 1.80 % which provided a solution of the formulation: CX gluconate 0.004 t Sorbitol 2.64 % Sodium gluconate 1.80 % Poloxamer 188 1.00 ss Hydroxyethyl cellulose 0.10 % Water to 100 % Example 8 The procedure of Example 1 was repeated to provide a powder of the following formulation:: CX gluconate 0.047 % Xylitol 43.38 % Sodium gluconate 22.00 % Poloxamer 184 3.14 % Polyvinyl alcohol 31.43 96 which provided a solution of the formulation: CX gluconate 0.003 % Xylitol 2.76 % Sodium gluconate 1.40 % Poloxamer 184 0.20 % Polyvinyl alcohol 2.00 % water to 100 % Example 9 The procedure of Example 1 was repeated to provide a powder of the following formulation: LX acetate 0.029 % Gulose 44.10 % Potassium gluconate 23.52 % Cetomacrogol 2.94 % Polyacrylamide 29.40 % which provided a solution of the formulation: : CX acetate 0.002 % Gulose 3.00 26 Potassium gluconate 1.60 % Cetomacrogol 0.20 9s Polyacrylamide 2.00 % Water to 100 % Example 10 The procedure of Example 1 was repeated to provide a powder of the following formulation: CX gluconate 0.038 % Sorbitol 36.20 % Sodium glucoheptanoate 23.12 % Sucrose monooleate 2.54 % PEG 4000 19.05 % Polyvinyl alcohol 19.05 % which provided a solution of the formulation: CX gluconate 0.003 % Sorbitol 2.85 % Sodium glucoheptanoate 1.82 9s Sucrose monooleate 0.20 % @@G 4000 1.50 % Polyvinyl alcohol 1.50 % Water to 100 %

Claims

CLA Irt S : 1. A solid composition for addition to water to form a contact lens treating solution, said composition corrprising an antimicrobial effective amount of chlorhexidine or an ophthalmically acceptable salt thereof and a solid ophthalmically acceptable buffering agent, characterized in that said buffering agent is an alkali mortal or ammonium salt of a hydroxyalkane carboxylic acid.
2. A colrpositior as claimed in Claim 1 in the form of a powder in an ophthalmically acceptable hydrophilic, highly water-soluble, non-ionic tonicity adjusting agent as vehicle.
3. A composition as claimed in Claim 1, in the form of a powder.
4. A composition as claimed in Claim 2 or Claim 3, wherein the powder is free-flowing.
5. A composition as claimed in any one of the preceding claims, wherein the said buffering agent is an alkali metal or ammonium salt of a hydroxyalkane monocarboxylic acid.
6. A composition as claimed in Claim 5, wherein the said acid is an acid of the formula: HOCH2 (CHR) nCO2H wherein n is 1 to 5 and R represents hydroxyl or hydrogen with each R being the same or different when n is greater than 1.
7. A composition as claimed in Claim 5 or Claim 6, wherein the said acid is an alpha-omega polyhydroxyalkane monocarboxylic acid.
8. A composition as claimed in Claim 7, wherein the said salt is an alkali metal or ammonium gluconate.
9. A composition as claimed in Claim 8, wherein the gluconate is sodium gluconate.
10. A composition as chimed in any one of the preceding claims, wherein the said salt contributes 110 to 180 milliosmolal units to the tonicity of the resultant solution.
11. A composition as claimed in any one of the preceding claims, wherein the said salt is present in an amount which will provide the resultant solution with a pH in the range 6 to 7.5.
12. A composition as claimed in any one of the preceding claims, wherein the vehicle for the composition is a powdered sugar alcohol, sugar or solid hydrophilic glycol.
13. A composition as claimed in Claim 12, wherein the vehicle is a hexitol or pentitol.
14. A composition as claimed in Claim 13, wherein the vehicle is sorbitol.
15. A composition as claimed in Claim 14, wherein the vehicle is xylitol.
16. A composition as claimed in any one of the preceding claims, wherein the vehicle contributes 100 to 200 milliosmolal units to the tonicity of the resultant solution.
17. A composition as claimed in any one of the preceding claims, wherein the vehicle constitutes 60 to 80% by weight of the combined weight of said salt and vehicle
18. A composition as claimed in Claim 17, wherein the vehicle constitutes fror, 60 to 70% by weight of said combined weight.
19. A composition as claimed in any one of the preceding claims, wherein the chlorhexidine is present as chlorhexidine gluconate.
20. A composition as claimed in any one of the preceding claims, wherein the chlorhexidine or salt thereof is present in an amount of 0.01 to 0.1% by weight (calculated as gluconate).
21. A composition as claimed in Claim 20, wherein the chlorhexidine or salt thereof constitutes 0.04 to 0.09% by weight (calculated as gluconate).
22. A composition as claimed in any one of the preceding claims containing an ophthalmically acceptable non-ionic surfactant.
23. A composition as claimed in Claim 22, wherein the surfactant is a Poloxamer, Macrogol ester, rQacrogol ether, or sugar ester.
24. A composition as claimed in Claim 22, wherein the surfactant is a Poloxamer.
25. A composition as claimed in any one of Claims 22 to 24, wherein the surfactant is present in an amount up to 20% by weight of the composition.
26. A composition as claimed in Claim 25, whercin said surfactant is present in an amount of 2 to 10% by weight.
27. A composition as claimed in any one of the preceding claims containing a viscolysing ages.
28. A composition as claimed in Claim 27, wherein the viscolysing agent is a cellulose, polyvinyl alcohol, polyvinyl pyrrolidine, or polyacrylamide.
29. A composition as claimed in Claim 28, wherein the viscolysing agent is hydroxyethyl cellulose.
30. A composition as claimed in any one of Claims 27 to 29, wherein the viscolysing agent is present in an amount of up to 30% by weight of the composition.
31. A corrposition as claimed in Claim 30, wherein said viscolysing agent is present in an amount of 2 to 20% by weight.
32. A composition as claimed in Claim 1 and substantially as hereinbefore described.
33. A method of preparing a contact lens treating solution which comprises adding to purified water a composition as claimed in any one of the preceding claims.
34. A method as claimed in Claim 33, wherein the contact lens treating solution is made up in bulk and then bottled.
35. A method as claimed in Claim 33 or Claim 34, wherein the composition is formulated at one location and tn transported to a reroute location for dissolution in water purified at said remote location or otherwise supplied locally.
36. A method as claimed in any one of Claims 33 to 35, wherein the water has been purified by reverse osrnosis.
37. A method as claimed in any one of Clairrs 33 to 36, wherein the composition is dissolved in a sufficient quantity of water to provide a chlorhexidine salt concentration in the range 0.001 to 0.005 by weight (calculated as gluconate).
38. A method as claimed in Claim 37, wherein said chlorhexidine salt concentration is 0.002 to 0.003% by weight (calculated as gluconate).
39. A method as claimed in Claim 37 or Claim 38, wherein the alkali metal or ammonium salt concentration in the solution is 1 to 2% by weight.
40. A method as claimed in Claim 39, wherein the alkali metal or ammonium salt concentration in the solution is 1 to 1.596 by weight.
41. A method as claimed in any one of Claims 37 to 40, wherein the vehicle concentration in the solution is 2.5 to 3.596 by weight.
42. A method as claimed in Claim 41, wherein the vehicle concentration in the solution is 3% by weight.
43. A method as claimed in any one of Claims 33 to 42, wherein the solution is passed through a bacteria-proof grade filter.
44. A method as claimed in Claim 33 and substantially as hereinbefore described.
45. A contact lens disinfecting solution whenever oDçained by a method as claimed in any one of Claims 33 to 44.