BACKGROUND OF THE INVENTION

This application relates to contact lens disinfecting solutions using iodine as the disinfecting agent. The application further relates to a rapid contact lens disinfection and neutralization regimen.

Iodine is a well-known disinfecting agent. It is known to be useful against a variety of organisms including viruses, bacteria, spores, yeast, molds, protozoa, fungi, worms, nematodes and the like. Because of the wide range of disinfecting capabilities, iodine has been suggested for use as a contact lens disinfecting agent. See e.g. U.S. Patent Nos. 3,911,107 and 4,031,209. However, iodine also is a strong irritant and may, when used in concentrations required for disinfection, destroy animal proteins and otherwise be harmful. Therefore, because of the potential harm to the eye, iodine must be adequately inactivated or neutralized before the disinfected lens is inserted in the eye.

If iodine is allowed to remain in contact with contact lenses for more than a few minutes, the iodine may begin to discolor the lenses to a yellowish or brownish color. This is because iodine may enter the matrices of certain polymeric contact lens materials, especially hydrogel

materials. Therefore, improved methods are needed to avoid discolored lenses and to maintain clear lenses when disinfecting with an iodine-containing composition.

SUMMARY OF THE INVENTION

The present invention is a method for disinfecting contact lenses wherein the lenses are contacted with a solution formed by combining a first amount of a reducing solution and iodine, and a second amount of reducing solution is added to the resulting mixture. The iodine is preferably provided as a tablet. The amount of active iodine provided is such that a disinfecting amount remains after the iodine is combined with the first amount of reducing solution. The second amount of reducing solution is sufficient to neutralize the residual iodine in the resulting mixture.

One advantage of the method of this invention, in the preferred embodiments, is that lenses are exposed to the active iodine disinfectant for only a short duration and then neutralized in an equally rapid amount of time. In this way the rapid disinfection minimizes the opportunity the iodine has to migrate into the lens matrix. This reduces the chance of lens discoloration and provides a fast lens disinfection/neutralization regimen.

Disinfecting contact lenses, especially hydrogel contact lenses according to the regimen of the present invention provides a disinfection/neutralization regimen which is safe, rapid and easy to perform.

DETAILED DESCRIPTION OF THE INVENTION

The disinfecting solutions of the present invention use iodine as the disinfectant. In a preferred embodiment the iodine is provided to a solution as an iodophor. Any iodophor which provides active iodine upon solution is suitable for use in the present invention. Iodophors are commercially available and will provide a known amount of active iodine from the iodophor complex upon dissolving in an aqeuous solution. It is believed that the active iodine is responsible for the disinfection properties noted in the solutions of the present invention. The iodine associated with the iodophor complex and the active iodine free in the solution are collectively referred to as the total available iodine in the system.

Particularly useful carriers which associate with iodine to create iodophors include a variety of high molecular weight polymeric materials such as starch and various synthetic polymers. Preferred synthetic polymers

are polyvinyl pyrrolidone and copolymers of polyvinyl pyrrolidone such as vinyl acetate polyvinyl pyrrolidone, polyvinyl oxizolidone, caprolactam, polyvinyl alcohol, and ethylene and propylene oxide condensates with alcohols, amides and phenols, with polyvinyl pyrrolidone being the most preferred.

The iodophor may be provided as a solid or liquid to the disinfection system of the present invention. However, the iodophor is most conveniently provided in a solid form (e.g. tablet or powder, etc.). The amount of iodophor required to yield a desired amount of active iodine will vary slightly among different iodophors. USP grade polyvinyl pyrrolidone-iodine will provide from about 9% to about 12% active iodine in solution.

Once the desired concentration of active iodine has been selected, the corresponding amount of iodophor required can be easily determined. The iodine is preferably provided in tablets which, upon dissolution, produce concentrations of active iodine in solution within the range from about 20 ppm to about 200 ppm, more preferably from about 50 ppm to about 100 ppm, and most preferably about 70 ppm.

Any compound known as an antioxidant which has the appropriate redox potential to convert iodine (I2) to

iodide (I~) may be used as the reducing agent in the present invention. Examples include alkali metals (in particular sodium), thiosulfates, sulfites, thioglycerol, formates, pyruvic acid and salts of pyruvic acid, N- acetylcysteine,ene-diol compounds, e.g. ascorbic acid compounds, reductive acid compounds, isoascorbic compounds, glyoxylic acid compounds, dihydroxymaleic acid compounds, dihydroxyfumaric acid compounds, and mixtures thereof. Particularly preferred are ascorbic acid and derivatives thereof, the thiosulfates and derivatives thereof, with sodium thiosulfate being most preferred.

The reducing agent may be provided, in either a solid or liquid state, to neutralize the total available iodine in the disinfecting solution. The reducing agent is most conveniently provided to the reaction in a liquid state, as a reducing solution. In a preferred embodiment of the present invention, the concentration and volume (about 6 mis.) of reducing solution initially provided to the contact lenses (and into which the solid iodophor- containing tablet is placed) is such that about 50% of initial active iodine present from the tablet is neutralized. Partial neutralization of the iodine occurs initially, while sufficient iodine remains to disinfect the contact lenses. When sodium thiosulfate is employed as the reducing agent, the concentration of the sodium thiosulfate in the aqueous solution is preferably within the range of

from about 15 ppm to about 150 ppm, more preferably from about 40 ppm to about 75 ppm, and most preferably from about 50 ppm to about 60 ppm.

While the time required for the disinfection/ neutralization regimen is not narrowly critical, the whole regimen preferably requires about 3 to 15 minutes, more preferably about 10 minutes. Neutralization of the total available iodine in the solution is almost immediate. The iodine which may have migrated into the matrices of the contact lenses is believed to be neutralized more slowly. Preferably, the total available iodine present in the system (in solution and within the lens matrices) is preferably neutralized in about 15 minutes, and more preferably within about 2-5 minutes.

In one embodiment of this invention, one iodophor- containing disinfecting tablet and one reducing solution is needed for contact lens disinfection. The tablet is first placed into the contact lens container followed by reducing solution, or the tablet may be placed directly into the reducing solution. After lens disinfection, more reducing solution is added to neutralize the total available iodine.

In an another embodiment of this invention, one iodophor-containing solution and one reducing solution is provided for contact lens disinfection. The reducing

solution is combined with the iodophor solution and the lenses are disinfected. More reducing solution is then added to neutralize the total available iodine.

In still further embodiments of this invention, one tablet comprising both the iodophor and the reducing agent are provided to water (tap, purified or distilled) , saline or buffered salt solution, or other lens solutions. In other embodiments, two tablets are provided; one iodine disinfecting tablet and one reducing agent tablet. The tablets are added at the same time, with the reducing agent having a timed release, or other delayed release mechanism which allows the iodine the necessary disinfecting time before the reducing agent, now in solution neutralizes the lenses.

For greater comfort, reducing solution may be used for an optional rinse, or rub and rinse of the lens after the disinfecting/neutralizing regimen. The lenses may also be cleaned during the disinfection phase, or separate cleaners may be added such that cleaning and disinfection occur together.

Other components such as buffers, preservatives, surfactants, additional germicides or other components may be present in any of the solutions provided by the method of this invention. In a preferred embodiment where an

iodophor is provided in tablet form, the preservatives, buffers, etc. are included in the reducing solution. Specific preservatives including polyhexamethyl biguanide or polyaminopropyl biguanide may be included to improve solution shelf life and reduce the risk of the recontaminating the lenses with solution after lens disinfection.

Buffers are preferably selected from the group consisting of borate, phosphate, citrate buffers, and mixtures thereof. Borate buffers include boric acid, sodium borate, potassium tetraborate, potassium metaborate and mixtures thereof. Preferably, such buffers are used in a concentration ranging from about 0.05 weight % to about 2.5 weight %, and more preferably from about 0.1 weight % to about weight 1.5%. The concentration and volume of buffer used should be sufficient to preferably maintain the pH of the disinfection solution in contact with the lens at between about 6.5 to about 7.5, most preferably about 6.8 to about 7.2.

Optionally, secondary disinfectant/germicides may be employed as a solution preservative if the disinfecting regimen requires the lenses to remain in the disinfecting solution for extended periods. The secondary disinfectant may also function to potentiate, complement or broaden the spectrum of microbiocidal activity of the iodine. This

includes microbiocidally effective amounts of germicides which are compatible with and do not precipitate in the presence of iodine, and which comprise concentrations ranging from about 0.00001 weight % to about 0.5 weight %, and more preferably from about 0.0001 weight % to about 0.1 weight %. Suitable complementary germicidal agents include, but are not limited to, thimerisol, sorbic acid, 1,5-pentanedial, alkyl triethanolamines, phenyl mercuric salts, e.g. nitrate, borate, acetate, chloride and mixtures thereof.

The disinfecting method of the present invention is contemplated for use with any type of hard or soft contact lens. However, the rapid disinfecting system of the present invention is particularly useful for the disinfection of soft hydrogel contact lenses. Hydrogels are hydrophilic polymers that absorb water to an equilibrium value and are insoluble in water due to the presence of a three-dimensional network. Hydrogels are generally formed of a copolymer of at least one hydrophilic monomer and a crosslinking monomer. The swollen equilibrated state results from a balance between the osmostic driving forces that cause the water to enter the hydrophilic polymer and the forces exerted by the polymer chains in resisting expansion.

In one preferred embodiment, a colored redox indicator is provided to the system, preferably incorporated into the iodophor-containing tablet. The indicator provides a color to the disinfecting solution, indicating the continued presence of oxidative disinfectants. When the iodophor- containing tablet contacts the first amount of reducing solution, the indicator will turn the clear reducing solution, most desirably, to a blue or purple hue. When the second amount of reducing solution is added, the resulting solution almost immediately turns clear, indicating the neutralization of the iodine in solution. Preferably, an amount of amylose-containing starch or other amylose such as dextrin, most preferably maltodextrin, may be incorporated into the iodophor tablet, or may be provided in the reducing solution.

The invention is more fully described in the following examples which illustrate, but do not limit the present invention.

EXAMPLE 1

Preparation of Reducing Solution to Neutralize 70 ppm Active Iodine

The reducing solution was prepared by combining four solutions prepared separately: a borate buffer, a sterile diluent, a preservative, and a thiosulfate solution.

An aqueous contact lens solution was prepared according to the following method. A borate buffer was prepared by dissolving 7.65 grams of boric acid, 0.81 grams of sodium borate, and 2.88 grams of sodium chloride into 900 mis. This was heat sterilized in an autoclave above 120°C for 1 hour.

The sterile diluent was prepared by dissolving 0.85 grams of boric acid, 0.09 grams of sodium borate, and 0.36 grams of sodium chloride in 90 mis of purified water. The solution was brought up to a final volume of 100 mis, and sterile filtered through a Millipore Durapore 0.22 micron filter.

The preservative was prepared by dissolving 0.01 grams of polyaminopropyl biguanide (PAPB, from ICI Americas as Cos ocil CQ) into 10 mis of the sterile diluent, and sterile filtered through a Millipore Durapore 0.22 micron filter.

The thiosulfate solution was prepared by dissolving 0.36 grams of sodium chloride, 0.055 grams of sodium thiosulfate (USP pentahydrate form) and 0.1 grams of PVP/Dimethylaminoethylmethacrylate Copolymer (Copolymer 937, GAF) into 10 mis of the sterile diluent. The solution was sterile filtered through a Millipore Durapore 0.22

micron filter. Alternately, an amount of the anhydrous form of sodium thiosulfate to give a 35 ppm concentration may be used instead of the USP pentahydrate form.

All four of the solutions, the buffer, the sterile diluent, the preservative, and the thiosulfate solution were combined and brought up to a final volume of 1 liter. The final solution was adjusted with IN sodium hydroxide or IN hydrochloric acid to pH of 7.0. The osmolality of the solution was 260 mOs /kg. The concentration of sodium thiosulfate was 0.0055%, and the concentration of PAPB was about 1.0 ppm.

EXAMPLE 2

Preparation of Solution to Neutralize 35 ppm Active Iodine

To make a thiosulfate solution to neutralize a disinfecting solution having 35 ppm active iodine, the thiosulfate amount was changed such that the concentration of sodium thiosulfate was between 0.00314%. This was accomplished by adding 0.031 grams of sodium thiosulfate to the solution as described in Example 1. The neutralizing solution of Example 1 may also be used to neutralize disinfecting solutions having 35 ppm active iodine. That is, an excess amount of thiosulfate neutralizing solution above that which is needed to neutralize 35 ppm active iodine is not detrimental to the lens or the lens wearer.

EXAMPLE 3

Preparation of Disinfecting Tablet .70 ppm Active Iodine.

An iodine disinfecting tablet designed to be dissolved in 6 mis of reducing solution was prepared having the following formulation:

4.2 mg or 700 ppm of PVP-Iodine (70 ppm active iodine) USP grade (BASF) ;

3.6 mg Maltodextrin (Maltrin ^R M040, GPC, Muscatine, Iowa)

50 mg Sodium Chloride

20 mg Tartaric Acid

22.5 mg Sodium Carbonate

Prior to compounding, tartaric acid was milled and passed through an 80 mesh sieve and dried 24 hours at 70 degrees C. Sodium carbonate was also passed through an 80 mesh sieve and dried for 24 hours at 70 degrees C. Sodium chloride was also dried at 70 degrees for 24 hours. The components were combined and the mixture passed through a 30 mesh sieve. The remaining larger particles were crushed with a pestle-mortar. The combined mixture was V-blended for 1 hour and then tableted with a 6 mm punch for a 100 mg weight.

EXAMPLE 4

Preparation of Disinfecting Tablet .61 ppm Active Iodine.

An iodine disinfectant tablet designed to be dissolved in 6 is of reducing solution was prepared having the following formulation:

3.7 mg (614 ppm) of PVP-Iodine (61 ppm active iodine) USP grade (BASF) ;

3.6 mg Maltodextrin (Maltrin ^R M040, GPC, Muscatine, Iowa)

40 mg Sodium Chloride

15 mg Tartaric Acid 5 mg Fumaric Acid 5 mg Polyethylene glycol 8000 (Spectra)

22.5 mg Sodium Carbonate

Prior to compounding, tartaric acid was milled and passed through an 80 mesh sieve and dried 24 hours at 70 degrees C. Sodium carbonate was also passed through an 80 mesh sieve and dried for 24 hours at 70 degrees C. Sodium chloride was also dried at 70 degrees C for 24 hours. The components were combined and the mixture passed through a 30 mesh sieve. The remaining larger particles were crushed with a pestle-mortar. The combined mixture was V-blended for 1 hour and then tableted with a 6 mm punch for a 94 mg weight.

EXAMPLE 5

Preparation of Disinfecting Tablet (32 ppm Active Iodine)

An iodine disinfectant tablet designed to be dissolved in 6 mis of reducing solution was prepared having the following formulation:

1.9 mg (320 ppm) of PVP-Iodine (32 ppm active iodine) USP grade (BASF) ;

3.0 mg Maltodextrin (Maltrin ^R M040, GPC, Muscatine, Iowa)

40 mg Sodium Chloride

20 mg Tartaric Acid 5 mg Polyethylene glycol 8000 (Spectra)

22.5 mg Sodium Carbonate 5 mg Sodium Benzoate

Prior to compounding, tartaric acid was milled and passed through an 80 mesh sieve and dried 24 hours at 70 degrees C. Separately, the polyethylene glycol and sodium carbonate was also passed through an 80 mesh sieve and dried for 24 hours at 70 degrees C. Sodium chloride was passed through a 60 mesh sieve and also dried at 70 degrees C for 24 hours. Separately, the PVP-I ₂ and the maltodextrin were passed through a 200 mesh sieve. The components were combined and the mixture passed through a 30 mesh sieve. The remaining larger particles were crushed with a pestle-mortar. The combined mixture was V-blended

for 1 hour, again passed through a 60 mesh sieve, and then tableted with a 6 mm punch for a 100 mg weight.

EXAMPLE 6

Preparation of Disinfecting Tablet (32 ppm Active Iodine)

An iodine disinfectant tablet designed to be dissolved in 6 mis of reducing solution was prepared having the following formulation:

1.9 mg (320 ppm) of PVP-Iodine (32 ppm active iodine) USP grade (BASF) ;

3.0 mg Maltodextrin (Maltrin ^R M040, GPC, Muscatine, Iowa)

40 mg Sodium Chloride

20 mg Tartaric Acid 5 mg Polyethylene glycol 8000 (Spectra)

22.5 mg Sodium Carbonate 5 mg Sodium Benzoate

Prior to compounding, tartaric acid was milled and passed through an 80 mesh sieve and dried 24 hours at 70 degrees C. Separately, the polyethylene glycol and sodium carbonate was also passed through an 80 mesh sieve and dried for 24 hours at 70 degrees C. Sodium chloride was passed through a 60 mesh sieve and also dried at 70 degrees C for 24 hours. The components were combined and the mixture passed through a 30 mesh sieve. The remaining larger particles were crushed with a pestle-mortar. The

combined mixture was V-blended for 1 hour, again passed through a 60 mesh sieve, and then tableted with a 6 mm punch for a 100 mg weight.

EXAMPLE 7

Regimen

Upon removing a contact lens from the eye, 3 drops of the reducing solution of Example 1 was placed on each side of the contact lens. Two lenses were sequentially rubbed for 20 seconds. Surface debris was then removed by rinsing the lenses thoroughly with the reducing solution. The lenses were then placed into lens baskets attached to the inner cover of the lens container cap. The disinfecting tablet of Example 3 was placed into the lens container and 6 ml of reducing solution added. The lens basket was placed into the container. The tablet was effervescent and the solution turned dark blue/purple in color.

After 5 minutes, the cover was opened, the lenses temporarily removed while an additional 9 ml of reducing solution was added. The solution almost immediately became clear. The lenses were replaced into the container, and soaked for 5 minutes. The lenses were removed from the solution and placed directly on the eye.

EXAMPLE 8

Antimicrobial Activity

The antimicrobial activity of the iodophor solutions was tested by exposing the test organism at about 1.0 x 10 ⁶ to about 1.0 x 10 ⁷ colony forming units per milliliter (CFU/ l) to 10 ml. of each composition at room temperature for the intervals of 5, 15 or 20 minutes, and 30 minutes. An aliquot of each inoculated sample was removed at the measured time, diluted in a neutralizing broth (dey-Engley) and plated with neutralizing agar. The agar plates were incubated for 2 to 5 days and plate counts were determined to calculate reduction in CFU/ml. for each organisms.

A disinfecting solution made from the tablet of Example 3 was tested against the following organisms S. aureus (ATCC 6538P) , P_j_ aeruginosa (ATCC 9027) , S. marcescens (ATCC 13880) , C_j_ albicans (ATCC 10231) , and F. solani (ATCC 36031) . No viable organisms were recovered after exposure to the above-mentioned solution after 2.5 minutes.

Many other modifications and variations of the present invention are possible and will be apparent to the skilled practitioner in the field in light of the teachings herein. It is therefore understood that, within the scope of the

claims, the present invention can be practiced other than as herein specifically described.