Background of the Invention:

The present invention relates to the field of ophthalmology. More particularly, the invention is directed to compositions and methods for disinfecting contact lenses.

Contact lenses are exposed to a broad spectrum of microbes during normal wear and become soiled relatively quickly. Routine cleaning and disinfecting of the lenses are therefore required. Although the frequency of cleaning and disinfecting may vary somewhat among different types of lenses and lens care regimens, daily cleaning and disinfecting is normally required. Failure to clean, disinfect and store the lens properly can lead to a multitude of problems ranging from mere discomfort when the lenses are being worn to serious ocular infections. Ocular infections caused by particularly virulent microbes, such as pseudomonas aeruginosa, can lead to loss of the infected eye(s) if left untreated or if allowed to reach an advanced stage before treatment is initiated. It is therefore extremely important that patients disinfect their contact lenses in accordance with the regimen prescribed by their optometrist or ophthalmologist.

Various types of systems are currently available for disinfecting contact lenses. The systems most frequently utilized involve the use of: 1) heat; 2) hydrogen peroxide; or 3) a chemical agent other than hydrogen peroxide. The present invention is directed to the provision of an improved hydrogen peroxide disinfection system.

Hydrogen peroxide, and other peroxides, such as sodium perborate, are well known antimicrobial agents, and have been employed as such in various fields, including the field of contact lens disinfection. However, the use of peroxides in the disinfection of contact lenses has been complicated by one significant drawback. Peroxides are very toxic to the cornea of the eye. Consequently, if peroxides are not completely removed from the disinfected contact lenses prior to reinsertion of the lenses in the eyes, severe ocular

irritation can result. This problem has required special systems for ensuring that all of the peroxide is neutralized following disinfection of the lenses.

United States Patent No. 3,912,451 describes the use of a transition metal, such as platinum, as a catalyst to accelerate the decomposition of hydrogen peroxide. This type of system has been marketed for several years under the name AOSept® (CibaVision). The system is relatively expensive, and the platinum disk used as the neutralizing component is susceptible to being contaminated by proteins or other debris. Such contamination may effectively destroy or limit the ability of the disk to neutralize hydrogen peroxide.

The use of catalase to neutralize hydrogen peroxide enzymatically is described in United States Patent No. 4,585,488. This type of system has also been utilized in commercial hydrogen peroxide disinfection systems, such as the Lensan® system marketed by CibaVision. Although more economical than the platinum disk system, the prior catalase- based systems are rather inconvenient to use, because once the lens is disinfected, it is necessary to remove it from the hydrogen peroxide solution and place it in a separate solution containing catalase.

There have been attempts to improve the convenience of catalase-based systems by placing the catalase in a coated tablet, so as to delay die release of catalase into a solution. Such systems are described in United States Patent No. 5,011,661. A commercial system of this type is sold by Allergan, Inc., under the name Ultracare®. The inclusion of the neutralizing agent in a delayed-release tablet improves the convenience of the system, since a tablet is generally easier to use than a solution. Also, the delayed-release tablet can be added direcdy to the hydrogen peroxide solution at the beginning of the disinfection step. This eliminates the additional steps of removing the disinfected lenses from the hydrogen peroxide solution and placing the lenses in a separate catalase solution. However, the prior delayed-release catalase tablets do not provide for preservation of the solution containing the contact lenses once the hydrogen peroxide is neutralized. More specifically, the prior art tablets do not include an agent having sustained antimicrobial activity, and consequently are not capable of preventing recontamination of the lens by microorganisms during storage of the lens in the neutralized solution following the disinfection and neutralization steps. Viable microorganisms have been found to be present in 30 to 70% of contact lens cases. The risk of recontamination is therefore significant. Such recontamination of the lenses may

be highly detrimental to the vision of the patient, particularly when the regrowth involves Pseudomonas aeruginosa.

Systems which utilize hydrogen peroxide neutralizing agents other than catalase are also known. For example, United States Patent No. 4,521,375 describes the use of sodium pyruvate as the neutralizing agent, and United States Patent No. 4,880,601 describes the use of sodium thiosulfate for this purpose.

The above-described neutralization systems are generally expensive and/or complicated to use. Moreover, as discussed above, once the hydrogen peroxide is neutralized, there is a risk that the lenses can be contaminated by microorganisms before being removed from the neutralizing solution. Thus, there is a need for an improved peroxide disinfection system which is economical, convenient and safe. The present invention is directed to satisfying this need.

Summary of the Invention:

The present invention is based on the discovery that the inclusion of boric acid and glycine in a composition containing a hydrogen peroxide neutralizing agent, such as catalase, results in a superior hydrogen peroxide disinfection system. The system is believed to be superior to prior systems in several respects, but the ability of the system to ensure that the neutralizing solution does not become contaminated by microorganisms, particularly pathogenic microorganisms such as Pseudomonas aeruginosa, is considered to be one of the most significant improvements provided by the present invention.

The hydrogen peroxide disinfecting system of the present invention also contributes to the removal of deposits from contact lenses and helps to prevent deposits from forming. Contact lenses accumulate deposits which are predominantly proteins and lipids. Divalent cations present in tear films, such as calcium and magnesium, may also become a part of the deposits, and thereby form complex deposits which are even more difficult to remove.

Consequently, formulations for cleaning contact lenses typically contain a chelating agent, such as EDTA, in order to prevent the formation of such deposits. The presence of glycine in the hydrogen peroxide disinfection system of the present invention helps to reduce the formation of complex deposits involving divalent cations. This is an incidental, but significant advantage of the invention.

Other advantages of the present invention will be apparent to those skilled in the art based on d e description of the preferred embodiments of the invention presented below.

Description of Preferred Embodiments:

The improved hydrogen peroxide disinfecting system of the present invention includes a disinfection component and a neutralization component.

The disinfection component is a solution containing hydrogen peroxide in a concentration of from about 0.05 to about 5.0 percent by weight/volume ("w/v%"). The most preferred concentration is about 3 w/v%. As will be appreciated by those skilled in the art, the hydrogen peroxide solution may be formed by dissolving a solid peroxide, such as sodium perborate or persulfate, in an aqueous solution. The disinfection component may therefore be provided in the form of a tablet, granules or powder containing a solid peroxide which is dissolved in an aqueous solution at the time of use. However, the use of a hydrogen peroxide solution as the disinfection component is preferred.

The neutralization component is preferably formulated as a tablet, granules or powder, but may also be formulated as a liquid. The neutralization component includes a hydrogen peroxide neutralizing agent, boric acid and glycine. Examples of the neutralizing agents which may be utilized in the present invention include catalase, sodium pyruvate and sodium thiosulfate. The preferred hydrogen peroxide neutralizing agent is catalase. The most preferred neutralization component of the present invention is a delayed release tablet which contains catalase, boric acid and glycine.

The neutralization component will be utilized in an amount sufficient to totally decompose all hydrogen peroxide remaining after disinfection of the lenses. The amount of neutralizing agent required for this purpose will vary depending on various factors, such as the peroxide concentration, the neutralizing agent selected, and the length of time in which the neutralization step is to be completed. The most preferred neutralizing agent, catalase, will generally be utilized in an amount of from about 500 to about 10,000 activity units, preferably about 1,000 to about 5,000 activity units. The latter range is particularly appropriate for neutralization of a 3.0 w/v% hydrogen peroxide solution by catalase derived from a mammalian source. Sodium pyruvate will generally be utilized in an amount of from about 100 milligrams ("mg") to about 1 gram ("g"), and sodium thiosulfate will generally

be utilized in an amount of from about 140 mg to about 1.4 g. The amounts of other neutralizing agents required can be readily determined by those skilled in the art. The foregoing amounts of neutralizing agents may be utilized to neutralize 10 milliliters ("ml") of a 0.3 to 3.0 w/v% hydrogen peroxide solution. The neutralization component is preferably formulated so as to provide for delayed release of the neutralizing agent into the hydrogen peroxide disinfecting solution. As will be appreciated by tiiose skilled in the art, the delayed release of the neutralizing agent can be achieved by various means, such as film-coated tablets, tablets made by compressing film-coated granules, matrix tablets, dry powder compression tablets, layered tablets, gelatin capsules filled with powder or granules, and gelatin capsules filled with coated granules. A tablet wherein the neutralizing agent is contained in an inner core surrounded by a layer of retardant material is preferred.

In addition to the neutralizing agent, the neutralization component contains boric acid and glycine. Boric acid serves as an antimicrobial agent when dissolved in the hydrogen peroxide disinfecting solution. The antimicrobial activity of boric acid helps to ensure that the solution containing the disinfected contact lenses does not become contaminated with microbes following neutralization of the hydrogen peroxide. Thus, the boric acid serves as an antimicrobial preservative. As noted above, this is believed to be a particularly important aspect of the present invention, and is believed to represent a significant improvement relative to prior hydrogen peroxide disinfection systems. The glycine also contributes to this aspect of the invention. More specifically, the glycine produces a significant enhancement in the antimicrobial activity of the boric acid. In addition, as mentioned above, the glycine helps to remove and or prevent complex deposits of proteins and lipids involving divalent cations. Boric acid and glycine will generally be utilized in amounts of from about 0.1 to about 3.0 w/v%.

The boric acid and glycine also increase the bulk and density of the neutralization component. It is highly desirable for the neutralization component to be more dense than the hydrogen peroxide solution in which the contact lenses are contained, so that the neutralizing agent will be present in the bottom of the container. If the neutralization component is not relatively dense, it will tend to float in the hydrogen peroxide solution, particularly if the solution becomes effervescent when the neutralizing agent begins to

dissolve. This is potentially a problem, since the neutralizing agent may not be adequately dispersed in the hydrogen peroxide solution to neutralize all of the hydrogen peroxide if the tablet or capsule only releases d e neutralizing agent in the upper portion of the container. The neutralization component of the present invention therefore contains boric acid and glycine in amounts sufficient to ensure that me density of this component is greater tiian that of the hydrogen peroxide solution in which it is to be placed.

It is not necessary for the release of die boric acid and glycine from the neutralization component to be delayed. However, delayed release is preferred. The boric acid and glycine are therefore preferably included in die inner core of a multi-layer tablet or in the coated particles of a matrix tablet, along with die neutralizing agent.

The neutralization component of die present invention will preferably also include one or more coating agents to retard (i.e., delay) the release of the neutralizing agents in solution. As will be appreciated by tiiose skilled in die art, various materials can be utilized as die coating agents. Such coating agents can be generally described as being cellulose derivatives, such as hydroxy propyl methyl cellulose ("HPMC"), or synd etic polymers, such as polyacrylic acid polymers. These polymers are commercially available. For example, HPMC is available from Aqualon under the name "Klucel™" and polyacrylic acid polymers are available from Rohm Tech, Inc. under the name "Eudragit™".

The amount of coating agent required may vary considerably depending on d e particular coating agent selected and the form of d e neutralization component (i.e., tablets, or encapsulated granules or powders). One or more coating agents will be utilized in an amount sufficient to delay die release of die neutralizing agent in die hydrogen peroxide solution until disinfection of die contact lenses is either completed or substantially completed. The neutralization component may also contain miscellaneous ingredients, such as antifoaming agents (e.g., Pluronic™ L61, a nonionic surfactant; simethicone; or tributyl phosphate), tonicity-adjusting agents (e.g., mannnitol) and buffers (e.g., phosphates, borates or citrates). The use of a borate/polyol buffering system is preferred. As used herein, d e term "borate" shall refer to boric acid, salts of boric acid and other pharmaceutically acceptable borates, or combinations tiiereof. Most suitable are: boric acid, sodium borate, potassium borate, calcium borate, magnesium borate, manganese borate, and otiier such

borate salts. As used herein, the term "polyol" refers to any compound having at least two adjacent -OH groups which are not in trans configuration relative to each otiier. The polyols can be linear or circular, substituted or unsubstituted, or mixtures thereof, so long as die resultant complex is water-soluble and pharmaceutically acceptable. Such compounds include sugars, sugar alcohols, sugar acids and uronic acids. Preferred polyols are sugars, sugar alcohols and sugar acids, including, but not limited to: mannitol, glycerin, propylene glycol and sorbitol. Especially preferred polyols are mannitol and glycerin; mannitol is most preferred. The use of borate-polyol complexes in ophthalmic compositions is described in copending, commonly assigned United States Patent Application Serial No. 08/198,427 filed February 21, 1994, and in corresponding PCT International Application Number

PCT/US93/04226 (International Publication Number WO 93/21903); the entire contents of die foregoing applications are hereby incorporated in the present specification by reference.

The above-described hydrogen peroxide disinfection system may be utilized to disinfect contact lenses in accordance witii techniques known to diose skilled in d e art. Such techniques generally involve placing the lenses in a hydrogen peroxide solution, adding a delayed-release neutralizing tablet to that solution, and then allowing die lenses to soak in die solution a length of time sufficient to disinfect the lenses and to neutralize die hydrogen peroxide. The amount of time required to complete tiiis process may vary between different embodiments of die invention, but will generally be from about ten minutes to about two hours.

Although the neutralizing component of the above-described system is preferably provided as a delayed-release tablet for purposes of convenience, it is also possible to utilize die neutralization component of die present invention in otiier forms. For example, tiiis component can be formulated as conventional tablets or solutions which do not provide for delayed release of die neutralizing agent into solution. In tiiese embodiments of die invention, die neutralization component is added to the hydrogen peroxide solution after disinfection is completed. Although tiiese embodiments of die invention are somewhat less convenient, die principal benefits of die invention, particularly die preservative effect of die boric acid and glycine in die neutralizing solution, are retained.

The present invention are further illustrated by die following examples.

Example 1

The following formulation represents an example of a particularly preferred embodiment of die present invention, wherein d e neutralization component is provided as a delayed release tablet, witii die neutralizing agent contained in an inner core of d e tablet along witii the boric acid and glycine.

Inner Core

Ingredient Amount (per tablet

Catalase 5000 IU Boric acid 100 mg

Glycine 50 mg Pluronic™ L61 0.3 mg Povidone 1.2 mg Sodium Carbonate 2.5 mg PEG 3350 4.5 mg

The inner core may be prepared as follows. First, half of die boric acid is granulated by mixing with the surfactant (i.e., Pluronic™ L61) in alcohol. The remainder of die boric acid is then combined widi die glycine and granulated by mixing with the povidone in alcohol. Botii of the granulated mixtures are dried overnight in an oven at approximately 50°C. The dried granules are tiien passed dirough a Fitz mill equipped widi a size 20 sieve. The catalase and sodium carbonate are then combined widi die sieved granules and blended for 30 minutes. The polyethylene glycol (i.e., PEG 3350) is dien added, and the resulting mixture is blended for 5 minutes. The mixture is tiien compressed into a tablet.

Outer Layer Ingredient Amount (per tablet)

Klucel™ EF 10 gm

Purified water q.s.100 gm

The outer layer may be formed by dissolving die HPMC (i.e., Klucel EF) in the purified water at 70°C, using constant stirring. After allowing die solution to cool to room temperature, it is filtered dirough a size 50 mesh. The filtered solution is then sprayed on die inner core tablet in small quantities, wid die inner core tablet being dried after each application of polymer.

Example 2 Experiments were conducted to compare the antimicrobial activity of the hydrogen peroxide contact lens disinfection system of die present invention to that of other systems. The experiments involved five (5) different neutralizing components, all of which were formulated as delayed release tablets. The compositions of four of the tablets are shown below:

Amount

Ingredient Formula A Formula B

Catalase 0.715 mg 0.715 mg

Sodium Chloride 85.0 mg 85.0 mg

Sodium Phosphate, Dibasic 14.0 mg 14.0 mg

Pluronic™ L60 0.5 mg 0.5 mg

Povidone 0.8 mg 0.8 mg

PEG 3350 3.0 mg 3.0 mg

Klucel™ - - 20.0 mg

Eudragit™ 6.0 mg -

Amount

Ingredient Formula C Formula D

Catalase 0.715 mg 0.715 mg Boric Acid 100.0 mg 100.0 mg Glycine 50.0 mg 50.0 mg Pluronic™ L61 0.3 mg 0.3 mg Povidone 1.2 mg 1.2 mg Sodium Carbonate 2.5 mg 2.5 mg PEG 3350 4.5 mg 4.5 mg Klucel™ 26.0 mg Eudragit™ 7.5 mg

Formulations A and B represent examples of conventional neutralizing tablets containing catalase as the neutralizing agent and sodium chloride as a major excipient for tonicity adjustment. Formulations C and D represent examples of the neutralization component of the present invention, wherein the sodium chloride has been replaced by boric acid and glycine. The fiftii tablet utilized in die experiments was die UltraCare™ neutralizing tablet marketed by Allergan Optical. This tablet contains catalase and sodium chloride, and is otiierwise generally similar in composition to Formulations A and B above.

The antimicrobial activity of the above-described tablets was evaluated as follows. Each tablet was allowed to neutralize 10 ml of 3% hydrogen peroxide. Each of die neutralized solutions was then inoculated widi a titer of 1.0 x 10 ³ microorganisms (i.e., Staph. aureus, Pseudomonas aeruginosa and Aspergillus niger). Samples of die solutions were taken at 6, 24 and 168 hours and die microbial population of die solutions were calculated based on tiiese samples. The results are presented below:

Time Formula A Formula B Ultra Care Sa Pa An Sa Pa An Sa Pa An

Initial 1.0 x lO ³ 1.0 x lO ³ 1.0 x lO ³ 1.0 x lO ³ 1.0 x 10 ³ 1.0 x lO ³ 1.0 x 10 ³ 1.0 x lO ³ 1.0 x 10 ³

6 rs. 4.3 x 10 ³ 5.2 x 10 ³ 1.7 x 10 ³ 4.9 x 10 ³ 3.2 x 10 ³ 2.4 x 10 ³ 5.7 x 10 ³ 3.6 x 10 ³ 2.7 x 10 ³

24 hrs. 5.1 x 10 ³ 6.06 10 ^s 1.9 x 10 ³ 6.2 x 10 ³ 2.5 x 10 ⁵ 3.1 x 10 ³ 3.9 x 10 ³ 2.1 x 10 ^s 1.4 x 10 ³

168 hrs. 8.8 x 10 ³ 5.6 x 10* 2.5 x 10 ³ 1.5 x 10 ³ 6.5 x 10 ⁶ 2.4 x 10 ³ 5.8 x 10 ² 6.9 x 10 ⁶ 2.0 x 10 ³

LOG REDUCTION

Time Formula A Formula B Ultra Care

Sa Pa An Sa Pa An Sa Pa An

Initial 1.0 x lO ³ 1.0 x 10 ³ 1.0 x lO ⁵ 1.0 x 10 ³ 1.0 x lO ³ 1.0 x 10 ³ 1.0 x 10 ³ 1.0 x lO ³ 1.0 x 10 ³

6 hrs. 4.4 x 10 ³ 4.9 x 10 ³ 3.5 x 10 ² 4.4 x 10 ⁵ 4.4 x 10 ³ 3.5 x 10 ² 5.7 x 10 ³ 3.6 x 10 ³ 2.7 x 10 ³ 24 hrs. 3.7 x 10 ³ 3.1 x 10 ³ 1.4 x lO ² 4.9 x 10 ³ 8.4 x 10 ³ 1.4 x 10 ² 3.9 x 10 ³ 2.1 x 10 ⁵ 1.4 x 10 ³

168 hrs. 1.4 x 10 ³ 4.6 x 10 ² 2.5 x 10 ² 3.6 x 10 ² 8.5 x 10 ² 3.2 x 10 ² 5.8 x 10 ² 6.9 x 10' 2.0 x 10 ³

Note: Sa = Slap, aureus

Pa = Pseudomonas aeruginosa

An = Aspergillus niger

The foregoing results show tiiat die conventional neutralizing components (i.e., Formulas A, Formula B and UltraCare™) have a comparable microbiological profile. More specifically, all diree of tiiese compositions demonstrated an inability to restrain the growth of Pseudomonas aeruginosa in the neutralized solutions. In fact, this organism proliferated in die solutions containing tiiese compositions. The results obtained witii die compositions of the present invention (i.e., Formulations C and D) show tiiat these compositions not only prevented die proliferation of Pseudomonas aeruginosa, but actually reduced the number of viable organisms.