JP3243759B2 - Antimicrobial / enzyme aqueous solution composition for cleaning and disinfecting contact lenses - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to the field of cleaning and disinfecting contact lenses, and more particularly to a method for simultaneously cleaning and disinfecting contact lenses worn on a human body and a composition used therefor.

[0002]

2. Description of the Related Art Many methods of sterilizing contact lenses have been disclosed. These methods are typically characterized in that they involve the use of heat and / or chemicals. Typical chemicals that can be used for this purpose include:
Organic antibacterial agents such as benzalkonium chloride and chlorhexidine, and inorganic antibacterial agents such as hydrogen peroxide and peroxide-forming compounds are known. U.S. Patent No. 4,
Nos. 407,791 and 4,525,346 [Stark] disclose the use of quaternary ammonium compound polymers in contact lens sterilization and preservation of contact lens care products. European Patent Application No. 18
No. 0309 [Ogunbiyi] discloses the use of biguanide polymers for the same purpose.

[0003] Numerous methods are also known for cleaning contact lenses. Some well-known methods use surfactants and enzymes to facilitate lens cleaning. The first proposal to use an enzyme with proteolytic activity to clean contact lenses was Lo.
[The Journal of the American Optical Society (Journal of
the American Optometric
Association) 40 , 1106-1109
(1969)]. Numerous methods for removing protein deposits from contact lenses by proteolytic enzymes have been published since the first report by Lo et al., For example, US Pat. No. 3,910,296 [Karageozian, et al. al)]
There is.

[0004] Many methods have been proposed for simultaneously cleaning and sterilizing contact lenses. Such methods include, for example, U.S. Pat. Nos. 3,873,696 [Randeri, et al.] And U.S. Pat.
14,127 [Fu]. A representative example of a simultaneous cleaning and disinfection method for contact lenses that includes the use of a proteolytic enzyme to remove protein deposits and a chemical disinfectant (quaternary ammonium compound monomer) is disclosed in Japanese Patent Publication No. 57-24526. No. [Boghosian, et al]. A combination method using proteolytic enzymes for washing and heating for sterilization is disclosed in European Patent Application No. 0 141 607 [Ogunbiyi] and PCT Publication No. W.
O 85/03247 [Perlma
n)]. A combination method of washing with a proteolytic enzyme and sterilizing with an inorganic bactericide (peroxide) is disclosed in US Pat. No. Re32,672 [Hus et al.
al)].

[0005]

SUMMARY OF THE INVENTION The present invention relates to an improved method for simultaneously cleaning and disinfecting contact lenses, and more particularly to an enzyme for cleaning and a very low concentration of a polymeric antimicrobial for disinfection. It relates to the use of a combination of agents. The present invention is based on the finding that combining the above antibacterial agent with an enzyme can be used very effectively for cleaning and sterilizing contact lenses under certain conditions. Previous experiments have shown that binding is likely to occur between the enzyme and the antimicrobial agent, resulting in mutual inhibition of efficacy, and cleaning and disinfection using a combination of the enzyme and the antimicrobial agent results in a large excess of one or both of the two materials. This finding is surprising given previous predictions that it would need to be used for

[0006] The present invention is derived, in part, from the knowledge of the use of certain composition types to enable the above-described enzyme-antimicrobial bonds to be removed or weakened. More specifically, the binding of the enzyme to the antimicrobial agent is a complexing agent that inhibits the binding between the enzyme and the antimicrobial agent.
agents (defined below) are substantially eliminated, maintaining the efficacy of both. Further, by maintaining the tonicity of the solution containing the antimicrobial agent isotonic or hypotonic to maximize the activity of the antimicrobial agent, and by controlling the concentrations of both the enzyme and the antimicrobial agent, Can be overcome. According to this technique,
The antibacterial agent to be used can be used at a very low concentration while maintaining the sterilizing / cleaning action of the lens.

The enzyme used in the composition of the present invention comprises:
(1) Effective in removing contact lens deposits. (2) Insufficient rinsing of washed and sterilized contact lenses causes at most minimal eye irritation, even if a small amount of enzyme remains in contact with the eyes. (3) an enzyme that is chemically stable and effective even in the presence of the polymeric antimicrobial agent described below, and (4) does not adversely affect the physical and chemical properties of the lens to be treated. There are no particular restrictions. In the present invention, an enzyme that satisfies the above requirements is “ophthalmically acceptable”.
acceptable) "enzyme.

[0008] Using the above requirements as an index, those skilled in the art of contact lens maintenance can easily list many enzymes that can be used in the present invention. In the art, it is common practice to classify enzymes based on activity, so that enzymes useful in the present invention have proteolytic activity, lipolytic activity, mucilage degrading activity, and / or amylose degrading activity. Enzymes having proteolytic activity are particularly important, as proteins can be described as enzymes and protein deposits on contact lenses are a common problem. For a detailed list of enzymes generally recognized as useful for cleaning contact lenses, see US Pat. No. 3,910,296, cited above.
No. and Re. No. 32,672. The entire contents of these two patents relating to such use of the enzyme are incorporated herein by reference.

Generally, if not all, the enzymes used in the present invention are proteins, since the deposits usually formed on human-worn contact lenses are proteins, lipids and viscous polysaccharides. Degradation activity, lipolysis activity and / or
Or it has amylose degrading activity. Examples of preferred proteolytic enzymes include pancreatin, subtilisin, papain, ficin, and bromelain. Examples of preferred lipolytic enzymes include Lipase K
-3000 and Lipase AP6 (available from Amano Corp., Troy, VA, USA) and pancreatic lipase. Examples of preferred amylose-degrading enzymes include α-amylase, β
-Amylase, aminoglucosidase (glucoamylase), fungal amylase and pullulanase. These enzymes are available from Novo Industry (Nos.) Of Bagsvaerd, Denmark.
vo Industries, Sigma, St. Louis, Mo., USA and Boehringer Mannheim, Boe, Indianapolis, Indiana, USA
(M.Hringer Mannheim) and the like. Engineers in the art are aware of other plant, animal,
It can easily be analogized that enzymes of bacterial, fungal or synthetic origin can equally be used in the present invention. Certain enzymes require a combination of stabilizers, such as acetylcysteine.

[0010] In the method of the present invention, one or more effective ones are used to substantially remove or substantially reduce the sediment composed of proteins, lipids, mucous polysaccharides and other substances on the lens. Use a certain amount of enzyme. In the present invention, such an amount is referred to as an “effective amount for cleaning the lens”. The amount of one or more enzymes used in certain embodiments of the invention depends on the type of enzyme used,
Various factors such as the time of contacting the lens with the enzyme, the nature of the lens care (eg, frequency of lens disinfection and cleaning), the type of lens being treated, and the use of auxiliary cleaning agents (eg, surfactants). It depends on. However, in general, an amount equal to or less than about 50 proteolytic activity units / ml in solution, preferably less than about 26 proteolytic activity units / ml, most preferably about 13 proteolytic activity units / ml.
One or more enzymes are used in amounts less than ml. In the present invention, "1 proteolytic activity unit" (pr
The term “oteolytic activity unit” is defined as the amount of enzyme activity required to generate tyrosine at 1 microgram (mcg) / min (mcg Tyr / min) measured by the casein digestion / colorimetric method described below.

[0011]Casein digestion analysis  Casein substrate (0.65% w / v casein)
Equilibrate 5.0 ml for 10 minutes ± 5 seconds, then dissolve enzyme
Add 1 ml of the solution (0.2 mg / ml) to the casein substrate.
The mixture is shaken with a tow and stirred for 10 minutes ± 5 seconds.
Lab. 14% Trichloro after incubation
5 ml of acetic acid is added and the mixture is immediately shaken and stirred.
You. Incubate the mixture for at least another 30 minutes.
And then centrifuge for 15-20 minutes after shaking tow (approximately
2000 rpm). Filter serum from centrifuged sample supernatant
Filter into a sampler and collect 2.0 ml of filtrate. So
5.3% sodium carbonate aqueous solution to 2.0 ml sample
Add 0 ml, shake and stir, and add 0.67N
1.0 ml of phenol reagent and immediately shake again.
Stir and then incubate at 37 ° C. for 30 minutes.
The sample is then 660 nm in a visible light spectrophotometer
(Nm) Colorimetric determination using pure water as a control. Sample concentration
It is calculated based on a comparison with a tyrosine standard curve. Fat
Degradation activity, amylose degradation activity, and / or mucilage
Enzymes with decomposing activity are usually present in solution at about 5 U.S.P.
nited States Pharmacopei
a) Use an amount equal to or less than units / ml.

In the present invention, "polymeric antibacterial agent" or "antibacterial agent" refers to any nitrogen-containing homopolymer or copolymer having antibacterial activity. The antibacterial agent is not particularly limited, but a preferable example is US Pat. No. 3,931,3.
No. 19 [Green, et al], No. 4,026,945 [Green, et al.
al)] and 4,615,882 [Stockel, et al], quaternary ammonium compound polymers, US Pat.
No. 537,746 [Ogunbiyi, et al.
et al)] and European patent application 0 180 309 [Ogunbiyi].
uanides) and the like. The contents of such foreign documents are incorporated herein by reference. Particularly preferred are the following two. (I) a quaternary ammonium compound polymer represented by the following structural formula:

Embedded image Wherein: R ₁ , R ₂ ＯＨOH, N (CH ₃ ) ₂ , or N ⁺ (CH ₂ CH ₂ OH) ₃ ; X is a pharmaceutically acceptable anion, preferably chloride; m = 0, 1 or 2 And n is a positive number determined by the number average molecular weight described below; the average molecular weight usually ranges from about 2000 to 30,000;
And preferably in the range of about 3000 to about 14000; or a mixture thereof, and (II) a biguanide polymer represented by the following structural formula or a pharmaceutically acceptable salt thereof:

Embedded image Here, the average molecular weight is usually about 500 to about 12,000.
It is in the range of 0, preferably in the range of about 500 to about 2500, and n is a positive number determined by the number average molecular weight. The use of these particularly preferred antimicrobial agents for sterilization purposes is disclosed in U.S. Pat. No. 4,407,791 [Stark (S.
star), No. 4,525,346 [Stark (S
) and European Patent Application No. 0 180 309 [Ogunbiyi], respectively. By reference to these foreign documents, the entire contents thereof are incorporated herein.

In the method of the present invention, the United States Food and Drug Administration (United States Foods and D
In accordance with the requirements of U.S. government enforcement agencies such as Rug Administration (e.g., 1985 guidelines), the antimicrobial agents described above substantially reduce or substantially reduce the number of viable microorganisms found on contact lenses. An effective amount is used. In the present specification, the above effective amount is referred to as “a sterilizing effective amount” or “an antibacterial effective amount”. The amount of antimicrobial agent used will depend on, for example, how the method of the present invention is used for lens care. For example, the effective use of the cleaner daily for cleaning the lens can substantially reduce the amount of adherents to the lens, including microorganisms, and thus reduce the amount of antimicrobial required to sterilize the lens. It also depends on the type of lens being treated (e.g., "hard" or "soft"). However, generally, one or more of the aforementioned antimicrobial agents are used at a concentration in the range of about 0.000001 to about 0.01% by weight. The most preferred concentration of the quaternary ammonium compound polymer of formula (I) is about 0.001% by weight, and the most preferred concentration of the biguanide polymer of formula (II) is about 0.00005% by weight.

As explained above, if certain conditions are maintained, even if the antimicrobial agent is extremely low in concentration, it can be effectively used in combination with one or more enzymes to form contact lenses. It has been found that washing and sterilization can be performed simultaneously. Specifically, certain low molecular weight compounds having at least one carboxyl functionality are
It has been found that it has the function of substantially reducing the binding between the positively charged antimicrobial agent and the negatively charged site in the enzyme. Although the mechanism cannot be stated with certainty, this complexing agent reduces the binding between the enzyme and the antimicrobial agent because the complexing agent binds to the antimicrobial agent and thus effects the positively charged site of the antimicrobial agent. It is believed that the antimicrobial agent blocks the antimicrobial agent from binding or complexing to the negatively charged site of the enzyme. In this way, the bactericidal activity inhibiting action of the antibacterial agent by the enzyme is effectively suppressed, so that the antibacterial agent can be used at a very low concentration. In the present invention, at least one
These low molecular weight compounds having two carboxyl functions are called "complexing agents". The complexing agent significantly enhances the action of the antimicrobial without compromising the action of enzymes present in the same solution. Solution ionic strength at isotonic or hypotonic levels
Maintaining and limiting the enzyme concentration further enhances the activity of the antimicrobial agent.

The complexing agent used is not particularly limited, but includes ethylenediaminetetraacetic acid, citric acid, acetic acid and pharmaceutically acceptable salts thereof. The amount of complexing agent used depends on several factors, such as the type of complexing agent selected and the relative concentrations of the enzyme and antimicrobial agent used. Typical concentration ranges are from about 0.03 to about 0.7 weight /
% By volume, preferably 0.05 to 0.6% by weight / volume.

It has been found that the ionic strength or osmotic power of the cleaning / sterilizing solution of the present invention is also an important factor. Specifically, it has been found that the antibacterial activity of the ammonium compound polymer, particularly the compound represented by the above formula (I), is lost as the osmotic power of the solution increases. Therefore,
The osmotic power is 150-300 milliosmol (milliOs
(mole) (mOs) / kg, more preferably in the range of 210-240 mOs / kg, the most preferred osmotic power is 220 mOs / kg. The osmolarity of a solution is affected by various components of the solution, but is usually a function of the salt concentration.

It has been found that other factors also greatly affect the simultaneous use of the enzyme and the antimicrobial agent in the present invention. In particular, in using one or more enzymes, the contact lens to be treated, the antimicrobial agent in an ophthalmically acceptable liquid (eg, saline or distilled water), the order of release into the liquid, etc. may be important. Was found. To maximize microbial germicidal activity, it is better for the lens and the antimicrobial agent to contact in the liquid before the enzyme is released into the liquid. Thus, if the enzyme is in the form of a conventional tablet (or another solution), the enzyme tablet (or solution) should be added to the solution after the lens and antimicrobial are combined in a liquid. But here, if the enzyme is a tablet with a sustained release coating,
If the release of the enzyme into the liquid occurs after the lens and antimicrobial have been combined in the liquid, the enzyme tablet may be added to the liquid at any point in the ingredient addition sequence. . In addition, it is surprising that the antimicrobial activity of the combination of the enzyme and the antimicrobial agent is much more effective when the lens is treated for a long time of about 1 hour to overnight, preferably 4 to 8 hours, compared to the use of the antimicrobial agent alone. Was found. Considering workability, this finding is of practical importance since contact lenses are usually immersed overnight for cleaning with enzymes or sterilization with chemicals.

In the present invention, both the first component and the second component may be solid or liquid. The composition of the present invention for forming an antimicrobial / enzyme aqueous solution for cleaning and disinfecting contact lenses can be implemented in various ways. For example, the two main components (the antimicrobial agent and the enzyme) can be formulated separately or used in a single formulation (see Example 2). In the case of separate formulations, the antimicrobial agent can be provided in a solid form, but is usually provided in the form of a solution. Although the enzyme detergent component can be provided in either solid or liquid form, an effervescent tablet composition is desirable in consideration of packaging and dosing. Dosage forms that allow the gradual release of the enzyme into the solution are particularly preferred. If the two are combined in a single formulation, the two components can be layered with the enzyme component as the core of the tablet and the antimicrobial agent as an outer layer around the enzyme core, and A sealant and / or sustained release coating may be interposed between the core and the outer layer antimicrobial agent.

In the embodiments of the invention described above wherein the enzyme is formulated as a sustained release tablet or the enzyme and an antimicrobial agent are combined into a single tablet, the sustained release coating comprises cellulose ether, vinyl, glycol, acrylic or the like. Any of several polymeric materials. Sustained-release coatings may additionally use propylene glycol, polyethylene glycol, glycerin, mineral oil, vegetable oil, or other known plasticizers. The seal coating may be composed of any of a number of polymeric materials such as cellulose ethers, vinyl, glycols and acrylics, and may be made of synthetic or natural gums, gelatin, shellac, salts, etc. (Eg, sodium chloride), sugar alcohols (eg, mannitol or sorbitol), or other materials commonly used as seal coating materials. The method of practicing the invention will depend on the dosage form used, but the method of Example 4 will generally apply. The following examples further illustrate various aspects of the present invention, but do not limit the present invention.

Example 1 One formulation for separately providing an antibacterial agent and an enzyme cleaning component is as follows:
Shown inA. Sterilizing solution The following composition represents a preferred germicidal solution:Ingredient (% by weight / volume)  Polyquad * 0.001 + 10% excess salt 0.48 sodium EDTA 0.05 citric acid monohydrate 0.021 sodium citrate dihydrate 0.56Sufficient amount of purified water  * Polyquad® has a number average molecular weight of 5,000
Quaternary ammonium having 7000 and represented by the formula (I)
A chloride salt of a polymer compound having a chemical name of α-4-
[1-Tris (2-hydroxyethyl) ammonium-
2-butenyl] poly [1-dimethylammonium-2-
Butenyl] -ω-tris (2-hydroxyethyl) anne
Monium chloride.

To prepare the above formulation, sodium citrate dihydrate, citric acid monohydrate, disodium EDTA, salt, and polyquad are prepared in the indicated amounts, mixed with purified water, and then mixed with a mixer. Stir to dissolve the components.
Purified water is added to the solution to make it almost 100%. pH is 6.
3, but adjust to 7.0 with caustic soda. Purified water is added to bring the solution to 100%. Stir the solution to pH 7.
Get a value of 0. The solution is then filtered and placed in a sterile container,
Put on the cap.

B. Enzyme Detergent Tablets The following compositions represent preferred enzyme detergent ingredient tablets: The above components are mixed and a tablet having an appropriate size and hardness is formed by a known conventional method. The tablets may also be formulated with a seal coating and / or a sustained release coating such that dissolution may require up to about 2 hours.

[0023]Example 2  A single dosage form containing both an antimicrobial agent and an enzyme is shown below.Ingredient Amount Enzyme detergent core (Mg / tablet) Pancreatin (6X) 1.38 * Citric acid (anhydrous) 4.0 Sodium bicarbonate 8.5 Polyethylene glycol (3350 powder) 2.0 Lactose 42.5Seal coat section(% By weight) Hydroxymethylcellulose 5.0 Ethanol (USP, dehydrated) 75.8 Purified water 19.2Sustained release coating(% By weight) Acrylic ester (30% solid content weight / weight) 29.7 Polyethylene glycol (8000) 1.0 Purified water 69.3Fungicide coating(% By weight) Polyquad ** 0.16 Salt 4.8 Hydroxypropyl methylcellulose 0.8 [2910, E-5 Premium]Purified water 94.24  * To 105.5 + 10% excess mcg tyrosine / min
Equivalent ** registered trademark

In order to form a nucleus consisting of an enzyme detergent, pancreatin, polyethylene glycol and lactose were prepared in the above amounts, mixed in a blender for 5 minutes, citric acid was added and mixed for another 5 minutes, and then sodium bicarbonate was added. Add and mix for an additional 20 minutes. The granules thus obtained are placed on a rotary tabletting machine equipped with a suitable mold.
The tablet is compressed into tablets using an appropriate size and 5 to 10 Strong Cobb units (Strong-C).
obb units (representing the force required to crush the tablet). The tablets are then coated in the following order: seal coat (2.5% increase in tablet weight), sustained release coat (17.5% increase in tablet weight), and fungicide coat (3.6% increase in tablet weight). Each coating solution is similarly prepared by mixing the components until a homogeneous mixture is obtained. Each coating solution is applied by spraying the coating solution onto the tablet while rotating the tablet.
After each coating solution is applied, the tablets are dried before applying the next coating solution. It is better to carry out all the steps of preparing tablets under low humidity conditions (20% or less relative humidity).

[0025]Example 3  The bactericidal efficacy of the composition of the present invention was determined by inoculating six species in the logarithmic growth phase.
Measures the sterilization rate and degree of sterilization for the original (microorganism)
Evaluate by doing. The six microorganisms used are as follows
is there:Staphylococcus Epidermidis(Sta
phylococcus epidermidis),
Pseudomonas Aeruginosa(Pseudomon
as aeruginosa),Serratia Marsesen
S(Serratia marcescens),Can
Jida Albicans(Candida albican
s),Aspergillus Fumigatus(Aspergi
lplus fumigatus)as well asHerpes Simp
Rex(Herpes simplex).

0.1 ml of the inoculum was used as the sterilizing solution 1 of Example 1.
0 ml, then 50 mg of the enzyme detergent of Example 1
Add one tablet. Example 1 inoculated similarly
10 ml of a germicide solution as a control. The solution is kept at room temperature during the experiment. Each microorganism is tested individually. The number of samples is 4 (n = 4) for each microorganism, except for herpes simplex, where the number of samples is 2 (n = 2).

At 0, 1, 4, 8, and 24 hours, 1 ml was taken from the inoculation test solution and sterilized.
Dilute to the required concentration with% saline. Pour flat media using soy-casein digested agar containing 0.07% Azolectin and 0.5% Polysorbate 80. Elapsed time 0
In, 1.0 ml of saline control was collected,
Make a series of pour flat plates using the same collection media and diluent. The count in the saline control at time 0 is used as the initial value. 30 pour plate
Incubate at ~ 35 ° C for a predetermined time. The number of surviving microorganisms at each time is measured. Stumbo method [Stambo, C.I. R. (Stumbo, C .;
R. ), “Research Methods for Resistance of Bacterial Spores in High Temperature Range”
(A Technique for Studying
Resistance of Bacterial
Spores to Temperature in
the Higher Range, Food Technology 2 228, 1
948] to obtain the D-value per time. The results are summarized in Tables I-VI below and are plotted in FIGS.

[0028] Table I es. Epidermidis (S. Ep
bactericidal activity sample against Idermidis ) Time (hr) Log reduction 1 2.0 Enzyme Detergent in Disinfectant Solution 4 3.6 8 4.0 24 5.1 5.1 ----------------------------------------- −−−−−−− Control disinfectant solution 1 2.2 4 3.0 8 3.5 24 4.2

[0029] Table II peak. Aeruginosa ( P.
Bactericidal activity sample against Aluginose ) Time (hr) Log reduction 1 2.2 Enzyme detergent in germicide solution 4 3.2 8 4.2 24 6.5 6.5 ------------------------------------------- −−−−−−− Control disinfectant solution 1 2.8 4 3.3 8 3.4 24 5.4

Table III S. Marcessance ( S.
marcescens) bactericidal activity sample time for the (hr) logarithmic decrement rate 1 0.4 Enzyme detergent in disinfectant solution 4 1.5 8 2.6 24 5.2 ------------------------------------------- −−−−−−− Control disinfectant solution 1 0.44 0.98 1.3 24 2.9

[0031] Table IV Sea. Albicans (C. A
Ibicans ) Bactericidal activity sample of the composition against time (hr) Log reduction 10.3 Enzyme detergent in disinfectant solution 4 0.38 0.3 24 0.9 ------------------------------------------------- −−−−−−− Control disinfectant solution 1 0.34 0.78 0.7 0.7 24 0.9

Table V A. Fumigatus ( A. fu)
bactericidal activity sample of the composition against M. igatus time (hr) Log reduction 10.3 Enzyme detergent in disinfectant solution 4 0.2 8 0.3 24 0.2 ------------------------------------------------------------ −−−−−−− Control germicide solution 1 0.4 4 0.4 8 0.4 24 0.5

Table VIHerpes Simplex
(Herpas simplexKilling the composition against)
Bacterial activitySample time (min) Log reduction rate  5 0.7 Enzyme detergent in germicide solution 10 0.7 20 0.7 60 4.0 240 4.0 480 4.0 ---------------------------------- −−−−−−−−−−−−−−− Control disinfectant solution 5 0.3 10 0.3 20 0.3 60 0.5 240 1.0 1.0 480 1.3

The average D values (see Table VII) of the compositions comprising the combination of the enzyme detergent and the disinfectant solution and the control disinfectant solution are described in S.D. Epidermidis and P. Aerugino
Less than or equal to 0.5 hours for the service, S.. Ma
Less than or equal to 2.5 hours for lusences ,
Sea . Less than or equal to 3.9 hours for C. albicans, er. For Fumigatus , less than or equal to 3.4 hours. For herpes simplex , the average D-value of a composition comprising a combination of an enzyme detergent and a germicide solution is less than one-fourth that of a germicide solution control.

S. Epidermidis , S. Marces
Sense , sea . Albicans and A. For Fumigatus there is no statistically significant difference between the D value control of the composition comprising the enzyme detergent-disinfectant solution combination and the D value of the disinfectant solution. P. Small but statistically significant difference between D values for Aeruginosa (Table II) (0.1 h)
Is calculated. However, this difference is not considered significant microbiologically. Further, the combination composition is
It can be seen that the bactericidal and virucidal effects are faster overall than the control bactericide solution.

Table VII D value summaryAverage D value (hr) ± SD ¹  In the disinfectant solutionMicrobial enzyme detergent control analysis S .Epidermidis0.5 ± 0.1 0.5 ± 0.1 t = 1.24 (6.0)^Two  n = 4^Threen = 4 p = 0.13Pea .Aeruginosa0.5 ± 0.0^Four0.4 ± 0.0 t = 4.35 (6.0) n = 4 n = 4 p = 0.00S .Marcessance2.5 ± 0.7 2.3 ± 0.7 t = 0.28 (6.0) n = 4 n = 4 p = 0.40C .Albicans3.9 ± 0.3 3.4 ± 0.6 t = 1.59 (6.0) n = 4 n = 4 p = 0.08A .Fumigatus3.4 ± 1.1 2.6 ± 0.4 t = 1.32 (6.0) n = 4 n = 4 p = 0.12Herpes Simplex0.17,0.38 2.9,2.0n = 2 n = 2 ¹  Standard deviation (Standard deviation)
n)^Two Degrees of freedom^Three Number of test repetitions^Four The 0.00 value is for truncation.

Significantly statistically significant between the composition comprising the enzyme detergent-disinfectant solution combination and the control disinfectant solution is the difference in log reduction from the mean D value. Comparison of the actual log reduction rate using a single, specific time for microbial kill rather than comparison of the D value, since the D value is calculated from the initial value of the log reduction rate and therefore does not take into account any further reductions. Allows a more accurate calculation of the antimicrobial activity.

As it is apparent from the figure, the enzyme cleaners - the difference between the initial logarithmic decrement index between the composition comprising disinfectant solution combined with the control disinfectant solution is a slight, Sea. Albi
Kansu and A. The difference in log reduction after about 2 hours is significant for all microorganisms tested with the exception of Fumigatus . By comparing the areas under the curves, it can be seen from the enzyme-bactericide solution combination that the composition has a greater bactericidal activity than the D-value comparison indicates.

[0039]Example 4  About 10 ml of the disinfectant solution of Example 1 is placed in a suitable container.
You. Contact lenses to be cleaned and sterilized first
Wash with a common cleaning solution such as a composition containing
Rinse with liquid and place in disinfectant solution. Next, the yeast of Example 1
Add one 50 mg tablet of plain detergent. This tablet kills
Dissolves easily in bacterial solution (about 3 minutes). Remove the lens
Allow enough time for washing and sterilization in the solution, for example, 4 to 8 hours, or
Or soak overnight. Then take out the lens and saline solution
Rinse the immersion liquid. Enzyme into solution containing antibacterial agent
In the embodiment of the present invention using a means for gradually releasing
The method used involves adding the lens to be treated to a solution of the enzyme.
Method except that it can be done at the same time
Similar.

The above method can be used with minor modifications to the composition of Example 2. Instead of the disinfectant solution of Example 1, a saline solution or other suitable diluent (eg, distilled water) is used. Dissolve the tablet of Example 2 containing both the fungicide and the enzyme in saline solution or other diluent,
The lens to be treated is immersed in the solution. The lens can be added to the solution before or simultaneously with the addition of the tablet.
According to the broader aspects of the invention, the invention is not limited to the specific details shown and described above. Without departing from the principles of the invention and without diminishing its advantages, the above details may be modified within the scope of the appended claims.
It is possible to change .

[Brief description of the drawings]

[Figure 1] es. The relationship between the number of surviving Epidermidis and the contact time (hr) is shown.

FIG. 2 is a copy. Aeruginosa survival and contact time (h
r).

[Figure 3] es. Marcessance survivors and contact time (h
r).

[Figure 4] Sea. Albicans survival and contact time (h
r).

[Figure 5] er. Survival number of Fumigatus and contact time (h
r).

FIG. 6 shows the relationship between the number of surviving herpes simplex and the contact time (min).

[Explanation of symbols]

◇-◇-◇ indicates a control. +-++-indicates an enzyme-bactericide solution.

──────────────────────────────────────────────────の Continuation of front page (72) Barry F. inventor. Van Dougy, United States, Texas 76087, Willow Park, Fairway Drive, 204 (72) Inventor Rajkumar Batia United States, Texas 76017, Arlington, Deer Lodge Court, 4511 (56) References JP-A-2-289255 (JP, A) (58) Field surveyed (Int. Cl. ⁷ , DB name) G02C 13/00 A61L 2/18

Claims (17)

(57) [Claims] An antibacterial agent / enzyme comprising a first component comprising a polymeric antibacterial agent and a complexing agent in an amount effective for disinfecting contact lenses, and a second component comprising an ophthalmologically acceptable proteolytic enzyme. In a composition for forming an aqueous solution, the polymer type antibacterial agent of the first component is a nitrogen-containing homopolymer or copolymer; the amount of the complexing agent of the first component is a predetermined amount of the composition From about 0.03 to about 0.7% w / v in the solution when the article is dissolved in a sufficient amount of an ophthalmically acceptable liquid to wash contact lenses and form an aqueous antimicrobial / enzyme solution. An amount sufficient to provide a concentration of the complexing agent, wherein the complexing agent is selected from the group consisting of citric acid, ethylenediaminetetraacetic acid, acetic acid, and pharmaceutically acceptable salts thereof; The amount of proteolytic enzyme that can be tolerated is approximately 26% in the solution. An amount sufficient to provide an enzyme concentration of less than whitening activity units / ml; the first component and the second component are separately stored prior to use, and the ionic strength of the antimicrobial / enzyme aqueous solution is isotonic or An antimicrobial / enzyme aqueous solution forming composition for cleaning and disinfecting hypotonic contact lenses; wherein the polymeric antimicrobial comprises: (a) a number average molecular weight in the range of about 2,000 to about 30,000. And a quaternary ammonium compound polymer represented by the following structural formula (I): X is a pharmaceutically acceptable anion; m = 0, 1 or 2, and n each represent a positive number determined by the number average molecular weight; and (b) in the range of about 500 to about 120,000. A biguanide polymer having the number average molecular weight and represented by the following structural formula (II), or a pharmaceutically acceptable salt thereof: n is a positive number determined by the number average molecular weight, and is selected from the following: 2. The concentration of the polymer type antibacterial agent in the solution,
The composition of claim 1, wherein the composition ranges from about 0.000001 to about 0.01% w / v. 3. The polymer type antibacterial agent has a number average molecular weight of 5,
The composition according to claim 1 or 2, wherein the composition is a chloride salt of a quaternary ammonium compound polymer represented by the formula (I) having a molecular weight of 000 to 7,000. 4. The method according to claim 3, wherein the concentration of the chloride salt of the quaternary ammonium compound polymer represented by the formula (I) in the solution is about 0.001% by weight / volume. Composition. 5. The composition according to claim 1, wherein the polymer type antibacterial agent is a mixture of a quaternary ammonium compound polymer represented by the formula (I). 6. The polymer type antibacterial agent has a number average molecular weight of about 5
3. The composition according to claim 1, wherein the composition is a biguanide polymer having the formula (II) and a pharmaceutically acceptable salt thereof. 7. The composition of claim 6, wherein the concentration of the biguanide polymer in the solution is about 0.00005% w / v. 8. The tablet according to claim 8, wherein said second component is in the form of a tablet, said tablet comprising a core part comprising an enzyme and a coating part outside said core, said coating part comprising said enzyme when said tablet is added to said first component. 8. The composition according to claim 1, which acts to delay the release of the enzyme from the nucleus. 9. A method for simultaneously cleaning and disinfecting a contact lens by immersing the contact lens in an antibacterial / enzyme aqueous solution, comprising an effective amount of a nitrogen-containing homopolymer or copolymer for disinfecting the contact lens. A polymer-type antibacterial agent comprising:
Selected from the group consisting of citric acid, ethylenediaminetetraacetic acid, acetic acid, and pharmaceutically acceptable salts thereof in an amount sufficient to provide a concentration of about 0.03-0.7% w / v in the aqueous enzyme solution. A contact lens is immersed in an aqueous solution in which a first component comprising a complexing agent is dissolved: either before or after the contact lens immersion, a proteolytic enzyme as an ophthalmically acceptable second component,
An amount is provided to provide a concentration of less than about 26 proteolytic activity units / ml in the aqueous solution to form the antimicrobial / enzyme aqueous solution; A method for washing and disinfecting a contact lens by immersing the contact lens for a sufficient time for washing and disinfection, wherein the ionic strength of the antibacterial agent / enzyme aqueous solution is isotonic or hypotonic. The polymer-type antibacterial agent is (a) a quaternary ammonium compound polymer having a number average molecular weight in the range of about 2,000 to about 30,000 and represented by the following structural formula (I): X is a pharmaceutically acceptable anion; m = 0, 1 or 2, and n each represent a positive number determined by the number average molecular weight; and (b) a number ranging from about 500 to about 120,000. Biguanide polymers of average molecular weight represented by the following structural formula (II), and pharmaceutically acceptable salts thereof: wherein n is a positive number determined by the number average molecular weight. 10. The method of claim 9, wherein the concentration of the polymeric antimicrobial agent in the antimicrobial / enzyme aqueous solution ranges from about 0.000001 to about 0.01% w / v. the method of. 11. The polymer type antibacterial agent is a chloride salt of a quaternary ammonium compound polymer having a number average molecular weight of 5,000 to 7,000 and represented by the formula (I). Item 10. The method according to Item 9. 12. The antimicrobial / enzyme aqueous solution,
The method according to claim 11, wherein the concentration of the chloride salt of the quaternary ammonium compound polymer represented by the formula (I) is about 0.001% by weight / volume. 13. The polymer type antibacterial agent is a biguanide polymer represented by the formula (II) having a number average molecular weight of about 500 to about 2,500 or a pharmaceutically acceptable salt thereof. The method according to claim 9, wherein 14. The method of claim 13, wherein the concentration of the biguanide polymer in the aqueous antimicrobial / enzyme solution is about 0.00005% w / v. 15. A method of washing and disinfecting contact lenses simultaneously, comprising immersing the contact lenses in an antimicrobial / enzyme aqueous solution, wherein the aqueous solution comprises (a) the polymer of claim 3. About 0.001% by weight, or (b) about 0.00005% by weight of the polymer of claim 6.
And an aqueous solution containing an antibacterial agent selected from 0.03 to 0.7% by weight / volume of a complexing agent selected from the group consisting of citric acid, ethylenediaminetetraacetic acid, acetic acid, and pharmaceutically acceptable salts thereof. A sterilizing solution; and further comprising a proteolytic enzyme selected from pancreatin and subtilisin, such that the aqueous sterilizing solution has a concentration equal to or less than about 26 proteolytic activity units / ml. The contact lens is immersed in the resulting antibacterial agent / enzyme aqueous solution for a time sufficient for cleaning and disinfecting the lens, and the ionic strength of the antibacterial agent / enzyme aqueous solution is isotonic or hypotonic. Wherein the proteolytic enzyme is provided in a form contained in an enzymatic cleaning composition, wherein the enzymatic cleaning composition comprises approximately 1.3.
8 mg pancreatin (6X), approximately 5.95 mg citric acid, approximately 13.135 mg sodium bicarbonate, approximately 0.415 mg povidone, approximately 0.75
mg of polyethylene glycol (3350) and an enzyme-washing component tablet containing a sufficient amount of tableting sugar to make a total amount of 50 mg. 16. The sustained-release coating is applied to the protease so that it takes 2 hours for the protease to dissolve in the antibacterial / enzyme aqueous solution. 16. The method according to any of 15 above. 17. A method for simultaneously cleaning and disinfecting contact lenses, comprising a quaternary ammonium compound polymer having a number average molecular weight of 5,000 to 7,000 and represented by the following structural formula (I): 0.001% w / v + 10% excess chloride chloride, 0.48% w / v sodium chloride, 0.05% w / v% disodium EDTA, 0.0% citric acid monohydrate
21% w / v, 0.1% sodium citrate dihydrate.
Pour 10 ml of a sterile solution containing 56% w / v and a sufficient amount of purified water to a final volume of 10 ml into a container, immerse contact lenses in the sterile solution, and add approximately 1 .38 mg pancreatin
(6X), approximately 5.95 mg citric acid, approximately 13.
135 mg of sodium bicarbonate, approximately 0.415 mg
Dissolve 50 mg of an enzyme wash component tablet containing povidone, approximately 0.75 mg of polyethylene glycol (3350), and a sufficient amount of tableting sugar to make a total amount of 50 mg to form an antimicrobial / enzyme aqueous solution And immersing the contact lens in the antimicrobial / enzyme aqueous solution for a time sufficient to clean and disinfect the lens: X is a pharmaceutically acceptable anion; m = 0, 1 or 2, and n each represents a positive number determined by the number average molecular weight.