JP2001163709A - Liquid agent for ophthalmic use and liquid agent for contact lens - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a liquid agent for ophthalmia use and a liquid agent for contact lens containing a cationic polymer exhibiting effective bactericidal activity and antibacterial activity at a concentration lower than the effective concentration of conventional cationic polymer, giving low stimulation and having high safety to ocular mucous membrane. SOLUTION: The liquid agent for ophthalmic use and the liquid agent for contact lens contain a cationic polymer expressed by formula [1] (R is a 2-6C heteroalkylene group or hydroxyl-containing heteroalkylene group; Y is a 2-10C alkylene; A- is an anion; and (n) is 40-500).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an ophthalmic solution and a contact lens solution. More specifically, the present invention relates to an ophthalmic solution and a contact lens solution containing a cationic polymer having an effective antibacterial or bactericidal property even at a low concentration and having high safety for ocular mucosa.

[0002]

2. Description of the Related Art A disinfectant or an antibacterial agent is usually added to an ophthalmic solution in order to suppress the growth of bacteria and to have an antiseptic effect. Conventionally, various compounds have been used for the purpose of preservation, and examples thereof include p-hydroxybenzoate and benzalkonium chloride.
However, these compounds are known as causative substances that cause allergies and irritants to the ocular mucosa, and at concentrations that exhibit sufficient bactericidal and antibacterial effects, ocular mucosa such as corneal opacity and eyelid conjunctival hyperemia. May cause irritation or irritation and may be safer
At present, antibacterial agents are desired. In addition, various agents are used as disinfectants, antibacterial agents, and preservatives for contact lenses so that the contact lenses can be used safely, comfortably, and conveniently. As antimicrobial agents, low molecular weight quaternary ammonium compounds are most commonly used, but are known to be irritating to the eyes and cause hypersensitivity. In addition, since this compound is a low-molecular compound, it is adsorbed or absorbed by a contact lens, and wearing of such a contact lens may cause ocular mucosal irritation or hypersensitivity. Various compounds have been tried to improve the disadvantages of low molecular weight quaternary ammonium compounds as antibacterial agents. For example, JP-A-63-131124
Japanese Patent Application Laid-Open Publication No. 2000-181873 has a sufficient antibacterial property even in a small amount, does not adversely affect ocular tissues, is highly safe for living organisms, and is used for contact lenses using a sterilizing component having a high molecular weight that is not absorbed in the lens. As a liquid composition, a liquid composition for contact lenses containing a condensate containing diamines and dihalides as main components has been proposed. JP-A-5-502874 discloses poly (oxyethylene (dimethylimineio) as a safe and effective composition that can be used as a contact lens disinfectant and preservative, and as a preserved contact lens care agent. Non-oxidizable compositions containing ionene polymers having oxygen atoms covalently bonded to two carbon atoms, such as ethylene (dimethyliminio) ethylene dichloride) have been proposed. It is known that these cationic polymers are less irritating to the skin and mucous membranes and less adsorbed, absorbed, and retained on contact lenses as compared with low molecular weight quaternary ammonium compounds. However, these cationic polymers require a high concentration of contact in order to obtain sufficient antibacterial properties, resulting in reduced safety on the user's ocular mucosa, increased adsorption to contact lenses, There has been a problem that the residue easily causes damage such as irritation of the eye mucosa.

[0003]

DISCLOSURE OF THE INVENTION The present invention contains a cationic polymer having a bactericidal and antibacterial property which is effective at a lower concentration than conventional cationic polymers, and has low irritation.
An object of the present invention is to provide an ophthalmic solution and a contact lens solution which are highly safe for ocular mucosa.

[0004]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, a quaternary ammonium polymer having a high degree of polymerization having a heteroalkylene structure in the main chain has been reduced. It has been found that it exhibits effective bactericidal and antibacterial properties at a concentration and is effective as a component of ophthalmic solutions and contact lens solutions. Based on this finding, the present invention has been completed. That is, the present invention provides (1) an ophthalmic solution containing a cationic polymer represented by the general formula [1],

Embedded image (Wherein, R is a heteroalkylene group having 2 to 6 carbon atoms or a heteroalkylene group having a hydroxyl group, Y is an alkylene group having 2 to 10 carbon atoms, A ⁻ is an anion, and n is 40-500), (2)
The weight average molecular weight of the cationic polymer is 10,000 to
2. The ophthalmic solution according to item 1, which is 50,000, and (3) containing 0.0001 to 2 parts by weight of a cationic polymer represented by the general formula [1] based on 100 parts by weight of an aqueous medium. An ophthalmic solution, (4) a solution for a contact lens comprising a cationic polymer represented by the general formula [1],

Embedded image (Wherein, R is a heteroalkylene group having 2 to 6 carbon atoms or a heteroalkylene group having a hydroxyl group, Y is an alkylene group having 2 to 10 carbon atoms, A ⁻ is an anion, and n is 40 to 500), and
(5) The weight average molecular weight of the cationic polymer is 10,000
5. The liquid preparation for a contact lens according to item 4, wherein the liquid preparation is from 00 to 50,000. Further, as a preferred embodiment of the present invention, (6) a method for cleaning a contact lens, wherein the liquid preparation for a contact lens according to item 4 is brought into contact with the contact lens, and (7) a method for contact lens according to item 4. A method for disinfecting a contact lens, which comprises contacting the solution with the contact lens,
And (8) the contact lens solution according to item 4,
And a method for storing a contact lens, which is characterized by being brought into contact with a contact lens.

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The ophthalmic solution and contact lens solution of the present invention contain a cationic polymer represented by the general formula [1].

Embedded image In the general formula [1], R is a heteroalkylene group having 2 to 6 carbon atoms or a heteroalkylene group having a hydroxyl group, Y is an alkylene group having 2 to 10 carbon atoms,
A ^- is an anion, and n is 40 to 500. The heteroalkylene group having 2 to 6 carbon atoms or the heteroalkylene group having a hydroxyl group is not particularly limited, but the hetero atom is preferably oxygen or sulfur. Examples of such a heteroalkylene group include a 3-oxapentylene group represented by the formula [2] and a 3,5 represented by the formula [3].
-Dioxaheptylene group, 3-thiopentylene group represented by the formula [4], and the like. Examples of the heteroalkylene group having a hydroxyl group include, for example, 2-hydroxy represented by the formula [5]. -3-oxapentylene group and the like. _{-CH 2 CH 2 OCH 2 CH 2} - ... [2] -CH 2 CH 2 OCH 2 OCH 2 CH 2 - ... [3] -CH 2 CH 2 SCH 2 CH 2 - ... [4] -CH 2 CH (OH ) OCH ₂ CH ₂ -... [5] The alkylene group having 2 to 10 carbon atoms is not particularly limited, and any of a linear alkylene group and a branched alkylene group can be used. Examples of such an alkylene group include an ethylene group, a propylene group, a butylene group, a hexamethylene group, an octamethylene group, and a decamethylene group. The anion represented by A ⁻ is not particularly limited as long as it is an anion that forms a quaternary ammonium salt. For example, a chloride ion, a bromine ion,
Inorganic anions such as iodine ion, sulfate ion, nitrate ion, phosphate ion, and carbonate ion, and organic anions derived from acids such as formic acid, acetic acid, propionic acid, gluconic acid, lactic acid, fumaric acid, and adipic acid. it can. Among them, chlorine ions can be suitably used. N in the general formula [1] is an average degree of polymerization of the cationic polymer. The average polymerization degree n can be determined by measuring the average molecular weight of the cationic polymer and dividing by the molecular weight of the repeating unit. If n is less than 40, the antibacterial property against bacteria becomes insufficient, and irritation to the ocular mucosa may occur. If n exceeds 500, the viscosity of the cationic polymer increases, and the workability may be poor.

The method for producing the cationic polymer represented by the general formula [1] is not particularly limited. For example, N, N, N ', N'
-It can be produced by a polymerization reaction of a tetramethylalkylenediamine and a dihaloheteroalkylene compound. For N, N, N ', N'-tetramethylalkylenediamine, the alkylene chain may be linear or branched, for example, tetramethylethylenediamine, tetramethylpropylenediamine, tetramethylhexamethylenediamine, and the like. Can be mentioned. Examples of dihaloheteroalkylene compounds include, for example, di (chloromethyl) ether, bis (1-chloroethyl) ether,
(2-chloroethyl) ether, 1,2′-dichlorodiethylether, bis (3-chloropropyl) ether,
(Chloromethyl) formal, bis (2-chloroethyl) formal, 1,2-bis (chloroethoxy) ethane, 1.5
-Dichloro-2-hydroxy-3-oxapentane and the like. These polymerization reactions are 60 to 1
It is preferably performed at 50 ° C. In the ophthalmic solution and the contact lens solution of the present invention, the weight average molecular weight of the cationic polymer represented by the general formula [1] is 8,000.
~ 50,000, preferably 20,000 ~ 4
More preferably, it is 0.000. If the weight average molecular weight is less than 8,000, the antibacterial property against bacteria becomes insufficient, and irritation to the ocular mucosa may occur. If the weight average molecular weight exceeds 50,000, the viscosity of the cationic polymer will increase, and the workability may be poor. The cationic polymer represented by the general formula [1] exhibits effective bactericidal and antibacterial properties at a low concentration and has low irritation to the ocular mucosa and high safety. Therefore, the ophthalmic solution, for example, a preservative for eye drops It can be suitably used as such. Further, the cationic polymer represented by the general formula [1] has a high degree of polymerization and is therefore hardly adsorbed or absorbed by a contact lens, and can be suitably used as a component of a contact lens solution. Liquid lenses for contact lenses are quaternary in addition to the cationic polymer represented by the general formula [1] in order to be used as various liquids such as cleaning agents, antibacterial agents or disinfectants, and preservatives. An aqueous solution can be prepared by adding components such as an ammonium compound, a surfactant, an enzyme, a buffer, a tonicity agent, a thickener, a chelating agent, and a builder. In the case of preparing an aqueous solution, for example, after sufficiently mixing and dissolving various components in distilled water or purified water and dissolving, the pH and the osmotic pressure are adjusted, and the solution can be filtered to obtain a liquid agent for contact lenses. .

[0007] The ophthalmic solution of the present invention preferably contains 0.0001 to 2 parts by weight of a cationic polymer represented by the general formula [1] based on 100 parts by weight of an aqueous medium.
More preferably, the content is 0.001 to 1 part by weight.
If the content of the cationic polymer is less than 0.000001 parts by weight based on 100 parts by weight of the aqueous medium, the antibacterial properties may be insufficient. When the content of the cationic polymer exceeds 2 parts by weight based on 100 parts by weight of the aqueous medium, irritation to the ocular mucosa may appear. The contact lens solution of the present invention may be used as it is, or may be used after being prepared as a concentrated solution, appropriately diluted with distilled water or purified water. The cationic polymer represented by the general formula [1] is preferably contained in an amount of 0.0001 to 2 parts by weight, more preferably 0.001 to 1 part by weight, based on 100 parts by weight of the aqueous medium. Examples of the quaternary ammonium compound to be added to the contact lens solution of the present invention include N-alkyl-N, N-dimethyl-N-benzylammonium chloride (for example, a benzyl chloride having an alkyl group having 8 to 17 carbon atoms). Ruconium), benzethonium chloride, alkylpyridinium chloride and the like. Examples of the surfactant to be added to the contact lens solution of the present invention include alkylene oxide adducts of higher alkylamines, alkylene oxide adducts of higher fatty acid amides, alkylene oxide adducts of higher fatty acids, and alkylene oxide additions of higher fatty acids. Nonionics such as esters of products with polyhydric alcohols, esters of higher alcohols, esters of alkylphenols, sucrose monofatty acid esters, or alkylene oxide adducts such as castor oil, hydrogenated castor oil, polyethylene glycol sorbitan alkyl esters, and sterols Surfactant, sodium alkylbenzenesulfonate, sodium alkylsulfate, sodium alkyloylmethyltaurine, sodium alkyloylsarcosine, α-olefinsulfonic acid sodium Potassium, polyoxyalkylene alkyl ether sulfate can be cited polyoxyalkylene alkyl ether sodium phosphate, anionic surfactants such as polyoxyalkylene alkyl phenyl ether sulfate and the like. One of these surfactants can be used alone, or two or more thereof can be used in combination.

The enzyme to be added to the contact lens solution of the present invention includes, for example, proteolytic enzymes such as pancreatin, trypsin, aminopeptidase, keratinase and amylase. One of these enzymes can be used alone, or
Two or more kinds can be used in combination. Examples of the buffer added to the contact lens solution of the present invention include boric acid, phosphoric acid, citric acid, lactic acid, amino acid, malic acid, and sodium salts thereof. One of these buffers may be used alone, or two or more thereof may be used in combination. Examples of the tonicity agent added to the contact lens solution of the present invention include sodium chloride, potassium chloride, calcium chloride and the like. One of these tonicity agents can be used alone, or two or more can be used in combination. Examples of the thickener added to the contact lens solution of the present invention include polyvinyl alcohol, polyethylene glycol, polyacrylamide or a hydrolyzate thereof, celluloses such as hydroxyalkylcellulose or derivatives thereof, dextran, gelatin, gum arabic, Gums such as tragacanth gum; One of these thickeners can be used alone, or two or more can be used in combination. Examples of the chelating agent to be added to the contact lens solution of the present invention include ethylenediaminetetraacetic acid, phytic acid, citric acid, and water-soluble salts thereof. One of these chelating agents can be used alone, or two or more can be used in combination. The cationic polymer having a high degree of polymerization used in the ophthalmic solution and the contact lens solution of the present invention exhibits excellent antibacterial properties even at a low concentration, and the irritancy to the ocular mucosa is low molecular weight quaternary ammonium conventionally used. It is much lower than compounds and cationic polymers with low degrees of polymerization.
Furthermore, since the cationic polymer used in the present invention has a high degree of polymerization, it is not adsorbed or absorbed by contact lenses. Therefore, the liquid preparation for contact lenses of the present invention exhibits excellent performance in cleaning, disinfecting, and preserving contact lenses.

[0009]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, which should not be construed as limiting the present invention. The weight average molecular weight of the cationic polymer was determined using a gel permeation chromatograph (GPC) [Tosoh Corporation, HLC-8120GPC] and using an acetate buffer (pH 4.7) as an eluent. It was determined by conversion. Further, the minimum bactericidal concentration (MBC (ppm)) was measured by the following method to evaluate bactericidal properties. (1) Test bacteria S. aureus (ATCC 653
8P)), methicillin-resistant Staphylococcus aureus (MRSA)
(IID 1677)), methicillin-resistant Staphylococcus aureus (MRSA (clinical isolate)), E. coli (E. coli)
(IFO 3301)), Klebsiella pneumoniae (K. pneumo)
niae (IFO ATCC 4352)), Pseudomonas aeruginosa (P. aeruginosa (IFO 3080)) and Serratia bacteria (S. marcescens (clinical isolate)). (2) Preparation of Test Bacterial Solution One platinum loop of the test bacterium was inoculated into 8 mL of Soybean Casein Digest (SCD) medium, and cultured at 37 ° C. for 18 hours, and 1 mL of the culture was diluted 10-fold with SCD medium. . Further, 2 mL of this diluted solution was brought into contact with 100 mL of SCD medium, and cultured at 37 ° C. for 2 hours (however, Pseudomonas aeruginosa was 4 hours) to obtain a test bacterial solution. MRSA (IID1677)
And 10 ⁴ to 10 ⁵ cells / mL (10 ⁴ to 10 ⁵ CFU / mL) for the test bacterial solution of MRSA (clinical isolate), and 10 ⁵ to 10 ⁶ cells / mL for the other test bacterial solutions. 10 ⁵ ~
10 ⁶ CFU / mL). (3) Operation method For a 40% by weight aqueous solution of a cationic polymer and benzalkonium chloride, a two-fold dilution series was prepared with physiological saline,
10 mL of each diluted solution was dispensed into a test tube, and sterilized in an autoclave to prepare a specimen. 0.1 mL of the test bacterial solution prepared in advance was added to each sample, mixed and contacted for 1 minute.
The inoculum was added to and mixed with three SCD-LP media (9 mL each) which had been sterilized in advance. This at 37 ° C for 2
After culturing for 0 hour, the presence or absence of turbidity of the medium was evaluated. If the culture medium is transparent, the growth of bacteria is not recognized-
If it became cloudy, it was determined that the bacterium had grown, and was determined as +, and two or more of the three were used. -The determined minimum concentration was defined as the minimum bactericidal concentration (MBC (ppm)). The lower the minimum germicidal concentration, the more bactericidal. Further, the irritation to the ocular mucosa was evaluated by the following method. Japanese white male rabbits (10-11 weeks old) were conditioned at room temperature 23 ± 2 ° C. and humidity 55 ± 1.
After pre-breeding at 5% for one week, the test was performed. A 40 wt% solution of the cationic polymer and benzalkonium chloride was diluted with physiological saline to prepare 1 wt%, 0.01 wt% and 0.001 wt% solutions. These solutions were instilled into one eye of each rabbit and 200 μL of physiological saline was instilled into the other eye using a micropipette, and the state of the ocular mucosa after 3 hours was observed. It was evaluated based on: Corneal condition 0; transparent, no turbidity. 1: There is diffuse or diffuse turbidity. 2: There is a translucent area that can be easily identified. 3: Emulsification is observed. 4: white turbidity is observed. Eyelid conjunctiva status 0; no hyperemia. 1: very reddish. 2; clearly hyperemia beyond normal. 3: The redness of the eyelid mucosa is very remarkable. Ocular mucosal condition 0; no hyperemia. 1: The blood vessels around the cornea slightly expand. 2: causes more pronounced vasodilation. 3: Dilation of blood vessels running toward the lid margin is remarkably observed.

Example 1 50 g of water, 25 g of N, N, N ', N'-tetramethyl-1,3-propylenediamine and 27 g of bis (2-chloroethyl) ether were mixed and reacted at 95 ° C. for 30 hours. Thereafter, 28 g of water was added to adjust the concentration of the obtained cationic polymer to 40% by weight. The weight average molecular weight of this cationic polymer was 32,000, and the value of n in the general formula [1] was 117. This cationic polymer solution was evaluated for bactericidal properties and irritation to the ocular mucosa. Example 2 50 g of water, 25 g of N, N, N ', N'-tetramethylhexamethylenediamine and 21 g of bis (2-chloroethyl) ether were mixed and reacted at 100 ° C for 48 hours.
The concentration of the cationic polymer obtained by adding 19 g of water was 4
It was adjusted to 0% by weight. The weight average molecular weight of this cationic polymer is 35,000, and n in the general formula [1]
Was 111. This cationic polymer solution was evaluated for bactericidal properties and irritation to the ocular mucosa. Example 3 A mixture of 50 g of water, 23 g of N, N, N ', N'-tetramethyl-1,3-propylenediamine and 37.5 g of 83% by weight bis (2-chloroethyl) formal was mixed at 56 ° C at 100 ° C.
After reacting for an hour, 25 g of water was added to adjust the concentration of the obtained cationic polymer to 40% by weight. The weight average molecular weight of this cationic polymer was 25,400, and the value of n in the general formula [1] was 84. This cationic polymer solution was evaluated for bactericidal properties and irritation to the ocular mucosa. Comparative Example 1 50 g of water, 25 g of N, N, N ′, N′-tetramethyl-1,3-propylenediamine and 27 g of bis (2-chloroethyl) ether were mixed, reacted at 60 ° C. for 72 hours, and then mixed with water. The concentration of the cationic polymer obtained by adding 28 g was adjusted to 40% by weight. The weight average molecular weight of this cationic polymer was 7,500, and the value of n in the general formula [1] was 27. This cationic polymer solution was evaluated for bactericidal properties and irritation to the ocular mucosa. Comparative Example 2 40% by weight of poly (oxyethylene (dimethyliminio) ethylene (dimethyliminio) ethylenedichloride) having a weight average molecular weight of 2,500 and a value of n in the general formula [1] of 9.7. An aqueous solution was prepared. This cationic polymer solution was evaluated for bactericidal properties and irritation to the ocular mucosa. Comparative Example 3 A 40% by weight aqueous solution of benzalkonium chloride was prepared and evaluated for bactericidal properties and irritation to the ocular mucosa. Table 1 shows the evaluation results of the bactericidal properties of Examples 1 to 3 and Comparative Examples 1 to 3, and Table 2 shows the evaluation results of the irritation to the ocular mucosa.

[0011]

[Table 1]

As shown in Table 1, the high polymerization degree of the cationic polymers of Examples 1 to 3 was lower than that of Comparative Examples 1 and 2 for all the test bacteria. Shows excellent bactericidal properties at concentrations
And Pseudomonas aeruginosa shows more excellent bactericidal activity than the widely used benzalkonium chloride of Comparative Example 3.

[0013]

[Table 2]

As can be seen from Table 2, the cationic polymer having a high degree of polymerization of Example 1 showed no turbidity or hyperemia in all the tests and low irritation to the ocular mucosa. The cationic polymer having a low degree of polymerization of 1 to 2 has irritation to the ocular mucosa at a concentration of 0.01% by weight or more, and the benzalkonium chloride of Comparative Example 3 which is widely used shows strong irritation to the ocular mucosa. ing.

[0015]

The cationic polymer having a high degree of polymerization used in the ophthalmic solution and the contact lens solution of the present invention exhibits excellent antibacterial properties even at a low concentration, and has an irritation to the ocular mucosa.
It is much lower than conventionally used low molecular weight quaternary ammonium compounds and low polymerization degree cationic polymers. Furthermore, since the cationic polymer used in the present invention has a high degree of polymerization, it is not adsorbed or absorbed by contact lenses. Therefore, the liquid preparation for contact lenses of the present invention exhibits excellent performance in cleaning, disinfecting, and preserving contact lenses.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (reference) G02C 13/00 G02C 13/00 F term (reference) 2H006 DA08 4C076 AA12 BB24 CC10 EE13 EE23 EE60 FF56 FF67 4H003 BA12 DA16 EB38 ED02 FA02 FA34 4H011 AA02 BA01 BB04 BB19 BC18 DA12 DD07 DG05 4J002 CM001 DE026 FD310 FD330 GB00 GB01 HA04

Claims (5)

[Claims] 1. An ophthalmic solution containing a cationic polymer represented by the general formula [1]. Embedded image (Wherein, R is a heteroalkylene group having 2 to 6 carbon atoms or a heteroalkylene group having a hydroxyl group, Y is an alkylene group having 2 to 10 carbon atoms, A ⁻ is an anion, and n is 40 to 500.) 2. The cationic polymer has a weight average molecular weight of 1
2. The ophthalmic solution according to claim 1, wherein the amount is from 000 to 50,000. 3. A cationic polymer represented by the general formula [1]: 0.0001 to 2 based on 100 parts by weight of an aqueous medium.
The ophthalmic solution according to claim 1, which contains parts by weight. 4. A liquid preparation for a contact lens, comprising a cationic polymer represented by the general formula [1]. Embedded image (Wherein, R is a heteroalkylene group having 2 to 6 carbon atoms or a heteroalkylene group having a hydroxyl group, Y is an alkylene group having 2 to 10 carbon atoms, A ⁻ is an anion, and n is 40 to 500.) 5. The cationic polymer has a weight average molecular weight of 1
The liquid preparation for a contact lens according to claim 4, which has a molecular weight of 000 to 50,000.