JP2550036B2 - Liquid composition for contact lens - Google Patents

Description

TECHNICAL FIELD The present invention relates to a liquid composition for contact lenses, which is used for cleaning, preserving or disinfecting medical devices such as contact lenses, for example, preservatives and cleaning agents. Available as a wash preservative or disinfectant.

[Conventional technology]

Contact lenses should be removed from the eye on a regular basis, washed and stored. For more information, contact lenses
During use, stains such as proteins, lipids or calcium, which are secretions in the eye, adhere to the lens surface.To remove these stains, you must clean thoroughly with a contact lens cleaning agent. I won't. Further, in order to always keep the contact lens in the best condition even after the contact lens is removed from the eye, it is necessary to immerse the contact lens in the contact lens preservative and store it.

In recent years, contact lens cleaning preservatives having both cleaning and preserving effects have been developed.

In addition, especially with respect to hydrous contact lenses, bacteria may be present on the lens surface and the inside thereof, and therefore it is necessary to disinfect them regularly. Boiled disinfection is obligatory in Japan, but there are cases in which chemical disinfection methods using disinfectants are also accepted overseas.

Preservatives for contact lenses, cleaning agents, or liquid agents such as cleaning preservatives must have antibacterial properties so that bacteria and the like do not propagate in the liquid agents while they are used. In particular, preservatives and washing preservatives are indispensable to have antibacterial properties from the viewpoint of keeping contact lenses, which are medical devices, for a long time so as not to be contaminated by bacteria and the like.

Therefore, such liquid agents usually contain a bactericidal component capable of exhibiting antibacterial properties.

Liquids for conventional contact lenses include thimerosal,
Sorbic acid, boric acid, chlorhexidine gluconate,
Bactericidal components such as benzalkonium chloride were used.

However, since these bactericidal components have a low molecular weight, the bactericidal components are likely to penetrate and be sorbed into the lens, especially for water-containing contact lenses. And if you wear contact lenses that have sterilized components sorbed,
Not only does it cause unpleasant stimuli to the eyes, but it may cause harmful effects on the eye tissue.

Further, JP-A-55-13778 proposes an invention relating to a water-soluble polymer having a quaternary ammonium group. The harmful water-soluble polymer is used for preparing a sterilizing solution for storage of artificial prostheses such as contact lenses. However, even with the water-soluble polymer, the effectiveness of antibacterial action and safety against living bodies are still insufficient, and it is not satisfactory.

[Problems to be solved by the invention]

Due to this background, even a trace amount has sufficient antibacterial properties,
A contact that uses a sterilizing component with a high molecular weight that is not sorbed into the lens even if it is highly safe for the living body and does not cause damage to the eye tissue, and is even more hydrated. A liquid agent composition for lenses has been proposed.

[Means for solving problems]

Therefore, the present inventor has conducted intensive studies in view of the drawbacks of the prior art, and as a result, found that the present invention is extremely effective in solving the above-mentioned problems, and completed the present invention.

That is, the present invention has the general formula (I): (In the formula, R ₁ , R ₂ , R ₃ and R ₄ are each independently C _m H
_{2m + 1} (m is an integer of 1 to 6), R ₅ is C _n H _2n (n is 2
A diamine represented by
General formula (II): (In the formula, R ₆ and R ₇ are each independently C _m H _{2m + 1} (m is the same as above), and R ₈ and R ₉ are independently C _n H
_2n (n is the same as above) and a diamine represented by the general formula (III): (Wherein, R ₁₀ independently represents C _n H _2n (n is the same as above)) and a diamine selected from the diamines represented by the general formula (IV): X ₁ -R ₁₁ -X ₂ (IV) (wherein, X ₁ and X ₂ are each independently chlorine, bromine or iodine, R ₁₁ is C _h H _2h-i (OH) _i (h is an integer of 2 to 18,
i represents an integer of 0 to 3) or the formula: The present invention relates to a liquid composition for contact lenses, which contains a condensate essentially containing a dihalogen compound represented by

[Action]

The condensate (A) used in the liquid composition for contact lenses of the present invention is a cationic polymer having a quaternary nitrogen atom in the polymer main chain. The quaternary nitrogen atom in the polymer main chain usually pairs with an anion derived from an inorganic or organic acid to form a quaternary ammonium salt. The presence of this quaternary nitrogen atom kills the bacteria and the like that have come into contact with the condensate (A). That is, the condensate (A) is a bactericidal component that exhibits an effective antibacterial action. Further, since the condensate (A) has a high molecular weight, it is not sorbed in a lens such as a water-containing contact lens.

[Structure of Invention]

First, the diamines and dihalogen compounds, which are the essential main components of the condensate (A), will be described.

The diamines include the following general formula (I) and general formula (I
Examples thereof include diamines selected from the group consisting of compounds represented by formula (I) and general formula (III).

(In the formula, R ₁ , R ₂ , R ₃ , R ₄ , R ₆ or R ₇ are each independently C _m H
_{2m + 1} (m is an integer of 1 to 6), R ₅ , R ₈ , R ₉ or R ₁₀ are each independently C _n H _2n (n is an integer of 2 to 18)] Specifically, Examples of diamines represented by the general formula (I) include, for example, N, N, N ', N'-tetramethyl-1,2-diaminoethane, N, N, N', N'-tetramethyl-1. , 3-diaminopropane, N, N, N ', N'-tetramethyl-1,4-diaminobutane, N, N, N', N'-tetramethyl-1,5-diaminopentane, N, N, N ', N'-tetramethyl-1,6-diaminohexane, N, N, N', N'-tetramethyl-1,10-diaminodecane, N, N, N ', N'-tetramethyl-1 , 12-Diaminododecane, N, N, N ', N'-tetramethyl-1,18-diaminooctadecane, N, N, N', N'-tetraethyl-1,2
-Diaminoethane, N, N, N ', N'-tetraethyl-1,3-
Diaminopropane, N, N, N ', N'-tetraethyl-1,6-
Diaminohexane, N, N, N ', N'-tetrapropyl-1,2
-Diaminoethane, N, N, N ', N'-tetrapropyl-1,3
-Diaminopropane, N, N, N ', N'-tetrapropyl-
1,6-diaminohexane, N, N, N ', N'-tetrahexyl-1,2-diaminoethane, N, N, N', N'-tetrahexyl-1,3-diaminopropane, N, N , N ', N'-tetrahexyl-1,6-diaminohexane, N, N'-diethyl-N, N'
-Dimethyl-1,2-diaminoethane, N, N'-diethyl-
N, N'-dimethyl-1,3-diaminopropane, N, N'-diethyl-N, N'-dimethyl-1,6-diaminohexane, N,
N-diethyl-N ', N'-dimethyl-1,2-diaminoethane, N, N-diethyl-N', N'-dimethyl-1,3-diaminopropane, N, N-diethyl-N ', N ′ -Dimethyl-1,6
-N, N, N ', N'-tetraalkyldiaminoalkanes such as diaminohexane, and examples of diamines represented by the general formula (II) include, for example, N, N'-dimethylpiperazine, N, N '-Diethylpiperazine, N, N'-dipropylpiperazine, N, N'-dibutylpiperazine, N, N'-
Dipentylpiperazine, N, N'-dihexylpiperazine, N-ethyl-N'-methylpiperazine, N-methyl-N'-propylpiperazine, N-ethyl-N'-propylpiperazine, N, N'-dimethylhomopiperazine, N,
N'-diethylhomopiperazine, N, N'-dipropropylhomopiperazine, N, N'-dihexylhomopiperazine and other N, N'-dialkylpiperazines are mentioned, and diamines represented by the general formula (III) Examples of trialkylenediamine such as triethylenediamine, tri (trimethylene) diamine, tri (tetramethylene) diamine, and tri (hexamethylene) diamine. One or more of these may be selected and used.

Examples of the dihalogen compound include dihalogen compounds selected from the group consisting of compounds represented by the following general formula (IV).

X ₁ —R ₁₁ —X ₂ (IV) [wherein, X ₁ or X ₂ is each an independent halogen atom selected from chlorine, bromine, or iodine, and R ₁₁ is C _h H _2h-i (OH) _i (h
Is an integer of 2 to 18, i is an integer of 0 to 3) or Specifically, examples of the dihalogen compound represented by the general formula (IV) include, for example, 1,2-dichloroethane, 1,3-dichloropropane, 1,6-dichlorohexane and 1,12-dichlorododecane. , 1,2-dibromoethane, 1,3-dibromopropane, 1,4-dibromobutane, 1,5-dibromopentane, 1,6-dibromohexane, 1,10-dibromodecane,
1,12-dibromododecane, 1,18-dibromooctadecane, 1-bromo-2-chloroethane, 1-bromo-3-
Chloropropane, 1-bromo-6-chlorohexane, 1
Examples thereof include dihalogenoalkanes such as -bromo-12-chlorododecane; aromatic ring-containing dihalides such as xylylene dichloride and xylylene dibromide. One or more of these may be selected and used.

To obtain the condensate (A), it is synthesized as follows.
For example, diamines, a mixture essentially containing a dihalogen compound as a main component is dissolved in a suitable solvent such as alcohols represented by methanol, ethanol, butanol or N, N-dimethyl sulfoxide, and the like,
The reaction is carried out at a temperature of not higher than 0 ° C, preferably 50 to 90 ° C for several hours to several tens of hours. Then, the reaction mixture is poured into a large amount of ethers represented by diethyl ether, the formed precipitate is washed with a small amount of ether, and dried to obtain a purified condensate (A).

As for the use ratio of these components, it is preferable to use the diamines and the dihalogen compound in equimolar amounts. because,
Theoretically, diamines and dihalogen compounds react alternately, and the diamines and dihalogen compounds have a molar ratio of 1: 1.
This is because an alternate condensate obtained by the condensation reaction of is obtained. However, the molar ratio of the amount of the diamines to the amount of the dihalogen compound used is not necessarily 1: 1 and the ratio of each component used may be an arbitrary molar ratio depending on the purpose.

The proportion of the condensate (A) used in the liquid composition for contact lenses varies depending on the intended use, and is appropriately used. For example, when used as a preservative, detergent or cleaning preservative, 0.001 ~
0.00001% (W / V), preferably 0.0005 to 0.00005% (W / V
V), and when used as a disinfectant or the like, 0.01 to 0.0001% (W / V) in an aqueous solution state, preferably 0.005 to 0.
It is 0005% (W / V).

The contact lens solution composition of the present invention is a preservative,
In addition to the condensate (A), a buffer, a tonicity agent, a thickener, a surfactant, a chelating agent, or a condensate (A) for use as a liquid agent such as a cleaning agent, a cleaning preservative, or a disinfectant. Other components such as a builder are appropriately added to prepare an aqueous solution or granules.

In the case of preparing an aqueous solution, various components are sufficiently mixed and stirred in distilled water or purified water to dissolve them, and then pH, osmotic pressure, etc. are adjusted and filtered to obtain an aqueous solution.

In the case of preparing a granular form, various components are made into fine powder, mixed and stirred in purified water, and if necessary, an excipient is added and kneaded. After passing this through a mesh, it is heated under reduced pressure and dried to form granules.

In the case of granules, the user dissolves the granules in a specified amount of distilled water or purified water to form an aqueous solution before use.

In addition, a sequestering agent (one kind of chelating agent) and a residual free chlorine reducing agent may be further added so that it can be prepared with tap water.

Examples of the buffer include ophthalmophysiologically acceptable ones such as boric acid, phosphoric acid, citric acid, lactic acid, amino acids, malic acid or sodium salts thereof. One or more of these may be selected and used, and the range of the amount used is in the state of an aqueous solution.
It is 0.01 to 0.5 mol /. These buffers are the pH of the liquid
To suppress and stabilize the change in the pH of the tear fluid.
PH of 4.8 to 8.5, preferably pH 7.0 to 7.8, to make the contact lens specifications, shape, optical properties, etc. during storage, washing or disinfection equal to those in tear fluid. Have advantages. This advantage is especially important when storing hydrous contact lenses.

Examples of the tonicity agent include ophthalmophysiologically acceptable inorganic salts such as sodium chloride, potassium chloride and calcium chloride. One or more of these may be selected and used, and the range of the amount used is 0.01 to 0.5 mol / in the state of an aqueous solution. Such an isotonicity agent is important as a component for adjusting the osmotic pressure of the liquid agent to an osmotic pressure (280 to 300 mOs / Kg) which is almost the same as that of the tear fluid.

Examples of thickeners include polyvinyl alcohol,
Polyvinylpyrrolidone, polyacrylamide, polyethylene glycol and hydrolysates thereof; celluloses such as hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose and methylcellulose or derivatives thereof; dextran; derivatives of pectic acid; gelatin; agar; Ophthalmophysiologically acceptable water-soluble polymers such as gums such as gum arabic, guar gum, tragacanth gum, locust bean gum, guar gum and the like can be mentioned. One or more of these may be selected and used, and the use ratio is about 0.01 to 30% (W / V) in the state of an aqueous solution. Such a thickener is a component that makes the feel of the product good during cleaning and also protects the contact lens from external physical force during storage or cleaning.

Examples of the surfactant include sodium alkylbenzene sulfonate, sodium alkyl sulfate, sodium alkyloylmethyl taurine, sodium alkyloyl sarcosine, sodium α-olefin sulfonate, sodium polyoxyethylene alkyl ether sulfate, and polyoxyethylene alkyl ether phosphorus. Anionic surfactants such as sodium acid salt, sodium polyoxyethylene alkylphenyl ether sulfate, sodium di (polyoxyethylene alkyl ether) phosphate; polyethylene glycol adducts of higher alkyl amines, polyethylene glycol adducts of higher fatty acid amides, higher Polyglycerin ester of fatty acid, polyethylene glycol ester of higher fatty acid, polyalkylene glycol of higher fatty acid, poly Tylene glycol copolymer ester, polyhydric alcohol ester of higher fatty acid polyethylene glycol added, higher alcohol polyethylene glycol ether, higher alcohol polyglycerin ether, alkylphenol polyethylene glycol ether, alkylphenol polyethylene glycol ether formaldehyde condensate, polypropylene glycol -Nonionic surfactants such as polyethylene glycol copolymer, phosphate ester, castor oil, hydrogenated castor oil, polyethylene glycol sorbitan alkyl ester, polyethylene glycol adduct of sterol; saccharose monodecylate, saccharose monoundecylate, saccharose. Monolaurate, sucrose monotridecylate, sucrose Monomyristate, saccharose monocaprate, sucrose monononanate, sucrose monopentadecylate, sucrose monopalmitate, sucrose monoheptadecanoate, sucrose monostearate, sucrose monooleate, sucrose monolinoleate, saccharose monolinoleate, etc. Ophthalmophysiologically acceptable ones such as sucrose monofatty acid ester. One or more of these may be selected and used, and the usage ratio is about 0.01 in the state of an aqueous solution.
~ 3% (W / V). Such a surfactant is a component required when used as a cleaning agent or a cleaning preservative.

Examples of the chelating agent (sequestering agent) include ophthalmophysiologically acceptable ones such as ethylenediaminetetraacetic acid, nitrilotriacetic acid, uramildiacetic acid, phytic acid, citric acid or water-soluble salts thereof. One or more of these may be selected and used, and the range of the amount used is 0.001 in the state of an aqueous solution.
~ 0.1 mol /. These chelating agents are important for preventing the deposition of calcium and the like. Further, particularly when tap water is used as the preparation water, it may be used in an amount sufficient to block the metal ions in the tap water.

Examples of the residual free chlorine reducing agent include, for example, sodium thiosulfate, sodium sulfite, dehydroacetic acid, sorbic acid, etc., which may be appropriately selected and used in an appropriate amount.

Further, hydrogen bond breaking agents such as guanidine and urea, and salts exhibiting a salt-dissolving effect such as sodium thiocyanate may be added.

In addition, in addition to the diamines and the dihalogen compound, a dihalogen compound having a polymerizing group may be used for condensation to obtain an antibacterial polymer having a polymerizing group. By copolymerizing the antibacterial polymer having the polymerizable group with another polymerizable monomer, another water-soluble polymer having an antibacterial property can be obtained, and a water-insoluble material having an antibacterial property can be obtained by crosslinking. It is also possible to obtain In particular, water-insoluble materials may be applied as materials for medical devices such as contact lenses and intraocular lenses that require antibacterial properties, and sponges for cleaning contact lenses.

〔Example〕

Next, the solvent composition for a contact lens of the present invention will be described in more detail based on specific examples, but the present invention is not limited to these examples.

"Synthesis of Condensate (A)" Example 1 N, N, N ', N'-tetramethyl-1,6-diaminohexane
34.4 g and 65.0 g of 1,12-dibromododecane were reacted in 200 ml of ethanol at 70 ° C for 24 hours. The reacted ethanol solution was poured into 1.7 of ether and then stirred, and then the produced white precipitate was collected by filtration and dried. The yield of the obtained condensate (A) was 75.5 g.

Example 2 N, N, N ', N'-tetramethyl-1,6-diaminohexane
34.4 g and 48.0 g of 1,6-dibromohexane were reacted in 200 ml of ethanol at 70 ° C. for 24 hours. The reacted ethanol solution was poured into 1.7 of ether and then stirred, and then the produced white precipitate was collected by filtration and dried. The yield of the obtained condensate (A) was 59.3 g.

Example 3 N, N, N ', N'-tetramethyl-1,2-diaminoethane 2
3.2 g and 65.0 g of 1,12-dibromododecane were reacted in 200 ml of butanol at 70 ° C for 24 hours. The reacted butanol solution was poured into 1.7 of ether and then stirred, and then the formed white precipitate was collected by filtration and dried. The yield of the obtained condensate (A) was 61.8 g.

Example 4 N, N, N ', N'-tetramethyl-1,6-diaminohexane
24.4 g and xylylene dibromide 52.3 g to 200 ml of N, N
-Reacted in dimethyl sulfoxide at 70 ° C for 24 hours. The reacted N, N-dimethyl sulfoxide solution
The mixture was poured into 1.7 of ether and stirred, and then the formed white precipitate was collected by filtration and dried. Obtained condensate (A)
Yield was 48.3g.

Example 5 22.4 g of triethylenediamine and 65.0 g of 1,12-dibromododecane were reacted in 200 ml of N, N-dimethylsulfoxide at 70 ° C. for 24 hours. The reacted N, N-dimethyl sulfoxide solution was poured into 1.7 of ether and then stirred, and then the white precipitate formed was collected by filtration and dried. The yield of the obtained condensate (A) was 52.4 g.

"Antibacterial efficacy test" Example 6 The antibacterial efficacy of the various condensates (A) synthesized in Examples 1 to 4 was examined as follows.

Using Escherichia coli as a test bacterium, the test bacterium was dispersed in distilled water to prepare a microbial suspension so that the bacterium concentration was 1.0 × 10 ⁶ cells / ml.

On the other hand, various condensates (A) obtained in Examples 1 to 4 were dissolved in distilled water to give a condensate (A) concentration of 0.001% (W / V),
Three kinds of test solutions of 0.0001% (W / V) and 0.00001% (W / V) were prepared.

Add 0.1 ml of the bacterial suspension to 10 ml of each test solution,
A sample having an inoculum concentration of 1.0 × 10 ⁵ cells / ml was prepared, and then Escherichia coli was contacted with the test solution at room temperature for 24 hours.

0.5 ml of each sample was diluted with 19.5 ml of physiological saline, and 0.2 ml of the diluted solution was added to SCD (Soybean Casein Digest)
It was spread on an agar medium plate and E. coli was cultured at 31 ° C. The number of surviving Escherichia coli was examined from the number of colonies, and contact was made to the viable cell count when E. coli was contacted with each test solution.
The dead cell rate was calculated from the viable cell count after 24 hours as follows.

Then, the mortality rate was divided into the following three ranks, and the results are shown in Tables 1 to 3.

Rank A: killed bacteria rate is 99% or more B rank: killed bacteria rate is less than 99% to 80% or more C rank: killed bacteria rate is less than 80% It should be noted that the higher the killed bacteria rate, the greater the antibacterial efficacy. .

The condensate (A) concentration of the test solution was adjusted to 0.001% (W / V) The condensate (A) concentration of the test solution was adjusted to 0.0001% (W / V) The condensate (A) concentration of the test solution was adjusted to 0.00001% (W / V) From the above, the condensate (A) of the present invention has a low concentration (concentration of the condensate (A) in the test solution is about 0.0001% (W /
It can be seen that V)) effectively exhibits antibacterial action.

"Fish toxicity test" Example 7 Concentrations of three kinds of condensates (A) prepared in the same manner as in Example 6 (0.001% (W / V), 0.0001% (W / V), 0.000
Toxicity of condensate (A), in other words, safety to the living body, by putting 3 medaka in 500 ml of each test solution of 01% (W / V) I investigated the sex.

The results of the fish toxicity test are shown in Tables 4 to 6. (Percentages in parentheses) The concentration of the condensate (A) in the test solution was adjusted to 0.001% (W / V) The condensate (A) concentration of the test solution was adjusted to 0.0001% (W / V) The condensate (A) concentration of the test solution was adjusted to 0.00001% (W / V) I repeated the same thing again, but with the same result.

Comparative Example 1 In the same manner as in Example 7, a benzalkonium chloride aqueous solution having a concentration of 0.0001% (W / V) was prepared, and the test solution was prepared.
Three medaka fish were put in 500 ml and bred, and the existence of survival after 2 hours was confirmed.

As a result of this fish toxicity test, none of the three medaka fishes survived.

I repeated the same thing again, but with the same result.

From the above, it can be seen that the condensate (A) of the present invention is safer to the living body than benzalkonium chloride, which is a typical bactericide conventionally used.

〔The invention's effect〕

The liquid composition for contact lenses of the present invention has the following effects.

(1) Since the condensate (A) used in the liquid composition for contact lenses of the present invention is a component exhibiting an antibacterial action, it is a liquid for contact lenses which is not contaminated by bacteria and the like, for example, a preservative, a cleaning agent or a cleaning agent Preservatives and the like can be provided. It can also be used as a disinfectant.

(2) The condensate (A) used in the liquid composition for contact lenses of the present invention has effective antibacterial properties even in an extremely small amount,
The safety to the living body is also higher than that of a typical bactericide conventionally used (benzalkonium chloride).
Therefore, only a small amount of the bactericidal component may be used, and the risk of damaging the eyes can be further reduced.

(3) Since the condensate (A) used in the liquid composition for contact lenses of the present invention has a high molecular weight, it does not penetrate into the material of the contact lens. In particular, even in the case of hydrous contact lenses, there is no concern that bactericidal components will be sorbed in the material.

Due to the effects described above, the liquid composition for contact lenses of the present invention is a liquid agent used for cleaning, storing or disinfecting medical devices such as contact lenses, for example, a preservative, a cleaning agent, a cleaning preservative or a disinfectant. Can be suitably used as. Particularly, it is highly useful as a liquid agent for hydrous contact lenses.

Claims (1)

(57) [Claims] 1. General formula (I): (In the formula, R ₁ , R ₂ , R ₃ and R ₄ are each independently C _m H
_{2m + 1} (m is an integer of 1 to 6), R ₅ is C _n H _2n (n is 2
A diamine represented by
General formula (II): (In the formula, R ₆ and R ₇ are each independently C _m H _{2m + 1} (m is the same as above), and R ₈ and R ₉ are independently C _n H
_2n (n is the same as above) and a diamine represented by the general formula (III): (Wherein, R ₁₀ independently represents C _n H _2n (n is the same as above)) and a diamine selected from the diamines represented by the general formula (IV): X ₁ -R ₁₁ -X ₂ (IV) (wherein, X ₁ and X ₂ are each independently chlorine, bromine or iodine, R ₁₁ is C _h H _2h-i (OH) _i (h is an integer of 2 to 18,
i represents an integer of 0 to 3) or the formula: The liquid composition for contact lenses, which comprises a condensate essentially containing a dihalogen compound represented by