JPS63500426A - Improved methods to sterilize and store contact lenses - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] BACKGROUND OF THE INVENTION Improved Method for Sterilizing and Preserving Contact Lenses Generally speaking, the present invention provides an improved method for sterilizing and/or storing contact lenses. method and contact lens protection solution. This solution is used as the main active fungicide. Contains monomeric biguanides, which cause dissolved substances to cackle or deposit on the lens surface. It is non-toxic and has low toxicity. The solution of the present invention is compatible with other disinfectants for solution preservation. They can be used together and increase or expand the bactericidal effective range. case In some cases, such fungicides can be used at lower concentrations, in which case Deposition of dissolved substances on soft contact lenses and irritation and inflammation of ocular tissues The number of accidents can be further reduced.

In general, widely used contact lenses can be classified into two types. Wear. In other words, acrylic acid esters such as polymethyl methacrylate (PMMA) Rigid lenses made from materials produced by the polymerization of Stell, i.e. hard lenses. hydrophilic monomers such as 2-hydroxyethyl methacrylate (HEMA) Glue or hydrogel type lenses made of solid or hydrophobic monocapsular polymers, i.e. There are soft lenses.

Acrylic hard contact lenses have a low water vapor diffusion coefficient and are sensitive to light, oxygen and resistance to the effects of hydrolysis and hydrolysis, and the presence of only a small amount of violet in aqueous media. It is characterized by simply absorbing the body. For hard contact lenses , because of its penetrability and its property of not absorbing much water. Choosing the right disinfectant, cleaning agent or other lens protection compound is no less important. isn't it.

However, unlike hard lenses, soft contact lenses and new Some types of hard, gas-permeable contact lenses contain a lot of fluid. , commonly present in ambient contaminants, water impurities and disinfectants and lens care solutions. It has a tendency to caking and depositing other active ingredients. In most cases, lens protection Such components i! in solution! Due to its low concentration, if used properly it will It doesn't irritate the organization. Although it traps deposited proteins and soft Due to the inherent caking behavior of lens materials, bactericides and preservatives will deposit on the lens surface. It has a tendency to accumulate, and in some cases it can become concentrated to dangerous levels. When you remove the lenses, remove the eyelids that have caused inflammation of the cornea and irritated other ocular tissues.

Reduces the problem of caking and depositing disinfectants and preservatives on contact lens surfaces Previous successes in reducing the risk of irritation and ocular tissue irritation have been shown to be completely It is difficult to say that the results were satisfactory. For example, just because it has low toxicity All these types of disinfectants are safe for all types of contact lenses. That's not to say it can be used. Many hard lens sterilization and preservation solutions contain salt. Contains benzalkonium chloride or chlorotutanol.

Although these compounds are effective antimicrobial agents, their use can cause damage to the lens. Loss of hydrophilicity, reduced stability to solutions, and special types of hartalin For example, it may no longer be possible to use it for hard lenses that contain silicon. be.

More compatible with contact lenses and less prone to caking on the lens surface Other antibacterial agents are also being developed. U.S. Pat. No. 4,361.548 describes dimethychloride /I/Schiff Lylammonium (DMDAAC) pesticide for contact lenses and a preservative-containing cold aqueous solution, in which thimerosar DMDAA is C is used in an amount as small as 0.00001% by weight. Caking on the lens and Although the stimulation of the ocular tissue caused by DIylDAAC and the associated stimulation to the ocular tissue was slightly reduced, However, it turns out that the situation is actually quite bad for some users.

In an attempt to reduce or eliminate soft lens caking, polyvinylpyrrolid anti-caking agents or demulcents such as vinyl alcohol (pvp) and polyvinyl alcohol (PVA). It was proposed to use poisonous agents. However, these polymers alone can hardly It was found that there was no effect in reducing lens caking and ocular tissue irritation.

To date, monomeric biguanides have been used in lens sterilization and preservation solutions. came. For example, the biguanide chlorhexidine is available from DeJ Pharmaceutica. Le Pharmacology (the J, Phohrm Pharmacol,), No. 32, 1980, pp. 453-459, Pea Nis Plant (B, S., Platzt), this document is a soft contact Using biguanide chlorhexidine as an ff i agent with lenses is suggesting. However, chlorhexicine is not effective with such lenses. It turns out that it is not an ideal drug because it is absorbed to a certain extent. This problem 1 One solution was proposed in U.S. Pat. No. 4,354,952, which Chlorhexidine or its salts with certain amphoteric and nonionic surfactants Discloses a very dilute disinfecting and cleaning solution comprising: These solutions are sticky Although effective in reducing their bactericidal effectiveness is reduced. In the case of chlorhexidine, surfactants and Fungicides are not used in the proper proportions and surfactants are not used in combination together. It has been found that in the absence of such surfactants and bactericides, they precipitate.

As previously reported, the soft contours of conventional chlorhexidine-containing fungicides Benzalkonium chloride has a low caking property of 177, but protein-containing Chlorhexa absorbed onto the surface of a clean lens in the presence of oily tear film deposits Double the amount of Shijin.

Attempts to reduce problems with contact lens stickiness and ocular tissue irritation Other results may be found in U.S. Patent Application No. 52, filed August 31, 1983. No. 8.322. In this U.S. patent application, 100.000 When using water-soluble biguanide polymers with the following molecular weights, contact lenses This indicates that the absorption and deposition of dissolved components on the surface of the glass is extremely low. for example, Polyhexamethylene biguanide has extremely low levels in contact lens disinfection solutions. can be used in high concentrations, yet the bactericidal effect is widespread and the viscosity It was found that there was almost no conjunctive effect and no cytotoxic response was induced.

Biguanide polymers have unusually low lens absorption, caking and toxicity responses, but surprisingly It turns out that monomers of such polymers also have similar effects. Ta. The fact that the same effect can be obtained when using monomers in this way means that Lens absorption and Judging from past results in solving the above problem of the lowest caking effect, It was something I had never expected. In other words, the general idea so far is that polymers Mockicides are the most reliable solution to lens caking and ocular tissue irritation problems. It was said that it had a strong logical basis. Because such polymers This is because these monomers were thought to be difficult to penetrate into the micropores of the lens.

Accordingly, the present invention provides an unexpected and novel innovation for processing contact lenses. It provides a good method. The solution of the invention is suitable for hard contact lenses and It can be used with any soft contact lens and is virtually commonly known. can be used by any of the following sterilization techniques.

In addition, the above-mentioned known sterilization techniques include the "low temperature" infiltration method under ambient temperature conditions. There is also a high temperature sterilization method. The sterilizers used by the methods described herein and preservative solutions have broad-spectrum bactericidal and antifungal effects at low concentrations with low toxicity. Particular attention should be paid to the use of fc and soft contact lenses. It has the effect of reducing caking and depositing properties.

Disclosure of invention The present invention provides an effective bactericidal and co-active agent for a biguanide or a water-soluble salt thereof having the following general formula: Sterilizing and/or provides two ways to save (In the formula, B and R3 may be the same or different, and these are hydrogen, halo Gen, alkyl, alkoxy, nitro, -8o2R4, cal is xyl or hydro selected from roxyl, and the above R4 is -NH2, -NHR', -凰'R', -OR' or -0-aryl, and R' and Bi are alkyl or alkoxy. A: 82 is selected from hydrogen or halogen: and X is hydrogen or alkyl. However, when R2 is halogen, R1 and R6 are both hydrogen, and X is alkyl).

The biguanides mentioned above can be used in lens disinfection and/or preservation solutions at germicidal effective concentrations. It will be done. The bactericidal and antifungal action of the biguanide-containing solutions described here is similar to that of other It can also be fortified by adding fungicides. Each such fungicide is The overall convergent effect when combined is better than when each is used separately. Also greatly reduces the concentration of the total disinfectant in the solution under such circumstances can be reduced, thus further reducing caking, depositing and toxic effects. can be done.

BEST MODE FOR CARRYING OUT THE INVENTION The present invention provides hard contact lenses and soft contact lenses as well as e.g. Novel gas-permeable coats such as those described in U.S. Pat. No. 4,327,203 Those who sterilize and/or store most contact lenses, including contact lenses. Regarding the law. The term "soft contact lenses" used here is A contour that can be easily bent with a small amount of force and returns to its original shape when the force is released. meaning ctlens. Soft contact lenses usually have a preferred construction; Poly(hydroxyethylene) cross-linked with ethylene glycol dimethacrylate methacrylate). For convenience, this polymer is usually PH F: Known as JMA. Soft contact lenses can also be used, e.g. It can also be made from silicon polymers cross-linked with tylborisiloxane. eyeball Conventional "hard contact lenses" that only cover the cornea are usually made of ethylene glycol. Constructed from poly(methyl methacrylate) cross-linked with dimethacrylate. ing.

The sterilizing solution used in the method of the invention has a low concentration against various types of microorganisms. be effective. The above microorganisms include S, epid@rmidls, C, al bieans, A, fumigatus, etc., but these are limited isn't it. The above solution contains as the main fungicide a biguanide with the formula: : (In the formula, R1 and R5 may be the same or different, and these represent hydrogen, chlorine, , bromine, iodine or fluorine, having from 1 to about 6 carbon atoms; alkyl, alkoxy having 1 to about 6 carbon atoms, nitro, -8O2R 4. Cal? selected from xyl and hydroxyl, and the above R4 is -NH,, -NH R', -d'bi, -〇R' or 10-aryl, where R' and Bi are C 1-C6 alkyl or alkoxy, substituted and unsubstituted as aryl Phenyl, naphthyl and anthryl are 9; R2 is hydrogen, chlorine, bromine, A halogen selected from iodine or fluorine; and X is hydrogen or C1<5 It is alkyl, but when R2 is halogen, R1 and R3 are both hydrogen. and X is alkyl).

More specifically, among the above groups of monomer biguanides, the most desirable one is methyl, ethyl globil and impro and lower alkyls such as methoxy and ethoxy. Contains lucoxy. Within this preferred group, R1 and R3 are hydrogen. Compounds in which R2 is chlorine or bromine and X is a lower alkyl group are included. be caught.

In addition to the above-mentioned base agents, the present invention also includes, for example, hydrochlorides and borates, acetates, glucosolates, Water-soluble salts and free salts such as phosphates, sulfonates, tartrates, citrates, etc. Contains free bases.

Special representative examples of biguanides used in contact lens sterilization methods and There are free bases and water-bathable salts that can be represented as follows: R,R 2H,X HBY　HCHs-CH2- C1HHH CL　HCL　H -OCR3H-0CH5H -No2HHH Hemicapsular biguanides can be successfully prepared according to methods described in the literature. can. For example, Rose et al. J. Chem, Soe, 1956, pp. 4422-4425. Regarding the production method of bisdiguanide, which has a bactericidal effect and contains chlorhexidine. It is stated that Generally, these compounds combine 1 mole of biscyanoguanidine with 2 by condensing with 2 mol of amine hydrochloride or conversely 2 mol of N-aryl It is produced by interreacting cyanoguanizone with 1 mole of a salt of noamine. Ru. These common methods of preparation proceed according to the following reaction: 1. The reaction involved in the production of 6-no(N5-cyano-N-granidino)hexane is It is carried out using a hexamethylene crosslinking system. 1.6-diaminohexane dihydroc The loride is prepared by first dissolving the appropriate amine in ether, then adding hydrochloric acid to the resulting solution. It is produced by blowing gas to precipitate the amine salt and filtering it. Therefore, l), this 1,6-diaminohexane dihydrochloride is n-! Tanol It reacts with sodium dicyanimide dihydrochloride in the solution.

The mixture is refluxed for 9 hours. The resulting product is isolated and purified. Then the production within the reaction bisbis by reacting with a suitable arylamine hydrochloride in Generates guanide. Alternatively, this bisbiguanide can be used as an arylamine hydrochloride. Heating the chloride with the products in the reaction at 160°C for 2 hours without using solvent sound. It is also possible to generate a combination by

This solution is normally effective even when the biguanide concentration is 0.000011% by weight. It is something. More specifically, this sterilization and preservation solution is approximately Contains about 7 ff14 active biguanides.

In some cases, the bactericidal efficacy of the solution may also be improved by using an effective amount of a second bactericide. It has been found that it is possible to increase the effectiveness or expand the range of efficacy.

In such cases, when biguanides are used with other fungicides, all of the fungicide needed is The concentration can be further reduced for additional bactericidal action, which means that the lens Most desirable for minimizing caking properties, deposition properties and irritation of ocular tissues. That's true. Therefore, the effective concentration of biguanide is approximately o, o　o　o　o　i weight φ It can be lowered to ~5 Jt%.

The above secondary fungicides can be used as preservatives for solutions, but in some cases biguanides It is also possible to act to strengthen, increase or expand the bactericidal power of the bactericide. child As a fungicide, it can be used with biguanides and the presence of biguanides A bactericidal effective amount of a fungicide that does not precipitate under to about 0.5% by weight, preferably from about 0.0001 to about 0.1% by weight. desirable Additional fungicides include thimerosal, lupic acid, ols, alkyltriethanolamines, phenylmercuric salts, e.g. nitrates, boric acid Salts, acetates, chlorides and mixtures thereof are sb, although these compounds are limited It's not a thing. Other fungicidal compounds and salts can also be used. desirable The salt is one that dissolves in water to an extent of at least 0.5 weight more at the same temperature. this Salts include gluconate, isothionate (2-hydroxyethanesulfonate), $-)), formate, acetate, glutamate, succinate, monodiglycolic acid salts, dimethane sulfonate, lactate, diisobutyrate and glucohagetonate. be.

Other examples of enhanced or augmented fungicides used with biguanides include There are certain quaternary ammonium compounds that have a wide range of fungicidal and wetting properties. child A typical example of the quaternary ammonium compound is h-alkyldimethylpenzylamine. Monium chloride and n-furkyldimethylethylpenzylammonium chloride A composition consisting of an equilibrium mixture of lids. The more binary quaternary ammonium The compositions are described in U.S. Pat. No. 3,525,793 and U.S. Pat. No. 3,472,939. Beloved, and two, Oex Ke of Jazzy City, Chassis. From Mikal Kan i4ny (0nyx Chemical Company) It is commercially available under the trademark BTC2125M.

The aqueous solution used in the method of the present invention is made isotonic to approximate the osmotic pressure of normal tear fluid. It is preferable to adjust it with an agent. The normal tear fluid mentioned above has a sodium chloride solubility of 0.9. equal to 2.5% of the liquid or glycerol solution. The above solutions can be used in single or Make it almost isotonic with physiological saline combined with water. In this way, make it isotonic. If you simply mix it with sterile water instead of using it, it will create a hypotonic state, and the treated lens will become less sensitive to the cornea. Closely attached. In contrast, excess saline creates a hypertonic solution. A stinging sensation occurs and the eyeballs tl-Ma.

Isotonic aqueous solutions containing any additional biocide are sterile without the addition of further additives. Useful for both hard and soft contact lenses. It is a disinfectant. However, the solutions of the present invention do not require the use of various buffers, optional washes and and wetting agents, sequestering agents, viscosity increasing agents, etc. and mixtures thereof. Toyoshi wetting solution, soaking solution, washing and conditioning, conditioning solution and Formulated in the form of specific contact lens protection products, such as an all-purpose lens protection solution. can be done. Solutions containing such additives are often ephemeral and comfortable. Tonaru users will appreciate it. However, these additives are non-toxic and It must be compatible with the lens.

Preferred buffering agents include, for example, sodium citrate, potassium citrate, quench acid, boric acid, sodium bicarbonate and Na2Tll'Oa, NaH2PO4 and There are a variety of mixed phosphate buffers, such as combinations of KH2PO4 and KH2PO4. Typically , the buffering agent is about O,OS~2.5%, preferably about 061~1.5% (w/ma). ) is used in amounts within the range.

Neutral or non-ionic surfactants should be used for cleaning and conditioning, Jungian It imparts properties and is usually used in an amount of 15 weight or less.

The surfactant is a substance that dissolves in the lens protection solution and is non-irritating to the ocular tissues. It must also have an acid-water-lipophilic balance (usually between 12.4 and 18.8). HI, B) has k. A satisfactory nonionic surfactant is fatty acid polyethylene. Rene glycol esters such as coconut oil, polysorbates and higher alcohols Polyoxyethylene ether and polyoxypropylene of can (C12-Cl8) There is Ren Ether. A preferred specific example of solera is polysorbate 2o [ Trademark Twsen 20], polyoxyethylene (23) lauri ether [trademark Brij 35], polyoxyethylene (40) Stearate [trademark Myrj 52], polyoxyethylene (25) plastic Ropylene glycol stearate c Trademark Atlas G 2612 ]There is.

In particular, polyethylenediamine having a molecular weight of about 7,500 to about 27,000 (oxypropylene)-poly(oxyethylene) adduct, the adduct A nonionic surfactant in which at least 40% by weight of is poly(oxyethylene) is , when used in an amount of about 0.01 to about 15 parts JEt'Z, soft contact lenses Especially when cleaning, conticing, and hard contact lenses. found to be desirable. Such surfactants are BASF-Wire Registered trademark Tetronic (T@tronie) from Wyandott. ) is commercially available.

In addition to the buffering, cleaning, and wetting agents listed above, contact lens protective solutions may also be used. It is desirable to add a sequestering agent to the liquid to bind metal ions. Up Note: If sequestering agents are not added, metal ions may react with protein deposits. It will be accumulated on the lens surface. Ethylenediaminetetraacetic acid (EDTA) and sodium salts thereof) are preferred examples. These sequestering agents are commonly Usually 0.1 to about 2. ．． It is added in an amount within the range of 0% by weight.

It may also be desirable to include a water-soluble viscosity-enhancing agent in the biguanide-containing lens sterilizing solution. That's a good thing. Due to the analgesic effect of these viscosity increasing agents, and A soothing coating on the lens surface improves the comfort of contact lens wearers. can be increased. As a water-soluble viscosity increasing agent, Hydroxyfluoride such as loin, hydroxyglopylcellulose, calgyxymethylcellulose, etc. There are seven lulose polymers. Such viscosity increase n' is about 0.01 to about 4.0 Heavy! % or less.

The above aqueous solution may be used to sterilize contact lenses by any known method. can be used effectively. For example, lenses may be washed using the "cold" soaking method. The lens is then treated at a constant temperature for a sufficient period of time to kill the lens. Above sterilization time F1 Usually within the range of 4 to 12 hours. Next, remove these lenses from the T-solution and store them. The eyelid is rinsed in a previously reserved isotonic saline solution and then placed on the eye.

In addition to the cold soaking method described above, the solution of the present invention can be The solution of the present invention can also be used in all sterilizers when heated. Since it is also stable, it can also be used in conjunction with high temperature sterilization methods. In this case, usually The lens is placed in a sterilization unit containing the above solution at a temperature of 80 to 90°C. Heat for 10 minutes, then remove and rinse with isotonic saline.

The following specific examples serve as a detailed explanation of the invention. however, It will be understood that these examples are merely illustrative and do not reflect the terms and conditions of the invention. It is not intended to limit the scope and scope.

Example 1 Synthesis of 1.6-di(N3-cyano-N1-guanidino)hexane 103.9 ( 1 mol) of sodium dicyanimide and 94.5# (0.5 mol) of 1,6-dicyanimide. Mix amitsuhexane dihydrochloride and add 700m/m of the mixture. Add to Nord. The mixture is refluxed with stirring for 8.5 hours. Then the reaction mixture Cool on ice. The product is precipitated, separated from F, washed with ice water and further dried. Living The composition has a melting point of 200-203°C.

This product was dissolved in aqueous methanol (1.5 liters of methanol and 2.5 liters). recrystallize from water).

The above product thus obtained (116,5!!, 0.47 mol, 94%) yield) had a melting point of 206-208°C.

6.0F (0,024 mol) of the product of Example I and 8.0.19 (0,0 48 mol) no-orthochloroaniline hydrochloride to 60-2-ditoxyene Add to the ethanol and reflux the entire mixture with stirring for 11.5 hours. cooling During this process, small amounts of substances are separated. This substance has a melting point exceeding 300℃ and is rejected. It is a quality product. Total evaporation of F solution to dryness [rotavap] L, 1.26. The residue of 9 (0,0022 mol) was recrystallized from water (25 w) to give a melting point of 231 1.0 II (7% yield) of the above product at ~234°C is produced.

Example■ N,N'-dimethyl-bis(p-chlorophenyl)-3,12-diamino-2, 4,11,13-tetraaza-tetradecanediimideamide dihydrochloride synthesis 6.0 liters (0,024 mol) of the product of Example II and 8.6 liters (0,024 mol) 048 mol) ON-methyl-p-chloroaniline hydrochloride was placed in an oil bath. and heat at 160°C (±5°C) for 2 hours. The resulting mixture was cooled and heated to 50 g. Dissolve in 50 mL of ethanol to which 50 mL of ethyl acetate is added. The weight of the crude sediment is The melting point of 5.5.9 (0,009 mol) is 159-162°C. water The product obtained after recrystallization from 3,3F (0,005 mol, 21% yield) and has a melting point of 171-173°C.

Example■ Prepare a contact lens sterilizing aqueous solution with the following composition: Perhint (w/ma) NIN'-bis(0-chlorof, =A/)-3,12-diimino-2,4,11 , 13-tetraadetetradecane soimide amidozohydrochloride... ・・・・・・・・・－・・・・・・－・・・・・・ 0.0025 boric acid and boric acid sales Sodium (necessary to maintain pHk7.2) Na2 EDTA = ・=・・=　”・=・=・=・−・−・0.103 Tonicity includes 0.9% NaCL. Adjust with isotonic saline and add deionized water to 100 Prepare the solution by dissolving sodium borate in approximately 80% deionized water. Ru. Disodium EDTA was then added to the sodium borate solution, followed by Dissolve the boric acid and sodium chloride in the solution, add the biguanide, Subsequently add the remaining deionized water. 0.22 micron by peristaltic pump The above solution is sterilized by forcing it through a cellulose acetate filter, and then sterilized. Fill a plastic container with the above solution.

Biguanide aqueous solutions with concentrations of 0.1, 0.01 and 0.001% (v/ma) were prepared. make ep1dermidim, C, Albiean for each solution of 20W1t s and A, $’x In vitro sterilization of the solution by exposing it to room temperature for 5 hours Measure force. Each aliquot sample was then placed on an agar plate and heated for 48 hours at elevated temperature. Incubate for hours. After culturing, check whether colonies have developed. The following table shows the test tube Indicates the results of the test.

According to the above in vitro test, the bactericidal efficacy of the biguanide isomer is higher than that of the p-chloro derivative ( Chlorhexidine) was better.

Although the invention has been described in accordance with specific embodiments, this is by way of example only. Ru. Accordingly, many modifications and variations of this invention will occur to those skilled in the art in light of the above description. as may be obvious, and all such modifications and changes are within the spirit and scope of the invention. should be included within the

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Claims (17)

[Claims] 1. Contour the effective bactericidal dose of a solution of a biguanide or its water-soluble salt with the following formula: Sterilizing and/or preserving contact lenses consists of processing contact lenses how to: ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R1 and R3 are independently hydrogen, halogen, alkyl, alkoxy, nitrogen selected from tro, -SO2R4, carboxyl or hydroxyl, where R4 is -NH2, -NHR', -NR'R'', -OR' or -O-aryl , R' and R'' above are alkyl or alkoxy, and R2 is hydrogen or is halogen, and X is hydrogen or alkyl, provided that R2 is halogen (Sometimes R1 and R3 are both hydrogen and X is alkyl). 2. R1 and R3 are independently hydrogen, chlorine, bromine, lower alkyl or lower alkyl; R2 is hydrogen, chlorine or bromine, and X is hydrogen or class alkyl, provided that when R2 is chlorine or bromine, R1 and R3 are 2. The method according to claim 1, wherein both are hydrogen and X is lower alkyl. 3. At least one of R1 and R3 is substituted with halogen, and R2 is water. 2. The method according to claim 1, wherein 4. Claim No. 1, wherein R1 is chlorine and R2, R3 and X are each hydrogen. The method described in Section 3. 5. 5. The method of claim 4, wherein R1, R2, R3, and X are hydrogen. 6. R1 and R3 are hydrogen, R2 is halogen, and X is alkyl; The method according to claim 1. 7. The method according to claim 6, wherein R2 is chlorine and X is lower alkyl. . 8. The person according to claim 1, wherein the biguanide-containing solution contains an isotonic agent and a buffering agent. Law. 9. A fungicidally effective mixture of a biguanide and at least one other fungicide having the formula: contact lenses consisting of treating the contact lenses with an effective amount of a solution of How to sterilize and/or preserve: ▲Mathematical formulas, chemical formulas, tables, etc.▼ (In the formula, R1 and R3 are independently hydrogen, halogen, alkyl, alkoxy, nitrogen selected from tro, -SO2R4, carboxyl or hydroxyl, where R4 is -NH2, -NHR', -NR'R'', -OR' or -O-aryl; , R' and R'' above are alkyl or alkoxy, and R2 is hydrogen or is halogen, and X is hydrogen or alkyl, provided that R2 is halogen In some cases, R1 and R3 are both hydrogen and X is alkyl). 10. R1 and R3 are independently hydrogen, chlorine, bromine, lower alkyl or lower alkyl; R2 is hydrogen, chlorine or bromine, and X is hydrogen or lower alkyl, provided that when R2 is chlorine or bromine, R1 and R3 are 10. The method according to claim 9, wherein both are hydrogen and X is lower alkyl. 11. The fungicide is from the group consisting of thimerosal, sorbic acid and phenylmercury salts. 10. The method of claim 9 which is selected. 12. 12. The method of claim 11, wherein the method includes an isotonic agent and a buffer. 13. R1 and R3 are hydrogen, R2 is halogen, and X is alkyl A method according to certain claim 9. 14. Claim 13, wherein R2 is chlorine and X is lower alkyl Method. 15. At least one of R1 and R3 is halogen and R2 is hydrogen. The method described in item 9 of the scope of the request. 16. In the above biguanide, R1 is chlorine, and R2, R3 and X are each water. 16. The method of claim 15, wherein the method comprises a material that is 17. The above biguanide is composed of a substance in which R1, R2, R3 and X are hydrogen. The method described in item 9 of the scope of the request.