DD299267A5 - ANTIMICROBIAL COMPOSITIONS - Google Patents

Abstract

Antimicrobial ophthalmic compositions containing compounds of the formula I <IMAGE> in which Ar, Alk, alk1, alk2, alk3 and X<(-)> are as defined in the description, and the use of these compounds of the formula I for preserving ophthalmic medicinal agents and for the treatment of contact lenses are disclosed.

Description

wherein Ar is aryl, Alk is alkyl, alk _{1 (} alk ₂ and alk _{3 are} independently alkylene and Χ ^{θ is} an ophthalmically acceptable anion, for the preservation of contact lenses.

30. Use according to claim 29, characterized in that at least one compound of the formula !, in which Ar is phenyl, Alk is C ₈ -C ₁₈ -alkyl, alk, and alk _{2 is} 1,2-ethylene, alk _{3 is} methylene is, and X ^{0 is} chloride, is applied.

The invention relates to antimicrobial ophthalmic compositions containing certain quaternary ammonium salts as preservatives.

The invention particularly relates to antimicrobial ophthalmic compositions containing at least one compound of the formula I

alk, OH

el χ ^θ

Ar alk-i-N - alk

^J ι (I)

alk ₂ -OH

wherein Ar is aryl, Alk is alkyl, alk _t , alk ₂ and alk _{3 are} independently alkylene and Χ ^{Θ is} an ophthalmically acceptable anion, and one or more ophthalmically acceptable or contact lens compatible excipients.

The invention relates to an eye remedy, z. As eye drops, eye gels or eye ointments containing certain quaternary ammonium salts as preservatives, as well as the use of these quaternary ammonium salts for the preservation of ophthalmic drugs.

On the other hand, the invention relates to z. As well as solutions for the treatment of contact lenses containing certain quaternary ammonium salts as preservatives, scwie the use of these quaternary ammonium salts for the preservation of contact lenses.

Drugs for the treatment of diseases in the eye are often formulated in liquid form and administered in drops. In the case of eye drops, preservation of the preparations is prescribed in most European and other countries, i. protection against infestation and subsequent proliferation of microorganisms by the addition of at least one component capable of preventing or at least containing secondary contamination. Furthermore, ophthalmic drugs are often formulated as a gel. For aqueous gels, the same applies to preservation.

It is known that N-alkyl-N-arylalkyl-N, N-bis (hydroxyalkyl) ammonium salts can be used as disinfectants. In particular, the substance benzoxonium chloride [& N-benzyl-N- (n-dodecyl) -N, N-bis- (2-hydroxyethyl) -ammonium chloride] is now for over 30 years (see Drug Research 9,622-625 [1959]) on many areas used for disinfection. For example, benzoxonium chloride is used in gargles for the disinfection of the oropharynx, in laryngotracheitis, against dental plaque, against decay, for skin disinfection, in particular the hands in surgery, for dermatological-cosmetic purposes or for disinfection in the hospital, eg. B. of medical instruments. In addition, benzoxonium chloride is also used as a veterinary antiseptic, for. B. used as a fungicide and bactericide for the udder or for the treatment of dermatomycoses in horses. Further uses of benzoxonium chloride are: disinfection in the food and beverage industry, in the wine industry and in slaughterhouses, disinfection of animal hides, bactericide for textile fibers and bactericide and fungicide for sugar beet.

It is also known to preserve ophthalmic drugs by quaternary ammonium salts (see eg EP-A-306984). Practical application for the preservation of ophthalmological drugs have - apparently due to the many requirements that must be met - found only a very few quaternary ammonium salts, especially the three explicitly mentioned in EP-A-306984 cetyltrimethylammonium bromide, cetylpyridinium chloride and benzalkonium chloride (see also EP -A-242328). The preservative of choice for ophthalmic drugs6l is clearly the latter

Benzalkonium chloride (see EP-A-306984, page 2, lines 31-33), which has the structure: N-benzyl-N- (Cr-C, _8- alkyl) -N, N-dimethylammonium chloride ,

The very small number of quaternary ammonium salts used in ophthalmic preservatives for preservation is contrasted by a variety of known quaternary ammonium salts ("quats") used in other fields for preservation.

An object of the present invention is to find other quaternary ammonium salts which are suitable for the preservation of eye medicines. This would extend the hitherto very small range of possible preservatives for the manufacturer of ophthalmic drugs, and the latter would have more alternatives in the preservation of its formulations. The above object is achieved by the finding that the N-alkyl-N-arylalkyl-N, N-bis (hydroxyalkyl) -arnmoniurnsalze of formula I, which also benzoxonium belongs, are ideal for the preservation of ophthalmic drugs. This finding is by no means obvious, because there are hundreds of quaternary ammonium salts for disinfection generally known, of which surprisingly a very small group, namely the compounds of formula I. has proven to be suitable for the preservation of ophthalmic drugs. As stated above, a compound of the formula I, benzoxonium chloride, has been used for disinfection in many fields for more than 30 years. It has never been suggested for the preservation of eye medicines. It was therefore not obvious to use the compounds of the formula I, including benzoxonium chloride, for the preservation of eye medicines. Another object of the invention is to find certain quaternary ammonium salts which are better suited than benzalkonium chloride for the preservation of eye medicines. As already explained above, benzilconium chloride is probably the world's most widely used preservative for eye remedies, along with chlorhexidine, thiomersal and chlorobutanol. But it is by no means the case that benzalkonium chloride I is ideal and satisfies in every respect. In particular, in long-term use, e.g. may be required in the treatment of glaucoma, cataract or "dry eye", ocular tolerability problems occur, for example, changes in the corneal and conjunctival epithelium and in the eyelids.The task of finding preservatives for ophthalmic medicines with improved tolerability with long-term use, is achieved by providing ophthalmic drugs containing compounds of formula I for preservation

 The present invention accordingly relates to an ophthalmological medicament containing at least one compound of the formula I

alk, OH

el χ ^θ

Ar alk ₃ -N-Alk _(|)

alk _r 0H

wherein Ar is aryl, Alk is alkyl, alk, alk ₂ and alk _{3 are} independently alkylene and X ° is an ophthalmically acceptable anion, and one or more ophthalmically acceptable excipients.

Aryl is z. As phenyl or naphthyl, such as 1- or 2-naphthyl. The phenyl and naphthyl radicals may be unsubstituted or substituted, in particular as indicated below for phenyl. Aryl is preferably phenyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and / or trifluoromethyl, and is primarily phenyl.

Lower alkyl is C, -C ₇ alkyl, z. For example, n-propyl, isopropyl, η-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, preferably ethyl and especially methyl.

Lower alkoxy means Ci-C ₇ alkoxy, z. Example, n-propoxy, isopropoxy, n-butoxy or tert-butoxy, preferably ethoxy, and especially methoxy.

Halogen is in particular fluorine, chlorine or bromine, but may also mean iodine.

The alkyl and alkylene groups Alk, alki, alk2 and alk3 are preferably straight-chain, but may also be branched.

The alkyl group Alk means z. B. C, -C ₂₆ alkyl and is z. B. for methyl, ethyl, n-propyl, η-butyl, sec-butyl, r-pentyl, n-hexyl, n-heptyl, n-nonadecyl, n-eicocyl, n-heneicosyl, n-docosyl, n Tricosyl, n-tetracosyl or n-hexacosyl, preferred for n-octyl, n-nonyl, n-decyl, n-undecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl or n Octadecyl, and primarily n-dodecyl.

The alkyl group Alk preferably represents C, -CJ _O -alkyl, in particular C ₁ -C _ie alkyl and primarily Cg-C ₁₈ alkyl.

"Mixed Ce-C | _8- alkyl "means a mixture consisting essentially of n-octyl, n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl and n-octadecyl, which contains 40-60%, in particular approximately 50%, of the n- Dodecyl component contains.

The alkylene group alk ,, alk ₂ and alk _{3 are} z. B. Ci-C7-alkylene and z. For methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 2,4-butylene, 1,5-pentylene, 1,6-hexylene or 1,7-heptylene.

The alkylene groups Alk, and AIk ₂ independently of one another preferably represent C ₂ -C ₄ -alkylene, are in the first place identical to one another and are above all 1,2-ethylene.

The alkylene group AIk ₃ is preferably C, -C ₄ -alkylene and especially methylene.

The anion Χ ^Θ is derived from an ophthalmically acceptable acid. Ophthalmically acceptable acids are, for example, strong mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or organic acids, especially aliphatic or aromatic carboxylic acids, eg. Acetic, propionic, lactic, tartaric, citric, maleic, fumaric, hydroxymaleic, phenylacetic, gluconic or nicotinic; or other acidic organic substances, e.g. B. ascorbic acid, further z. As well as amino acids, such as arginine or lysine, in question. Preferably, the anion X ^{e is} bromide and primarily chloride.

The compounds of formula I are distinguished as preservatives for ophthalmic drugs, inter alia, that they have an excellent preserving effect and are well tolerated by the eye even with long-term use.

The preservative effect of the compounds of formula I is z. B. clearly from the results of the following Kon: .ervicrungsmittelbelastunp tests:

Preservative loading test, substance: Benzoxonlumchlorld, 0.1 mg / ml, pH 6 Exposure to the following microorganisms: E. coli St.aureus Ps.aoruginosa 1.5-10VmI 1.4-10VmI 1.1-1OVmI K. W. K. W. K. W. K. W. K. W. K. W. C. albicans 9.9-10VmI -5- 299 267 Contact time with the microorganism 99.99% k.W. K. W. 99.97% k.W. K. W. 10min 6h 24 h Data in%: reduction of growth k.w.: no growth

The surprisingly improved eye tolerance of the compounds of formula I compared to benzalkonium chloride is z. B. from the results of the following described 5-day-Vorträglichkeitsprüfung in animals clearly: Compared in each case 0.01% solutions of benzoxonium chloride and benzalkonium chloride. These solutions were dropped five minutes (at 90 minute intervals) into the rabbit conjunctival sack for 5 days. At the end of the experiment, the treated eyes were examined for clinical findings such. As reddening of the conjunctiva, corneal opacities, secretion and conjunctival swelling, examined. The results were as follows:

Benzoxonium chloride (A compound of formula I), 0.01%

5 instillations / animal / day at intervals of 90 minutes no findings

Benzalkonium chloride (£ reference compound), 0.01%

5 lnstillations / animal / day in each 90min 4 findings

The better eye tolerance of the compounds of formula I compared to benzalkonium chloride is z. B. also from the results of the described in the following 4 weeks ocular, local tolerance study in rabbits clearly: Compared in each case 0.01% solutions of N-benzyl-N- (mixed C _e -C | _8- alkyl) -N , N-bis (2-hydroxyethyl) ammonium chloride and benzalkonium chloride. The experimental animals were pigmented Himalayan rabbits. They were each given 50 μΙ of the appropriate solution in the conjunctival sac of the right eye ten times daily (at 45-minute intervals) for 4 weeks. As a control, a comparative solution containing no preservative was added dropwise to the left eye. The animals were ophthalmologically examined on the first and fifth day of treatment. After termination of the experiment, the experimental animals were also examined histopathologically and the following results were determined: In the animals treated with the solution according to the invention, the N-benzyl-N-mixed C ₈ -C ₁₈ -alkyl) -N, N-bis Contained (2-hydroxyethyl) ammonium chloride, no ocular lesions were found. In contrast, lesions in the conjunctiva, and a ') acanthosis and hyperkeratosis at the edge of the lower right eyelid were observed in 4 of 6 animals treated with benzalkonium chloride. The benzalkonium chloride solution therefore caused changes in the conjunctival epithelium, which did not occur in the solution according to the invention. This is convincingly demonstrated that the compounds of formula I have a surprisingly improved long-term tolerance in comparison to ben / alkoniumchlorid in the eye.

The compounds of the formula I are normally added to the eye medicine in a concentration of 0.0001% -0.10% (in each case weight / volume [G / V]), in particular 0.001% -0.02% and especially 0.002% -0.015%. added.

Preferably, the invention relates to an ophthalmic medicament containing at least one compound of the formula I in which Ar is phenyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl, Alk is C ₁ -C ₂₀ -alkyl, alk, and alk ₂ independently of one another are C ₂ -C ₄ -alkylene, alk _{3 is} C 1 -C ₄ -alkylene, and X ^{e is} an ophthalmically acceptable anion.

Most preferably, the invention relates to an eye medicament containing at least one compound of the formula I in which Ar is phenyl, Alk is C, -C, ₈ -alkyl, alk, and alk _{2 is} 1,2-ethylene, alk _{3 is} methylene , and X ^{3 is} bromide or chloride.

More particularly, the invention relates to an eye medicament containing at least one compound of formula I, wherein Ar is phenyl, Alk is Ce-C ₁₈ alkyl, alk, and alk _{2 is} 1,2-ethylene, alk _{3 is} methylene and Χ ^Θ means chloride.

Primarily, the invention relates to an ophthalmic drug containing N-benzyl-N- (n-dodecyl) -N, N-bis (2-hydroxyethyl) ammonium chloride or N-benzyl-N- (mixed Ca-C ₁₈ -alkyl) -N , N-bis- (2-hydroxyethyl) ammonium chloride.

Above all, the invention relates to an eye medicine containing N-benzyl-N- (n-dodecyl) -N, N-bis (2-hydroxyethyl) ammonium chloride (= benzoxonium chloride).

A special embodiment of the invention is an eye medicine containing at least one compound of the formula I as defined above, and EDTA or a salt thereof, e.g. Disodium EDTA. If EDTA or a salt davo.i is included in the eye medicine of the invention, it is preferably in a concentration of 0.01-0.2% (w / v), especially about Ο, Οδ-Ο, Ί% (w / v) ), in front.

The compounds of formula I which are added to ophthalmic drugs must have sufficient purity for ophthalmic purposes. Preferably, e.g. The used benzoxonium chloride maximally 2.5% by weight of by-products, whereby each by-product may only be represented by 0.5% by weight in each case.

Eye medicines may contain, in addition to the preservative z. B. contain the following ingredients:

(a) optionally one or more pharmaceutically active substances, e.g. B. steroidal anti-inflammatory substances, eg. B.

fluorometholone; non-steroidal anti-inflammatory substances, e.g. Diclofenac or ophthalmologically acceptable salts thereof, especially diclofenac sodium (diclofenac-Na); Antibiotics, e.g. Quinolones, chloramphenicol or gentamicin; Antiglaucoma agents, e.g. Pilocarpine hydrochloride or pirbuterol hydrochloride; keratolytic substances, e.g.

Vitamin A acid; Vascular constricting substances (vasoconstrictors), eg. Naphazoline nitrate, tetrahydrozoline (A tetryzoline), phenylephrine or xylometazoline; Antiallergic agents, e.g. Isospaglumic acid or spaglumic acid and their magnesium or

Sodium salts; astringent substances, e.g. Zinc sulfate; Anti-cataract agents, e.g. Methosorbinil [A (2R, 4S) -2-methyl-6-fluoro-spirolchroman-4,4'-imidazolidine] -2 ', 5'-dione); or also e.g. Medicinal plant extracts; e.g. Euphrasiatinktur. Eye medicines containing no active pharmaceutical ingredient are exemplified by certain tear replacement formulations ("artificial tears"). Furthermore, ophthalmic drugs contain ophthalmically acceptable excipients, e.g.

(b) if appropriate, one or more buffer substances, for example boric acid, borates, for example borax (Na ₂ B ₄ O ₇ 1OH ₂ O), phosphates, for example Na ₂ HPO ₄ .2H ₂ O / NaH ₂ PO ₄ .2H ₂ O- Buffer, trometamol (A 2-amino-2-hydroxymethyl-1,3-propanediol A TRIS), or organic acids, e.g. Ascorbic, acetic, propionic or citric acid;

(c) optionally one or more isotonizing agents, e.g. Sodium chloride, sorbitol (A d-sorbitol), mannitol or glycerin;

(d) optionally one or more solubilizers, e.g. As fatty acid glycerol polyglycol esters, fatty acid polyglycol esters, polyethylene glycols, glycerol ethers or mixtures of these compounds. A specific example of a particularly preferred solubilizer are reaction products of castor oil and ethylene oxide, for example the commercial product Cremophor® EL (A Polyoxyl 35 Castor Oil). Reaction products of castor oil and ethylene oxide have proven to be particularly good solubilizers / with excellent eye tolerance.

Further examples of solubilizers are Luviquat® FC 905 (A copolymer of vinylimidazolium methochloride and vinylpyrrolidone 95: 5, BASF), Solutol® HS 15 (A polyethylene glycol 660-12-hydroxystearat, BASF) and Macrogol 400 (A polyethylene glycol 400, Lutrol®E 400, BASF).

(e) optionally solvent to provide certain components of the formulation, e.g. B. to bring the active ingredient or essential oils that are used as odors in solution. Examples include: ethanol abs., Polypropylene glycol or polyethylene glycol 400 (A Macrogol 400, see also under Solubilizers);

(f) optionally antioxidants, e.g. A-tocopherol acetate or BHA (A 3-tert-butyl-4-hydroxy-anisole);

(g) optionally thickeners which serve to increase the viscosity of the formulation, for. For example, methylhydroxypropylcellulose, e.g. Methocel F4M® (Dow Chemicals), or the sodium salt of hyaluronic acid; (h) optionally strong thickening agents which cause gelation, e.g. Polyacrylic acid, Carbopol® 934 P (A carboxyvinyl polymer, BF Goodrich), Polymer JR 30M® (A polymeric quaternary ammonium salt obtained by

iaction of hydroxyethylcellulose with a trimethylammonium-substituted epoxide, cf. U.S. Patent 3,472,840, Union Carbide), alginates or polyvinylpyrrolidone;

(i) optionally complexing agents, e.g. B. to increase the preservative effect of the preservative of the invention and / or complexation and thus masking of any heavy metal impurities, eg. EDTA or salts thereof, such as disodium EDTA;

(j) optionally odorants, e.g. Orange blossom oil, lavender oil or witch hazel water; (k) optionally, substances which affect the pH, e.g. Hydrochloric acid or sodium hydroxide; (I) optionally dyes, e.g. Fluorescein sodium; and (m) normally water for injections or demineralised water.

Normally, it is endeavored to adjust eye medicines isotonic with the human tear fluid (A 270 to 330mOsmol / kg, especially 300mOsmol / kg). However, there may be exceptional cases where the osmolality of ophthalmic medicines is outside the specified range

 The invention further relates to the use of at least one compound of the formula I,

alk, OH

el χ ^θ

Ar alk ₃ N -Alk (I)

alk ₂ · OH

wherein Ar is aryl, Alk is alkyl, aik _t , alk ₂ and alk _{3 are} independently alkylene and Χ ^{Θ is} an ophthalmically acceptable anion, for the preservation of ophthalmic drugs.

In particular, the invention relates to the use of at least one compound of formula I wherein Ar is phenyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl, Alk is C 1 -C ₂₀ alkyl, alky and alk _{2 are} independently each other is C 1 -C ₄ -alkylene, alk _{2 is} C 1 -C ₄ -alkylene, and X ^{e is} an ophthalmically acceptable anion, for the preservation of eye medicines.

More preferably, the invention relates to the use of at least one compound of formula I, wherein Ar is phenyl, Alk is C, -C ₁₈ alkyl, alki and alk _{2 is} 1,2-ethylene, alk _{3 is} methylene, and Χ ^Θ bromide or chloride, for the preservation of ophthalmic medicines.

More particularly, the invention relates to the use of at least one compound of formula I in which Ar is phenyl, Alk is Cff-Cie-alkyl, alki and alk _{2 are} 1,2-ethylene, alk _{3 is} methylene, and X ^{e is} chloride means for the preservation of eye medicines.

Primarily, the invention relates to the use of N-benzyl-N- (n-dodecyl) -N, N-bis- (2-hydroxyethyl) ammonium chloride or N-benzyl-N- (mixed Cg-C | ₈ alkyl ) -N, N-bis (2-hydroxyethyl) ammonium chloride for the preservation of ophthalmic medicines.

Above all, the invention relates to the use of N-benzyl-N- (n-dodecyl) -N, N-bis (2-hydroxyethyl) ammonium chloride for the preservation of eye medicines.

The invention further relates to solutions for the treatment of contact lenses, containing at least one compound of formula I, alk.-OH

el χ ^θ

Ar alk ₃ N -Alk (I)

alk ₂ -OH

wherein Ar is aryl, Alk is alkyl, alk, alk ₂ and SIk _{3 are} independently alkylene and X ^{e is} an ophthalmically acceptable anion, and one or more contact lens compatible excipients. Solutions for the treatment of contact lenses include in particular: (a) cleaning solutions for contact lenses and (b) conditioners for gas-permeable and hard contact lenses.

The preferred subgroups of compounds of the formula I are the same here as in the case of the ophthalmologists containing compounds of the formula I.

In particular, therefore, the invention relates to z. B. Solutions for the treatment of contact lenses, containing at least one compound of formula I, wherein Ar is phenyl, Alk is C _e -C _{) 8} alkyl, alki andalk _{2 is} 1,2-ethylene, alk _{3 is} methylene, and Χ ^Θ means chloride.

A preferred cleaning solution for contact lenses according to the invention comprises: (a) a compound of formula I wherein Ar is phenyl, Alk is Cg-C, _e- alkyl, alki and alk _{2 are} 1,2-ethylene, alka is methylene , and Χ ^Θ chloride in a concentration (w / v) of 0.005 to 0.8%, (b) an isotonizing agent, for. Example, sodium chloride, (c) a buffer substance, for example a phosphate buffer, (d) a complexing agent, for example EDTA or a salt thereof, (e) a solubilizer, for. B. amine oxide detergents, eg. Varox® 365 (Sherex Chemical), or the Triton® series (A polyethylene glycol-p-isooctylphenyl ether) from Rohm and Haas, in particular Triton® X-100, and optionally (f) a thickener, ζ. B. rapidly soluble hydroxyethyl cellulose, e.g. Cellosize® QP-40 HEC (Union Carbide). A preferred contact lens conditioner according to the invention comprises: (a) a compound of formula I ₁ wherein Ar is phenyl, Alk is Cg-C ₁₈ alkyl, alk _t and alk _{2 are} 1,2-ethylene, alk _{3 is} methylene stands, and X ^e chloride in a concentration (w / v) of 0.002 to 0.8%, (b) a humectant, z. Example, polyvinyl alcohol, such as Vinol® 350 PVA (Air Products, Inc.), or mixtures of polyvinyl alcohol and polyvinylpyrrolidone (ζ B. Vinol® 350 PVA + Plasdone K-90 PVP, GAF), (c) a buffer substance, eg a phosphate buffer, (d) an isotonizing agent, eg sodium chloride, and optionally (e) a complexing agent, ζ. B. EDTA or a salt thereof.

The components mentioned above in the preferred cleaning solution or the preferred conditioner for contact lenses under (b) - (f) or (b) - (e) are examples of contact lens compatible excipients. The invention further relates to the use of at least one compound of the formula I,

alk, OH

el χ ^θ

Ar alk ₃ -N - Alk (I)

alk ₂ -OH

wherein Ar is aryl, Alk is alkyl, alk, alk ₂ and aik _{3 are} independently alkylene and X ^{s is} an ophthalmically acceptable anion, for the preservation of contact lenses.

The subgroups of compounds of the formula I which are preferably used here are the same as stated above for the ophthalmic medicaments containing compounds of the formula I.

In particular, therefore, the invention relates to z. B. the use of at least one compound of formula I wherein Ar is phenyl, Alk is C ₈ -C ₁₈ alkyl, alki and alk _{2 is} 1,2-ethylene, alk _{3 is} methylene, and X® is chloride , for the preservation of contact lenses.

The antimicrobial ophthalmic compositions according to the invention preferably contain quaternary ammonium salts selected from certain subgroups of compounds of formula I. These preferred subgroups of compounds of the formula I are the same as given above in the ophthalmic medicaments containing compounds of the formula I.

In particular, therefore, the invention relates to z. B. antimicrobial ophthalmic compositions containing at least one compound of formula I, wherein Ar is phenyl, Alk is C-Ce-alkyl, alkt and alk _{2 is} 1,2-ethylene, alk _{3 is} methylene, and Χ ^θ chloride means.

In the manufacture of ophthalmic medicines-as well as solutions for the treatment of contact lenses-according to the invention, an effective, i.e. H. sufficient for preserving, mixed amount of one odfir several compounds of formula I and the remaining ingredients according to conventional methods. The following formulation examples illustrate the invention:

example 1

Eye drops containing diclofenac-Na

component amount Diclofenac sodium 1.00 mg Cremophor®EL 10.00 mg Luviquat ^s FC905 5.00 mg trometamol 6.00 mg boric acid 19.50 mg Disodium EDTA 1.00 mg benzoxonium 0.10 mg Water for injection purposes ad 1.00 ml

Example 2 Eye drops containing Naphazollnnitrat and zinc sulfate

component amount Naphazollnnitrat 0.050 mg zinc sulfate 0.200 mg sodium chloride 4.050 mg benzoxonium 0.100 mg methylhydroxypropylcellulose 3,000 mg Hamameliswasser 40,000 mg Orange blossom oil 5,00 \ ig lavender oil 1,80Mg Euphrasiatinktur 0.800 mg Ethanol abs. 1.393 mg Hydrochloric acid 1N 0.100 mg Water for injections ad 1,000 ml

Example 3 Eye drops containing naphazoline nitrate and zinc sulfate

component amount naphazoline 0.0525 mg zinc sulfate 0.200 mg boric acid 7,000 mg trometamol 5,000 mg Hydrochloric acid 1 N 34,000 mg benzoxonium 0.100 mg methylhydroxypropylcellulose 3,000 mg Hamameliswasser 40,000 mg Orange blossom oil 5.00 pg lavender oil 1,80Mg Euphrasiatinktur 0,800Mg Ethanol abs. 1.393 mg Water for Iniektionszwecke ad 1,000 ml

Example 4

Eye drops containing chloramphenicol

component amount amount chloramphenicol 6.00 mg 6.00 mg Disodium EDTA 0.10 mg 0.10 mg Macrogol400 80.00 mg 80.00 mg trometamol 0.10 mg 0.10 mg Benzcxoniumchlorid 0.10 mg 0.10 mg Cremophor * Ell 4.00 mg 10.00 mg Water for injections ad 1.00 ml 5.00 mg Example 5 ad 1.00 ml Eye drops containing chloramphenicol component chloramphenicol Disodium EDTA Macrogol 400 trometamol benzoxonium a-tocopherol acetate Solutol ⁸ HS 15 Water for Iniektionszwecke

Example 6

Eye drops containing chloramphenicol

Component quantity

chloramphenicol 6.00 mg amount amount amount amount amount Disodium EDTA 0.10 mg 6.00 rng 6.00 mg 6.00 rng 6.00 mg 12.80 mg Macrogol 400 80.00 mg 0.10 mg 0.10 mg 0.10 mg 0.10 mg 0.15 mg benzoxonium 0.10 mg 80.00 mg 80.00 mg 80.00 mg 80.00 mg 1.00 mg Water for injections ad 1.00 ml 0.10 mg 10.00 mg 4.00 mg 0.10 mg 5.00 mg Example 7 0.10 mg 0.10 mg 0.10 mg 0.10 mg 0.10 mg Eye drops containing chloramphenicol ad 1.00 ml ad 1.00 ml ad 1.00 ml 5.00 mg 10.00 mg component ad 1.00 ml 0.50 mg chloramphenicol Eye drops containing chlorampher..col Eye drops containing chloramphenicol Eye drops containing chloramphenicol 60.00 mg Disodium EDTA component component component Eye gel containing vitamin A acid, tear substitutes 30.00 mg Macrogol 400 chloramphenicol chloramphenicol chloramphenicol component 0.15 mg trometamol Disodium EDTA Disodium EDTA Disodium EDTA Polymer JR 30 M® ad 1.00 ml benzoxonium Macrogol 400 Macrogol 400 Macrogol 400 Vitamin A acid Water for injections u-Tocophorolacetat Cremophor'EL trometamol Disodium EDTA Example 8 benzoxonium Benzoxcniumchlorid benzoxonium Luviquat®FC905 Water for injections Water for injections Solutol HS15 * benzoxonium Example 9 Example 10 Water for injections a-tocopherol acetate l.eispielH trometamol Poiypropylenglykol Cremophor EL * BHA Water for injections

Example 12 Eye gel containing vinyl-A-acid, Trisne substitute

component amount Polymer JR 30 M » 12.80 mg Vitamin A acid 0.15 mg Dinatriuni EDTA 1.00 mg Luviquat®FC905 5.00 mg benzoxonium 0.20 mg a-tocopherol acetate 10.00 mg trometamol 0.50 mg Polypropylonglykol 60.00 mg Cremophor EL * 30.00 mg BHA 0.15 mg Water for injections ad 1.00 ml

Example 13 Eye gel containing Vitaml-A-sure, Trisne substitute

component amount Polymer JR 30 M® 12.00 mg Vitamin A acid 0.15 mg Disodium EDTA 1.00 mg benzoxonium 0.10 mg trometamol 0.40 mg sodium chloride 6.00 mg Solutol®HS15 20.00 mg BHA 0.15 mg Water for injections ad 1.00 ml

Example 14

Eye gel containing vitamin A acid, tear substitutes

component amount PolymerJR30M " 12.00 mg Vitamin A acid 0.15 mg Disodium EDTA 1.00 mg benzoxonium 0.10 mg trometamol 0.40 mg sodium chloride 6.00 mg Solutol®HS15 20.00 mg Luviquat®FC905 5.00 mg a-tocopherol acetate 10.00 mg Water for injections ad 1,00ml

Snlsplel 15

Aogen gel containing vitamin A acid, TrSnenersatz

component amount Polymer JR 30 M » 12.00 mg Vitamin A acid 0.15 mg Dinatriun EDTA 1.00 mg Luviquat®FC905 5.00 mg benzoxonium 0.10 mg trometamol 0.40 mg sodium chloride 6.00 mg Solutol »HS15 20.00 mg Water for injections ad 1.00 ml

Boisplel 16

Eye gel containing valeric acid, tear substitute

component amount 0.10 mg Polymer JR 30 M ^s 12.00 mg ad 1.00 ml Vitamin A acid 0.15 mg Disodium EDTA 1.00 mg benzoxonium 0.10 mg trometamol 0.40 mg sodium chloride 6.00 mg Solutol »HS15 20.00 mg Water for injections ad 1.00 ml Example 17 Eye gel, tear substitute component amount Polymer JR 30 M » 12.00 mg sorbitol 43.00 mg Disodium EDTA 1.00 mg Luviquat®FC905 5.00 mg benzoxonium 0.10 mg Water for injections ad 1.00 ml Example 18 Eye gel, tear substitute component amount polyacrylic acid 4.00 mg sorbitol 43.00 mg Disodium EDTA 1.00 mg Sodium hydroxide (10% aqueous solution) 1.50 mg benzoxonium Water for injections

Example 19

Eye gel containing valeric acid, tear substitute

component amount polyacrylic acid 5.00 mg Vitamin A acid 0.15 mg Disodium EDTA 1.00 mg benzoxonium 0.10 mg sodium chloride 6.00 mg Solutol®HS15 20.00 mg Water for injections ad 1.00 ml

Example 20

Eye drops containing naphazoline nitrate and zinc sulfate

component amount naphazoline 0.0525 mg zinc sulfate 0.200 mg boric acid 7,000 mg trometamol 5,000 mg Hydrochloric acid 1 N 34,000 mg N-benzyl-N-lgemischtesCe-Cie-AlkvD- N, N-bis- (2-hydroxyethyl) -ammonium chloride 0.100 mg methylhydroxypropylcellulose 3,000 mg Hamameliswasser 40,000 mg Orange blossom oil 5.00 ng lavender oil 1,80Mg Euphrasiatinktur 0.300 mg Ethanol abs. 1.393 mg Water for injections ad 1,000 ml

Example 21

Eye drops containing chloramphenicol

component

amount

chloramphenicol 6.00 mg amount DinaUium EDTA 0.10 mg Macrogol 400 80.00 mg tromethamol 0.10 mg N-benzyl-N-lgemischtesCg-Cu-alkyl) - N, N-bis- (2-hydroxyethyl) -ammonium chloride 0.10 mg Cremophor EL * 4.00 mg Water for injections ad 1.00 ml Example 22 Eye drops containing chloramphenicol component

chloramphenicol 6.00 mg amount Disodium EDTA 0.10 mg 6.00 mg Macrogol 400 80.00 mg 0.10 mg Troinetamol 0.10 mg 8C, 00 mg N-benzyl-N-lgemischtesCe Cte-alkyl) - N, N-bis- (2-hydroxyethyl) -ammonium chloride 0.10 mg 0.10 mg Water for injections ad 1,00 ml 5.00 mg Example 23 1,00 ml Eye drops containing chloramphenicol component chloramphenicol Disodium EDTA Macrogol 400 N-benzyl-N- (mixed C ₈ -C ₁₈ -alkyl) - N, N-bis- (2-hydroxyethyl) -ammonium chloride Solutol®HS15 Water ^for injections ad

Example i4

Eye drops containing pirbuterol hydrochloride

component

amount

Pirbuterol Hydrochloride 3.00 mg

Disodium EDTA 0.10 mg

Benzoxonium chloride 0.10 mg

Sodium chloride 8.25 mg

Sodium hydroxide (1 N aqueous solution) 0.10 mg

Water for injections ad 1.00 ml

Example 25

Eye drops containing pirbuterol hydrochloride

component

amount

Pirbuterol hydrochloride 5.00 mg

Disodium EDTA 0.10 ng

Benzoxonium chloride 0.10 mg

Sodium chloride 7.50 mg

Sodium hydroxide (1N aqueous solution) 0.10 mg

Water for injections ad 1.00 ml

Example 26

Eye drops containing Pirbuterol-Hydrojhlorld

Component quantity

Pirbuterol hydrochloride 8.00 mg

Disodium EDTA 0.10 mg

Benzoxonium chloride 0.10 mg

Sodium chloride 6.75 mg

Sodium hydroxide (1 N aqueous solution) 0.10 mg

Water for injections ad 1.00 ml

Example 27

Eye gel containing Dlclofenac-Na and Qentamlcln

component amount Diclofenac sodium 1.00 mg gentamicin 3.00 mg Cremophor EL * 10.00 mg Disodium EDTA 1.00 mg benzoxonium 0.10 mg Borax (Na ₂ B ₄ O ₇ - 10H ₂ O) 1.50 mg boric acid 13.00 mg Polymer JR-30 * 12.50 mg Water for injections ad 1.00 ml

Example 28

Eye drops containing diclofenac-Na and gentamicin

Component quantity

Diclofenac sodium 1.00 mg gentamicin 3.30 mg Cremophor EL * 50.00 mg boric acid 13.00 mg trometamol 6.00 mg Disodium EDTA 1.00 mg benzoxonium 0.10 mg sodium chloride 2.80 mg Water for k: jektionszwecke ad 1.00 ml Example 29 Cleaning solution for contact lenses component amount benzoxonium 0.01g sodium chloride 0.36 g Na ₂ HPO ₄ 0.73 g NaH ₂ PO ₄ .H ₂ O 0.21 g Disodium EDTA 0.10 g Varox »365 1,00 ml Triton® X-100 0.33 ml Cello Size "QP 40HEC 1.50 g demineralised water ad 100.00 ml

Example 30

Conditioning solution for gas-permeable and hard contact lenses

component amount benzoxonium 0.005 g Vinol®350PVA 0,5COg PlasdoneK-90PVP 1,000 g Na ₂ HPO ₄ 0.720 g NaH ₂ PO ₄ .H ₂ O 0.220 g sodium chloride 0.440 g Disodium EDTA 0.100 g demineralised water ad 100,000 ml

Claims (29)

1. An antimicrobial ophthalmic composition containing at least one compound of the formula I, alki-OH Ai alk ₃ N-Alk (|) alk _r 0H wherein Ar is aryl, Alk is alkyl, alki, alk ₂ and alk _{3 are} independently alkyl and X ^{e is} an ophthalmically acceptable anion, and one or more ophthalmically compatible or contact lens compatible excipients. 2. Antimicrobial ophthalmic composition according to claim 1, comprising at least one compound of formula I, wherein Ar is phenyl, Alk is C ₈ -C ₁₉ alkyl, alk, and alk _{2 is} 1,2-ethylene, alk _{3 is} methylene , and X ^{e is} chloride. 3. ophthalmic medicament according to claim 1, containing at least one compound of formula I, alk, OH J χ ^θ Ar alk ₃ N-Alk (!) alkr OH wherein Ar is aryl, Alk is alkyl, alk _{1 (} alk ₂ and alk _{3 are} independently alkylene and Χ ^{θ is} an ophthalmically acceptable anion, and one or more ophthalmically acceptable excipients. 4. ophthalmic medicament according to claim 3, containing at least one compound of formula I, wherein Ar is phenyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl, Alk is C ₁ -C ₂ O-AIkYl, alk, and alk ₂ independently of one another are C ₂ -C 4 -alkylene, alk _{3 is} C ₁ -C 12 -alkylene, and d ^{θ is} an ophthalmically acceptable anion. 5. eye medicine according to claim 3, containing at least one compound of formula I, wherein Ar is phenyl, Alk is Ci-C ₁₈ alkyl, alk, and alk _{2 is} 1,2-F.thylene, alk _{3 is} methylene, and Χ ^{θ is} bromide or chloride. 6. ophthalmic medicament according to claim 3, containing at least one compound of formula I, wherein Ar is phenyl, Alk is C ₈ -C ₁₈ -Alkyl, 8Ik ₁ and alk _{2 is} 1,2-ethylene, alk _{3 is} methylene, and X ^e means chloride. 7. eye medicine according to claim 3, containing N-benzyl-N- (n-dodecyl) -N, N-bis- (2-hydroxyethyl) -ammonium chloride or N-benzyl-N- (mixed C ₈ -C ₁₈ -alkyl) -N, N-bis- (2-hydroxyethyD chloride. 8. eye medicine according to claim 3, containing N-benzyl-N- (n-dodecyl) -N, N-bis- (2-hydroxyethyO-ammonium chloride. 9. ophthalmic medicament according to one of claims 3 to 8, characterized in that it contains the compounds of formula I in a concentration (w / v) of 0.0001% to 0.10%. 10. ophthalmic medicament according to one of claims 3 to 8, characterized in that it contains the compounds of formula I in a concentration (w / v) of 0.001% to 0.02%. 11. ophthalmic medicament according to one of claims 3 to 8, characterized in that it contains the compounds of formula I in a concentration (w / v) of 0.002% to 0.015%. 12. ophthalmic medicament according to any one of claims 3-11, containing the pharmaceutical active ingredient diclofenac or an ophthalmically acceptable salt thereof. 13. eye medicine according to any one of claims 3-11, containing the pharmaceutical active ingredient diclofenac sodium. 14. ophthalmic medicament according to one of claims 3-11, containing the active pharmaceutical ingredients diclofenac sodium and gentamicin. 15. eye medicine according to any one of claims 3-11, containing the pharmaceutical agent naphazoline nitrate. 16. Use of at least one compound of the formula I, alk _r 0H ml _χ ^θ Ar alk-i-N-alk (I) alk ₂ -OH wherein Ar is aryl, Alk is alkyl, alk _{1 (} alk ₂ and alk _{3 are} independently alkylene and Χ ^{θ is} an ophthalmically acceptable anion, for the preservation of ophthalmic drugs. 17. Use according to claim 16, characterized in that at least one compound of the formula I ₁ in which Ar is phenyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl, Alk is C ₁ -C ₂₀ -alkyl, 8Ik ₁ and alk _{2 are} independently C ₂ -C ₄ -alkylene, alk _{3 is} C ₁ -C ₄ -alkylene, and ^{θ θ is} an ophthalmically-acceptable anion. 18. Use according to claim 16, characterized in that at least one compound of formula I in which Ar is phenyl, Alk is C ₁ -C ₁₈ -Alkyl, SIk ₁ and alk _{2 are} 1,2-ethylene, alk ₃ for methylene stands, and Χ ^Θ bromide or chloride means is applied. 19. Use according to claim 16, characterized in that at least one compound of formula I wherein Ar is phenyl, Alk is C ₈ -C ₁₈ alkyl, alk, and alk _{2 is} 1,2-ethylene, alk ₃ for methylene stands, and Χ ^θ means chloride is applied. 20. Use according to claim 16, characterized in that N-benzyl-N- (n-dodecyl) -N, N-bis (2-hydroxyethyl) -ammonium chloride or N-benzyl-N- (mixed C ₈ -C ₁₈ -Alkyl) -N, N-bis- (2-hydroxyethyl-ammonium chloride). 21. Use according to claim 16, characterized in that N-benzyl-N- (n-dodecyl) -N, N-bis (2-hydroxyethyl) ammonium chloride is used. 22. Use according to any one of claims 16-21, characterized in that the compounds of the formula I are used in ophthalmic medicines in a concentration (w / v) of 0.0001% to 0.10%. 23. Use according to any one of claims 16-21, characterized in that the compounds of the formula I are used in ophthalmic medicines in a concentration (w / v) of 0.001% to 0.02%. 24. Use according to any one of claims 16-21, characterized in that the compounds of the formula I are used in ophthalmic medicines in a concentration (w / v) of 0.002% to 0.015%. 25. A solution for the treatment of contact lenses according to claim 1, comprising at least one compound of formula I, alk, OH φΙ Χ ^θ Ai alk ₃ N - Alk (I) alk _r 0H wherein Ar is aryl, Alk is alkyl, alk _{1 #} alk ₂ and alk _{3 are} independently alkylene and Χ ^{θ is} an ophthalmically acceptable anion, and one or more contact lens compatible excipients. 26. A solution for the treatment of contact lenses according to claim 25, comprising at least one compound of formula I wherein Ar is phenyl, Alk is C ₈ -C ₁₈ alkyl, 8Ik ₁ and alk _{2 is} 1,2-ethylene, alk ₃ is methylene, and Χ ^{θ is} chloride. 27. A cleaning solution for contact lenses according to claim 26, comprising: (a) a compound of the formula I ₁ in which Ar is phenyl, Alk is C ₈ -C ₁₈ -alkyl, SIk ₁ and alk _{2 are} 1,2-ethylene, alk _{3 is} methylene, and X ^{e is} chloride in one Concentration (w / v) from 0.005% to 0.8%, (b) an isotonizing agent, (c) a buffer substance, (d) a complexing agent, (e) a solubilizer, and if necessary (f) a thickener. 28. A contact lens conditioner according to claim 26, comprising (A) a compound of formula I ₁ wherein Ar is phenyl, Alk is C ₈ -C ₈ -alkyl, 3Ik ₁ and alk _{2 is} 1,2-ethylene, alk _{3 is} methylene, and Χ ^Θ chloride means in one Concentration (w / v) of 0.002 to 0.8%. (b) a humectant, (c) a buffer substance, (d) an isotonizing agent, and optionally (e) a complexing agent. 29. Use of at least one compound of the formula I, alk, OH el χ ^Θ Ar alk ₃ N - Alk (|) alk ₂ -OH