IL95720A

IL95720A - Antimicrobial ophthalmic compositions containing quaternary ammonium salts

Info

Publication number: IL95720A
Application number: IL9572090A
Authority: IL
Original assignee: Ciba Vision Ag
Priority date: 1989-09-21
Filing date: 1990-09-18
Publication date: 1996-07-23
Also published as: NO179472B; HU210525A9; HU905995D0; CA2025728C; DK0420798T3; AU640687B2; HUT59001A; IE903406A1; IE71639B1; FI101849B; PT95355B; NO904112D0; NZ235377A; PH29982A; ZA907536B; EP0420798B1; JPH03130219A; NO904112L; DE59005084D1; PT95355A

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

95720/2 Antimicrobial ophthalmic compositions containing quaternary ammonium salts Ciba Vision AG, Hettlingen C: 81318 The invention relates to antimicrobial, ophthalmic compositions containing certain quaternary ammonium salts as preservatives.

The invention relates particularly to antimicrobial, ophthalmic compositions containing at least one compound of the formula I in which Ar is aryl which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl, Alk is alkyl, alk^ alk2 and alk3 independendy of one another are alkylene, and X® is an ophthalmically acceptable anion, and one or more adjuncts which are ophthalmically acceptable or acceptable to contact lenses, which composition is substantially isotonic with the human lacrimal fluid.

The invention relaces firstly to an eye medicamenc, for example eye drops, eye gels or eye ointments, containing certain quacemary ammonium salts as preservatives, and to the use of these quaternary ammonium salts for the preservation of eye medicamencs.

Secondly, the invention also relates, for example, to solutions for the treacmenc of contact lenses which contain certain quaternary ammonium salts as preservatives and to the use of these quaternary ammonium-salts for the preservation of concact lenses.

Medicaments for the treacmenc of diseases of the eye are often formulated in liquid form and administered in the form of drops. In most European and other councries preservation of the preparations is prescribed for eye drops, ie. protection against an attack by, and subsequent propagation of, microorganisms by means of the addition of ac lease one component capable of preventing, or at lease controlling, a secondary contamination. In addition, eye medicaments are often formulated as gels. As far as preservation is concerned, the same aDoiies to aaueous sels.

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] has now been employed for disinfection in many fields for over 30 years [see Arzneimittelforschung 9, 622-625 (1959)]. For example, benzoxonium chloride is used in gargle solutions for disinfecting the mouth and pharyngeal cavities, in laryngotracheitis, against dental plaque, against caries, for skin disinfection, particularly of the hands in surgery, for dermatological-cosmetic purposes or for disinfection in hospitals, for example of medical instruments. In addition, benzoxonium chloride is also employed as a veterinary antiseptic, for example as a fungicide and bactericide for the udder or for the treatment of dermatomycoses in horses. Other fields of use for benzoxonium chloride are as follows: disinfection in the food and beverages industry, in the wine industry and in slaughterhouses, the disinfection of animal hides, a bactericide for textile fibres and a bactericide and fungicide for sugar beet.

It is also known to preserve eye medicaments by means of quaternary ammonium salts (see, for example, EP-A-306,984). Only a very few quaternary ammonium salts have found practical application for the preservation of eye medicaments - evidendy because of the multifarious requirements which must be fulfilled - these are, in particular, the three substances mentioned explicitly in EP-A-306,984, cetyltrimethylammonium bromide, cetylpyridinium chloride and benzalkonium chloride (cf. also EP-A-242,328). The preferred preservative for eye medicaments at the present time is quite definitely the last-mentioned benzalkonium chloride (see, for example, EP-A-306,984, page 2, lines 31-33), which has the following structure: N-benzyl-N-(Cg-C18alkyl)-N,N-dimethylammonium chloride.

The very small number of quaternary ammonium salts used in eye medicaments for preservation is in contrast with a large number of known quaternary ammonium salts ("quats") which are employed for preservation in other fields.

It is an object of the present invention to find further quaternary ammonium salts suitable for the preservation of eye medicaments. By this means the hitherto very small range of possible preservatives for the manufacturer of eye medicaments would be enlarged, and the latter would have more alternatives for the preservation of his formulations. The object mentioned is achieved as a result of finding that the N-alkyl-N-arylalkyl-N,N-bis- (hydroxyalkyl)-ammonium salts of the formula I, to which benzoxonium chloride also belongs, are excellently suitable for the preservation of eye medicaments. This result is by no means obvious, since hundreds of quaternary ammonium salts are known in general for disinfection, and of these, surprisingly, a very small group, namely the compounds of the formula I, has proved suitable for the preservation of eye medicaments. As indicated above, one compound of the formula I, benzoxonium chloride, has already been used for disinfection in many fields for over 30 years. It has, however, never been suggested for the preservation of eye medicaments. It was therefore not obvious to use the compounds of the formula I, including benzoxonium chloride, for the preservation of eye medicaments.

It is another object of the invention to find specific quaternary ammonium salts which are more suitable than benzalkonium chloride for the preservation of eye medicaments. As already mentioned above, benzalkonium chloride, together with chlorohexidine, thiomersal and chiorobutanoi, is probably the most frequently used preservative for eye medicaments in the world at the present time. However, it is by no means the case that benzalkonium chloride is ideal and gives satisfaction in every respect. Particularly in the case of long-term application, which can be necessary, for example, in the treatment of glaucoma, cataract or "dry eye", problems of toleration by the eye can arise, for example changes in the corneal and conjunctival epithelium, and at the eyelids. The object of finding preservatives for eye medicaments having an improved acceptability for long-term application is achieved by the provision of eye medicaments containing, for preservation, compounds of the formula I.

Accordingly, the present invention relates to an eye medicament containing at least one compound of the formula I alk2- OH in which Ar is aryl which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen or rrifluoromethyl, Alk is alkyl, alklf alk2 and alk3 independendy of one another are aikylene, and Χθ is an ophthalmically acceptable anion, and one. or more adjuncts which are ophthalmically acceptable or acceptable to contact lenses.

Aryl is, for example, phenyl or naphthyl, such as 1-naphthyl or 2-naphthyl. The phenyl 9 5 72 0/2 - 4 - and naphthyl radicals can be unsubstituted or substituted as defined above.

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 CrC7aLkyl for example n-propyl, isopropyl, n-butyl, isobutyl, sec-buty!, ten-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, preferably ethyl and particularly methyl.

Lower alkoxy is C Cyalkoxy, for example n-propoxy, isopropoxy, n-butoxy or tert-butoxy, preferably ethoxy and particularly methoxy.

Halogen is especially fluorine, chlorine or bromine, but can also be iodine.

The alkyl and alkylene groups Alk, alkj, alk2 and alk3 are preferably linear, but can also be branched.

The alkyl group Alk is, for example, Q-C^alkyl, for example methyl, ethyl, n-propyl, n-butyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-nonadecyl, n-eicosyl, n-heneicosyl, n-docosyl, n-tricosyl, n-tetracosyl or n-hexacosyl, preferably 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 is preferably CrC2oalkyl, particularly Q-Qgalkyl and primarily C8-C18alkyl.

"Mixed Cg-Cjgalkyl" is a mixture consisting essentially of n-octyl, n-decyl, n-dodecyl, n-tetradecyl, n-hexadecyl and n-octadecyl, containing 40-60 %, in particular approximately 50 , of the n-dodecyl component.

The alkylene groups alkj, alk2 and alk3 are, for example, C C- alkylene; examples are 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 a\kl and al k independently of one another are preferably C2-C4alkylene, are primarily identical with one another and above all are 1,2-ethylene.

The alkylene group Alk3 is preferably Q^alkylene and is primarily methylene.

The anion X® is derived from an ophthalmically acceptable acid. Examples of ophthalmically acceptable acids are strong mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or organic acids, in particular aliphatic or aromatic carboxylic acids, for example acetic, propionic, lactic, tartaric, citric, maleic, fumaric, hydroxy maleic, phenylacetic, gluconic or nicotinic acid; or other acidic organic substances, for example ascorbic acid. Further suitable examples are also amino acids, for instance arginine or lysine. The anion X® is preferably bromide and primarily chloride.

As preservatives for eye medicaments, the compounds of the formula I are distinguished, inter alia, by the fact that they have an excellent preservative action and are well tolerated by the eye even in the case of long-term application.

The preservative action of the compounds of the formula I is evident, for example, from the results of the following preservative challenge test: Preservative challenge test, substance: benzoxonium chloride, 0.1 mg/ml, pH 6 Percentages: reduction n.g.: no growth The surprisingly improved toleration by the eye of the compounds of the formula I in comparison with benzalkonium chloride is evident, for example, from the results of the 5-day animal toleration test described below: in each case 0.01 % solutions of benzoxonium chloride and benzalkonium chloride were compared. These solutions were added dropwise to the conjunctival sac of rabbits five times (in 90 minute intervals) for 5 days. At the end of the test the treated eyes were examined for clinical results, for example reddening of the conjunctiva, cloudiness of the cornea, secretion and chemosis. The following results were obtained: Benzoxonium chloride (= compound of the formula I), 0.01 % 5 Instillations/animal/day at intervals of 90 minutes each no result Benzalkonium chloride (= comparison compound), 0.01 % 5 Instillations/animal/day at intervals of 90 minues each 4 results The improved toleration by the eye of the compounds of the formula I compared with benzalkonium chloride is also evident, for example, from the results of the occular, local toleration study in rabbits lasting 4 weeks, described below: in each case 0.01 % solutions of N-benzyl-N-(mixed C8-C18alkyl)-N,N-bis-(2-hydroxyethyl)-ammonium chloride and benzalkonium chloride were compared. Pigmented Himalaya rabbits were used as test animals. In each case 50 μΐ of the corresponding solution was administered to the conjunctival sac of the right eye of these rabbits ten times a day (at 45 minute intervals) for 4 weeks. As a control, a comparison solution containing no preservative was added dropwise to the left eye in each case. The animals were subjected to an opthalmological examination on the first day of treatment and on the fifth day. When the test was complete, the test animals were also subjected to a histopathological examination, and the following results were found: in the case of the animals treated with the solution according to the invention, which contained N-benzyl-N-(mixed C8-C18alkyl)-N,N-bis-(2-hydroxy-ethyl)-ammonium chloride, no occular lesions were found. On the other hand, in 4 out of 6 animals treated with benzalkonium chloride solution lesions in the conjunctiva and an acanthosis and hyperkeratosis at the edge of the lower right eyelid were observed.

Accordingly, the benzalkonium chloride solution caused changes at the conjunctival epithelium which did not occur with the solution according to the invention. This demonstrates convincingly that the compounds of the formula I have a surprisingly improved long-term toleration in the eye compared with benzalkonium chloride.

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

The invention preferably relates to an eye 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 CrC2oalkyl, alkj and alk2 independently of one another are C2-C4alkylene, alk3 is CrC4alkylene and X® is an ophthalmically acceptable anion.

The invention particularly preferably relates to an eye medicament containing at least one compound of the formula I in which Ar is phenyl, Alk is Cj-Cjgalkyl, all and alk2 are 1,2-ethylene, alk3 is methylene and is bromide or chloride.

The invention relates very particularly to an eye medicament containing at least one compound of the formula I in which Ar is phenyl, Alk is Cg-Cjgalkyl, alkj and alk2 are 1,2-ethylene, alk3 is methylene and X® is chloride.

The invention relates primarily to an eye medicament containing N-benzyl-N-(n-dodecyl)-N,N-bis-(2-hydroxyethyl)-ammonium chloride or N-benzyl-N-(mixed C8-C18alkyl)-N,N-bis-(2-hydroxyethyl)-ammonium chloride.

The invention relates above all to an eye medicament containing N-benzyl-N-(n-dodecyl)-N,N-bis-(2-hydroxyethyl)-ammonium chloride ( = benzoxonium chloride).

A particular embodiment of the invention consists in an eye medicament containing at least compound of the formula I as defined above and EDTA or a salt thereof, for example disodium EDTA. If EDTA, or a salt thereof, is present in the eye medicament of the invention, it is preferably present in a concentration of 0.01 - 0.2 % (W/V), in particular about 0.05 - 0.1 % (W/V).

The compounds of the formula I which are added to the eye medicaments must have a purity sufficient for ophthalmic purposes. The benzoxonium chloride employed, for example, preferably contains not more than 2.5 % by weight of by-products, and each individual by-product must not represent more than 0.5 % by weight.

In addition to the preservative, eye medicaments can contain, for example, the following constituents: (a) if appropriate one or more pharmaceutical active ingredients, for example steroidal anti-inflammatory substances, for example fluorometholon; non-steroidal anti-inflammatory substances, for example diclofenac or ophthalmologically acceptable salts thereof, in particular diclofenac sodium (diclofenac Na); antibiotics, for example quinolones, chloramphenicol or gentamicin; anti-glaucoma acitve ingredients, for example pilocarpine hydrochloride or pirbuterol hydrochloride; substances having a keratolytic action, for example vitamin A acid; vasoconstrictive substances, for example naphazoline nitrate, tetrahydrozolirie ( = tetryzoline), phenylephrine or xylometazoline; anti-allergic agents, for example isospaglumic acid or spaglumic acid and magnesium or sodium salts thereof; astringent substances, for example zinc sulfate; anti-cataract active ingredients, for example methosorbinil [= (2R,4S)-2-methyl-6-fluorospiro-[chroman-4,4'-imidazolidine]-2',5'-dione]; or medicinal plant extracts, for example euphrasia tincture.

Examples which may be mentioned of eye medicaments containing no pharmaceutical active ingredient are certain tear replacement formulations ("artificial tears").

Eye medicaments also contain ophthalmically acceptable adjuncts, for example (b) if appropriate one or more buffer substances, for example boric acid, borates, for example borax (Na2B407 · 10H2O), phosphates, for example the Na2HP04.2H20/NaH2P04.2H20 buffer, trometamol (= 2-amino-2-hydroxymethyl-l,3-propanediol = TRIS) or organic acids, for example ascorbic, acetic, propionic or citric acid; (c) if appropriate one or more isotonising agents, for example sodium chloride, sorbitol (= d-sorbitol), mannitol or glycerol; (d) if appropriate one or more solubilizers, for example fatty acid glycerol-polyglycol esters, fatty acid polyglycol esters, polyethylene glycols, glycerol ethers or mixtures of these compounds. Reaction products formed from castor oil and ethylene oxide, for example the commercial product Cremophor® EL polyoxyl 35 castor oil) are a special example of a particularly preferred solubilizer. Reaction products formed from castor oil and ethylene oxide have proved to be particularly good solubilizers having an excellent toleration by the eye.

Further examples of solubilizers are Luviquat® FC 905 (= copolymer formed from vinylimidazolium methochloride and vinylpyrrolidone, 95:5, BASF), Solutol® HS 15 (= polyethyleneglycol 660 12-hydroxystearate, BASF) and macrogol 400 (= polyethylene glycol 400, Lutrol® E 400, BASF). (e) if appropriate solvents in order to dissolve certain components of the formulation, for example the active ingredient or ethereal oils used as odorants. The following may be mentioned as examples: absolute ethanol, polypropylene glycol or polyethylene glycol 400 (= macrogol 400, see also under solubilizers); (f) if appropriate antioxidants, for example a-tocopherol acetate or BHA 3-tert-butyl-4-hydroxyanisole); (g) if appropriate thickeners used to increase the viscosity of the formulation, for example methylhydroxypropylcellulose, for example Methocel F4M® (Dow Chemicals), or the sodium salt of hyaluronic acid; (h) if appropriate powerful thickeners which result in gel formation, for example polyacrylic acid, Carbopol® 934 P (= carboxy vinyl polymer, BF Goodrich), Polymer JR 30 M® (=≥ polymeric quaternary ammonium salt obtained by reacting hydroxyethylcellulose with a trimethylammonium-substituted epoxide, cf. US Patent 3,472,840, Union Carbide), alginates or polyvinylpyrrolidone; (i) if appropriate complex-formers, for example for increasing the preservative action of the preservatives according to the invention and/or for complexing and hence masking any heavy metal impurities present, for example EDTA or salts thereof, such as disodium EDTA; (j) if appropriate odorants, for example orange blossom oil, lavender oil or hamamelis lotion; (k) if appropriate substances which affect the pH, for example hydrochloric acid or sodium hydroxide; (1) if appropriate dyes, for example sodium fluoresceine; and (m) normally water for injection purposes or deionized water.

In the normal case endeavours are made to formulate eye medicaments so as to be isotonic with the human lacrimal fluid (= 270 to 330 mosmol/kg, in particular 300 mosmol/kg). There can, however, also be exceptional cases in which the osmolality of eye medicaments is outside the range indicated.

The invention also relates to the use of at least one compound of the formula I in which Ar is aryl, Alk is alkyl, alkj, alk2 and alk3 independendy of one another are alkylene and X® is an ophthalmically acceptable anion, for the preservation of eye medicaments.

The invention relates particularly to the use of 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 CrC2oalkyl, ah and alk2 independendy of one another are C2-C4alkylene, alk3 is C C4alkylene and X® is an ophthalmically acceptable anion, for the preservation of eye medicaments.

The invention relates particularly preferably to the use of at least one compound of the formula I in which Ar is phenyl, Alk is Cj-Qgalkyl, alkj and alk2 are 1,2-ethylene, alk3 is methylene and X® is bromide or chloride, for the preservation of eye medicaments.

The invention relates very particularly to the use of at least one compound of the formula I in which Ar is phenyl, Alk is Cg-Cjgalkyl, alkj and alk2 are 1,2-ethylene, alk3 is methylene and X© is chloride, for the preservation of eye medicaments.

The invention relates primarily to the use of N-benzyl-N-(n-dodecyl)-N,N-bis-(2-hydroxy-ethyl)-ammonium chloride or N-benzyl-N-(mixed Cg-C18alkyl)N,N-bis-(2-hydroxyethyl)-ammonium chloride for the preservation of eye medicaments.

The invention relates above all to the use of N-benzyl-N-(n-dodecyl)-N,N-bis-(2-hydroxy-ethyl)-ammonium chloride for the preservation of eye medicaments.

The invention also relates to solutions for the treatment of contact lenses, containing at least one compound of the formula I in which Ar is aryl, Alk is alkyl, alkl5 alk2 and alk3 independently of one another are alkylene and X® is an ophthalmically acceptable anion, and one or more adjuncts which are acceptable to contact lenses.

Solutions for the treatment of contact lenses are to be understood as meaning, in particular, the following: (a) cleansing solutions for contact lenses and (b) conditioners for contact lenses which are permeable to gas and hard.

The preferred subgroups of compounds of the formula I in this respect are the same as those indicated above for eye medicaments containing compounds of the formula I.

In particular, therefore, the invention relates, for example, to solutions for the treatment of contact lenses, containing at least one compound of the formula I in which Ar is phenyl, Alk is C8-C18alkyl, aU and alk2 are 1,2-ethylene, alk3 is methylene and X® is chloride.

A preferred cleansing solution for contact lenses according to the invention contains: (a) a compound of the formula I in which Ar is phenyl, Alk is Cg-Cjgalkyl, alki and alk2 are 1,2-ethylene, alk3 is methylene and X® chloride, in a concentration (W/V) of 0.005 to 0.8 , (b) an isotonising agent, for example sodium chloride, (c) a buffer substance, for example a phosphate buffer, (d) a complex-former, for example EDTA or a salt thereof, (e) a solubilizer, for example amine oxide detergents, for example Varox® 365 (Sherex Chemical), or the Triton® series (= polyethylene glycol p-isooctylphenylether) made by Rohm and Haas, in particular Triton® X-100, and, if appropriate, (f) a thickener, for example rapid-soluble hydroxyethylcellulose, for example Cellosize® QP-40 HEC (Union Carbide).

A preferred conditioner for contact lenses according to the invention contains: (a) a compound of the formula I in which Ar is phenyl, Alk is Cg- galkyl, alkj and alk2 are 1,2-ethylene, alk3 is methylene and X® is chloride in a concentration (W/V) of 0.002 to 0.8 %, (b) a moistening agent, for example polyvinyl alcohol, for instance Vinol® 350 PVA (Air Products, Inc.), or mixtures of polyvinyl alcohol and polyvinylpyrrolidone (for example Vinol®350 PVA + Plasdone K-90 PVP, made by GAF), (c) a buffer substance, for example a phosphate buffer, (d) an isotonising agent, for example sodium chloride, and, if appropriate, (e) a complex-former, for example EDTA or a salt thereof.

The components indicated above for the preferred cleansing solution or for the preferred conditioner for contact lenses under (b)-(f) or (b)-(e) are examples of adjuncts which are acceptable to contact lenses.

The invention also relates to the use of at least one compound of the formula I in which Ar is aryl, Alk is alkyl, alk alk2 and alk3 independently of one another are alkylene and X® is an ophthalmically acceptable anion, for the preservation of contact lenses.

The subgroups of compounds of the formula I which are used here preferably are the same as those indicated above for the eye medicaments containing compounds of the formula I.

In particular, therefore, the invention relates, for example, to the use of at least one compound of the formula I, in which Ar is phenyl, Alk is Cg-Cjgalkyl, alkj and alk2 are 1,2-ethylene, alk3 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 the formula I. These preferred subgroups of compounds of the formula I are the same as those indicated above for the eye medicaments containing compounds of the formula I.

In particular, therefore, the invention also relates, for example, to antimicrobial ophthalmic compositions containing at least one compound of the formula I in which Ar is phenyl, Alk is C8-C18alkyl, alkt and alk2 are 1,2-ethylene, alk3 is methylene and X® is chloride.

The procedure used in the preparation of eye medicaments - and also solutions for the treatment of contact lenses - in accordance with the invention is to mix an effective, i.e. sufficient for preservation, amount of one or more compounds of the formula I and the remaining constituents in accordance with conventional methods.

The following formulation examples illustrate the invention: Example 1: Eye drops containing diclofenac Na Ingredient Amount Diclofenac -Na 1.00 mg Cremophor® EL 10.00 mg Luviquat® FC 905 5.00 mg Trometamol 6.00 mg Boric acid 19.50 mg Disodium EDTA 1.00 mg Benzoxonium chloride 0.10 mg Water for injection purposes ad 1.00 ml Example 2: Eve drops containing naphazoline nitrate and zinc sulfate Ingredient Amount Naphazoline nitrate 0.050 mg Zinc sulfate 0.200 mg Sodium chloride 4.050 mg Benzoxonium chloride 0.100 mg Methylhydroxypropylcellulose 3.000 mg Hamamelis lotion 40.000 mg Orange blossom oil 5.00 Lavender oil 1.80 μ Euphrasia tincture 0.800 mg Absolute ethanol 1.393 mg IN hydrochloric acid 0.100 mg Water for injection purposes ad 1.000 ml Example 3: Eve drops containing naphazoline nitrate and zinc sulfate Ingredient Amount Naphazoline nitrate 0.0525 Zinc sulfate 0.200 Boric acid 7.000 Trometamol 5.000 IN hydrochloric acid 34.000 Benzoxonium chloride 0.100 Methylhydroxypropylcellulose 3.000 Hamamelis lotion 40.000 Orange blossom oil 5.00 Lavender oil 1.80 Euphrasia tincture 0.800 Absolute ethanol 1.393 Water for injection purposes ad 1.000 Example 4: Eye drops containing chloramphenicol Ingredient Amount Chloramphenicol 6.00 Disodium EDTA 0.10 Macrogol 400 80.00 Trometamol 0.10 Benzoxonium chloride 0.10 Cremophor® EL 4.00 Water for injection purposes ad 1.00 Example 5: Eye drops containing chloramphenicol Ingredient Amount Chloramphenicol 6.00 Disodium EDTA 0.10 Macrogol 400 80.00 Trometamol 0.10 B enzoxonium chloride 0.10 a-Tocopherol acetate 10.00 Solutol® HS 15 5,00 Water for injection purposes ad 1.00 Example 6: Eye drops containing chloramphenicol Ingredient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogol 400 80.00 mg Benzoxonium chloride 0.10 mg Water for injection purposes ad 1.00 ml Example 7: Eye drops containing chloramphenicol Ingredient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogol 400 80.00 mg Trometamol 0.10 mg Benzoxonium chloride 0.10 mg Water for injection purposes ad 1.00 ml Example 8: Eye drops containing chloramphenicol Ingredient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogol 400 80.00 mg a-Tocopherol acetate 10.00 mg Benzoxonium chloride 0.10 mg Water for injection purposes ad 1.00 ml Example 9: Eye drops containing chloramphenicol Ingredient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogol 400 80.00 mg Cremophor® EL 4.00 mg Benzoxonium chloride 0.10 mg Water for injection purposes ad 1.00 ml Example 10: Eye drops containing chloramphenicol Ingredient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogol 400 80.00 mg Trometamol 0.10 mg Benzoxonium chloride 0.10 mg Solutol® HS 15 5.00 mg Water for injection purposes ad 1.00 ml Example 11 : Eye gel containing vitamin A acid, tear replacement Ingredient Amount Polymer JR 30 M® 12.80 mg Vitamin A acid 0.15 mg Disodium EDTA 1.00 mg Luviquat® FC 905 5.00 mg Benzoxonium chloride 0.10 mg a-Tocopherol acetate 10.00 mg Trometamol 0.50 mg Polypropylene glycol 60.00 mg Cremophor® EL 30.00 mg BHA 0.15 mg Water for injection purposes ad 1.00 ml Example 12: Eye gel containing vitamin A acid, tear replacement Ingredient Amount Polymer JR 30 M® 12.80 mg Vitamin A acid 0.15 mg Disodium EDTA 1.00 mg Luviquat® FC 905 5.00 mg Benzoxonium chloride 0.20 mg a-Tocopherol acetate 10.00 mg Trometamol 0.50 mg Polypropylene glycol 60.00 mg Cremophor® EL 30.00 mg BHA 0.15 mg Water for injection purposes ad 1.00 ml Example 13: Eye gel containing vitamin A acid, tear replacement Ingredient Amount Polymer JR 30 M® 12.00 mg Vitamin A acid 0.15 mg Disodium EDTA 1.00 mg Benzoxonium chloride 0.10 mg Trometamol 0.40 mg Sodium chloride 6.00 mg Solutol® HS 15 20.00 mg BHA 0.15 mg Water for injection purposes ad 1.00 ml Example 14: Eye gel containing vitamin A acid, tear replacement Ingredient Amount Polymer JR 30 M® 12.00 mg Vitamin A acid 0.15 mg Disodium EDTA 1.00 mg Benzoxonium chloride 0.10 mg Trometamol 0.40 mg Sodium chloride 6.00 mg Solutol® HS 15 20.00 mg Luviquat® FC 905 5.00 mg a-Tocopherol acetate 10.00 mg Water for injection purposes ad 1.00 ml Example 15: Eye gel containing vitamin A acid, tear replacement Ingredient Amount Polymer JR 30 M® 12.00 mg Vitamin A acid 0.15 mg Disodium EDTA 1.00 mg Luviquat® FC 905 5.00 mg Benzoxonium chloride 0.10 mg Trometamol 0.40 mg Sodium chloride 6.00 mg Solutol® HS 15 mg Water for injection purposes 1.00 ml Example 16: Eye gel containing vitamin A acid, tear replacement Ingredient Amount Polymer JR 30 M® 12.00 mg Vitamin A acid 0.15 mg Disodium EDTA 1.00 mg Benzoxonium chloride 0.10 mg Trometamol 0.40 mg Sodium chloride 6.00 mg Solutol® HS 15 20.00 mg Water for injection purposes ad 1.00 ml Example 17: Eye gel, tear replacement Ingredient Amount Polymer JR 30 My 12.00 mg Sorbitol 43.00 mg Disodium EDTA 1.00 mg Luviquat® FC 905 5.00 mg Benzoxonium chloride 0.10 mg Water for injection purposes ad 1.00 ml Example 18: Eye gel, tear replacement Ingredient Amount Polyacrylic acid 4.00 mg Sorbitol 43.00 mg Disodium EDTA 1.00 mg Sodium hydroxide (10 % aqueous solution) 1.50 mg Benzoxonium chloride 0.10 mg Water for injection purposes ad 1.00 ml Example 19: Eve eel containing vitamin A acid, tear replacement Ingredient Amount Polyacrylic acid 5.00 mg Vitamin A acid 0.15 mg Disodium EDTA 1.00 mg Benzoxonium chloride 0.10 mg Sodium chloride 6.00 mg Solutol® HS 15 20.00 mg Water for injection purposes ad 1.00 . ml Example 20: Eve drops containing naphazoline nitrate and zinc sulfate Ingredient Amount Naphazoline nitrate 0.0525 mg Zinc sulfate 0.200 mg Boric acid 7.000 mg Trometamol 5.000 mg IN hydrochloric acid 34.000 mg N-Benzyl-N-(mixed Cg-Cisalkyl)- N,N-bis-(2-hydroxyethyl)-ammonium-chloride 0.100 mg Methylhydroxypropylcellulose 3.000 mg Hamamelis lotion 40.000 mg Orange blossom oil 5.00 g Lavender oil 1.80 Euphrasia tincture 0.800 Absolute ethanol 1.393 mg Water for injection purposes ad 1.000 ml Example 21: Eve drops containing chloramphenicol Ingredient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogol 400 80.00 mg Trometamol 0.10. mg N-Benzyl-N-(mixed Cg-Cigalkyl)-N,N-bis-(2-hydroxyethyl)-ammonium- chloride 0.10 mg Cremophor® EL 4.00 mg Water for injection purposes ad 1.00 ml Example 22: Eve drops containing chloramphenicol Ingredient Amount Chloramphenicol 6.00 mg Disodium-EDTA 0.10 mg Macrogol 400 80.00 . mg Trometamol 0.10 mg N-Benzyl-N- (mixed Cg-Cigalkyl)- N,N-bis-(2-hydroxyethyl)-ammonium-chloride 0.10 mg Water for injection purposes ad 1.00 ml Example 23: Eve drops containing chloramphenicol Ingredient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogol 400 80.00 mg N-Benzyl-N-(mixed Cg-Cigalkyl)- N,N-bis-(2-hydroxyethyl)-ammonium-chloride 0.10 mg Solutol® HS 15 5.00 mg Water for injection purposes ad 1.00 ml Example 24: Eve drops containing pirbuterol hydrochloride Ingredient Amount Pirbuterol hydrochloride 3.00 mg Disodium EDTA 0.10 mg Benzoxonium chloride 0.10 mg Sodium chloride 8.25 mg Sodium hydroxide (IN aqueous solution) 0.10 mg Water for injection purposes ad 1.00 ml Example 25: Eve drops containing pirbuterol hydrochloride Ingredient Amount Pirbuterol hydrochloride 5.00 mg Disodium EDTA 0.10 mg Benzoxonium chloride 0.10 mg Sodium chloride 7.50 mg Sodium hydroxide (IN aqueous solution) 0.10 mg Water for injection purposes ad 1.00 ml Example 26: Eye drops containing pirbuterol hydrochloride Ingredient Amount Pirbuterol hydrochloride 8.00 mg Disodium EDTA 0.10 mg Benzoxonium chloride 0.10 mg Sodium chloride 6.75 mg Sodium hydroxide (IN aqueous solution) 0.10 mg Water for injection purposes ad 1.00 ml Example 27: Eye gel containing diclofenac Na and gentamicin Ingredient Amount Diclofenac Na 1.00 mg Gentamicin 3.00 mg Cremophor® EL 10.00 mg Disodium EDTA 1.00 mg Benzoxonium chloride 0.10 mg Borax (Ν32Β4θ7·10 ¾0) 1.50 mg Boric acid 13.00 mg Polymer JR-30® 12.50 mg Water for injection purposes ad 1.00 ml Example 28: Eve drops containing diclofenac Na and gentamicin Ingredient Amount Diclofenac Na 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 chloride 0.10 mg Sodium chloride 2.80 mg Water for injection purposes ad 1.00 ml Example 29: Cleansing solution for contact lenses Ingredient Amount Benzoxonium chloride 0.01. g Sodium chloride 0.36 g Na2HP04 0.73 g NaH2P04.H20 0.21 g Disodium EDTA 0.10 g Varox® 365 1.00 ml Triton® X-100 0.33 ml Cellosize® QP-40 HEC 1.50 g Deionized water ad 100.00 ml Example 30: Conditioning solution for contact lenses which are permeable to gas and hard Ingredient Amount Benzoxonium chloride 0.005 g Vinol® 350 PVA 0.500 g Plasdone K-90 PVP 1.000 g Na2HP04 0.720 g NaH2P04.H20 0.220 g Sodium chloride 0.440 g Disodium EDTA 0.100 g Deionized water ad 100.00 ml

Claims

95720/2 - 23 - What is claimed is:

1. An antimicrobial ophthalmic composition comprising an antimicrobially effective amount of at least one compound of the formula I in which Ar is aryl which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen or trifluoromethyl, Alk is alkyl, aU , alk2 and alk3 independently of one another are alkylene, and X® is an ophthalmically acceptable anion, and one or more adjuncts which axe ophthalmically acceptable or acceptable to contact lenses, which composition is substantially isotonic with the human lacrimal fluid.

2. An antimicrobial ophthalmic composition according to claim 1 comprising at least one compound of the formula I in which Ar is phenyl, Alk is Cg-Cjgalkyl, aD and alk2 are 1,2-ethylene, alk3 is methylene and X® is chloride.

3. An antimicrobial ophthalmic composition according to claim 1 which is an eye medicament comprising a preservatively effective amount of at least one compound of the formula I as defined in claim 1, and one or more ophthalmically acceptable adjuncts, which eye medicament is substantially isotonic with the human lacrimal fluid.

4. An eye medicament according to claim 3 comprising 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 independently of one another are C2-C4alkylene, alk3 is Cj^alkylene and X© is an ophthalmically acceptable anion.

5. An eye medicament according to claim 3 comprising at least one compound of the formula I in which Ar is phenyl, Alk is - galkyl, al^ and alk2 are 1,2-ethylene, alk3 is methylene and X® is bromide or chloride. 95720/2 - 24 -

6. An eye medicament according to claim 3 comprising at least one compound of the formula I in which Ar is phenyl, Alk is Cg-Cjgalkyl, alk! and aU-2 are 1,2-ethylene, alk3 is methylene and X® is chloride.

7. An eye medicament according to claim 3 comprising N-benzyl-N-(mixed Cg-C1gall yl)-N,N-bis-(2-hydroxyethyl)-ammonium chloride.

8. An eye medicament according to claim 3 comprising N-benzyl-N-(n-dodecyl)-N,N-bis-(2-hydroxyethyl)-ammonium chloride.

9. An eye medicament according to any one of claims 3 to 8, which comprises the compounds of the formula I in a concentration (W/V) of 0.0001 % to 0.10 %.

10. An eye medicament according to any one of claims 3 to 8, which comprises the compounds of the formula I in a concentration (W/V) of 0.001 % to 0.02 %.

11. An eye medicament according to any one of claims 3 to 8, which comprises the compounds of the formula I in a concentration (W/V) of 0.002 % to 0.015 .

12. An eye medicament according to any one of claims 3-11, comprising the pharmaceutical active ingredient diclofenac or an ophthalmically acceptable salt thereof.

13. An eye medicament according to any one of claims 3-11, comprising the pharmaceutical active ingredient diclofenac sodium.

14. An eye medicament according to any one of claims 3-11, comprising the pharmaceutical active ingredients diclofenac sodium and gentamicin.

15. An eye medicament according to any one of claims 3-11, comprising the pharmaceutical active ingredient naphazoline nitrate.

16. At least one compound of the formula I as defined in claim 1, for use as an agent for the preservation of eye medicaments.

17. At least one compound of the formula I according to claim 16, in which Ar is phenyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen or 95720/2 - 25 - trifluoromethyl, Alk is C C^alkyl. al^ and alk2 independendy of one another are C2-C4alkylene, alk3 is C1-C4alkylene and X® is an ophthalmically acceptable anion, for use as an agent for the preservation of eye medicaments.

18. At least one compound of the formula I according to claim 16, in which Ar is phenyl, Alk is C C^alkyl, aU and alk2 are 1,2-ethylene, aU-3 is methylene and X® is bromide or chloride, for use as an agent for the preservation of eye medicaments.

19. At least one compound of the formula I according to claim 16, in which Ar is phenyl, Alk is Cg-C18alkyl, alkj and alk2 are 1,2-ethylene, alk3 is methylene and X® is chloride, for use as an agent for the preservation of eye medicaments.

20. N-benzyl-N-(mixed Cg-C1galkyl)-N,N-bis-(2-hydroxyethyl)-ammonium chloride according to claim 16, for use as an agent for the preservation of eye medicaments.

21. N-ben2yl-N-(n-dodecyl)-N,N-bis-(2-hydroxyethyl)-ammonium chloride according to claim 16, for use as an agent for the preservation of eye medicaments.

22. The compounds of the formula I according to any one of claims 16-21, for use as an agent for the preservation of eye medicaments, used in the eye medicament in a concentration (W/V) of 0.0001 % to 0.10 .

23. The compounds of the formula I according to any one of claims 16-21, for use as an agent for the preservation of eye medicaments, used in the eye medicament in a concentration (W V) of 0.001 % to 0.02 %.

24. The compounds of the formula I according to any one of claims 16-21, for use as an agent for the preservation of eye medicaments, used in the eye medicament in a concentration (W/V) of 0.002 % to 0.015 %.

25. An antimicrobial ophthalmic composition according to claim 1 which is a solution for the treatment of contact lenses comprising at least one compound of the formula I as defined in claim 1, and one or more adjuncts which are acceptable to contact lenses, which solution is substantially isotonic with the human lacrimal fluid.

26. A solution for the treatment of contact lenses according to claim 25 comprising at least 9572Q/2 - 26 - one compound of the formula I in which Ar is phenyl, Alk is Cg-C^aUcyl, alk! and alk2 are 1,2-ethylene, alk3 is methylene and is chloride.

27. A cleansing solution for contact lenses according to claim 26 comprising: (a) a compound of the formula I in which Ar is phenyl, Alk is Cg- galkyl, aU and alk2 are 1,2-ethylene, alk3 is methylene and X® is chloride in a concentration (W/V) of 0.005 to 0.8 , (b) an isotonising agent, (c) a buffer substance, (d) a complex-former, (e) a solubilizer and, if appropriate, (f) a thickener.

28. A conditioner for contact lenses according to claim 26 comprising: (a) a compound of the formula I in which Ar is phenyl, Alk is C8-C18alkyl, alkj and alk2 are 1,2-ethylene, alk3 is methylene and X® is chloride in a concentration (W V) of 0.002 to 0.8 %, (b) a moistening agent, (c) a buffer substance, (d) an isotonising agent and, if appropriate, (e) a complex-former.

29. At least one compound of the formula I as defined in claim 1 for use as an agent for the preservation of contact lenses.

30. At least one compound of the formula I according to claim 29, in which Ar is phenyl, Alk is Cg-C18alkyl, alkj and alk2 are 1,2-ethylene, alk3 is methylene and X® is chloride, for use as an agent for the preservation of contact lenses. For the Appl icants , DR. REIWOTOv COH AND PARTNER. BY :