IE71639B1 - Antimicrobial compositions - Google Patents
Antimicrobial compositionsInfo
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- IE71639B1 IE71639B1 IE340690A IE340690A IE71639B1 IE 71639 B1 IE71639 B1 IE 71639B1 IE 340690 A IE340690 A IE 340690A IE 340690 A IE340690 A IE 340690A IE 71639 B1 IE71639 B1 IE 71639B1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L12/00—Methods or apparatus for disinfecting or sterilising contact lenses; Accessories therefor
- A61L12/08—Methods or apparatus for disinfecting or sterilising contact lenses; Accessories therefor using chemical substances
- A61L12/14—Organic compounds not covered by groups A61L12/10 or A61L12/12
- A61L12/143—Quaternary ammonium compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/186—Quaternary ammonium compounds, e.g. benzalkonium chloride or cetrimide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Ophthalmology & Optometry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Apparatus For Disinfection Or Sterilisation (AREA)
- Eyeglasses (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
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
The invention relates to antimicrobial, ophthalmic compositions containing certain quaternary ammonium salts as preservatives.
The invention relates particularly to antimicrobial, ophthalmic compositions vhich are isotonic with human lachrymal fluid, containing at least one compound of the formula I alk,-OH J v® φ· X Ar «Ikj 1 1 ·Ν—Alk (I) alkrOH in which Ar is aryl, Aik is alkyl, allq, alk, and alk, independently of one another are alkylene, and X® is an ophthalmically acceptable anion, and one or more adjuncts which are ophthalmically acceptable and acceptable to contact lenses.
The invention relates firstly to an eye medicament, for example eye drops, eye gels or eye ointments, containing certain quaternary ammonium salts as preservatives, and to the use of these quaternary ammonium salts for the preservation of eye medicaments.
Secondly, the invention also relates, for example, to solutions for the treatment of contact lenses which contain certain quaternary ammonium salts as preservatives and to the use of these quaternary ammonium salts for the preservation of contact lenses.
Medicaments for the treatment of diseases of the eye are often formulated in liquid form and administered in the form of drops. In most European and other countries 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 at least one component capable of preventing, or at least controlling, a secondary contamination. In addition, eye medicaments are often formulated as gels. As far as preservation is concerned, the same applies to aqueous gels.
It is known that N-alkyl-N-arylalkyl-N,N-bis-(hydroxyalkyl)-ammonium 639 - 2 salts can be used as disinfectants. In particular, the substance henzoxonium chloride [· N-benzyl-N-(n-dodecyl)-Ν,Ν-bls-(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, henzoxonium 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, henzoxonium chloride is also employed as a veterinary antiseptic, for example ae a fungicide and bactericide for the udder or for the treatment of dermatomycoses in horses. Other fields of use for henzoxonium 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 hy 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 - evidently 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- ( C, - C1(alkyl) -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 - 3 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 5 I, to which benzoxonium chloride also belongs, are excellently suitable for the preservation of eye medicaments. This result is hy 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 then benzalkonium chloride for the preservation of eye medicaments. As already mentioned above, benzalkonium chloride, together with chlorohexidine, thiomersal and chlorobutanol, 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 which are [sic] isotonic with human lachrymal fluid, containing at least one compound of the formula I - 4 alk-» alk,-OH I aikjOH (D in which Ar is aryl, Aik. is alkyl, allq, alk, and alk, independently of 5 one another are alkylene and X* is an ophthalmically acceptable anion, and one or more ophthalmically acceptable adjuncts.
Aryl is phenyl or naphthyl, such as 1-naphthyl or 2-naphthyl. The phenyl and naphthyl radicals can be unsubstituted or substituted, in particular ΐθ 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 Cx-CTalkyl, for example n-propyl, Isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-butyl, neopentyl, n-hexyl or nheptyl, preferably ethyl and particularly methyl.
Lower alkoxy is Cj-C^alkoxy, 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 Aik, alk,, alk, and alk, are preferably linear, but can also be branched.
The alkyl group Alk is C1-CJ0alkyl, 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, ntetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl or n-octadecyl and primarily n-dodecyl.
The alkyl group Alk is particularly C,-Cualkyl and primarily C,-Ciealkyl.
Mixed Ce-Ciealkyl is a mixture consisting essentially of n-octyl, ndecyl, n-dodecyl, n-tetradecyl, n-hexadecyl and n-octadecyl, containing 40-60 X, in particular approximately 50 X, of the n-dodecyl component.
The alkylene groups alk,, alk, and alk, are C^-Cyalkylene; examples are 5 methylene, 1,2-ethylene, 1,3-propylene, 1,4-butylene, 2,4-hutylene, 1,5pentylene, 1,6-hexylene or 1,7-heptylene.
The alkylene groups alk, and alk, independently of one another are preferably C,-C4alkylene, are primarily identical with one another and above all are 1,2-ethylene.
The alkylene group alk, is preferably C,-C,alky lene 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, fusaxlc, hydroxymale ic, 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 Contact time with the microorganism Challenge hy the following microorganisms: E.coli 1.5xl0*/ml St.aureus 1.4xl0*/ml Ps. aeruginosa l.lxl0*/ml C.albicans 9.9xl0s/ml 10 minutes 99.99 X n.g. n.g. 99.97 X 6 hours n.g. n.g. n.g. n.g. 10 24 hours n.g. n.g. n.g. n.g.
Percentages: reduction in growth n.g.: no growth 15 The surprisingly improved toleration by the eye of the compounds of the formula I in comparison vith benzalkonium chloride is evident, for example, from the results of the 5-day animal toleration test described below: in each case 0.01 X 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 folloving results were obtained: Benzoxonium chloride (= compound of the formula I), 0.01 X 5 Instillations/animal/day at intervals of 90 minutes each no result Benzalkonium chloride (= comparison compound) , 0.01 X Instillations/animal/day at intervals of 90 minutes each 4 results The improved toleration by the eye of the compounds of the formula I compared vith benzalkonium chloride is also evident, for example, from the results of the ocular, local toleration study in rabbits lasting 4 weeks, described below: in each case 0.01 X solutions of N-benzyl-N(mixed C,-C11alkyl)-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 vas added dropwise to the left eye in each case. The animals were subjected to an ophthalmological examination on the first day of treatment and on the fifth day. When the test was complete, the test animals vere 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 Ca-Ciaalkyl)-N,N-bis-(2-hydroxyethyl)-ammonium chloride, no ocular lesions were found. On the other hand, in 4 out of 6 animals treated vith 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 vith 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 X - 0.10 X [in each case weight/volume (W/V)], in particular 0.001 X - 0.02 X and especially 0.002 X - 0.015 X.
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 2Q trifluoromethyl, Alk is C1-Caoalkyl, allq and alk, Independently of one another are Ca-Chalky lene, alk, is C1-C The invention particularly preferably relates to an eye medicament containing at least one compound of the formula I in vhich Ar is phenyl, Alk is Ct-Ct(alkyl, alk, and alk, are 1,2-ethylene, alk, is methylene and X* is bromide or chloride. - 8 The invention relates very particularly to an eye medicament containing at least one compound of the formula I in which Ar is phenyl, Aik is Ct-Cualkyl, alkj. and alk, are 1,2-ethylene, alk, is methylene and X* is chloride.
The invention relates primarily to an eye medicament containing N-benzylN-(n-dodecyl)-N,N-bis-(2-hydroxyethyl)-ammonium chloride or N-benzyl-N(mixed C,-CMalkyl)-Ν,Ν-bis-(2-hydroxyethyl)-ammonium chloride.
The invention relates above all to an eye medicament containing Nbenzyl-N- (n-dodecyl) -Ν,Ν-bis-(2-hydroxyethyl)-ammonium chloride (benzoxonium chloride) .
A particular embodiment of the invention consists in an eye medicament containing at least one 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 X (V/V), in particular 0.05 -0.1 X (V/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 X by weight of by-products, and each individual by-product must not represent more than 0.5 X 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, 35 chloramphenicol or gentamicin; anti-glaucoma active ingredients, for example pilocarpine hydrochloride or pirbuterol hydrochloride; substances having a keratolytic action, for example vitamin A acid; vasoconstrictive substances, for example naphazoline nitrate, tetrahydrozoline (= tetryzoline), phenylephrine or xylometazollne; anti allergic agents, for example isospaglumic acid or spaglnmic 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 vhich 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 (Na,B407 · 10HaO), phosphates, for example the Na3HP04·2H,0/NaH,P04·2H,0 buffer, trometamol (= 2-amino-2hydroxymethyl-1,3-propanediol = TRIS) or organic acids, for example ascorbic, acetic, propionic or citric acid; (c) if appropriate one or more isotonizing 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 (= polyethylene glycol 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 α-tocopherol acetate or BHA (A 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 (- carboxyvinyl polymer, BF Goodrich), Polymer JR 30 M® (- polymeric quaternary ammonium salt obtained by reacting hydroxyethylcellulose with a trimethylammoniumsubstituted 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; (o) 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 lachrymal fluid (- 270 to 330 mosmol/kg, in particular 300 mosmol/kg) .
The Invention also relates to the use of at least one compound of the formula I alk p OH (I) elkyOH in which Ar is aryl, Alk is alkyl, alk,, alk, and alk, independently 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 C,-C,oalkyl, alk, and alk, independently of one another are 0,C4alkylene, alk, is C,-C4alkylene and Xs 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 0,-0,,alkyl, alk, and alk, are 1,2-ethylene, alk, 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 0,-0,,alkyl, alk, and alk, are 1,2-ethylene, alk, 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) Ν,Ν-bis-(2-hydroxyethyl)-ammonium chloride or N-benzyl-N-(mixed 0,-0,,alkyl)-Ν,Ν-bis-(2-hydroxyethyl)-ammonium chloride for the preservation of eye medicaments. - 12 The invention relates above all to the use of V-benzyl-N-(n-dodecyl)Ν,Ν-bis-(2-hydroxyethyl)-ammonium chloride for the preservation of eye medicaments.
The invention also relates to solutions for the treatment of contact lenses, vhich are isotonic vith human lachrymal fluid, containing at least one compound of the formula I Ik,-OH el χθ Ar— «Ug—-N—Alk φ «lk^OH in which Ar is aryl, Alk is alkyl, alk,, alk, and alk, 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 he understood as meaning, in particular, the following: (a) cleansing solutions for contact lenses and (h) conditioners for contact lenses vhich 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 C,-CMalkyl, alk, and alk, are 1,2-ethylene, alk, 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 C,-Cualkyl, alk, and alk, are 1,2-ethylene, alk, is methylene and X" chloride, in a concentration (V/V) of 0.005 to 0.8 X, (b) an isotonizing 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 - 13 oxide detergents, for exanple Varox® 365 (Sherex Chemical), or the Triton® series ( polyethylene glycol p-isooetylphenyl ether) made by Rdhm [sic] and Haas, in particular Triton® X-100, and, if appropriate, (£) a thickener, for exanple quick-dissolving hydroxy ethyl cellulose, for exanple Cellosize® QP-40 HHC (Union Carbide). λ preferred conditioner for contact lenses according to the invention contains: (a) a conpound of the fornula I in which Ar is phenyl, Aik is C,-C18alkyl, alkj and elk, are 1,2-ethylene, alk, is methylene and X* is chloride in a concentration (W/V) of 0.002 to 0.8 %, (b) a moistening agent, for exanple polyvinyl alcohol, for exanple Vinol® 350 PVA (Air Products, Inc.), or mixtures of polyvinyl alcohol and polyvinylpyrrolidone (for example Vinol® 350 PVA + Plasdone K-90 PVP, made by GAP), (c) a buffer substance, for example a phosphate buffer, (d) an isotonizing agent, for example sodium chloride, and, if appropriate, (e) a conplex-foxmer, for example HDTA 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 for contact lenses.
The invention also relates to formula I the use of at least one compound of the alk,-OH alk-»—- N — Alk I alk2-OH 0) in which Ar is aryl, Alk is alkyl, alk,, alk, and alk, independently of one another are alkylene and X* is an ophthalmicelly acceptable anion, for the preservation of contact lenses.
The subgroups of compounds of the fornula I which are used here preferably are the sane es those indicated above for the eye medicaments containing conpounds of tbs formula I.
In particular, therefore, the invention relates, for exanple, to the use - 14 of at least one compound of the formula I, ln which Ar is phenyl, Alk is C,-C,,alkyl, alk, and alk, are 1,2-ethylene, alk, 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 C,-Cualkyl, alk, and alk, are 1,2-ethylene, alk, is methylene and X* is chloride.
The procedure used in the preparation of eye medicaments - and also solutions for the treatment of contact lenses - ln 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 vith conventional methods.
The following formulation examples illustrate the invention: Example I: Eve 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 Kranmle 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 MS Lavender oil 1.80 Mg Euphrasia tincture 0.800 mg Absolute ethanol 1.393 mg 1 N hydrochloric acid 0.100 mg Vater for injection purposes ad 1.000 ml Example 3: 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 Benzoxonium chloride 0.100 mg Methylhydroxypropylcellulose 3.000 mg Hamamelis lotion 40.000 mg Orange blossom oil 5.00 MS Lavender oil 1.80 Mg Euphrasia tincture 0.800 MS Absolute ethanol 1.393 mg Vater for injection purposes ad 1.000 ml Ingredient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogol 400 80.00 mg 5 Trometamol 0.10 mg Benzoxonium chloride 0.10 mg Cremophor® EL 4.00 mg Water for injection purposes ad 1.00 ml ΊΟ Example 5: Eve drops containing chloramphenicol Ingredient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg 15 Macrogol 400 80.00 mg Trometamol 0.10 mg Benzoxonium chloride 0.10 mg α-Tocopherol acetate 10.00 mg Solutol® HS 15 5.00 mg Water for injection purposes ad 1.00 ml 20 Example 6: Eve drops containing chloramphenicol Ingredient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg 25 Macrogol 400 80.00 mg Benzoxonium chloride 0.10 mg Water for injection purposes ad 1.00 ml Example 7: Eve drops containing chloramphenicol 30 Ingredient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogol 400 80.00 mg Trometamol 0.10 mg 35 Benzoxonium chloride 0.10 mg Water for injection purposes ad 1.00 ml Examule 8: Eve drops containine ehloranmhenir.nl JnRged.ient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogol 400 80.00 mg α-Tocopherol acetate 10.00 mg Benzoxonlum chloride 0.10 mg Water for injection purposes ad 1.00 ml Example 9: Eve drops containing chloramphenicol Ineredient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogol 400 80.00 Og Cremophox® 4.00 mg Benzoxoninm chloride 0.10 mg Water for injection purposes ad 1.00 ml Example 10; Eve drops containing chloramphenicol Ineredient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogol 400 80.00 mg Trometamol 0.10 mg Benzoxonlum chloride 0.10 mg Solutol® HS 15 5.00 mg Water for injection purposes ad 1.00 ml Example 11: Eve 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 Vater for injection purposes ad 1.00 ml Example 12: Eve 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 ag BHA 0.15 mg Vater for injection purposes ad 1.00 ml Example 13: Eve 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 0.15 BHA Vater for injection purposes ad 1.00 ml Examole 14: Eve 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 α-Tocopherol acetate 10.00 mg Vater for injection purposes ad 1.00 ml Example 15: Eve 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 20.00 mg Vater for injection purposes ad 1.00 ml Example 16: Eve eel 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: Eve gel. tear replacement Ingredient Amount Polymer JR 30 M® 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: Eve gel. tear replacement Ingredifipt Amount Polyacrylic acid 4.00 mg Sorbitol 43.00 mg Disodium EDTA 1.00 mg Sodium hydroxide (10 X 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 InSEg.dlgnt 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 naphazollne 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 aicd 34.000 mg N-Benzyl-N-(mixed C,-C,,alkyl) - N, N-bis - (2-hydroxyethyl) - ammonium - chloride 0.100 mg Methylhydroxypropylcellulose 3.000 mg Hamamelis lotion 40.000 mg Orange blossom oil 5.00 Mg Lavender oil 1.80 Mg Euphrasia tincture 0.800 Mg 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 C,-C,,alkyl)- Ν,Ν-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 0,-0,,alkyl) N,N-bis-(2-hydroxyethyl) -ammonium-chloride 0.10 Water for injection purposes ad 1.00 mg ml - 22 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 0,-0,,alkyl)- N, N-bis-(2-hydroxyethyl)-ammonium-chloride 0.10 mg Solutol® HS 15 5.00 mg Vater for injection purposes ad 1.00 ml Rvample 24: Eve drops containing pirbuterol hydrochloride Ineredient 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 Vater for injection purposes ad 1.00 ml Example 25: Eve dropscontainine pirbuterol hydrochloride Ineredient Amoppt 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 Vater for injection purposes ad 1.00 ml Example 26: Eve drops containing pirbuterol hydrochloride Ingrfidignt 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 Vater for injection purposes ad 1.00 ml Example 27: Eve gel containing diclofenac Na and gentamicin Ingredient Amount Diclofenac Na 1.00 mg Gentamicin 3.00 mg Cremophox® E 10.00 mg Disodium EDTA 1.00 mg Benzoxoninm chloride 0.10 mg Borax 40,610 Η,Ο) 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 Cremophox® EL 50.00 mg Boric acid 13.00 mg Trometamol 6.00 mg Disodium EDTA 1.00 mg Benzoxonlum 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 Benzoxonlum chloride 0.01 g Sodium chloride 0.36 g Na,HPO« 0.73 g NaH,P04.H,0 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 vater ad 100.00 ml Example 30: Conditioning solution for contact lenses which are permeable to gas and hard Awwnt Benzoxonium chloride 0.005 8 f Vinol® 350 PVA 0.500 8 Plasdone K-90 PVP 1.000 8 Na2HP04 0.720 8 NaH3F04.H,0 0.220 8 Sodium chloride 0.440 8 Disodium EDTA 0.100 8 Deionized water ad 100.00 ml
Claims (34)
1. An antimicrobial ophthalmic composition which ia isotonic with η»™» lachrymal fluid, containing at least one compound of the fonaula I X® ω alkj-OH in which Ar is aryl, with aryl being one of the radicals naphthyl and phenyl which, independently of one another, are unsubstituted or substituted by C,-C,alkyl, Ο,-Ο,ηΙίΕΟΕκγ, halogen or trifluoromethyl, Alk is C,-C, o alkyl, alk,, alk, and alk, independently of one another are C,-G, alky lene, and X® ie an ophthalmically acceptable anion, and one or more adjuncts which are opthalaieally acceptable and compatible with contact lenses.
2. An antimicrobial ophthalmic composition according to claim 1 containing at least one compound of the formula I in which Ar is phenyl, Alk is C,-C, s alkyl, alk, and alk, are 1,2-ethylene, alk, ie methylene and Χθ is chloride.
3. An eye medicament according to claim 1 containing at least one compound of the formula I «Ik,-OH I .Θ alki—-N —Alk I alk 2 -OH (I) 30 in which Ar is aryl, with aryl being one of the radicals naphthyl and phenyl which, independently of one another, are unsubstituted or substituted by (^-(^alkylfCj-Cyalkoaey, halogen or trifluoromethyl, Alk ie C,-C, o alkyl, alk,, alk, mid alk, independently of one another are C,-(^alkylene and X® ie an ophthalmically acceptable anion, and one or 35 more ophthalmically acceptable adjuncts. - 26
4. An eye medicament according to claim 3 containing at least one compound of the formula I in which Ar is phenyl which is unsubstituted or substituted by Cx-Gjalkyl, C x -C,alkoxy, halogen or trifluoromethyl, Aik is C x -C 20 alkyl, allq and alk, independently of one another are C 2 -C 4 alkylene, alk, is Cx-C^alkylene and X® is an ophthalmically 5. Acceptable anion.
5. An eye medicament according to claim 3 containing at least one compound of the formula I in which Ar is phenyl, Alk is C x -C„alkyl, alk, and alk, are 1,2-ethylene, alk, is methylene and J® is bromide or chloride.
6. An eye medicament according to claim 3 containing at least one compound of the formula I in which Ar is phenyl, Alk is C e -C„alkyl, alk, and alk, are 1,2-ethylene, alk, is methylene and X® is chloride.
7. An eye medicament according to claim 3 containing N-benzyl-N- (ndodecyl)-N,N-his(2-hydroxyethyl)ammonium chloride or N-benzyl-N-(mixed C,-C„alkyl)-N,N-bis(2-hydroxyethyl)ammonium chloride.
8. An eye medicament according to claim 3 containing N-benzyl-N-(ndodecyl) -N,N-bis(2-hydroxyethyl)ammonium chloride. 25
9. An eye medicament according to any one of claims 3 to 8, which contains the compounds of the formula I in a concentration (V/V) of 0.0001 X to 0.10 X.
10. An eye medicament according to any one of claims 3 to 8, which 30 contains the compounds of the formula I in a concentration (V/V) of 0.001 X to 0.02 X.
11. An eye medicament according to any one of claims 3 to 8, which contains the compounds of the formula I in a concentration (V/V) of 35 0.002 X to 0.015 X.
12. An eye medicament according to any one of claims 3-11 containing the pharmaceutical active ingredient diclofenac or an ophthalmically - 27 acceptable salt thereof.
13. An eye medicament according to any one of claims 3-11 containing the pharmaceutical active ingredient diclofenac sodium.
14. An eye medicament according to any one of claims 3-11 containing the pharmaceutical active ingredients diclofenac sodium and gentamicin.
15. An eye medicament according to any one of claims 3-11 containing the pharmaceutical active ingredient naphazoline nitrate.
16. Use of at least one compound of the formula I alky alk,-OH I «&Alk alky OH ,θ (D in which Ar is aryl, with aryl being one of the radicals naphthyl and phenyl which, independently of one another, are unsubstituted or 20 substituted by C^-Cralkyl, C,-C 7 alkoxy, halogen or trifluoromethyl, Alk ls C,-C,.alkyl, alk,, alk, and alk, independently of one another are C,-C 7 alkylene and X® is an opthalmically acceptable anion, for the preservation of eye medicaments. 25
17. Use according to claim 16, wherein at least one compound of the formula I in which Ar is phenyl which is unsubstituted or substituted by C,-C 7 alkyl, C,-G,alkozy, halogen or trifluoromethyl, Alk is 0,-0,,alkyl, alk, and alk, independently of one another are C,-C,alkylene, alk, is C,-C,alkylene and Χθ is an ophthalmically acceptable anion, is used.
18. Use according to claim 16, wherein at least one compound of the formula I in which Ar is phenyl, Alk is C,-C„alkyl, alk, and alk, are 1,2-ethylene, alk, Is methylene and X9 ls bromide or chloride, is used. 35
19. Use according to claim 16, wherein at least one compound of the formula I in which Ar is phenyl, Alk is C, - C,,alkyl, alk, and alk, are 1,2-ethylene, alk, is methylene and Χθ is chloride, is used.
20. Use according to claim 16, wherein N-banzyl-W- (n-dodecyl) -W,M-bis(2hydroxyethy1)ammonium chloride or N-benzy 1-H- (mixed C,-C, B alkyl)-H,Nbis (2-hydroxyethyl) ammonium chloride ie used.
21. Use according to claim 16, wherein H-benzyl-N-(n-dodecyl)-N,N-bis(2hydroxyethy1)ammonium chloride is used.
22. Use according to any one of claims 16-21, wherein the compounds of the formula I are used in the eye medicament in a concentration (W/V) of 10 0.0001 % to 0.10 %.
23. Use according to any one of claims 16-21, wherein the compounds of the formula I are used in the eye medicament in a concentration (W/V) of 0.001 % to 0.02 *.
24. Use according to any one of claims 16-21, wherein the compounds of the formula I are used in the eye medicament in a concentration (W/V) of 0.002 % to 0.015 %.
25. A solution for the treatment of contact lenses which is isotonic with human lachrymal fluid, containing at least one compound of the formula I alk r OH .Θ •lk^· Alk alk? OH in which Ar is aryl, with aryl being one of the radicals naphthyl and phenyl which, independently of one another, are unsubstituted or substituted by C,-C,alkyl, C,-C,alkoxy, halogen or trifluoromethyl, Alk is Cx-CjgSlkyl, alk,, alk, and alk, independently of one another are Cx-Cralkylene and X s ia aa ophthalmically acceptable anion, and one or more adjuncts which are compatible with contact lenses.
26. A solution for the treatment of contact lenses according to claim 25 containing at least one compound of the fosmula I in which Ar is phenyl, Alk is Cg-Cualkyl, alk, and alk, are 1,2-ethylene, elk, is methylene and - 29 X® is chloride.
27. A cleansing solution for contact lenses according to claim 26 containing: (a) a compound of the formula I in which Ar is phenyl, Alk is C,-C„alkyl, alk, and alk, are 1,2-ethylene, alk, is methylene and X® is chloride in s concentration (W/V) of 0.005 to 0.8 X, (b) an isotonizing 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 containing: (a) a compound of the formula I in which Ar is phenyl, Alk is C,-C„alkyl, alk, and alk, are 1,2-ethylene, alk, is methylene and X® is chloride in a concentration (W/V) of 0.002 to 0.8 X, (b) a moistening agent. (c) a buffer substance, (d) an isotonizing agent and, if appropriate, (e) a complex-former.
29. Use of at least one compound of the formula I alk,-OH φΙ X® Ai-alki—N —Alk I alk 2 -OH (I) in which Ar is aryl, with aryl being one of the radicals naphthyl and '
30. Phenyl which, independently of one another, are unsubstituted or substituted hy C,-C,alkyl, C,-C T alkoxy, halogen or trifluoromethyl, Alk is C,-C, o alkyl, alk,, alk, and alk, independently of one another are C,-C T alkylene and X® is an ophthalmically acceptable anion, for the preservation of contact lenses. - 30 30. Use according to claim 29, wherein at least one compound of the formula I in which Ar is phenyl, Alk is Cg-C lg alkyl, alk! and alk 2 are 1,2-ethylene, alk 2 is methylene and X® is chloride, is used.
31. An antimicrobial ophthalmic composition according to claim 5 1, substantially as hereinbefore described and exemplified.
32. Use according to claim 16, substantially as hereinbefore described.
33. A solution according to claim 25, substantially as hereinbefore described and exemplified.
34. Use according to claim 29, substantially as hereinbefore described.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH344689 | 1989-09-21 |
Publications (2)
Publication Number | Publication Date |
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IE903406A1 IE903406A1 (en) | 1991-04-10 |
IE71639B1 true IE71639B1 (en) | 1997-02-26 |
Family
ID=4256126
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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IE340690A IE71639B1 (en) | 1989-09-21 | 1990-09-20 | Antimicrobial compositions |
Country Status (18)
Country | Link |
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EP (1) | EP0420798B1 (en) |
JP (1) | JP2960507B2 (en) |
AT (1) | ATE103182T1 (en) |
AU (1) | AU640687B2 (en) |
CA (1) | CA2025728C (en) |
DD (1) | DD299267A5 (en) |
DE (1) | DE59005084D1 (en) |
DK (1) | DK0420798T3 (en) |
ES (1) | ES2053161T3 (en) |
FI (1) | FI101849B1 (en) |
HU (2) | HUT59001A (en) |
IE (1) | IE71639B1 (en) |
IL (1) | IL95720A (en) |
NO (1) | NO179472C (en) |
NZ (1) | NZ235377A (en) |
PH (1) | PH29982A (en) |
PT (1) | PT95355B (en) |
ZA (1) | ZA907536B (en) |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5037647A (en) * | 1988-09-15 | 1991-08-06 | Alcon Laboratories, Inc. | Aqueous antimicrobial opthalmic solutions comprised of quaternary ammonium compound, citric acid, citrate and sodium chloride |
US5691371A (en) * | 1993-05-25 | 1997-11-25 | Auckland Uniservices Limited | Nitrobenzyl mustard quaternary salts and their use as hypoxia-selective cytotoxic agents |
JP4849288B2 (en) * | 2000-09-29 | 2012-01-11 | ライオン株式会社 | Eye drops and tear film stabilizer |
JP2010031052A (en) * | 2002-04-08 | 2010-02-12 | Lion Corp | Composition for ophthalmic use and antiseptic composition for ophthalmology preparation |
US20050214382A1 (en) * | 2004-03-29 | 2005-09-29 | Erning Xia | Zinc preservative composition and method of use |
DE202005005094U1 (en) * | 2005-03-31 | 2005-07-28 | Dr. Gerhard Mann Chem.-Pharm. Fabrik Gmbh | Composition, useful for the treatment of diseases or conditions of eye, comprises extract and/or tincture obtained from plant and/or plant parts of Euphrasia officinalis, and sodium chloride |
BRPI0921654A2 (en) * | 2008-11-28 | 2016-02-10 | Advance Holdings Ltd | pharmaceutical formulation |
JP2012006962A (en) * | 2011-08-22 | 2012-01-12 | Lion Corp | Ophthalmic composition |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
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AR204836A1 (en) * | 1973-09-24 | 1976-03-05 | Allergan Pharma | COMPOSITION TO STERILIZE SOFT CONTACT LENSES |
DE3612537C1 (en) * | 1986-04-14 | 1987-07-16 | Dispersa Ag | Medicines used to treat inflammation in the eye |
DE3870111D1 (en) * | 1987-09-11 | 1992-05-21 | Syntex Inc | PROTECTIVE AGENT FOR EYE PREPARATIONS. |
-
1990
- 1990-09-12 AT AT90810692T patent/ATE103182T1/en not_active IP Right Cessation
- 1990-09-12 DE DE90810692T patent/DE59005084D1/en not_active Expired - Fee Related
- 1990-09-12 DK DK90810692.5T patent/DK0420798T3/en not_active Application Discontinuation
- 1990-09-12 ES ES90810692T patent/ES2053161T3/en not_active Expired - Lifetime
- 1990-09-12 EP EP90810692A patent/EP0420798B1/en not_active Expired - Lifetime
- 1990-09-17 PH PH41216A patent/PH29982A/en unknown
- 1990-09-18 IL IL9572090A patent/IL95720A/en not_active IP Right Cessation
- 1990-09-19 NZ NZ235377A patent/NZ235377A/en unknown
- 1990-09-19 PT PT95355A patent/PT95355B/en not_active IP Right Cessation
- 1990-09-19 FI FI904616A patent/FI101849B1/en not_active IP Right Cessation
- 1990-09-19 AU AU63024/90A patent/AU640687B2/en not_active Ceased
- 1990-09-19 CA CA002025728A patent/CA2025728C/en not_active Expired - Fee Related
- 1990-09-20 HU HU905995A patent/HUT59001A/en unknown
- 1990-09-20 DD DD90344117A patent/DD299267A5/en not_active IP Right Cessation
- 1990-09-20 ZA ZA907536A patent/ZA907536B/en unknown
- 1990-09-20 IE IE340690A patent/IE71639B1/en not_active IP Right Cessation
- 1990-09-20 NO NO904112A patent/NO179472C/en unknown
- 1990-09-20 JP JP2248967A patent/JP2960507B2/en not_active Expired - Fee Related
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1994
- 1994-09-23 HU HU94P/P00030P patent/HU210525A9/en unknown
Also Published As
Publication number | Publication date |
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NO179472B (en) | 1996-07-08 |
HU210525A9 (en) | 1995-04-28 |
HU905995D0 (en) | 1991-03-28 |
CA2025728C (en) | 2002-02-26 |
DK0420798T3 (en) | 1994-04-11 |
AU640687B2 (en) | 1993-09-02 |
HUT59001A (en) | 1992-04-28 |
IE903406A1 (en) | 1991-04-10 |
FI101849B (en) | 1998-09-15 |
PT95355B (en) | 1997-06-30 |
NO904112D0 (en) | 1990-09-20 |
NZ235377A (en) | 1992-08-26 |
PH29982A (en) | 1996-10-29 |
ZA907536B (en) | 1991-05-29 |
EP0420798B1 (en) | 1994-03-23 |
JPH03130219A (en) | 1991-06-04 |
NO904112L (en) | 1991-03-22 |
DE59005084D1 (en) | 1994-04-28 |
PT95355A (en) | 1991-05-22 |
IL95720A0 (en) | 1991-06-30 |
ATE103182T1 (en) | 1994-04-15 |
JP2960507B2 (en) | 1999-10-06 |
NO179472C (en) | 1996-10-16 |
EP0420798A1 (en) | 1991-04-03 |
AU6302490A (en) | 1991-03-28 |
ES2053161T3 (en) | 1994-07-16 |
FI904616A0 (en) | 1990-09-19 |
IL95720A (en) | 1996-07-23 |
FI101849B1 (en) | 1998-09-15 |
CA2025728A1 (en) | 1991-03-22 |
DD299267A5 (en) | 1992-04-09 |
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