CA2025728C - Antimicrobial compositions - Google Patents
Antimicrobial compositions Download PDFInfo
- Publication number
- CA2025728C CA2025728C CA002025728A CA2025728A CA2025728C CA 2025728 C CA2025728 C CA 2025728C CA 002025728 A CA002025728 A CA 002025728A CA 2025728 A CA2025728 A CA 2025728A CA 2025728 C CA2025728 C CA 2025728C
- Authority
- CA
- Canada
- Prior art keywords
- formula
- alk
- alk2
- alk3
- chloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- 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
-
- 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
-
- 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
-
- 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
-
- 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
-
- 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
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- 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)
- Ophthalmology & Optometry (AREA)
- Communicable Diseases (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Bioinformatics & Cheminformatics (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
The disclosure relates to antimicrobial ophthalmic compositions containing compounds of the formula I
(See formula I) in which Ar, Alk, alk1, alk2, alk3 and X.THETA. are as defined in the description and to the use of these compounds of the formula I for the preservation of eye medicaments and for the treatment of contact lenses.
(See formula I) in which Ar, Alk, alk1, alk2, alk3 and X.THETA. are as defined in the description and to the use of these compounds of the formula I for the preservation of eye medicaments and for the treatment of contact lenses.
Description
~~~~~1~'~
-.1 4-17751/+/DIS 5 Antimicrobial compositions 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
. . ~kl_ ~~
. Ar-- alk3 ~N - Alk X ~I~
~2. pg in which Ar is aryl, Alk is alkyl, alkl, alk2 and alk3 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.
-.1 4-17751/+/DIS 5 Antimicrobial compositions 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
. . ~kl_ ~~
. Ar-- alk3 ~N - Alk X ~I~
~2. pg in which Ar is aryl, Alk is alkyl, alkl, alk2 and alk3 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 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 -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-(C8-CtBalkyl)-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 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 containing at least one compound of the formula I
alkl-OH
O
Ar- alkg ~N - Alk X (I~
alk2- OH
in which Ar is aryl, Alk is alkyl, alkt, alk2 and alk3 independently of one another are alkylene and X~ is an ophthalmically acceptable anion, and one or more ophthalmically acceptable adjuncts.
Aryl is, for example, phenyl or naphthyl, such as 1-naphthyl or 2-naphthyl.
The phenyl and naphthyl radicals can be unsubstituted or substituted, in particular as indicated below for phenyl. Aryl is preferably phenyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and/or trifluoromethyl, and is primarily phenyl.
Lower alkyl is Ct-C~alkyl for example n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, preferably ethyl and particularly methyl.
Lower alkoxy is Ct-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 Alk, alkt, alk2 and alkg are preferably linear, but can also be branched.
The alkyl group Alk is, for example, Ct-C26alkyl, 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 Ct-C2oalkyl, particularly Ct-Ct8alkyl and primarily Cs-Ctsa~Yl.
"Mixed Cs-Ctsalkyl" 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 alkt, alk2 and alk3 are, for example, Ct-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 Alkt and Alk2 independently of one another are preferably C2-C4alkylene, are primarily identical with one another and above all are 1,2-ethylene.
~~~ ~ ~r~
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 -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-(C8-CtBalkyl)-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 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 containing at least one compound of the formula I
alkl-OH
O
Ar- alkg ~N - Alk X (I~
alk2- OH
in which Ar is aryl, Alk is alkyl, alkt, alk2 and alk3 independently of one another are alkylene and X~ is an ophthalmically acceptable anion, and one or more ophthalmically acceptable adjuncts.
Aryl is, for example, phenyl or naphthyl, such as 1-naphthyl or 2-naphthyl.
The phenyl and naphthyl radicals can be unsubstituted or substituted, in particular as indicated below for phenyl. Aryl is preferably phenyl which is unsubstituted or substituted by lower alkyl, lower alkoxy, halogen and/or trifluoromethyl, and is primarily phenyl.
Lower alkyl is Ct-C~alkyl for example n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, preferably ethyl and particularly methyl.
Lower alkoxy is Ct-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 Alk, alkt, alk2 and alkg are preferably linear, but can also be branched.
The alkyl group Alk is, for example, Ct-C26alkyl, 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 Ct-C2oalkyl, particularly Ct-Ct8alkyl and primarily Cs-Ctsa~Yl.
"Mixed Cs-Ctsalkyl" 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 alkt, alk2 and alk3 are, for example, Ct-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 Alkt and Alk2 independently of one another are preferably C2-C4alkylene, are primarily identical with one another and above all are 1,2-ethylene.
~~~ ~ ~r~
The alkylene group Alk3 is preferably C1-C4alkylene 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, malefic, fumaric, hydroxymaleic, 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~pH 6 Contact Challenge time by the following microorganisms:
with the E. coli St. aureusPs. aeruginosaC. albicans microorganism1.5x106/ml1.4x106/ml1.1x106/ml 9.9x105/ml minutes 99.99 n. g. n, g. 99.97 % %
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, malefic, fumaric, hydroxymaleic, 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~pH 6 Contact Challenge time by the following microorganisms:
with the E. coli St. aureusPs. aeruginosaC. albicans microorganism1.5x106/ml1.4x106/ml1.1x106/ml 9.9x105/ml minutes 99.99 n. g. n, g. 99.97 % %
6 hours n. g. n. g. n. g. n. g.
24 hours n. g. n. g, n. g. n. g.
Percentages: reduction in growth 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 conjunctiva) 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:
~'o r'-~ :"~ ' f '~ ~
i~r . ;r r~r J
Benzoxonium chloride (= compound of the formula n, 0.01 %
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-Ctsalkyl)-N,N-bis-(2-hydroxyethyl)-ammonium chloride and benzalkonium chloride were compared. Pigmented Himalaya rabbits were used as test animals. In each case 50 wl of the corresponding solution was administered to the conjunctiva) 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 Cs-CtBalkyl)-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 conjunctiva) 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 io - 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 Ct-C2oalkyl, alkt and alk2 independently of one another are C2-C4alkylene, alk3 is Ct-C4alkylene 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 Ct-Clsalkyl, alkl and alk2 are 1,2-ethylene, alk3 is methylene and X~ 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 Cs-CtBalkyl, alkt 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 'Cg-Clsalkyl)-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 % (WN).
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 and-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 t s',.'. ; t ~J "~ rv1 _ g -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 (Na2B40~ ~ 1OH20), phosphates, for example the Na2HP04~2H20/NaH2P04~2H20 buffer, trometamol (= 2-amino-2-hydroxymethyl-1,3-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 66012-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 esed as odorants. The following may be mentioned as examples: absolute ethanol, polypropylene glycol or polyethylene glycol ~~ L~l ~,a~'~6~~e~~ ~ei1 400 (= macrogol 400, see also under solubilizers);
(f) if appropriate antioxidants, for example «-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 (= carboxyvinyl 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
- lo-alkt- OH
Ar- alk3 ~N - Alk ) alk2- OH
in which Ar is aryl, Alk is alkyl, alkl, alk2 and alk3 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 Ct-C2oalkyl, alkt and alk2 independently of one another are C2-C4alkylene, alk3 is Cl-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, Ally is Ct-Clgalkyl, alkt 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 C8-ClBalkyl, alkt 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 C8-CtBalkyl)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
alkl-OH
Ar- alkg ~N - Alk X~
~) atk2-OH
in which Ar is aryl, Alk is alkyl, alkl, 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 Cs-Clsalkyl, alkt 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-Ctsalkyl, alkt 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 RShm and Haas, in particular Tritons 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 Cs-Ctsalkyl, alkl 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 polyvinylpynolidone (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)-(fj or (b)-(e) are examples of adjuncts which are acceptable to contactlenses.
The invention also relates to the use of at least one compound of the formula I
alkt- OH
Ar- alkg ~N - Alk (n alk2- OH
in which Ar is aryl, Alk is alkyl, alkl, 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 Cs-Clsalkyl, alkt 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 Cs-Ctgalkyl, 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 In diem 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 purposesad 1.00 ml Example 2: Eye 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 Methylhydroxypropylcellulose3.000 mg Hamamelis lotion 40.000 mg Orange blossom oil 5.00 wg Lavender oil 1.80 wg Euphrasia tincture 0.800 mg Absolute ethanol 1.393 mg 1N hydrochloric acid 0.100 mg Water for injection purposesad 1.000 ml t~s~~~,yf~r~
Examyle 3: Eye 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 1N hydrochloric acid 34.000 mg Benzoxonium chloride 0.100 mg Methylhydroxypropylcellulose3.000 mg Hamamelis lotion 40.000 mg Orange blossom oil 5.00 wg Lavender oil 1.80 wg Euphrasia tincture 0.800 wg Absolute ethanol 1.393 mg Water for injection purposesad 1.000 ml Example 4: Eye drops containing chloramphenicol In diem Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogo1400 80.00 mg Trometamol U.10 mg Benzoxonium chloride 0.10 mg Cremophor~ EL 4.00 mg Water for injection purposes ad 1.00 ml Example 5: Eye drops containing chloramphenicol In~~r'edient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogo1400 80.00 mg Trometamol 0.10 mg Benzoxonium chloride 0.10 mg a-Tocopherol acetate 10.00 mg Solutol~ HS 15 5,00 mg Water for injection purposesad 1.00 ml ~'t, '~ r" ~ '' (.a ~ ~ :.~ ~ ke ~
Example 6: Eye drops containing chloramphenicol In r~edient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogo1400 80.00 mg Benzoxonium chloride 0.10 mg Water for injection purposesad 1.00 ml Example 7: Eke drops containing chloramphenicol In~ diem Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogo1400 80.00 mg Trometamol 0.10 mg Benzoxonium chloride 0.10 mg Water for injection purposesad 1.00 ml Example 8: Eke drops containing chloramphenicol In diem Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogo1400 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 In dient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogo1400 80.00 mg Cremophor~ EL 4.00 mg Benzoxonium chloride 0.10 mg Water for injection purposesad 1.00 ml r~,5~~~~'~~~
Example 10: Eye drops containing chloramphenicol Ingredient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogo1400 80.00 mg Trometamol 0.10 mg Benzoxonium chloride 0.10 mg Solutol~ HS 15 5.00 mg Water for injection purposesad 1.00 ml Example 11: Eye gel containin~~ 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 purposesad 1.00 ml Example 12: Eye~~el containing vitamin A acid, tear replacement In e~dient 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 ~x~~~~w~
Water for injection purposes ad 1.00 ml Example 13: E~gel containing vitamin A acid tear replacement In diem 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 B~ 0.15 mg Water for injection purposesad 1.00 ml Example 14: Eye gel containing vitamin A acid. tear replacement In e,~r diem 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 purposesad 1.00 ml Example 15: Eye gel containingwitamin A acid tear replacement In dient 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 2a~~'~~~
Solutol~ HS 15 20.00 mg Water for injection puiposes ad 1.00 ml Example 16: Eye gel containing vitamin A acid, tear replacement In diem 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 In egr diem 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: Eke gel, tear replacement In~ dient 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 ,.
ia~a.~ ~~sn1 Example 19: E~gel 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 purposesad 1.00 , ml Example 20: Eye 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 Trig 1N hydrochloric acid 34.000 mg N-Benzyl-N-(mixed Cg-Clgalkyl)-N,N-bis-(2-hydroxyethyl)-ammonium-chloride 0.100 mg Methylhydroxypropylcellulose3.000 mg Hamamelis lotion 40.000 mg Orange blossom oil 5.00 wg Lavender oil 1.80 wg Euphrasia tincture 0.800 wg Absolute ethanol 1.393 mg Water for injection purposesad 1.000 ml Example 21: Eye drops containing chloramphenicol In diem Amount Chloramphenicol 6.00 mg Disodium EDTA p.10 mg Macrogo1400 80.00 mg Trometamol 0.10, mg N-Benzyl-N-(mixed Cg-Clgalkyl)-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: Eye drops containing chloramphenicol In dient Amount Chloramphenicol 6.00 mg Disodium-EDTA 0.10 mg Macrogo1400 80.00 , mg Trometamol 0.10 mg N-Benzyl-N-(mixed Cg-Clgalkyl)-N,N-bis-(2-hydroxyethyl)-ammonium-~chloride 0.10 mg Water for injection purposesad 1.00 ml Example 23: Eire drops containing chloramphenicol In~ dient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogo1400 80.00 mg N-Benzyl-N-(mixed Cg-Clgalkyl)-N,N-bis-(2-hydroxyethyl)-ammonium-chloride 0.10 mg Solutol~ HS 15 5.00 mg Water for injection purposesad 1.00 ml Example 24: Eye drops containing nirbuterol hydrochloride In e~dient Amount Pirbuterol hydrochloride 3.00 mg Disodium EDTA 0.10 mg Benzoxonium chloride 0.10 mg Sodium chloride 8.25 mg Sodium hydroxide (1N aqueous0.10 mg solution) Water for injection purposesad 1.00, ml ;~
Example 25: Eye 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 (1N aqueous0.10 mg solution) Water for injection purposesad 1.00 ml Example 26: Eye drops containing pirbuterol hydrochloride In e~d~'ent Amount Pirbuterol hydrochloride 8.00 mg Disodium EDTA 0.10 mg $enzoxonium chloride 0.10 mg Sodium chloride 6.75 mg Sodium hydroxide (1N aqueous 0.10 mg solution) 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 rng Disodium EDTA 1.00 mg Benzoxoniurn chloride 0.10 mg Borax (Na2B407~ 10 H20) 1.50 mg Boric acid 13.00 mg Polymer JR-30~ 12.50 mg Water for injection purposesad 1.00 ml Example 28: Eye drops containing diclofenac Na and gentamicin In diem 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 purposesad 1.00 ml Example 29: Cleansin~a 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: Conditionin_pysolution for contact lenses which are permeable to gas and hard In d~ient Amount Benzoxonium chloride 0.005 g Vinol~ 350 PVA 0.500 g Plasdone K-90 PVP 1.000 g Na2HP04 0.720 g N~2pp4,H2p 0.220 g Sodium chloride 0.440 g Disodium EDTA 0.100 g Deionized water ad 100.00 ml
24 hours n. g. n. g, n. g. n. g.
Percentages: reduction in growth 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 conjunctiva) 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:
~'o r'-~ :"~ ' f '~ ~
i~r . ;r r~r J
Benzoxonium chloride (= compound of the formula n, 0.01 %
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-Ctsalkyl)-N,N-bis-(2-hydroxyethyl)-ammonium chloride and benzalkonium chloride were compared. Pigmented Himalaya rabbits were used as test animals. In each case 50 wl of the corresponding solution was administered to the conjunctiva) 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 Cs-CtBalkyl)-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 conjunctiva) 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 io - 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 Ct-C2oalkyl, alkt and alk2 independently of one another are C2-C4alkylene, alk3 is Ct-C4alkylene 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 Ct-Clsalkyl, alkl and alk2 are 1,2-ethylene, alk3 is methylene and X~ 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 Cs-CtBalkyl, alkt 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 'Cg-Clsalkyl)-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 % (WN).
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 and-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 t s',.'. ; t ~J "~ rv1 _ g -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 (Na2B40~ ~ 1OH20), phosphates, for example the Na2HP04~2H20/NaH2P04~2H20 buffer, trometamol (= 2-amino-2-hydroxymethyl-1,3-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 66012-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 esed as odorants. The following may be mentioned as examples: absolute ethanol, polypropylene glycol or polyethylene glycol ~~ L~l ~,a~'~6~~e~~ ~ei1 400 (= macrogol 400, see also under solubilizers);
(f) if appropriate antioxidants, for example «-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 (= carboxyvinyl 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
- lo-alkt- OH
Ar- alk3 ~N - Alk ) alk2- OH
in which Ar is aryl, Alk is alkyl, alkl, alk2 and alk3 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 Ct-C2oalkyl, alkt and alk2 independently of one another are C2-C4alkylene, alk3 is Cl-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, Ally is Ct-Clgalkyl, alkt 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 C8-ClBalkyl, alkt 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 C8-CtBalkyl)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
alkl-OH
Ar- alkg ~N - Alk X~
~) atk2-OH
in which Ar is aryl, Alk is alkyl, alkl, 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 Cs-Clsalkyl, alkt 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-Ctsalkyl, alkt 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 RShm and Haas, in particular Tritons 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 Cs-Ctsalkyl, alkl 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 polyvinylpynolidone (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)-(fj or (b)-(e) are examples of adjuncts which are acceptable to contactlenses.
The invention also relates to the use of at least one compound of the formula I
alkt- OH
Ar- alkg ~N - Alk (n alk2- OH
in which Ar is aryl, Alk is alkyl, alkl, 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 Cs-Clsalkyl, alkt 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 Cs-Ctgalkyl, 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 In diem 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 purposesad 1.00 ml Example 2: Eye 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 Methylhydroxypropylcellulose3.000 mg Hamamelis lotion 40.000 mg Orange blossom oil 5.00 wg Lavender oil 1.80 wg Euphrasia tincture 0.800 mg Absolute ethanol 1.393 mg 1N hydrochloric acid 0.100 mg Water for injection purposesad 1.000 ml t~s~~~,yf~r~
Examyle 3: Eye 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 1N hydrochloric acid 34.000 mg Benzoxonium chloride 0.100 mg Methylhydroxypropylcellulose3.000 mg Hamamelis lotion 40.000 mg Orange blossom oil 5.00 wg Lavender oil 1.80 wg Euphrasia tincture 0.800 wg Absolute ethanol 1.393 mg Water for injection purposesad 1.000 ml Example 4: Eye drops containing chloramphenicol In diem Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogo1400 80.00 mg Trometamol U.10 mg Benzoxonium chloride 0.10 mg Cremophor~ EL 4.00 mg Water for injection purposes ad 1.00 ml Example 5: Eye drops containing chloramphenicol In~~r'edient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogo1400 80.00 mg Trometamol 0.10 mg Benzoxonium chloride 0.10 mg a-Tocopherol acetate 10.00 mg Solutol~ HS 15 5,00 mg Water for injection purposesad 1.00 ml ~'t, '~ r" ~ '' (.a ~ ~ :.~ ~ ke ~
Example 6: Eye drops containing chloramphenicol In r~edient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogo1400 80.00 mg Benzoxonium chloride 0.10 mg Water for injection purposesad 1.00 ml Example 7: Eke drops containing chloramphenicol In~ diem Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogo1400 80.00 mg Trometamol 0.10 mg Benzoxonium chloride 0.10 mg Water for injection purposesad 1.00 ml Example 8: Eke drops containing chloramphenicol In diem Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogo1400 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 In dient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogo1400 80.00 mg Cremophor~ EL 4.00 mg Benzoxonium chloride 0.10 mg Water for injection purposesad 1.00 ml r~,5~~~~'~~~
Example 10: Eye drops containing chloramphenicol Ingredient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogo1400 80.00 mg Trometamol 0.10 mg Benzoxonium chloride 0.10 mg Solutol~ HS 15 5.00 mg Water for injection purposesad 1.00 ml Example 11: Eye gel containin~~ 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 purposesad 1.00 ml Example 12: Eye~~el containing vitamin A acid, tear replacement In e~dient 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 ~x~~~~w~
Water for injection purposes ad 1.00 ml Example 13: E~gel containing vitamin A acid tear replacement In diem 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 B~ 0.15 mg Water for injection purposesad 1.00 ml Example 14: Eye gel containing vitamin A acid. tear replacement In e,~r diem 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 purposesad 1.00 ml Example 15: Eye gel containingwitamin A acid tear replacement In dient 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 2a~~'~~~
Solutol~ HS 15 20.00 mg Water for injection puiposes ad 1.00 ml Example 16: Eye gel containing vitamin A acid, tear replacement In diem 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 In egr diem 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: Eke gel, tear replacement In~ dient 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 ,.
ia~a.~ ~~sn1 Example 19: E~gel 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 purposesad 1.00 , ml Example 20: Eye 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 Trig 1N hydrochloric acid 34.000 mg N-Benzyl-N-(mixed Cg-Clgalkyl)-N,N-bis-(2-hydroxyethyl)-ammonium-chloride 0.100 mg Methylhydroxypropylcellulose3.000 mg Hamamelis lotion 40.000 mg Orange blossom oil 5.00 wg Lavender oil 1.80 wg Euphrasia tincture 0.800 wg Absolute ethanol 1.393 mg Water for injection purposesad 1.000 ml Example 21: Eye drops containing chloramphenicol In diem Amount Chloramphenicol 6.00 mg Disodium EDTA p.10 mg Macrogo1400 80.00 mg Trometamol 0.10, mg N-Benzyl-N-(mixed Cg-Clgalkyl)-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: Eye drops containing chloramphenicol In dient Amount Chloramphenicol 6.00 mg Disodium-EDTA 0.10 mg Macrogo1400 80.00 , mg Trometamol 0.10 mg N-Benzyl-N-(mixed Cg-Clgalkyl)-N,N-bis-(2-hydroxyethyl)-ammonium-~chloride 0.10 mg Water for injection purposesad 1.00 ml Example 23: Eire drops containing chloramphenicol In~ dient Amount Chloramphenicol 6.00 mg Disodium EDTA 0.10 mg Macrogo1400 80.00 mg N-Benzyl-N-(mixed Cg-Clgalkyl)-N,N-bis-(2-hydroxyethyl)-ammonium-chloride 0.10 mg Solutol~ HS 15 5.00 mg Water for injection purposesad 1.00 ml Example 24: Eye drops containing nirbuterol hydrochloride In e~dient Amount Pirbuterol hydrochloride 3.00 mg Disodium EDTA 0.10 mg Benzoxonium chloride 0.10 mg Sodium chloride 8.25 mg Sodium hydroxide (1N aqueous0.10 mg solution) Water for injection purposesad 1.00, ml ;~
Example 25: Eye 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 (1N aqueous0.10 mg solution) Water for injection purposesad 1.00 ml Example 26: Eye drops containing pirbuterol hydrochloride In e~d~'ent Amount Pirbuterol hydrochloride 8.00 mg Disodium EDTA 0.10 mg $enzoxonium chloride 0.10 mg Sodium chloride 6.75 mg Sodium hydroxide (1N aqueous 0.10 mg solution) 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 rng Disodium EDTA 1.00 mg Benzoxoniurn chloride 0.10 mg Borax (Na2B407~ 10 H20) 1.50 mg Boric acid 13.00 mg Polymer JR-30~ 12.50 mg Water for injection purposesad 1.00 ml Example 28: Eye drops containing diclofenac Na and gentamicin In diem 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 purposesad 1.00 ml Example 29: Cleansin~a 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: Conditionin_pysolution for contact lenses which are permeable to gas and hard In d~ient Amount Benzoxonium chloride 0.005 g Vinol~ 350 PVA 0.500 g Plasdone K-90 PVP 1.000 g Na2HP04 0.720 g N~2pp4,H2p 0.220 g Sodium chloride 0.440 g Disodium EDTA 0.100 g Deionized water ad 100.00 ml
Claims (30)
1. An antimicrobial ophthalmic composition containing an antimicrobially effective amount of at least one compound of the formula I
in which Ar is selected from a phenyl and a naphthyl radical which is unsubstituted or substituted by C1-C7 alkyl, C1-C7 alkoxy, halogen or trifluoromethyl, Alk is C1-C20 alkyl, alk1, alk2 and alk3 independently of one another are C1-C7 alkylene, and X.THETA. is an ophthalmically acceptable anion, and one or more adjuncts which are ophthalmically acceptable and acceptable to contact lenses.
in which Ar is selected from a phenyl and a naphthyl radical which is unsubstituted or substituted by C1-C7 alkyl, C1-C7 alkoxy, halogen or trifluoromethyl, Alk is C1-C20 alkyl, alk1, alk2 and alk3 independently of one another are C1-C7 alkylene, and X.THETA. is an ophthalmically acceptable anion, and one or more adjuncts which are ophthalmically acceptable and acceptable to 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 C8-C18alkyl, alk1 and alk2 are 1,2-ethylene, alk3 is methylene and X.THETA. is chloride.
3.An eye medicament according to claim 1 containing at least one compound of formula I
in which Ar is selected from a phenyl and a naphthyl radical which is unsubstituted or substituted by C1-C7 alkyl, C1-C7 alkoxy, halogen or trifluoromethyl, Alk is C1-C20 alkyl, alk1, alk2 and alk3 independently of one another are C1-C7 alkylene, and X.THETA. is an ophthalmically acceptable anion, and one or more adjuncts.
in which Ar is selected from a phenyl and a naphthyl radical which is unsubstituted or substituted by C1-C7 alkyl, C1-C7 alkoxy, halogen or trifluoromethyl, Alk is C1-C20 alkyl, alk1, alk2 and alk3 independently of one another are C1-C7 alkylene, and X.THETA. is an ophthalmically acceptable anion, and one or more adjuncts.
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 C1-C7alkyl, C1-C7 alkoxy, halogen or trifluoromethyl, Alk is C1-C20alkyl, alk1 and alk2 independently of one another are C2-C4alkylene, alk3 is C1-C4alkylene and X.THETA. is an ophthalmically 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 C1-C18alkyl, alk1 and alk2 are 1,2-ethylene, alk3 is methylene and X.THETA. 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 C8-C18alkyl, alk1 and alk2 are 1,2-ethylene, alk3 is methylene and X.THETA. is chloride.
7. An eye medicament according to claim 3 containing N-benzyl-N-(mixed C8-C18alkyl)-N,N-bis-(2-hydroxyethyl)-ammonium chloride.
8. An eye medicament according to claim 3 containing 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 contains 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 contains 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 contains 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, containing the pharmaceutically active ingredient diclofenac.
13. An eye medicament according to any one of claims 3-11, containing the pharmaceutically active ingredient diclofenac sodium.
14. An eye medicament according to any one of claims 3-11, containing the pharmaceutically active ingredients diclofenac sodium and gentamicin.
15. An eye medicament according to any one of claims 3-11, containing the pharmaceutically active ingredient naphazoline nitrate.
16. Use of at least least one compound of the formula I
in which Ar is selected from a phenyl and a naphthyl radical which is unsubstituted or substituted by C1-C7 alkyl, C1-C7 alkoxy, halogen or trifluoromethyl, Alk is C1-C20 alkyl, alk1, alk2 and alk3 independently of one another are C1-C7 alkylene, and X.THETA. is an ophthalmically acceptable anion, for the preservation of eye medicaments.
in which Ar is selected from a phenyl and a naphthyl radical which is unsubstituted or substituted by C1-C7 alkyl, C1-C7 alkoxy, halogen or trifluoromethyl, Alk is C1-C20 alkyl, alk1, alk2 and alk3 independently of one another are C1-C7 alkylene, and X.THETA. is an ophthalmically acceptable anion, for the preservation of eye medicaments.
17. Use according to claim 16, wherein at least one compound of formula (I) in which Ar is phenyl which is unsubstituted or substituted by C1-C7 alkyl, C1-C7alkoxy, halogen or trifluoromethyl, Alk is C1-C20alkyl, alk1 and alk2 independently of one another are C2-C4alkylene, alk3 is C1-C4alkylene and X.THETA. is an ophthalmically acceptable anion, is used.
18. Use according to claim 16, wherein at least one compound of formula (I) in which Ar is phenyl, Alk is C1-C18alkyl, alk1 and alk2 are 1,2-ethylene, alk3 is methylene and X.THETA. is bromide or chloride, is used.
19. Use according to claim 16, wherein at least one compound of formula (I) in which Ar is phenyl, Alk is C8-C18alkyl, alk1 and alk2 are 1,2-ethylene, alk3 is methylene and X.THETA. is chloride, is used.
20. Use according to claim 16, wherein N-benzyl-N-(mixed C8-C18alkyl)-N,N-bis-(2-hydroxyethyl)-ammonium chloride is used.
21. Use according to claim 16, wherein N-benzyl-N-(n-dodecyl)-N,N-bis-(2-hydroxy-ethyl)-ammonium chloride is used.
22. Use according to any one of claims 16-21, wherein the compounds of formula I are used in the eye medicament in a concentration (W/V) of 0.0001 % to 0.10 %.
23. Use according to any one of claims 16-21, wherein the compounds of 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 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 according to claim 1 containing at least one compound of the formula I
in which Ar is selected from a phenyl and a naphthyl radical which is unsubstituted or substituted by C1-C7 alkyl, C1-C7 alkoxy, halogen or trifluoromethyl, Alk is C1-C20 alkyl, alk1, alk2 and alk3 independently of one another are C1-C7 alkylene, and X.THETA. is an ophthalmically acceptable anion, and one or more adjuncts which are acceptable to contact lenses.
in which Ar is selected from a phenyl and a naphthyl radical which is unsubstituted or substituted by C1-C7 alkyl, C1-C7 alkoxy, halogen or trifluoromethyl, Alk is C1-C20 alkyl, alk1, alk2 and alk3 independently of one another are C1-C7 alkylene, and X.THETA. is an ophthalmically acceptable anion, and one or more adjuncts which are acceptable to contact lenses.
26. A solution for the treatment of contact lenses according to claim 25 containing at least one compound of the formula I in which Ar is phenyl, Alk is C8-C18alkyl, alk1 and alk2 are 1,2-ethylene, alk3 is methylene and X.THETA. 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 C8-C18alkyl, alk1 and alk2 are 1,2-ethylene, alk3 is methylene and X.THETA. 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.
(a) a compound of the formula I in which Ar is phenyl, Alk is C8-C18alkyl, alk1 and alk2 are 1,2-ethylene, alk3 is methylene and X.THETA. 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 containing:
(a) a compound of the formula I in which Ar is phenyl, Alk is C8-C18alkyl, alk1 and alk2 are 1,2-ethylene, alk3 is methylene and X.THETA. 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.
(a) a compound of the formula I in which Ar is phenyl, Alk is C8-C18alkyl, alk1 and alk2 are 1,2-ethylene, alk3 is methylene and X.THETA. 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. Use of at least one compound of the formula I
in which Ar is selected from a phenyl and a naphthyl radical which is unsubstituted or substituted by C1-C7 alkyl, C1-C7 alkoxy, halogen or trifluoromethyl, Alk is C1-C20 alkyl, alk1, alk2 and alk3 independently of one another are C1-C7 alkylene, and X.THETA. is an ophthalmically acceptable anion, for the preservation of contact lenses.
in which Ar is selected from a phenyl and a naphthyl radical which is unsubstituted or substituted by C1-C7 alkyl, C1-C7 alkoxy, halogen or trifluoromethyl, Alk is C1-C20 alkyl, alk1, alk2 and alk3 independently of one another are C1-C7 alkylene, and X.THETA. is an ophthalmically acceptable anion, for the preservation of contact lenses.
30. Use according to claim 29, wherein at least one compound of the formula I
in which Ar is phenyl, Alk is C8-C18alkyl, alk1 and alk2 are 1,2-ethylene, alk3 is methylene and X.THETA.
is chloride, is used.
in which Ar is phenyl, Alk is C8-C18alkyl, alk1 and alk2 are 1,2-ethylene, alk3 is methylene and X.THETA.
is chloride, is used.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH3446/89-2 | 1989-09-21 | ||
| CH344689 | 1989-09-21 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2025728A1 CA2025728A1 (en) | 1991-03-22 |
| CA2025728C true CA2025728C (en) | 2002-02-26 |
Family
ID=4256126
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002025728A Expired - Fee Related CA2025728C (en) | 1989-09-21 | 1990-09-19 | Antimicrobial compositions |
Country Status (18)
| Country | Link |
|---|---|
| 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) | FI101849B (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 |
| AU6859394A (en) * | 1993-05-25 | 1994-12-20 | 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 |
| EP2364140A1 (en) * | 2008-11-28 | 2011-09-14 | Advance Holdings Limited | Pharmaceutical formulation comprising diclofenac and a hydroxy fatty acid polyoxyalkylene ester |
| JP2012006962A (en) * | 2011-08-22 | 2012-01-12 | Lion Corp | Ophthalmic composition |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| KR950013754B1 (en) * | 1987-09-11 | 1995-11-15 | 신텍스(미합중국)인코포레이티드 | Ophthalmic non-steroid formulations |
-
1990
- 1990-09-12 AT AT90810692T patent/ATE103182T1/en not_active IP Right Cessation
- 1990-09-12 ES ES90810692T patent/ES2053161T3/en not_active Expired - Lifetime
- 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 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 AU AU63024/90A patent/AU640687B2/en not_active Ceased
- 1990-09-19 PT PT95355A patent/PT95355B/en not_active IP Right Cessation
- 1990-09-19 CA CA002025728A patent/CA2025728C/en not_active Expired - Fee Related
- 1990-09-19 NZ NZ235377A patent/NZ235377A/en unknown
- 1990-09-19 FI FI904616A patent/FI101849B/en not_active IP Right Cessation
- 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 HU HU905995A patent/HUT59001A/en unknown
- 1990-09-20 JP JP2248967A patent/JP2960507B2/en not_active Expired - Fee Related
- 1990-09-20 NO NO904112A patent/NO179472C/en unknown
-
1994
- 1994-09-23 HU HU94P/P00030P patent/HU210525A9/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IL95720A0 (en) | 1991-06-30 |
| JPH03130219A (en) | 1991-06-04 |
| ATE103182T1 (en) | 1994-04-15 |
| ES2053161T3 (en) | 1994-07-16 |
| HU210525A9 (en) | 1995-04-28 |
| DK0420798T3 (en) | 1994-04-11 |
| IL95720A (en) | 1996-07-23 |
| AU6302490A (en) | 1991-03-28 |
| HUT59001A (en) | 1992-04-28 |
| NZ235377A (en) | 1992-08-26 |
| FI101849B1 (en) | 1998-09-15 |
| NO179472B (en) | 1996-07-08 |
| FI101849B (en) | 1998-09-15 |
| PH29982A (en) | 1996-10-29 |
| JP2960507B2 (en) | 1999-10-06 |
| EP0420798A1 (en) | 1991-04-03 |
| CA2025728A1 (en) | 1991-03-22 |
| IE71639B1 (en) | 1997-02-26 |
| FI904616A0 (en) | 1990-09-19 |
| DE59005084D1 (en) | 1994-04-28 |
| NO179472C (en) | 1996-10-16 |
| PT95355B (en) | 1997-06-30 |
| PT95355A (en) | 1991-05-22 |
| HU905995D0 (en) | 1991-03-28 |
| EP0420798B1 (en) | 1994-03-23 |
| NO904112L (en) | 1991-03-22 |
| AU640687B2 (en) | 1993-09-02 |
| IE903406A1 (en) | 1991-04-10 |
| NO904112D0 (en) | 1990-09-20 |
| ZA907536B (en) | 1991-05-29 |
| DD299267A5 (en) | 1992-04-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US4029817A (en) | Soft contact lens preserving solutions | |
| EP2155271B1 (en) | Phospholipid compositions for contact lens care and preservation of pharmaceutical compositions | |
| EP2254549B2 (en) | Aqueous pharmaceutical compositions containing borate-polyol complexes | |
| KR101421519B1 (en) | Self-preserved aqueous pharmaceutical compositions | |
| JP3200440B2 (en) | Use of amidoamines in ophthalmic compositions | |
| EP1399127A1 (en) | Olopatadine formulations for topical administration | |
| EP0824916B1 (en) | Pranoprofen eyedrops containing organic amine | |
| JP2001509476A (en) | Storage stable ophthalmic composition comprising diclofenac and ofloxacin | |
| CA2025728C (en) | Antimicrobial compositions | |
| WO1994027436A1 (en) | Preservative systems with enhanced antimicrobial activity | |
| JP4644682B2 (en) | Use of bisamines to enhance the antimicrobial activity of aqueous compositions | |
| JP4725699B2 (en) | Ophthalmic composition and preservative for blending ophthalmic composition | |
| JP5713034B2 (en) | Ophthalmic composition and antiseptic composition for ophthalmic preparation | |
| JP2007513951A (en) | Use of organic buffers to enhance the antimicrobial activity of pharmaceutical compositions | |
| EP0877553A1 (en) | Antiseptic composition containing a quaternary ammonium compound a chelating agent and a polyol | |
| JP5740666B2 (en) | Ophthalmic composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |