NO179472B - Solution comprising benzoxonium chloride for the treatment of contact lenses, and their use for preserving contact lenses and drugs for the eyes - Google Patents

Abstract

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

Description

The present invention relates to a solution for the treatment of contact lenses and its use.

Medicines for the treatment of diseases of the eye are often formulated in liquid form and administered in drop form. In eye drops, a preservation of the preparation is prescribed in most European and other countries, i.e. a protection against contamination and a subsequent multiplication of microorganisms through the addition of at least one component capable of preventing a secondary contamination or at least reduce. Furthermore, eye medicine is often formulated as a gel. The same applies to aqueous gels with regard to preservation.

It is known that N-alkyl-N-aralkyl-N,N-bis-(hydroxyalkyl)-ammonium salts can be used as a disinfectant. In particular, the compound benzoxonium chloride [=N-benzyl-N-(do-decyl)-N,N-bis-(2-hydroxyethyl)-ammonium chloride] has been used for 30 years (see Arzneimittelforschung 9., 622-625

(1959) in many areas of disinfection. For example, benzoxonium chloride is used in mouthwash for disinfection of the mouth and throat cavity, for inflammation of the larynx and trachea, against dental plaque, against cavities, for skin disinfection, especially the hands during surgery, for dermatological-cosmetic reasons or for disinfection in hospitals, for example of medical instruments. Benzoxonium chloride is also added as a veterinary antiseptic, for example as a fungicide and bactericide for udders or for the treatment of dermatomycoses in horses. Further areas of addition of benzoxonium chloride are: disinfection in the food and beverage industry, in the wine industry and in slaughterhouses, disinfection of animal skin, bactericide for textile fibers and bactericide and fungicide for sugar beet.

It is further known, ophthalmic drug through quaternary ammonium salts for preservation (see for example EP-A-306 984). Only very few quaternary ammonium salts have been discovered, and in particular the three in EP-A-306 984 explicitly mentioned the compounds cetyltrimethylammonium bromide, cetyl-pyridinium chloride and benzalkonium chloride (cf. also EP-A-242 328). The preservative of choice for ophthalmic drugs is currently quite unambiguously the latter benzalkonium chloride (see for example EP-A-306 984, p. 2, 1.31-33), which has the following structure: N-benzyl-N-(Cg-C^g- alkyl)-N,N-dimethylammonium chloride .

The small number of quaternary ammonium salts that are used for preservation in ophthalmic drugs is in contrast to a large number of known quaternary ammonium salts ("Quats") that are used in other areas for preservation.

A task according to the present invention is to find further quaternary ammonium salts which are suitable for preserving ophthalmic drugs. Thus, the long very small palette of possible preservatives was expanded for manufacturers of ophthalmic drugs. The task is solved through the invention that the N-alkyl-N-arylalkyl-N,N-bis-(hydroxyalkyl)-ammonium salts of formula I, which also includes benzoxonium chloride, are excellently suitable for preserving ophthalmic drugs. This discovery is by no means imminent, as hundreds of quaternary ammonium salts exist for disinfection alone, of which surprisingly a very small group, i.e. compounds of formula I, have been found to be suitable for the preservation of ophthalmic drugs . As indicated above, a compound of formula I, benzoxonium chloride, has been added for 30 years in many areas for disinfection. However, it has never been suggested for the preservation of eye medicines. It was therefore not obvious to use the compounds of formula I including benzoxonium chloride for the preservation of ophthalmic drugs.

A further task according to the invention is to invent certain quaternary ammonium salts which are better than benzalkonium chloride for preserving ophthalmic drugs. As explained above, benzalkonium chloride, next to chlorhexidine, thiomersal and chlorobutanol, is probably the currently most used preservative for ophthalmic drugs. However, it is not the case that benzalkonium chloride is ideal and satisfactory in every respect. In particular, with long-term use, which may for example be necessary in the treatment of glaucoma, cataracts or "dry eye", tolerability problems on the eye may occur, for example changes in the cornea and conjunctival epithelia and in the eyelids. The task of finding a preservative for an ophthalmic drug with improved tolerability during long-term use is solved through the provision of an ophthalmic drug that contains compounds of formula I for preservation.

The present invention relates to a solution for the treatment of contact lenses and its use.

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

where Ar means phenyl, Alk means C^-C^g-alkyl and X" means chloride, for preserving contact lenses and medicines for the eyes.

A solution for the treatment of contact lenses is further described, characterized in that it contains at least one compound of formula I where Ar means phenyl, Alk means C^-C^g-alkyl and X means chloride, and one or more contact lens-tolerable excipients.

The present invention also relates to cleaning solution for contact lenses characterized in that it contains: (a) a compound of formula I, where Ar means phenyl, Alk means Cg-C^g-alkyl and X" means chloride in a concentration (G/V) of 0.005 to 0.8%,

(b) an isotonizing agent,

(c) a buffer compound,

(d) a complexing agent,

(e) a solubilizing agent and optionally

(f) a thickening agent.

A contact lens conditioner is also described and contains (a) a compound of formula I, where Ar means phenyl, Alk means Cg-Ci-g-alkyl and X~ means chloride in a concentration (G/V) of 0.002 to 0.8 $,

(b) a wetting agent,

(c) a buffer compound,

(d) an isotonizing agent and optionally

(e) a complexing agent.

Alkyl group Alk is preferably linear, but can also be branched.

The alkyl group Alk means, for example, C₁-C₁₆ alkyl and stands for example for 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 for n-octyl, n-nonyl, n-decyl, n-undecyl, n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl or n-octadecyl, and primarily n-dodecyl.

The anion X- is derived from an ophthalmically usable acid, and means chloride.

The compounds of formula I excel as preservatives for ophthalmic drugs, among other things, through the fact that they exhibit an excellent preservative effect and are tolerable with long-term use on the eyes.

The preservative action of the compounds of formula I becomes evident, for example, through the results of the following preservative stress test: preservative stress test, compound: benzxonium chloride. 0.1 mg/ml. pH 6

The surprisingly improved ocular tolerability of the compounds of formula I compared to benzalkonium chloride is evident, for example, from the results of the following described 5-day animal tolerability test: 0.01$ solution of benzoxonium chloride and benzalkonium chloride were each time compared. These solutions were added drop by drop into the conjunctival sac of the eye of rabbits for 5 days, five days per day (in 90 minute intervals). At the end of the experiment, the treated eyes were examined with regard to clinical findings, such as redness of the conjunctiva, corneal clouding, secretion and conjunctival swelling. The following results were obtained:

Benzoxonium chloride (= compound of formula I), 0.01$,

5 installations/animal/day with a distance of 90 min No findings

Benzalkonium chloride comparative compound),0.01$

5 installations/animal/day at a distance of 90 min 4 finds

The better ocular tolerability of the compounds of formula I compared to benzalkonium chloride is also evident, for example, from the results of the following described 4-week ocular local tolerability studies in rabbits: 0.01$ solution of N-benzyl-N-(mixed Cg-<C >18-alkyl)-N,N-bis-(2-hydroxyethyl)-ammonium chloride and benzalkonium chloride were compared. Pigmented Himalayan rabbits served as experimental animals. These were administered for 4 weeks 10 times a day (in 45 min. intervals) each time with 50 µl of the corresponding solution in the conjunctival sac of the right eye. For control, a comparison solution containing no preservative was instilled into the left eye. The animals were examined ophthalmologically on the first and fifth day of treatment. After the experiments were completed, the test animals were also subjected to histopathology, and the following results were obtained: the animals treated with the solution according to the invention, which contained N-benzyl-N-(mixed Cs-C-^g-alkyl )-N,N-bis-(2 -hydroxyethyl )-ammonium chloride, no ocular damage was found. In contrast, in four out of six animals treated with benzalkonium chloride solution, damage was detected in the conjunctival sac and an acanthosis and hyperkeratosis in the edge of the lower right eyelid. The benzalkonium chloride solution thus caused changes in the conjunctival epithelium, which did not occur with the solution according to the invention. It is thus convincingly proven that the compounds of formula I have surprisingly improved long-term tolerability in the eye compared to benzalkonium chloride.

The compounds of formula I are usually added to the ophthalmic drug in a concentration of 0.00156-0.10$ [each time weight/volume (G/V)], especially 0.001#-0.02% and above all 0.002#-0 , 01596 .

An ophthalmic drug can, for example, contain at least one compound of 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 ophthalmic drug, it is present in a concentration of 0.01-0.2$ (G/V), especially about 0.05-0.1$ (G/V).

The compounds of formula I, which were added to the ophthalmic preparation, must exhibit a purity sufficient for ophthalmic reasons. Preferably, for example, the added benzoxonium chloride contains a maximum of 2.5% by weight by-products, where each individual by-product should represent a maximum of 0.5% by weight<.>

Apart from the preservative, for example, the medicine may contain the following ingredients: a) possibly one or more pharmaceutical active substances, for example steroidal anti-inflammatory compounds, for example fluorometholone, non-steroidal anti-inflammatory compounds, for example diclofenac or ophthalmologically tolerable salts thereof, especially diclofenac sodium (diclofenac- Now); antibiotics, such as quinolone, chloramphenicol or gentamicin; anti-glaucoma agents, for example pilocarpine hydrochloride or pirbuterol hydrochloride; keratolytic active compounds, for example vitamin A acid; vasoconstricting compounds (vasoconstrictors), for example naphazoline nitrate, tetrahydrozoline {= tetryzoline), phenylephrine or xylometazoline; antiallergics, for example isospaglumic acid or spaglumic acid and the magnesium or sodium salts thereof;

astringent compounds, for example zinc sulfate;

anti-cataract agents, for example methosorbinil (2R,4S)-2-methyl-6-fluoro-spiro[chromane-4,4'-imidazolidine]-2',5'-dione]; or also, for example, medicinal plant extracts, such as Euphrasia tincture.

Certain tear replacement formulations ("artificial tears") can be mentioned, for example, as ophthalmic drugs that do not contain pharmaceutical active substances.

Furthermore, the ophthalmic medicine contains ophthalmically tolerable excipients, for example

b) optionally one or more buffer compounds, for example boric acid, borate, optionally borax (Na2B407 . IOH2O), phosphate, for example Na2HP04.2H20/NaH2P04.2E20 buffer, trometamol (=2-amino-2-hydroxymethyl-1,3 -propanediol TRIS), or organic acids, for example ascorbic, acetic, propionic or citric acid; c) optionally one or more isotonizing agents, for example sodium chloride, sorbitol (=d-sorbitol), mannitol or glycerin; d) possibly one or more solubilizers, for example fatty acid glycerin polyglycol ester, fatty acid polyglycol ester, polyethylene glycols, glycerin ethers or mixtures of these compounds. A particular example for a particularly preferred solubilizer is reaction products of castor oil and ethylene oxide. For example, the commercial product Cremophor EL (= polyoxyl 35 castor oil). Reaction products from castor oil and ethylene oxide have proven to be particularly good dissolution mediators with excellent eye tolerance.

Further examples of solubilizers are Luviquat FC 905 copolymer of vinylimidazolium methochloride and vinylpyrrolidone 95:5, Fa. BASF), Solutol ES 15 polyethylene glycol 660-12-hydroxystearate, Fa. BASF) and solvent Macrogol 400 polyethylene glycol 400, Lutrol E 400, Fa. BASF); e) any solvent, to dissolve certain components of the formulation, for example the active substance or essential oils, which are used as odorants. Examples can be mentioned: ethanol abs., polypropylene glycol or polyethylene glycol 400 ( = Macrogol 400, see also under solvent); f) for example antioxidants, for example α-tocopherol acetate or BHA 3-tert-butyl-4-hydroxy-anisole); g) optional thickening agent, which serves to increase the viscosity of the formulation, for example methyl-hydroxypropyl cellulose, for example Methocel F4M (Fa. Dow. Chemicals), or the sodium salt of hyaluronic acid; h) possibly strong diluents which lead to gel formation, for example polyacrylic acid, Carbopol 934P carboxyvinyl polymer, Fa. BF Goodrich), Polymer JR 30M polymeric quaternary ammonium salt obtained through reaction between hydroxyethyl cellulose and a trimethylammonium substituted epoxide, cf. TJS patent 3 472 840, Fa. Union Carbide) alginate or polyvinylpyrrolidone; i) optional complex former, for example for increasing the preservative effect of the preservative and/or for complex formation and thus masking any heavy metal contaminants, for example EDTA or salts thereof, such as disodium EDTA; j) any fragrances, for example orange blossom oil, lavender oil or witch hazel water; k) possibly compounds that affect the pH value, for example hydrochloric acid or sodium hydroxide; 1) optional dyes, for example fluorescent sodium;

and

m) usually water for injection purposes or demineralized water.

In normal cases, one strives to set the eye medicine isotonic with human tear fluidity (= 270 to 330 mOsmol/kg, especially 300 mOsmol/kg). However, there may also be exceptional circumstances where the osmolality of the eye medication is outside the specified range.

Solutions for the treatment of contact lenses in particular mean: a) cleaning solutions for contact lenses and b) conditioning agent for gas-permeable and hard contact lenses.

A preferred cleaning solution for contact lenses according to the invention contains, as indicated above: a) a compound of formula I, where Ar means phenyl, Alk means Cg-C-Lg-alkyl, alkyl°S a1^2 means 1,2-ethylene, alks means methylene and X~ means chloride in a concentration (G/V) of 0.005 to 0.8%, b) an isotonizing agent, for example sodium chloride, c) a buffer compound, for example a phosphate buffer, d) a complexing agent, for example EDTA or a salt thereof, e) solubilizers, for example amine oxide detergents, for example Varox 365 (Company Sherex Chemical), or the Triton series ( = polyethyleneglycol-p-isooctylphenylether) from the Company Rohm und Haas, especially Triton X- 100, and optionally f) a thickening agent, for example fast-dissolving hydroxyethyl cellulose, for example Cellosize QP-40 EEC (Company Union Carbide).

A preferred conditioning agent for contact lenses according to the invention contains: a) a compound of formula I, where Ar means phenyl, Alk means Cg-C^g-alkyl, alk^ and alkg means 1,2-ethylene, alk3 means methylene and X" means chloride in a concentration (G/V) of 0.02 to 0.8$, b) a wetting agent, for example polyvinyl alcohol, Vinol 350 PVA (company Air Products, Inc.) or mixtures of polyvinyl alcohol and polyvinyl pyrrolidone (for example Vinol 350 PVA + Plasdone K-90 PVP, Firma GAF), c) a buffer compound, for example a phosphate buffer, d) an isotonizing agent, for example sodium chloride and optionally e) a complexing agent, for example EDTA or a

salt thereof.

The preferred cleaning solution and preferred conditioners for contact lenses mentioned under b)-f) and components indicated under b)-e) respectively are examples of contact lens-tolerable auxiliaries.

In the production of ophthalmic drugs, as well as solutions for the treatment of contact lenses, this takes place by mixing an effective, i.e. sufficient for preservation, quantity of one or more compounds of formula I and the usual components according to conventional methods.

The following formulation examples explain the invention:

Example 1: Eye drops containing diclofenac-Na

Example 2: eye drops containing naphazoline nitrate and zinc sulphate

Example 3: Eye drops containing naphazoline nitrate and zinc sulphate

Example 4: Eye drops containing chloramphenicol Example 5: Eye drops containing chloramphenicol Example 6: Eye drops containing chloramphenicol

Example 7: Eye drops containing chloramphenicol

Example 8: Eye drops containing chloramphenicol Example 9: Eye drops containing chloramphenicol

Example 10: Eye drops containing chloramphenicol

Example 11: Eye gel containing vitamin A acid.

tear replacement

Example 13: Eye gel containing vitamin A acid.

tear replacement

Example 14: Eye gel containing vitamin A acid. tear replacement

Example 16: Eye drops containing vitamin A acid.

tear replacement

Example 17: Eye gel. tear replacement

Example 18: Eye gel. tear replacement

Example 19: Eye gel containing vitamin Å acid. tear substitute Example 20: Eye drops containing naphazoline nitrate and zinc sulphate

Example 21: Eye drops containing chloramphenicol

Example 22: Eye drops containing chloramphenicol Example 23: Eye drops containing chloramphenicol

Example 24: Eye drops containing pirhuterol hydrochloride

Example 25: Eye drops containing pributerol hydrochloride Example 26: Eye drops containing pirhuterol hydrochloride

Example 27: Eye gel containing diclofenac-Na and gentamicin

Example 28: Eye drops containing diclofenac-Na and gentamicin Example 29: Cleaning solution for contact lenses

Example 30: Cond. ionizing solution for gas permeable and hard contact lenses

Claims (4)

1. Use of at least one compound of formula I where Ar means phenyl, Alk means C^^-Cig-alkyl and X" means chloride, for the preservation of contact lenses and medicines for the eyes. 2. Solution for the treatment of contact lenses characterized in that it contains at least one compound of formula I where Ar means phenyl, Alk means C1-<C>18-alkyl and X" means chloride, and one or more contact lens-tolerable excipients. 3. Cleaning solution for contact lenses according to claim 2, characterized in that it contains: (a) a compound of formula I, where Ar means phenyl, Alk means C8-C18 alkyl and X~ means chloride in a concentration (G/V) of 0.005 to 0.8$, (b) an isotonizing agent, (c) a buffering compound, (d) a complexing agent, (e) a solubilizing agent and optionally (f) a thickening agent. 4. Conditioning agent for contact lenses according to claim 2, characterized in that it contains (a) a compound of formula I, where Å means phenyl, Alk means Cg-C^g-alkyl and X" means chloride in a concentration (G/V) of 0.002 to 0.8$, (b) a wetting agent, (c) a buffer compound, (d) an isotonizing agent and optionally (e) a complexing agent.