WO2022060251A1 - Eye drops for the prophylaxis and treatment of age-related cataracts - Google Patents

Abstract

The invention relates to pharmacology, and more particularly to the preparation of compositions based on a serotonin receptor antagonist, which can be used in ophthalmology, therapy and geriatrics. Eye drops containing as active ingredient a serotonin receptor antagonist, more specifically ondansetron hydrochloride dehydrate in a broader range of a lower than normal dosage, additionally contain excipients which enhance the therapeutic effect of small doses of the active ingredient. The technical result is that of creating improved eye drops for the prophylaxis and treatment of early manifestations of age-related nuclear cataracts, which contain a broader range of a lower than normal dosage of a serotonin receptor antagonist and have a dosed prophylactic and therapeutic anti-dystrophic effect as a result of the solution having optimal physical and chemical properties which allow the small doses of the active ingredient to penetrate into the intraocular structures.

Description

Advanced Eye Drops for the Prevention and Treatment of Early Manifestations of Age-Related Nuclear Cataracts

The invention relates to pharmacology, specifically to the preparation of improved compositions based on a serotonin receptor antagonist, which can be used in ophthalmology, therapy and geriatrics. The invention contributes to the improvement of approaches to targeted prevention and treatment of age-related opacification of the lens (age-related cataract) of the nuclear type and other age-related degenerative diseases of the organ of vision with similar pathogenesis.

The range of anti-cataract eye drops currently used in practical ophthalmology is quite narrow. In the treatment of age-related cataract, a certain effectiveness of drugs with antioxidant and metabolic properties, as well as vitamin preparations when applied topically, has been shown.

Modern medicine has proven that with age-related cataracts, various chemical, morphological and clinical changes occur in the lens [Non-Patent Literature 1 - 4]. Therefore, it is necessary to apply a differentiated pathogenetically substantiated approach to the prevention and treatment of various types of age-related dystrophic lesions of the lens [Patent Literature 1 - 2]. This approach made it possible to supplement the list of modern anti-cataract eye drops with anti-dystrophic drugs based on a serotonin receptor antagonist, which in experiments demonstrates its therapeutic potential in relation to the nuclear cataract model on the lenses of laboratory rats and rabbits. At the same time, it is known that ondansetron hydrochloride dihydrate [Patent Literature 3], which exhibits the properties of an antagonist of 5 - HT ₃ - serotonin receptors, has anti-emetic activity [Patent Literature 4] and is currently used exclusively as a regulator of motor activity of the upper gastrointestinal tract with nausea and vomiting of various origins.

The most common means of prevention and conservative treatment of cataracts in the Russian Federation and in the world are: Oftan-Katachrom eye drops, including cytochrome C, adenosine, nicotinamide, as well as auxiliary components - benzalkonium chloride, sodium succinate hexahydrate, sorbitol, buffer and antiseptic substances , water for injection [Non-Patent Literature 5]; catalin eye drops containing pyrenoxine and auxiliary components - aminoethylsulfonic acid, boric acid, solvent (isotonic buffer solution containing methyl parahydroxybenzoate and propyl parahydroxybenzoate), preservatives - boric acid, sodium borate [Non-Patent Literature 6]; as well as eye drops "Taufon", "Taurine" containing the amino acid taurine, excipients - methyl parahydroxybenzoate (nipagin and methyl paraben), water for injection [Non-Patent Literature 7 and 8].

However, there are objective difficulties in the pharmacotherapy of age-related cataracts, due to the need to increase the preventive and therapeutic effect of the anti-cataract agents used, which is associated: on the one hand, with insufficient study of the pathogenesis of certain types of age-related cataracts (differentiated for nuclear and cortical types of age-related dystrophic lesions of the lens), on the other hand, the importance of increasing the penetrating ability of the active anti-cataract components of eye drops through the membranes of the eyeball into the intraocular media.

Currently widely used in ophthalmology, eye drops for the prevention and treatment of cataracts have certain disadvantages associated with the impossibility of achieving a stable clinical improvement in visual acuity of patients with cataracts for various reasons. For example, it has been proven that Oftan-Katachrom eye drops contain cytochrome C, one of the main anti-cataract components, which does not penetrate the cornea, which, having called into question the effectiveness of these eye drops, led to the need for new scientific studies, which resulted in the recommendation to combine eye drops "Oftan-Katahrom" with the simultaneous use of ultrasound to enhance the penetration of the drug into the intraocular environment [Non-Patent Literature 5]. Obviously, such a recommendation can only limit the practical use of Oftan-Katahrom eye drops.

It is important to note in particular that none of the modern anti-cataract eye drops currently used in practice take into account significant differences in the pathogenesis of different types of age-related cataracts (nuclear and cortical types), and, therefore, ignore the pathogenetically justified need for a differentiated therapeutic effect on cells. dystrophically altered lens, including for prophylactic purposes at the stage of formation of preclinical manifestations of age-related cataract [Patent Literature 5].

At the same time, in the Russian Federation, where the principle of a differentiated approach to the prevention and conservative treatment of age-related lens opacity depending on its type was first developed, for the first time, "New eye drops for the conservative treatment and prevention of age-related nuclear cataract" were proposed, containing as an active anti-cataract ( antidystrophic) component of the serotonin receptor antagonist [Patent Literature 6], which are the first closest analogue of the present invention according to the proposed essence, but are inferior in terms of optimal physico-chemical properties of the solution, limiting the possibility of achieving a dosed antidystrophic effect when using small doses of the active component, which is especially important it is in the conditions of prevention and treatment of early manifestations of this disease. Also accumulated in recent years own [Patent Literature 6] experience in the experimental use of this pharmaceutical composition, allows us to conclude that the previously proposed eye drops contain too narrow a range of prophylactic dosages of the active anti-cataract component, while not providing for the presence of components that increase the duration of contact of eye drops with the surface eyeball (prolongators), which leads to rapid leaching of the drug instilled into the conjunctival sac of the eye and, as a result, to a decrease in its preventive and therapeutic effect.

The second closest analogue of this invention according to the proposed essence are "Eye drops for the treatment of age-related nuclear cataract" [Patent Literature 7]. However, these eye drops contain a higher therapeutic dosage range of the active ingredient (serotonin receptor antagonist - ondansetron hydrochloride dihydrate), since these eye drops have an exclusively therapeutic, and not prophylactic, purpose of use and are intended for use in conditions of an already formed cataract process, accompanied by severe organic changes in the substance of the lens.

Eye drops are proposed, containing as an active ingredient a serotonin receptor antagonist in a wider range of reduced dosage, according to the invention also additionally containing auxiliary components that increase the therapeutic effect of the active ingredient: substances that provide the viscosity of the medium (prolongator), substances that maintain the pH of the medium (pH regulator ), a stabilizer of biological, physico-chemical properties and / or resistance to contamination by microorganisms in the following ratio of components in 1 ml of solution:
Ondansetron hydrochloride dihydrate, g - 0.000001 - 0.00029
Substances that provide the viscosity of the medium in the range of 5 - 100 mm ² / s
Substances that maintain the pH of the environment in the range of 3.5 - 8.5
Stabilizer, g - 0.00005 - 0.1
Solvent, g - 0.001 - 0.05
Distilled water, ml - the rest.

In addition, eye drops as substances that provide the viscosity of the medium (prolongator) contain one of the following substances: polyvinylpyrrolidone, polyvinyl alcohol, hydroxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose or sodium carboxymethylcellulose, or a mixture thereof.

Eye drops as substances that maintain the pH of the medium (pH regulator) contain an acetate or citrate, or phosphate, or borate buffer, or a mixture thereof.

Eye drops as a stabilizer of biological properties and / or resistance to contamination by microorganisms (preservatives) contain quaternary ammonium compounds or nipagin, or boric acid, or chlorhexidine, or methyl paraben.

As quaternary ammonium compounds, eye drops contain one of the following substances or their derivatives: aethonium, benzethonium chloride or benzalkonium chloride, or a mixture thereof.

Eye drops contain a stabilizer of physico-chemical properties (antioxidant): Trilon B or butylated hydroxytoluene in the amount of 0.0001 - 0.1 g in 1 ml of solution.

As a solvent, eye drops contain one of the following substances: sodium chloride, dextrose, sodium nitrate or sodium sulfate, or a mixture thereof.

The choice of a reduced dosage of the active ingredient is determined depending on the values of the optimal viscosity range of the solution (within 5–100 mm ² / s) and the pH of the medium (within 3.5–8.5) of the eye drops.

Development of improved ophthalmic dosage forms of a serotonin receptor antagonist for topical use with a dosed preventive and therapeutic anti-dystrophic anti-cataract effect by expanding the range of the applied reduced dosage of the active component and increasing the penetration of the above doses of the active component into the intraocular media.

To solve the stated technical problem, eye drops are proposed containing, as an active component, a serotonin receptor antagonist in a wider range of reduced dosage, according to the invention, they also additionally contain auxiliary components that increase the therapeutic effect of the active component: substances that provide the viscosity of the medium (prolongator), substances that support medium pH (pH regulator), stabilizer of biological, physico-chemical properties and/or resistance to contamination by microorganisms.

A positive effect of the invention is the creation of improved eye drops for the prevention and treatment of early manifestations of age-related nuclear cataracts, containing an extended range of reduced dosage of a serotonin receptor antagonist, which has a dosed preventive and therapeutic antidystrophic effect, which is due to the optimal physicochemical properties of the solution that promote penetration into the intraocular structures small doses of the active ingredient.

The essence of embodiments of the invention is illustrated by the following examples.

Example 1

Technology for the proposed eye drops. Prepare a solution of 0.1% polyvinylpyrrolidone, 0.5% aethonium, 0.9% sodium chloride solution. Acetate buffer is added until the pH of the medium is 3.5. The components are mixed. Add ondansetron hydrochloride dihydrate. Mix and sterilize. Poured into a container, sealed, labeled. These components are taken in the following ratio in 1 ml of solution:
Ondansetron hydrochloride dihydrate, g - 0.00029
Prolongator: polyvinylpyrrolidone, g - 0.001
Stabilizer: atonium, g - 0.005
pH adjuster: acetate buffer up to medium pH 3.5
Solvent: sodium chloride, g - 0.009
Distilled water, ml - the rest.

Example 2

Take 2% polyvinyl alcohol, 10% solution of ethonium. Add 10% Trilon B solution, mix everything with 5% dextrose solution. Citrate buffer is added until the pH of the medium is 6.0. The components are mixed. Add ondansetron hydrochloride dihydrate. Mix and sterilize. Further, as in example 1. These components are taken in the following ratio in 1 ml of solution:
Ondansetron hydrochloride dihydrate, g - 0.00029
Prolongator: polyvinyl alcohol, g - 0.02
Stabilizer: atonium, g - 0.1
Trilon B, g - 0.1
pH adjuster: citrate buffer up to medium pH 6.0
Solvent: dextrose, g - 0.05
Distilled water, ml - the rest.

Example 3

Take sodium carboxymethylcellulose, chlorhexidine, butyloxytoluene, sodium nitrate. Phosphate buffer is added until the pH of the medium is 7.0. The components are mixed. Add ondansetron hydrochloride dihydrate. Mixed, sterilized. Further, as in example 1. These components are taken in the following ratio in 1 ml of solution:
Ondansetron hydrochloride dihydrate, g - 0.00029
Prolongator: sodium carboxymethylcellulose, g - 0.02
Stabilizer: chlorhexidine, g - 0.0001
Butylated hydroxytoluene, g - 0.0001
pH regulator: Phosphate buffer up to medium pH 7.0
Solvent: sodium nitrate, g - 0.001
Distilled water, ml - the rest.

Example 4

Take hydroxymethylcellulose, benzethonium chloride, butylated hydroxytoluene, sodium sulfate. Borate buffer is added until the pH of the medium is 7.4. The components are mixed. Add ondansetron hydrochloride dihydrate. Mix and sterilize. Further, as in example 1. These components are taken in the following ratio in 1 ml of solution:
Ondansetron hydrochloride dihydrate, g - 0.00029
Prolongator: hydroxymethylcellulose, g - 0.003
Stabilizer: benzethonium chloride, g - 0.0005
Butylated hydroxytoluene, g - 0.0008
pH regulator: borate buffer up to medium pH 7.4
Solvent: sodium sulfate, g - 0.001
Distilled water, ml - the rest.

Example 5

Take methylcellulose, benzalkonium chloride, Trilon B, sodium chloride. Borate buffer is added until the pH of the medium is 8.5. The components are mixed. Add ondansetron hydrochloride dihydrate. Mix and sterilize. Further, as in example 1. These components are taken in the following ratio in 1 ml of solution:
Ondansetron hydrochloride dihydrate, g - 0.00029
Prolongator: methylcellulose, g - 0.001
Stabilizer: benzalkonium chloride, g - 0.00005
Trilon B, g - 0.0003
pH regulator: borate buffer up to medium pH 8.5
Solvent: sodium chloride, g - 0.009
Distilled water, ml - the rest.

Example 6

Take hydroxypropyl methylcellulose, boric acid, Trilon B, sodium chloride. Acetate-borate buffer is added to pH 7.0. The components are mixed. Add ondansetron hydrochloride dihydrate. Mix and sterilize. Further, as in example 1. These components are taken in the following ratio in 1 ml of solution:
Ondansetron hydrochloride dihydrate, g - 0.0001
Prolongator: hydroxypropyl methylcellulose, g - 0.005
Stabilizer: boric acid, g - 0.02
Trilon B, g - 0.0003
pH adjuster: Acetate-borate buffer up to medium pH 7.0
Solvent: sodium chloride, g - 0.009
Distilled water, ml - the rest.

Example 7

Take polyvinylpyrrolidone, benzalkonium chloride, trilon B, sodium chloride. Citrate buffer is added until the pH of the medium is 5.0. The components are mixed. Add ondansetron hydrochloride dihydrate. Mix and sterilize. Further, as in example 1. These components are taken in the following ratio in 1 ml of solution:
Ondansetron hydrochloride dihydrate, g - 0.000001
Prolongator: polyvinylpyrrolidone, g - 0.0005
Stabilizer: benzalkonium chloride, g - 0.00005
Trilon B, g - 0.0002
pH adjuster: citrate buffer up to medium pH 5.0
Solvent: sodium chloride, g - 0.009
Distilled water, ml - the rest.

Example 8

Take polyvinyl alcohol, nipagin, butyloxytoluene, sodium chloride. Citrate buffer is added until the pH of the medium is 6.6. The components are mixed. Add ondansetron hydrochloride dihydrate. Mix and sterilize. Further, as in example 1. These components are taken in the following ratio of components in 1 ml of solution:
Ondansetron hydrochloride dihydrate, g - 0.0001
Prolongator: polyvinyl alcohol, g - 0.02
Stabilizer: nipagin, g - 0.0015
Butylated hydroxytoluene, g - 0.0002
pH regulator: citrate buffer up to medium pH 6.6
Solvent: sodium chloride, g - 0.009
Distilled water, ml - the rest.

Example 9

They take sodium carboxymethylcellulose, methylparaben, Trilon B, sodium chloride. Acetate-borate buffer is added until the pH of the medium is 7.8. The components are mixed. Add ondansetron hydrochloride dihydrate. Mix and sterilize. Further, as in example 1. These components are taken in the following ratio of components in 1 ml of solution:
Ondansetron hydrochloride dihydrate, g - 0.000001
Prolongator: sodium carboxymethylcellulose, g - 0.02
Stabilizer: methylparaben, g - 0.02
Trilon B, g - 0.0002
pH adjuster: Acetate-borate buffer up to medium pH 7.8
Solvent: sodium chloride, g - 0.009
Distilled water, ml - the rest.

These compositions make it possible to provide a dosed preventive and therapeutic antidystrophic effect of the reduced doses of the active component contained in them, as well as sterility and the necessary physicochemical properties of the solution (viscosity, pH, transparency, color).

Laboratory tests of the listed compositions on the experimental cataract model of laboratory animals showed that it is non-toxic, non-pyrogenic, and does not have a local irritating effect.

The list of links is as follows:

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Claims (9)

Eye drops for the prevention and treatment of age-related nuclear cataracts containing a serotonin receptor antagonist, namely ondansetron hydrochloride dihydrate, as an active ingredient, characterized in that they contain ondansetron hydrochloride dihydrate in a wider range of reduced dosage, and they additionally contain auxiliary components , increasing the therapeutic effect of the active component: substances that provide the viscosity of the medium, substances that maintain the pH of the medium, a stabilizer of biological, physico-chemical properties and / or resistance to contamination by microorganisms in the following ratio of components in 1 ml of solution:
Ondansetron hydrochloride dihydrate, g - 0.000001 - 0.00029
Substances that provide the viscosity of the medium in the range of 5 - 100 mm ² / s
Substances that maintain the pH of the environment in the range of 3.5 - 8.5
Stabilizer, g - 0.00005 - 0.1
Solvent, g - 0.001 - 0.05
Distilled water, ml - the rest. Eye drops according to formula 1, characterized in that as substances that provide the viscosity of the medium, they contain one of the following substances: polyvinylpyrrolidone, polyvinyl alcohol, hydroxymethylcellulose, hydroxypropylmethylcellulose, methylcellulose or sodium carboxymethylcellulose, or a mixture thereof. Eye drops according to formula 1, characterized in that they contain an acetate or citrate, or phosphate, or borate buffer, or a mixture thereof, as substances that maintain the pH of the medium. Eye drops according to formula 1, characterized in that they contain quaternary ammonium compounds, or nipagin, or boric acid, or chlorhexidine, or methylparaben, as a stabilizer-preservative. Eye drops according to formula 1, characterized in that they contain an antioxidant stabilizer: Trilon B or butylated hydroxytoluene in the amount of 0.0001 - 0.1 g in 1 ml of solution. Eye drops according to formula 1, characterized in that they contain one of the following substances as a solvent: sodium chloride, dextrose, sodium nitrate or sodium sulfate, or a mixture thereof. Eye drops according to formula 4, characterized in that they contain one of the following substances or their derivatives as quaternary ammonium compounds: aethonium, benzethonium chloride or benzalkonium chloride, or a mixture thereof. Eye drops according to any one of the claims 1 - 7, characterized in that their optimal value of the viscosity of the solution is located in the range of 5 - 100 mm ² / from. Eye drops according to any one of the claims of the formula 1 - 7, characterized in that their optimal pH value is in the range of 3.5 - 8.5.