RU2139094C1 - Composition for treating contact lenses - Google Patents

Abstract

FIELD: ophthalmology. SUBSTANCE: composition for cleaning, disinfecting, and washing contact lenses contains, as active contact lens microbicidal substance - miramistin combined with carboxymethylcellulose sodium salt to form complex and ethylenediaminetetraacetic acid disodium salt as preservative and calcium-removal agent. Composition also contains surface-active cleansers: polysorbat-80 and polyethylene oxide in isotonic sodium chloride-based physiologic solution and phosphate buffer system in specified proportions. EFFECT: eliminated body sensitization and immunotoxic effect. 2 cl, 1 tbl

Description

 The invention relates to the field of medical equipment, in particular to means for cleaning, disinfecting, washing and storing contact lenses.

 Soft and hard contact lenses are currently being manufactured and marketed for users. Both those and others become polluted over time due to the deposition of ocular secretions, protein substances, inorganic substances, microorganisms on them.

 Removing contaminants present on contact lenses is a prerequisite for their use, as it helps to prevent possible eye damage.

 Currently, there are a number of cleaning solutions for contact lenses that provide various degrees of cleaning.

The requirements for such solutions are quite high:
- the absence of harmful effects on the eyes and lens material,
- removal of contaminants of different types and origin,
- stability of solutions,
- ease of use,
- universality (the possibility of using different types of lenses).

 Currently known compositions for treating contact lenses mainly consist of the following components - a bactericidal active agent, surfactants, preservative and physiological saline.

 The composition described in (I) contains bendazan as an active principle, hydroxyethyl cellulose, polyvinyl alcohol, octylphenoxyethanol, polysorbate-80 or their mixtures as surface-active agents - cleaners, thiomersal, chlorhexidine gluconate and sodium salt of ethylenedisides as preservatives acid, which in addition removes calcium, and isotonic saline based on sodium chloride and borate buffer system.

вызывает сильное раздражение слизистых оболочек глаз у пациентов. При длительном использовании композиций с тиомерсалом у многих пациентов развивается стойкая непереносимость этих компонентов.The main disadvantage of this composition is the need to use thiomersal. All examples of specific compositions contain thiomersal or thiomersal in combination with chlorhexidine gluconate. Both substances are highly toxic, thiomersal contains mercury -

causes severe irritation of the mucous membranes of the eyes in patients. With prolonged use of compositions with thiomersal, many patients develop persistent intolerance to these components.

 As for the properties of bendazan, which, being an active principle, in accordance with the description eliminates protein sedimentation and increases activity.

 It is known that the effectiveness of the active principle and composition as a whole is evaluated not only by the removal of protein deposits, but also by disinfecting properties, i.e. antimicrobial activity.

 It is not possible to evaluate the latter, both in view of the absence of any information in the materials describing the patent, and because of the unidentifiable structure of a substance called bandazan, since it is neither generally known in the art nor corresponding to the nomenclature of organic compounds.

 Currently, a number of compositions are known that use compounds from the class of salts of Quaternary ammonium bases as an active antimicrobial principle (2).

обладая эффективным антимикробным действием, токсичны и повреждают клетки тканей глаза, вызывая раздражение.It was shown that many of the indicated type of compounds, in particular benzalkonium chloride - alkyldimethylbenzylammonium chloride of the structural formula

Having an effective antimicrobial effect, they are toxic and damage the cells of the eye tissue, causing irritation.

 One of the modern methods for reducing the toxicity of quaternary ammonium bases is their modification with polymers, which is also the basis for the technical solution described in (3) and which is the closest analogue of the proposed solution to the technical essence and the achieved effect.

где R - насыщенный или ненасыщенный остаток жирных кислот или их смесей, состоящий из 12-18 атомов углерода,
A^- - Cl^-, NO₃ ^-, SO₄ ^-,
R₁, R₂, R₃ - одинаковые или различные алкил-группы, предпочтительно - этил в количестве 0,01 - 0,1%, предпочтительно 0,03 - 0,06%; конкретно в примерах представлен алкилтриэтаноламмоний хлорид, где алкил - остаток природной смеси олеиновых, стеариновых и пальмовых кислот, который имеет торговое название "мирамин" или "миранол".Patent (3) describes a method for treating contact lenses using a solution containing a quaternary ammonium base of the structural formula as an antimicrobial active principle

where R is a saturated or unsaturated residue of fatty acids or mixtures thereof, consisting of 12-18 carbon atoms,
A ^- - Cl ^- , NO ₃ ^- , SO ₄ ^- ,
R ₁ , R ₂ , R ₃ are the same or different alkyl groups, preferably ethyl in an amount of 0.01 - 0.1%, preferably 0.03 - 0.06%; specifically, the examples show alkyltriethanolammonium chloride, where alkyl is the residue of a natural mixture of oleic, stearic and palm acids, which has the trade name "miramine" or "miranol".

 To reduce toxicity, polymers are taken from the group: polyhydroxyethyl methacrylate, carboxymethyl cellulose, polyvinylpyrrolidone and mixtures thereof. In the claims only polyhydroxyethyl methacrylate is indicated in an amount of 0.04%, polysorbate-80 (0.2%), propylene glycol as surface-active cleaners, thiomersal - 0.002% and isotonic saline containing sodium bicarbonate, phosphate as a preservative sodium dibasic anhydrous, sodium phosphate monobasic monohydrate.

In accordance with the description of the above solutions exhibit antimicrobial activity against the following microorganisms: Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Candida albicans - after 6 hours of contact less than 10 ² microorganisms
Additionally S. marcescens requires 8 hours of contact.

 Comparative experiments with the known antimicrobial substance benzalkonium chloride (catamine AB, LHC) with the addition of polyhydroxymethylmethacrylate are shown and it is shown that the latter does not reduce the toxicity of catamine AB, and a significant polymer concentration leads to a decrease in antimicrobial activity.

 Based on examples with one polyhydroxymethylmethacrylate, it was concluded that polymers do not reduce its toxicity at a high concentration of LHC.

 All tested compositions, including those with a new antimicrobial substance, contained thimerosal as a preservative, although the description without experimental confirmation indicates the possibility of using disodium salt of ethylenediaminetetraacetic acid (trilon B, EDTA) instead of thimerosal (merthiolate, thiomerral).

 The disadvantages of the prototype are the limited spectrum of antimicrobial activity with a long time of neutralization and the use of thimerosal.

и его применение отрицательно сказывается на тканях глаза.Thimerosal is a very effective preservative, but it contains mercury (the structural formula of thimerosal is

and its use adversely affects the tissues of the eye.

 Currently, an indicator of the quality of compositions for cleaning contact lenses is the absence of this particular component, which is indicated on labels and in advertisements.

 The present invention solves the problem of increasing the cleaning efficiency by expanding the spectrum of antimicrobial activity and reducing the time of neutralization, as well as the exclusion of a highly toxic component.

где R ≈ CH₃(CH₂)₁₂,
в качестве полимера, снижающего токсичность при сохранении антимикробной активности - натриевую соль карбоксиметилцеллюлозы (Na - КМЦ); который образует комплекс с мирамистином, в качестве поверхностно-активных очистителей - полисорбит-80 (твин-80) и полиэтиленоксид (ПЭО - 400), в качестве консерванта и для удаления кальция - динатриевую соль этилендиаминотетрауксусной кислоты (трилон Б), и в качестве изотонического физиологического раствора
- хлорид натрия,
- натрия гидрофосфат 12-водный,
- калия дигидрофосфат
в воде при следующих соотношениях ингредиентов:
мирамистин - 0,01-0,05,
Na - КМЦ - 0,015 - 0,2,
полисорбат-80 - 0,015-0,05,
ПЭО - 400 - 0,015 - 0,2,
трилон Б - 0,01-0,05,
раствора - до 100 мл.The goal is achieved by the proposed composition for the treatment of contact lenses, which includes as an active antimicrobial substance - miramistin (myristamidopropyl dimethylbenzylammonium chloride) of the structural formula:

where R ≈ CH ₃ (CH ₂ ) ₁₂ ,
as a polymer that reduces toxicity while maintaining antimicrobial activity - sodium salt of carboxymethyl cellulose (Na - CMC); which forms a complex with miramistin, as surface-active cleaners - polysorbite-80 (tween-80) and polyethylene oxide (PEO - 400), as a preservative and for the removal of calcium - disodium salt of ethylenediaminetetraacetic acid (trilon B), and as isotonic saline
- sodium chloride,
- sodium hydrogen phosphate 12-water,
- potassium dihydrogen phosphate
in water with the following ratios of ingredients:
miramistin - 0.01-0.05,
Na - CMC - 0.015 - 0.2,
polysorbate-80 - 0.015-0.05,
PEO - 400 - 0.015 - 0.2,
Trilon B - 0.01-0.05,
solution - up to 100 ml.

Isotonic saline may have the following composition (per 100 ml of water):
sodium chloride - 0.5 - 0.6,
sodium hydrogen phosphate 12-water - 0.465 - 1.47,
potassium dihydrogen phosphate - 0.03 - 0.42
and should provide pH = 6.7 - 8.0
and osmolarity 280 - 300 mosm / l.

 The proposed technical solution differs from the prototype in that miramistin is used in combination with Na - CMC and trilon B. as an antimicrobial active substance. Miramistin is known as an antiseptic, its registration number is 91/146/2, and it is produced by domestic industry.

 However, the known antimicrobial properties of miramistin do not predetermine the obvious possibility of its use in compositions for processing contact lenses, since the latter requires knowledge of such specific properties as the effect on the material from which the lenses are made.

 Most cationic surfactants, which include miramistin, are not suitable for use in compositions for cleaning lenses, due to their interaction with the polymer matrix of lenses.

 An important role in achieving effectiveness is played by the fact that miramistin forms a complex with Na - CMC, which, while maintaining antimicrobial activity, reduces toxicity.

близок к мирамистину (структура 11), а потому можно было бы ожидать одинакового эффекта, т. е. его отсутствия. Однако нами в результате эксперимента было показано, что сочетание Na - КМЦ с трилоном Б позволяет снизить токсичность и сохранить бактерицидную активность и на БАК (катамин АБ), что не было достигнуто в прототипе и что свидетельствует об избирательности влияния типа полимера на определенные антимикробные соли четвертичных аммониевых оснований (сравнительные примеры с катамином АБ в таблице под NN 4, 5).Despite the fact that the prototype Na - CMC to reduce toxicity is described, however, firstly, it is not clear how it affects antimicrobial activity (data are missing), and secondly, as follows from the same description, it was not possible to obtain a toxicity reduction on the LHC, which in structure

is close to miramistin (structure 11), and therefore, one would expect the same effect, i.e., its absence. However, as a result of the experiment, we showed that the combination of Na - CMC with Trilon B can reduce toxicity and maintain bactericidal activity on LHC (catamine AB), which was not achieved in the prototype and which indicates the selectivity of the effect of the polymer type on certain quaternary antimicrobial salts ammonium bases (comparative examples with catamine AB in the table under NN 4, 5).

 Na - CMC with miramistin forms a complex that allows you to maintain antimicrobial activity and reduce the toxicity of using the complex with trilon B, eliminates toxic thiomersal.

 The foregoing allows us to conclude that a new combination of signs leads to a result that could not be predicted on the basis of well-known creativity.

 Miramistin compared with merthiolate (prototype) has a wider spectrum of antimicrobial activity at low concentrations, has specific activity and low toxicity.

Miramistin is active against gram-positive microorganisms: Staphylococci, Streptococci, Bacillus anthracoides;
against fungi: Candida albicans, C. tropicalis, Trichophiton rubrum, Microsporum lansum, Aspergillus niger (at a concentration of 0.0001% - 0.002%).

 The range of antimicrobial effects on gram-negative bacteria: gonococci (wild and museum strains), Escherichia (pathogenic and non-pathogenic serotypes), shigella (Sonne, Flexner, etc.), salmonella, spirochetes (Treponema pallidum, etc.) at a concentration of 0.005%.

 The effect on protozoa (Trichomonas vaginalis) is in the range of 0.002% - 0.02%. Specific activity - stops the mobility of Trichomonas at a concentration of 0.01% for 1-10 minutes.

 Miramistin is active against herpes viruses, influenza, adenovirus, HIV-1. According to toxicity, miramistin belongs to the 4th class of harmfulness (low toxicity), at a concentration of 0.01 - 0.1 - 1% - does not irritate the skin, at a concentration of 0.01 - does not irritate the mucous membranes (eyes, internal organs).

 Example (basic).

An isotonic solution containing 0.5 g of NaCl, 1.196 g of Na ₂ HPO ₄ • 12H ₂ O, 0.137 g of KH ₂ PO ₄ in 100 ml of water, is mixed with 0.005 g of miramistin, 0.03 g of Na - CMC, 0.03 g Tween - 80 and 0.05 g Trilon B.

 The resulting solution has a pH of 7.0 and an osmosis of 300 mosm / l.

 The solution is a transparent, colorless, slightly opalescent, colorless and odorless liquid intended for washing, storing and disinfecting contact lenses in clinical, outpatient and domestic conditions.

The transparency (optical density) of the solution was checked using a KFK-2 spectrophotometer in 10.070 optical cuvettes at a wavelength of 315 nm to 750 nm. The optical density (D) obtained under these conditions for different values of λ are as follows:
λ nm: 315 400 440 490 540 590 670 750
D: 0.25 0.18 0.16 0.15 0.15 0.23 0.20 0.16
Thus, the optical density of the solution differs from the optical density of pure water, taken as 0, which is typical for multicomponent saline solutions. The second peak of optical density at λ = 590 nm, which is associated with the presence in the solution of a fraction of stabilizing high molecular weight organic compounds. This ensures that the characteristics of the solution match the destination.

 Checking the color of the solution.

 The color of the solution was determined by comparison with the standard of pure water in chemical cups of the same diameter in daylight on a dull white background.

 Under these conditions, the color of the solution and the standard of water are indistinguishable.

 Checking the modifying effect of the solution on liquid protein media.

 After the lenses are immersed in the solution, traces of protein substrates on the lens surface (serous fluid, exudate, desquamated and migrated cells) interact with the solution. In this case, protein contaminants should undergo denaturation (or lysis), should not be adsorbed on the surface of contact lenses.

 To test the effect of the solution on the protein substrate, it was mixed with the gelatin protein preparation in a ratio of 1: 1 in chemical glasses.

 Then, using the KFK-2 spectrophotocolorimeter, the optical density of the resulting mixture was measured relative to the control. The preparation Gelatinol diluted with distilled water in a ratio of 1: 1 was used as a control sample. The optical density was determined in optical cuvettes of caliber 10.070 at a value of λ = 315 nm. Ditches from various materials were used (quartz glass, plexiglass, lavsan, low-pressure polyethylene).

Freshly obtained gelatinol mixtures with a solution and with water were poured into optical cuvettes and exposed in these cuvettes for 2 hours. Indicator D of a freshly prepared mixture of "Gelatin" with water was taken as the initial one. Subsequent determinations of D in mixtures of Gelatinol with a solution and Gelatinol with water were made every 20 min. The following results were obtained:
The initial average values of D control samples = 0.70.

 The initial average values of the tested samples D = 0.82.

 Mean D values of control samples after 2 hours exposure = 0.73.

 The average D values of the tested samples after a 2-hour exposure = 2.0 (with further exposure, D _ → ∞.

 The intense and irreversible turbidity of "Gelatin" when mixed with a solution is associated with the formation of protein microcoagulants. When filtering the resulting coagulated suspension through a paper ashless filter according to TU 6-09-1678-86 ("red strip"), the transmission selectivity of the coagulated particles is 0.69.

 Therefore, the solution causes irreversible denaturation (suspension of coagulated flakes) of liquid protein contaminants, which corresponds to the destination.

 Quality control of the removal of protein contaminants from glass and polymer surfaces after the action of the solution.

 After mixing with the gelatinol protein particles, after mixing with the solution, it was exposed for 24 hours in optical cuvettes of various materials closed by covers (10 cuvettes in total) and in a thin layer in open glass and polyethylene Petri dishes (20 samples). After a 24-hour exposure at room temperature, the protein suspension in the cuvettes remained in liquid form. Then, the optical cuvettes, after removing the protein suspension, were washed with a single volume of distilled water, and then filled with a new volume of distilled water and tested for optical transparency relative to the standard of pure water.

 In all observations, the photometric control did not reveal any traces of contamination in the cuvettes in which the coagulated mixture of Gelatin and the solution was exposed for 24 hours. Thus, protein contaminants after treatment with the solution were not sorbed on the material of the optical cuvettes, which corresponds to the purpose of the test solution.

 In open Petri dishes during daily exposure, the protein coagulated suspension dried out, which was completely washed off after 30 minutes of soaking in distilled water. After that, extremely small foci of contamination remained on the washed surfaces of the Petri dishes. In general, the purity coefficient of washing the surface of Petri dishes from dried coagulate according to a planimetric study was 99.0 - 99.5%.

 Thus, the proposed solution for cleaning, washing, disinfecting and storing contact lenses eliminates the time of their drying (or any other washable product) during the treatment cycle.

 Clinical trials of a solution for cleaning, washing, disinfecting and storing contact lenses were carried out at the Eye Disease Clinic of the Russian State Medical University (Department of Eye Diseases, Faculty of Medicine).

 For testing, samples were presented in an amount of 50 pieces.

 Medical research was carried out in accordance with the program and methodology of clinical trials.

 Among the 30 patient patients using soft contact lenses for vision correction, there were patients who corrected with lenses with varying degrees of hydrophilicity (from 38 to 70%).

As a result, the following conclusions were made:
- solutions are well tolerated by patients,
- the use of solutions does not require additional washing of contact lenses after their use (solutions),
- solutions have high efficiency cleaning and disinfecting properties.

 The compositions of the composition, confirming the scope of the proposed claims, are presented in the table (examples 1-10).

 Solutions were prepared and tested as in the main example.

 The local irritating effect of the miramistin interpolymer complex with Na-carboxymethyl cellulose in vivo was also studied in experiments on rabbits and guinea pigs. It was shown that daily application to the skin (dehydrated) for rabbits (18 pieces) and guinea pigs (15 pieces) daily for 30 days did not cause any irritation and inflammation of the skin, did not affect the general condition and behavior of animals, did not affect their dynamics body weight, the content of hemoglobin, red blood cells, white blood cells, did not lead to pathomorphological changes in the skin, liver, kidneys, spleen, heart and adrenal glands.

 The skin-resorptive effect of the complex was studied in experiments on white rats (15 in each group). The complex was used at a concentration of 0.2% and 5 times higher than that.

 The drug was applied to the depilated area of the skin for 30 days; only Na - CMC solution was applied to the control group of animals, without an antiseptic.

 Application was performed 4 hours a day.

 As a result of the studies, it was shown that the application of the drug on the intact skin surface did not reveal a skin-resorptive effect, as evidenced by the results of a blood test and experimental and control animals, whose biochemical parameters were almost the same.

 The allergenic and immunotoxic properties of the complex were studied. It is shown that the drug in concentration does not cause sensitization of the body and does not have an immunotoxic effect. Repeated administration in various doses did not affect the number of immunocompetent cells; it does not affect the mass and cellularity of the central and peripheral organs of the immune system.

Claims (1)

1. A composition for treating contact lenses containing an antimicrobial substance from the class of salts of Quaternary ammonium bases, polysorbate-80 and polyethylene oxide as surface-active cleaners, a polymer to reduce toxicity, a preservative and isotonic saline solution, characterized in that they take as an antimicrobial substance miramistin, as a polymer to reduce toxicity, sodium carboxymethyl cellulose (Na-CMC), and as a preservative and to remove calcium, disodium salt of ethylene diam otetrauksusnoy acid (Trilon B) in the following ratio, wt.%:
Miramistin - 0.001 - 0.05
Na-CMC - 0.015 - 0.05
Trilon B - 0.01 - 0.08
Isotonic saline - Up to 100 ml
2. The composition according to claim 1, characterized in that the isotonic saline solution contains
Sodium Chloride - 0.5 - 0.58
Sodium hydrogen phosphate 12-water - 0.465 - 1.47
Potassium dihydrogen phosphate - 0.03 - 0.42
Water - Up to 100 ml

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