Drops for the treatment of dry eye syndrome (options)

 

(57) Abstract:

The invention relates to medicine, in particular to ophthalmology. The invention discloses three different composition drops to treat dry eye syndrome. Composition No. 1 contains guanidine phosphate, phosphate buffer, sodium chloride, kollidon VA64 and purified water. Composition No. 2 contains guanidine phosphate, methylcellulose, phosphate buffer, sodium chloride and purified water. Composition No. 3 contains guanidine phosphate, dextran, phosphate buffer, sodium chloride and purified water. The proposed compositions have advantages over known, do not cause the formation of crusts in the eye, but also ensure the absence of toxic and irritating with prolonged use. 3 N. p. F.-ly, 9 PL.

The invention relates to ophthalmic preparations, namely, eye drops.

Dry eye syndrome is common among the population and is polyetiological: age-related professional activities, diseases of eye tissues and wearing contact lenses. Common symptoms are insufficient tear film on the cornea that causes redness of the mucous what's diseases of the eye due to the weakening of the local immune system protection. In this regard, the development of a drug, which make up for the lack of a water film on the eyeball and with bacteriostatic effect, seems relevant.

Drugs intended for local substitution therapy in dry eye syndrome, must comply with the tear fluid of a healthy person on a range of physico-chemical properties. The normal density of tears is 1,001-with 1.009, pH 6.5 to about 7.8. The tear film is kept on the corneal epithelium due to a special faction of proteins, mucines, due to the effect of wetting. Lipid molecules epithelium is poorly wetted by water, mucines form a hydrophobic connection with the hydrophobic surface of the cornea, and numerous hydrophilic groups (HE-- group) bind water molecules. As a result, the cornea is formed viscous murinova film, the adhesion force which is 39 Dyne/cm2and surface tension - 46 Dyne/cm2. When batting eyelids Mucins are able to form chemical complexes with proteins, resulting in surface tension SP is reduced to 30 Dyne/cm2(Materials - Som E. E., Brzeski centuries, Pies Yu GI Protective factors lacrimal fluid of healthy and sick people. // Eye magazine. acrylic acid and polyvinylpyrrolidone as a lubricant and benzalkonium salt as a preservative.

The compositions moisturizing drops on the basis of hydroxyethyl cellulose and poloxamer claimed in the patent EP 0198490 B1 (IPC a 61 K 9/08, 1996), contain as preservatives urea.

Also stated complex compositions (patent EP 0342297 A1, IPC a 61 K 9/08, 1993), which are hydrophilic-lipophilic components, with some help hydrophilization cornea (polyvinyl alcohol, dextran), while others increase the adhesion of the liquid with a hydrophobic surface of the eye (kollidon) in the presence of preservatives of thiomersal or chlorbutanol.

A common shortcoming of these solutions is the presence of allergenic preservative effect and damaging effects on soft contact lenses due to the high reaction activity of these molecules (the article Systems of care for contact lenses. / N.B. Demina, M. N. Chirkova, A. C. Astakhova, L. A. Travin // pharmaceutical journal, 2001, T. 35, No. 2).

Closest to the proposed solution is the composition specified in the patent GB 2169508 And (IPC a 61 K 9/08, 1986), containing 0,44% of hydroxyethyl cellulose as a lubricant, 0,34% sodium chloride as isotherwise agent, phosphate buffer to maintain ophthalmologist acceptable level Rennie dry crusts in the eye with long-term use, and the presence of irritating and toxic effects of preservative.

The objective of the invention is the creation of drugs for the treatment of dry eye syndrome that does not cause the formation of dry crusts in the eye and not having irritating and toxic effects with long-term use.

Used as a preservative, guanidine phosphate permitted for use as a disinfectant on the territory of the Russian Federation according to the certificate No. 0044-99/5. This antiseptic belongs to the 4th class of toxicity, i.e., is not dangerous to the human body after oral and cutaneous application. An important feature is the ability to form polymer microbicidal film on the treated surface, providing a prolonged effect. The drug has a pronounced microbicidal effect on the major causative agents of infectious conjunctivitis and keratitis, the most common among the population: Pseudomonas, Staphylococcus, Streptococcus, Serratia, Proteus, Enterobacteriaceae, Bacillus (see tab.1).

Efficiency pgmg phosphate relative to subsistence crops listed strains tested by serial dilution method with nutrient credai to 400 µg/ml (0,0003-0,04%), maximum resistance show Proteus and pseudomonad. Thus, the minimum bacteriostatic concentration pgmg phosphate is 0.04%.

Development of composition and technology of drugs for the treatment of dry eye syndrome was carried out with regard to drugs, installiruemye in the conjunctival cavity: 1) sterility, 2) transparency, 3) isotonicity, 4) comfortable pH, 5) prolongation of action.

Isatoribine composition was produced with the aim of creating comfortable for cells of the conjunctiva of the environment, without causing damage or burning sensations in the eye. Used phosphate buffer and sodium chloride as the most physiological liquid environment of the organism salt after theoretical calculation isotonic equivalents. The osmotic pressure of the developed formulations was monitored by the method of Geometrie using a Beckmann thermometer, calibrated in purified water, hypothermia was created ledno-salt mixture. Table 2 shows the partial osmolarity of the various components selected for manufacture, and ready stoneraven drugs. Navy creates a certain osmotic pressure, which is considered aaty buffer at a concentration of 0.4%, keep pH at certain indicators during storage, and sodium chloride at a concentration of 0.5-0.7% to create a comfortable osmotic pressure. The ratio of acid and basic components of the buffer was chosen based on the optimum pH for ophthalmic drugs: 7,4-7,8, which corresponds to the pH of the tear fluid of a healthy person.

Screening of lubricants was made with the introduction of the dry drug in isotonic solution of polyguanidine (table 3). Assessed the compatibility of different polymers used for prolonging the action of eye drops, with the base solution. Used polyvinyl alcohol (PVA) low molecular weight fractions (grade 9/11 GOST 10779-78), methylcellulose (MC) water-soluble mark MC-20 (TU-2231-107-05742755-96), the weight dextran 40000±10000 varieties for infusion solutions (poliglyukin, FS 42-2023-83), kollidon VA 64 (copolymer of vinylpyrrolidone/vinyl acetate 6:4, certificate BASF).

Watched the transparency formed by the drugs, the presence of sediment, as well as dynamic viscosity. Priority was given to polymers having physical and chemical compatibility with the base solution in concentrations that allow you to create a solution, similar in viscosity to lessonii with a basic solution began to noticeably opalisrobot, what was the reason for dropping this polymer.

Thus, the above task is solved drops of the composition, wt.%:

Composition No. 1

The guanidine phosphate 0,04-0,1

Sodium phosphate one-deputizing of 0.1-0.2

Sodium phosphate disubstituted of 0.2-0.3

Sodium chloride 0,5-0,7

Kollidon VA 64 of 3.0-3.5

Purified water Up to 100.0

or composition, wt.%:

Composition No. 2

The guanidine phosphate 0,04-0,1

Sodium phosphate one-deputizing of 0.1-0.2

Sodium phosphate disubstituted of 0.2-0.3

Sodium chloride 0,5-0,7

The Methylcellulose Of 0.05-0.1

Purified water Up to 100.0

or composition, wt.%:

Composition No. 3

The guanidine phosphate 0,04-0,1

Sodium phosphate one-deputizing of 0.1-0.2

Sodium phosphate disubstituted of 0.2-0.3

Sodium chloride 0,5-0,7

Dextran Of 3.0-3.5

Purified water Up to 100.0

The combination of these components and their ratio determined experimentally and is optimal according to the results of physico-chemical, pharmaco-technological and microbiological studies. Cited specific examples opisaniya phosphate, 0.1 g of sodium phosphate one-deputizing, 0.2 sodium phosphate (disubstituted), 0.5 g of sodium chloride, 3.0 g of kollidon VA64 and of 96.2 g of purified water. In accordance with the requirements of the GF-11 to eye dosage forms production solutions was conducted under aseptic conditions. In a sterile stand poured 48 ml of hot water and purified sequentially dissolved in it, 0.04 g of guanidine phosphate, 0.1 g of sodium phosphate one-deputizing, 0.2 g of sodium phosphate (disubstituted), 0.5 g of sodium chloride. Sterilized solution by vacuum installation with removable Sartorius membrane filter with a pore diameter of 0.22 μm. In the remaining 48,2 ml of water was dissolved 3.0 g of kollidon VA64. Sterilization of the solution was performed with saturated steam under a pressure of 1.1 ATM at 120°C for 8 minutes After sterilization, the two solutions were mixed under aseptic conditions and packaged in a sterile dropper from high-pressure polyethylene with a volume of 2 ml screw-on lids.

Example 2. Drops for the treatment of dry eye syndrome, containing 0.1 g of guanidine phosphate, 0.2 g of sodium phosphate one-deputizing, 0.3 sodium phosphate (disubstituted), 0.7 g of sodium chloride, 3.5 g of kollidon VA64 and is 95.2 g of purified water. Stages of the technology is similar to Prim the phosphate, 0.1 g of sodium phosphate one-deputizing, 0.2 sodium phosphate (disubstituted), 0.5 g of sodium chloride, 0.05 g of methylcellulose and of 99.1 g of purified water. In a sterile stand poured 49 ml of hot water and purified sequentially dissolved in it, 0.04 g of guanidine phosphate, 0.1 g of sodium phosphate one-deputizing, 0.2 g of sodium phosphate (disubstituted), 0.5 g of sodium chloride. Sterilized solution by vacuum installation with removable Sartorius membrane filter with a pore diameter of 0.22 μm. In the remainder of 50.1 ml of water, heated to 90°C, left 0.05 g of methyl cellulose to swell for 30 minutes, then abruptly cooled in the chiller to room temperature and achieved complete dissolution under dispersion. Sterilization of the solution was performed with saturated steam under a pressure of 1.1 ATM at 120°C for 8 minutes After sterilization, the two solutions were mixed under aseptic conditions and packaged in a sterile dropper from high-pressure polyethylene with a volume of 2 ml screw-on lids.

Example 4. Drops for the treatment of dry eye syndrome, containing 0.1 g of guanidine phosphate, 0.2 g of sodium phosphate one-deputizing, 0.3 g of sodium phosphate (disubstituted), 0.7 g of sodium chloride, 0.1 g of methylcellulose and OGO eyes, containing 0.04 g of guanidine phosphate, 0.1 g of sodium phosphate one-deputizing, 0.2 g of sodium phosphate (disubstituted), 0.5 g of sodium chloride, 3.0 g of dextran and 96.1 g of purified water. In a sterile stand poured 48 ml of hot water and purified sequentially dissolved in it, 0.04 g of guanidine phosphate, 0.1 g of sodium phosphate one-deputizing, 0.2 g of sodium phosphate (disubstituted), 0.5 g of sodium chloride. Sterilized solution by vacuum installation with removable Sartorius membrane filter with a pore diameter of 0.22 μm. In the remaining 58,1 ml of water was dissolved 3.0 g of dextran. Sterilization of the solution was performed with saturated steam under a pressure of 1.1 ATM at 120°C for 8 minutes After sterilization, the two solutions were mixed under aseptic conditions and packaged in a sterile dropper from high-pressure polyethylene with a volume of 2 ml screw-on lids.

Example 6. Drops for the treatment of dry eye syndrome, containing 0.1 g of guanidine phosphate, 0.2 g of sodium phosphate one-deputizing, 0.3 g of sodium phosphate (disubstituted), 0.7 g of sodium chloride, 3.5 g of methylcellulose and is 95.2 g of purified water. Stages of the technology is similar to example 5.

The resulting compositions were controlled by a number of characteristics about aricidea action moisturizing action, surface tension, dynamic viscosity, no irritating to the eyes, and the duration of retention of hydrated layer on the cornea.

The pH values of the developed compositions, measured potentiometric, were in the range of 7.2-7.8 and has undergone little change during storage (table 4).

The transparency of the investigated solutions was controlled by a black background and scattered light relative to the solvent. Developed formulations did not differ from water transparency. The solutions were also controlled for the presence of mechanical impurities and color when the light bulb 40 watt on black and white background, respectively. Not observed any visible particles, opalescence, solutions do not have color. The change in the number of mechanical inclusions that are not visible to the human eye, within 2 years of storage was indirectly determined by conductometric method, based on direct proportion to the electrical resistance of the solution and the amount therein solid particles. Significant changes in the concentration of mechanical inclusions were observed, which indicates the absence of long-term manifestations of physico-chemical neximage pressure of the bubble on the device Rehbinder relatively purified water. Take into account that salt pgmg as all ionic polymers are surface-active substances, the Navy used as prolongator, reduce surface tension, whereas isotherwise agents, as strong electrolytes, increase the tension on the boundary of the fluid/gas. Research results the total reduction of the surface tension developed eye drops are presented in table 6. The reduction of surface tension in the developed formulations is 2-3 times that corresponds to the natural action of mucines in the tear fluid. All the designed compounds have a pronounced surface activity, therefore, exhibit good flow and distribution of the drug through the cornea.

Solutions pgmg phosphate containing various salts and prolongator, transparent and, as can be seen from table 7, have a small refractive activity. Salt pgmg are substances with a low refractive power, despite the fact that they are polymers. The factor of refraction calculated for pgmg phosphate and small amounts of 0.002. Developed formulations should not cause hazy eyes, because the values of their refractive index generally similar e was determined by the method of the Nickel samples (Materials Amur-Sanan A. C. Research in the field of technology of eye drops prolonged action, containing antiviral drugs. Dissertation for the degree of Cand. Pharm. Sciences - M.: 1975. - 20 C.). The method allows to judge about the changes in the concentration of drug in the cornea over time in the experiment in vivo. It is based on the ability of Nickel to form complex compounds with organic substances, in particular, with the used polymers. Pharmacopoeia reagent for Nickel ion is dimethylglyoxime, forming a water-soluble chelate complex of pink. In the experiment, were used in groups of 5 healthy white rabbits for each type of drug.

In the left and right eyes of the rabbit put 2 drops of Nickel reagent, then made a visual colorimetric control the amount of drug in the eye by means of a strip of filter paper impregnated with a solution dimethylglyoxime. The paper was introduced under the lower eyelid rabbit 5-6 for impregnation of the lacrimal fluid. Noted the intensity of the pink paper, the evaluation were relatively colours aqueous salt solution pgmg phosphate. The measurements were carried out every hour to the lack of a positive result (ovice MC, whereas dextran and kollidon showed less prolonging the ability.

Bacteriostatic effect of the developed formulations was evaluated by the method of inhibiting the growth of standard strains of microorganisms when adding 10 ml of 0.2 ml of microbial suspension 107CFU/ml table 9 shows that the growth of microorganisms were noted as using freshly prepared drugs, and when testing drugs, past storage for 2 years.

During storage of the compositions were tested for sterility according to the method GF-11. The solutions were passed through a membrane filtration unit for microbiological research, the filters were cut and placed on a special nutrient medium: thioglycolate (group Pseudomonas aeruginosa), Saburo (mushrooms) and MPA (cocci). Within 1 week there was no evidence of growth of colonies of microorganisms that suggests maintaining sterility within 1 year.

Local irritant action of the compounds was studied on 10 rabbits with the introduction of medication into the conjunctival SAC in the amount of 0.05 ml daily for 14 days. In studies using a slit lamp was not detected redness, swelling cicnet drugs was evaluated in two animal species (mice and rats clean lines) with a dose of 5 ml to rats and 0.5 ml of mice at the rate of 6 animals for each drug. Within 2 weeks there were no reported deaths or acute poisoning.

Thus, the developed formulations drops to treat dry eye syndrome:

1. Meet the requirements of modern drugs of this type.

2. Do not cause the formation of dry skin, irritation and toxic effects on the body with long-term use.

1. Drops for the treatment of dry eye syndrome, containing a lubricant, preservative, phosphate buffer, sodium chloride, purified water, characterized in that they contain as preservatives, guanidine phosphate, kollidon VA 64 as a lubricant in the following ratio, wt.%:

The guanidine phosphate 0,04-0,1

Sodium phosphate one-deputizing of 0.1-0.2

Sodium phosphate disubstituted of 0.2-0.3

Sodium chloride 0,5-0,7

Kollidon VA 64 of 3.0-3.5

Purified water Up to 100.0

2. Drops for the treatment of dry eye syndrome, containing a lubricant, preservative, phosphate buffer, sodium chloride, purified water, characterized in that they contain as preservatives, guanidine phosphate, and as a lubricant methylcellulose with sledovat one-deputizing of 0.1-0.2

Sodium phosphate disubstituted of 0.2-0.3

Sodium chloride 0,5-0,7

The Methylcellulose Of 0.05-0.1

Purified water Up to 100.0

3. Drops for the treatment of dry eye syndrome, containing a lubricant, preservative, phosphate buffer complex, sodium chloride, purified water, characterized in that they contain as preservatives, guanidine phosphate, as a lubricant dextran in the following ratio, wt.%:

The guanidine phosphate 0,04-0,1

Sodium phosphate one-deputizing of 0.1-0.2

Sodium phosphate disubstituted of 0.2-0.3

Sodium chloride 0,5-0,7

Dextran Of 3.0-3.5

Purified water Up to 100.0



 

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