Gel for the treatment of bacterial conjunctivitis (options)

 

The invention relates to medicine, in particular to ophthalmology. The invention discloses two different gel composition for the treatment of bacterial conjunctivitis. Composition No. 1 contains guanidine phosphate, polyvinyl alcohol, borate buffer, sodium chloride, kollidon VA64 and purified water. Composition No. 2 contains guanidine phosphate, methylcellulose, borate buffer, sodium chloride, kollidon VA64 and purified water. The invention provides non-toxic and non-allergic action with long-term use. 2 N. p. F.-ly, 9 tab., 3 Il.

The invention relates to antibacterial drugs for topical use, in particular to ophthalmology soft medicinal forms.

Currently of great importance in ophthalmology acquire antimicrobial drugs as a method of prevention and treatment of infectious diseases of the eye. Bacterial conjunctivitis are the most common diseases of the eye due to the large variability and the prevalence of strains of their agents.

The safe use of antimicrobial substances with high efficiency is some of the dosage form. In most cases, there is a need to ensure uniform distribution of the drug across the surface of the conjunctival SAC to achieve total destruction of the pathogen, as well as increasing the time interval between instillation for the preservation of the natural factors of the immune protection of the eyes. Ophthalmic dosage form should provide comfort when introduced into the conjunctival cavity (requirements specific pH and osmotic pressure, lack of mechanical inclusions and rheological optimum) and be sterile. Soft dosage forms have the advantage over aqueous solutions, providing a more substantial prolongation of therapeutic effect due to the high viscosity and structure. Well-known advantages of hydrophilic polymers for ophthalmic ointments before lipophilic: comfortable spread to the cornea transparency, reducing the risk of microbial contamination.

Known compounds ophthalmic gels intended for the treatment of bacterial conjunctivitis and containing microbially agent as main active substance.

Famous inventions that tera is ü based on carboxymethylcellulose with ooxacin for the treatment of eye infections.

In the patent EP 1124535 (IPC a 61 K 9/06, 2000) announced the composition of the ophthalmic gel containing 0.3% ofloxacin in the basis of chitosan.

A common shortcoming of these solutions is the presence of side effects, allergic reactions and drug-resistant strains (Materials. Morozov, C. I., Yakovlev, R. A. Pharmacotherapy of eye diseases. - M: - 2001. - 471 S.)

Closest to our proposed solution is discussed in the patent EP 0056420 IPC (a 61 K 9/06, 1981). The present invention is specified composition antibacterial ophthalmic hydrogel containing 1% gentamicin sulfate, 2-3% of polyvinyl alcohol, the viscosity of which is modified 1-2% borate buffer.

The disadvantage of this solution is referred to an antimicrobial substance, representing an antibiotic and has a number of undesirable side effects: toxicity, allergenicity, the possibility of development of resistant organisms at the long-term use.

The objective of our proposal is the creation of antimicrobial compounds for the treatment of bacterial conjunctivitis that do not have allergenic and toxic effects, and do not cause the development of resistant microflora with long-term use.

Applied micro the irradiation means on the territory of the Russian Federation according to the certificate No. 0044-99/5. This antiseptic belongs to the 4th class of toxicity when administered orally and applied in the ordinary way, i.e., has no harmful effects on the human body. 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.

According to our research (table 1), the minimum inhibiting concentration (MIC) of guanidine phosphate for the listed genera of microorganisms is from 3.15 to 400 µg/ml (0.0003-0.04%). Therefore, therapeutic concentrations exceeding the MIC 5-10 times, 0.2-0.4%, and given the slow release from a gel base - 0.6-1.2%.

The choice of the gel was carried out by stepwise screening. In the first phase evaluated the physicochemical compatibility of the base and pgmg phosphate and the consistency of a gel at various concentrations of high-molecular substances. Because sediment were tsemesskoy compatibility with pgmg phosphate were selected polyvinyl alcohol (PVA) brand 9/8, GOST 10779-78 and methylcellulose (MC) mark MC-20, TU-2231-107-05742755-96.

Based on the optimal consistency, ensuring the normal drop during extrusion of the gel from the tube, for PVA was selected concentration of 10%, but upon further research it was found that the introduction of borate buffer reduces it to 7-8%. Borate buffer has a structuring effect on the solutions of PVA, but there is a danger vicalvaro effect. Experimentally found the concentration of boric acid and sodium tetraborate, does not cause irreversible coagulation of the gel and provide the pH between 7.2-7.4, but increases the viscosity amounted to 0.3-0.5%. The optimal consistency of the gel MC was achieved by using 2-2.5% of dry matter. The resulting hydrogels had a good drop due to pseudoplasticity and low thixotropy (table 2).

The second phase investigated the stability of physico-chemical properties of gels pgmg phosphate on different bases under the influence of heat sterilization. To increase and preserve the transparency of the gels in the composition, it was decided to introduce a factor of preserving the transparency of the copolymer of vinylpyrrolidone with vinyl acetate 6:4 is oklava at a pressure of 1.1 ATM and 120°C for 15 minutes, reducing the time of sterilization was caused by incomplete destruction of microorganisms, increase in irreversible coagulation of the gel.

The pH level, the corresponding values for the tear fluid of a healthy person (7.4-7.8), was created borate buffer. The introduction of 0.3-0.5% borate buffer in the PVA gels and MC has allowed a long time to maintain the desired pH level. The pH values of the developed compositions, measured potentiometrically using dilution 5 times, lay within the range of 7.2-7.8 and has undergone little change during 2 years of storage (table 4).

Isoosmotic gel tear fluid was created borate buffer and sodium chloride. The osmolarity of the developed formulations was determined using dilution in 2 times (with subsequent conversion results) on a programmable millionometer MT-5. Temperature depression of the studied drugs was relatively purified water characterized their osmotic pressure within 272-280 mOsm (table 4), which corresponds to normotimicescoe interval for eye protection - 270-310 mOsm.

Thus, the above task is solved in that for the treatment of bacterial is engandine

phosphate 0.6-1.2

Boric acid 0.25-0.5

Sodium tetraborate 0.02-0.05

Sodium chloride 0.5-0.7

Polyvinyl alcohol 7.0-8.0

Kollidon V64 1.0-2.0

Purified water To 100.0

or composition in wt.%:

Composition No. 2

The guanidine

phosphate 0.6-1.2

Boric acid 0.25-0.5

Sodium tetraborate 0.02-0.05

Sodium chloride 0.5-0.7

The methylcellulose 2.0-2.5

Kollidon V64 1.0-2.0

Purified water To 100.0

The combination of these components and their ratio was determined experimentally and is optimal according to the results of physico-chemical, pharmaco-technological and microbiological studies.

Cited specific examples describe compositions.

Example 1. Gel for the treatment of bacterial conjunctivitis, containing 0.6 g of guanidine phosphate, 0.25 g of boric acid, 0.02 g sodium tetraborate, 0.5 g of sodium chloride, 7.0 g of polyvinyl alcohol, 1.0 g of kollidon VA64 and 90.6 g of purified water. In accordance with the requirements of the GF-11 to eye dosage forms manufacture of the gel is carried out in aseptic conditions. In a sterile stand pour 45 g of hot water and purified successively dissolved therein 0.6 g of guanidine phosphate, 0.25 g of boric acid, 0.02 g tetrabor the Oia 7.0 g of polyvinyl alcohol at room temperature, after 30 minutes achieve homogenization by heating and thorough mixing. The solutions are mixed. The sterilization is carried out with saturated steam under a pressure of 1.1 ATM at 120°C for 15 minutes, Cooled gel is poured into sterile tubes of 3 ml with a twist by Bouchon.

Example 2. Gel for the treatment of bacterial conjunctivitis, containing 1.2 g of guanidine phosphate, 0.5 g of boric acid, 0.05 g of sodium tetraborate, 0.7 g of sodium chloride, 8.0 g of polyvinyl alcohol, 2.0 g of kollidon VA64 and 87.5 g of purified water. The stages of cooking correspond to example 1.

Example 3. Gel for the treatment of bacterial conjunctivitis, containing 0.6 g of guanidine phosphate, 0.25 g of boric acid, 0.02 g sodium tetraborate, 0.5 g sodium chloride 2.0 g methyl cellulose, 1.0 g of kollidon VA64 and 95.6 g of purified water. Production of lead in aseptic conditions. In a sterile stand pour 47 g of hot water and purified successively dissolved therein 0.6 g of guanidine phosphate, 0.25 g of boric acid, 0.02 g of sodium tetraborate, 0.5 g of sodium chloride and 1.0 kollidon VA64. The remaining volume of purified water heated to 90°C and leave in 2 g of methyl cellulose to swell for 30 minutes. The solutions are mixed and dabeva ATM at 120°C for 15 minutes The cooled gel is poured into sterile tubes of 3 ml with a twist by Bouchon.

Example 4. Gel for the treatment of bacterial conjunctivitis, containing 1.2 g of guanidine phosphate, 0.5 g of boric acid, 0.05 g of sodium tetraborate, 0.7 g of sodium chloride, 8.0 g of polyvinyl alcohol, 2.0 g of kollidon VA64 and 87.5 g of purified water. Stages of preparation corresponds to example 3.

The proposed compositions were investigated microbiological efficiency, transparency, consistency, bioavailability and pharmacological safety.

Bactericidal effect of the developed formulations was evaluated by the method of inhibiting the growth of standard strains of microorganisms by entering into a 10 ml 0.2 ml microbial suspension 107CFU/ml table 5 shows that the growth of microorganisms were noted as using freshly prepared drugs and testing gels stored for 2 years in natural conditions.

During storage of the compositions were tested for sterility in accordance with the method GF-11 in the absence of microbial growth groups Pseudomonas, Enterobacteriaceae, Staphylococcus. Gels were diluted with sterile water 1:10, the solutions were passed through a membrane filter Y: 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.

Gels controlled transparency, mechanical impurities and color when the light bulb 40 watt on black and white background, respectively. Not observed any visible particles, opalescence, drugs do not have color. Drugs are transparent highly viscous liquids.

Release pgmg phosphate was determined by the method of equilibrium dialysis through a semi-permeable cellulose acetate membrane permeable to substances with a molecular weight of not more than 10,000. Salt of polyguanidine represent a mixture of different along the length of the polymer chains with an average molecular weight of 10,000. Concentration pgmg phosphate in dialysis medium was determined by the method of fotoelektrokalorimetry with a color reagent according to THE 2499-001-36748375-97.

Was installed prolonged release pgmg phosphate gels relative to the aqueous solution 2-3 times (table 6), the PVA gels have the most powerful restraint effect compared to MC, probably due to the higher structure (Fig.3).

Gels are complex the spine, cause for gel cause a variety of resistance that characterizes the system's ability to change shape and the formation of a layer. Measurement of the dynamic viscosity of the gels carried out on capillary viscometer VPI-2 with a diameter of 2.1 mm capillary relative to glycerol. Re-determination was carried out after storage for 1 year in aluminium tubes of storage under normal conditions. There was a slight dilution of the gel during storage (table 7), does not affect use of the property.

Structural-mechanical characteristics for shape retention and internal friction in the gels was estimated by the values in certain intervals. The results of measurements on a rotational viscometer “Polymer re presented in table 8 as dependencies 1 shear stress (N/m2) from the logarithm of the velocity gradient shift(with-1). Graph(log2D) for compounds 1 and 2 has a slight hysteresis loop, indicating the presence of coagulation patterns, unstable when stored and prone to destruction-restoration at various V by mechanical action or quick recovery (table 8, Fig.1, figs.2).

Local irritant effect of compounds 1 and 2 were investigated in 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, or other changes of the conjunctiva.

Drug toxicity 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.

Pharmacological efficacy of the compositions was evaluated in the experience of the inoculated treatment of bacterial conjunctivitis in rabbits. The experiment was conducted on 10 white rabbits that have passed the quarantine. The infection produced isolated from sick animals culture of Staphylococcus intermediis. The pathogen was grown on a nutrient medium for 24 h, then was preparing microbial suspension concentration of 105CFU/ml Contamination eyes made 0.2 ml of microbial suspension method subconjunctival infection. At day 2, all animals were monitored picture of acute conjunctivitis with hyperemia and edema of the mucous Obolo evritania purified from pus cloth laid 1-2 drops of the developed part 2 times a day. Achieving pharmacological effect was assessed by the disappearance of the main symptoms of conjunctivitis: purulent discharge, redness and swelling of the sclera (table 9).

As can be seen from table 9, the improvement in the condition of the patient's eyes began to manifest itself in 3-4 days, complete healing occurred in 6-8 days of starting therapy. Both categories show approximately the same efficiency.

Thus, the developed formulations for the treatment of bacterial conjunctivitis have:

1) pharmacological safety, manifested in the absence of irritant, allergic and toxic effects;

2) pharmacological efficacy in the treatment of bacterial conjunctivitis;

3) compliance with the modern requirements of quality ophthalmic gels.

Claims

1. Gel for the treatment of bacterial conjunctivitis, containing microbially agent, polyvinyl alcohol, borate buffer, purified water, characterized in that it contains as microbicide agent, guanidine phosphate, sodium chloride and kollidon VA64 when clebur>Sodium tetraborate 0,02-0,05

Sodium chloride 0,5-0,7

Prinivilbuy alcohol 7,0-8,0

Kollidon VA64 1,0-2,0

Purified water Up to 100.0

2. Gel for the treatment of bacterial conjunctivitis, containing microbially agent, a borate buffer, purified water, characterized in that it contains as microbicide agent, guanidine phosphate, methylcellulose, sodium chloride and kollidon VA64 in the following ratio, wt.%:

The guanidine

phosphate 0,6-1,2

Boric acid 0,25-0,5

Sodium tetraborate 0,02-0,05

Sodium chloride 0,5-0,7

The methylcellulose of 2.0-2.5

Kollidon VA64 1,0-2,0

Purified water Up to 100.0



 

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