Ophthalmic preparation presented in form of eye drops and containing branched polyhexamethylene guanidines and poly(n-vinylpyrrolidone)

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely to ophthalmic preparations presented in the form of eye drops and applicable for treating dry eye syndrome and bacterial conjunctivitis. The preparation contains polyhexamethylene guanidine that is presented by branched oligomers in the form of hydrochloride; besides, phosphate buffered saline, poly(N-vinylpyrrolidone) and water are the ingredients.

EFFECT: using the invention provides the higher clinical effectiveness in dry eye syndrome, as well as potential comorbid bacterial infection whereas the declared preparation has no irritant effect if used for a long period of time.

3 cl, 2 tbl, 3 ex

 

The technical field to which the invention relates.

The invention relates to ophthalmic preparations, and more particularly to eye drops that can be used for the treatment of dry eye syndrome, as well as bacterial conjunctivitis.

The level of technology

Dry eye syndrome is a common pathological condition with different etiology. For example, it may be associated with age-related changes, wearing contact lenses, diseases of eye tissues and other Major manifestations are failure and discontinuity in the tear film on the cornea, irritation of mucous membranes and discomfort in the eye. In addition, the tear film plays a role of local immune barrier. Therefore, a violation of its integrity or the thickness may cause the emergence and development of infectious diseases of the eye.

Drugs designed to fill the tear fluid with dry eye syndrome, according to a range of physico-chemical properties should be close to the natural tear fluid of a healthy person. Thus, the density should be 1,001-with 1.009 g/ml, pH is in the range of 6.0-7,8, the adhesion force of the tear film to the cornea is 30-40 Dyne/cm2and the surface tension is 46 Dyne/cm2.

In the patent EP 0198490 (publ. 22.10.1986) disclosed compositions moisturizing drops n the basis of hydroxyethyl cellulose and poloxamer, containing urea as a preservative.

In the patent EP 0780121 (publ. 25.06.1997) disclosed are compounds of eye drops containing polyacrylic acid and polyvinylpyrrolidone as a lubricant and benzalkonium salt as a preservative.

In the patent EP 0342297 (publ. 23.11.1989) disclosed an aqueous solution having a low surface tension, forming a continuous wetted by water absorbed layer on the hydrophobic surface, comprising partially hydrolyzed polyvinyl acetate in combination with polyvinyl alcohol. The composition of the solution also includes dextran, kollidon, citrate-phosphate buffer solution, EDTA, sodium chloride, calcium and chlorbutanol as preservative.

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 "Systems of care for contact lenses" / Nbein, Menshikova, Avestha, Lauramine // pharmaceutical journal, 2001, t.35, No. 2).

The closest the authors consider the invention, disclosed in the patent RU 2241444 (publ. 10.12.2004)for creating drops to treat dry eye syndrome, containing a lubricant, preservative, phosphate buffer, sodium chloride, purified water, otlichayushiesya, which contain, as a preservative, guanidine phosphate, kollidon VA 64 as a lubricant in the following ratio of components (in wt.%):

The guanidine phosphate0,04-0,1
Sodium phosphate one-deputizing0,1-0,2
Sodium phosphate disubstitutedof 0.2-0.3
Sodium chloride0,5-0,7
Kollidon VA 64of 3.0-3.5
Purified waterto 100.0

The disadvantage of analog is weak bacteriostatic effect due to the essentially linear structure of the molecules used in the guanidine.

Therefore, there is a need to expand the Arsenal of hydrating and bacteriostatic means for the treatment of dry eye syndrome and combat its effects, especially with the development of bacterial infections.

Disclosure of inventions

The aim of the invention is the creation of a drug for treatment of dry eye syndrome, and possible bacterial infection, which has no irritant is about actions with long-term use.

As a result of studies, the inventors have found that the disadvantages of the known prior art can be overcome by the creation of an ophthalmic preparation in the form of droplets containing hexamethyleneimine, phosphate saline buffer, hydrating component, in which hexamethylenebiguanide presents branched oligomers of the formula (I) in the form of a hydrochloride

where R representsora n1n2and n3equal 1-3, a z is equal to 0.15-1,10 molecular weight distribution Mw/Mnfrom 5.4 to 9.3 when the mass-average molecular mass Mwin the range of from about 3800 to 6300 and srednetsenovoj molecular mass Mnin the range of from about 600 to 1100, and the preparation additionally contains a copolymer based on N-vinylpyrrolidone General formula (II):

where Monomeric link M is the fragment of 2-methyl-5-vinyltetrazole (MW) or 2-methyl-5-vinylpyridine) - derivatives (IMP):

,

and the content of monomer units n is 25-50 mole.%, and srednevozrastnoe molecular mass Mµthe copolymer depends on the nature of M: if M is MW, Mµ=30-50 kDa; if M is a profit center, then Mµ=15-40 kDa.

Hydrochloride polyhexamethylene Andina (phmg-GC) of the formula (I) belongs to the 4th class of toxicity, ie is not dangerous to the human body, he has a strong microbicidal effect against major pathogens of infectious conjunctivitis and keratitis: Pseudomonas, Staphylococcus, Streptococcus, Serratia, Proteus, Enterobacteriaceae, Bacillus.

Copolymer based on N-vinylpyrrolidone General formula (II) is also non-toxic and exhibits properties activator phagocytosis.

Efficiency pgmg-GC relative to the listed strains, determined by the serial dilution method with a nutrient medium, the estimated minimum inhibitory concentration ranges from 1.0 to 300 µg/ml Thus, the minimum bacteriostatic concentration pgmg-GC is 0.01%. To achieve a bactericidal effect can be used in a concentration of 0.1 to 1.5%.

The main requirements of solutions intended for instillation into the conjunctival cavity, are sterility, transparency, isotonicity, pH value close to the natural, and duration.

Sterility is necessary to ensure long-term storage of the drug before use. It also guarantees the absence of pathogenic microorganisms that produce toxic waste products that can multiply the conjunctiva after drug administration.

Transparency is a natural requirement for protected areas is economic environments. Isotonicity and close to the natural pH create a comfortable environment for the cells of the conjunctiva, which excludes them from damage and unpleasant feeling (feeling pain or burning sensation in the eye). The duration of action can reduce the number of instillations, which reduces drug burden and makes it possible for long-term use of the drug without serious side effects.

The person skilled in the art obvious theoretical and experimental methods for evaluation of concentrations of components in the preparations of this type, the most famous of which is theoretical calculation taking into account isotonic equivalents and geometria supercooling the mixture of salt/ice.

In the result of extensive research, the authors found that these requirements are best satisfied by compositions containing phosphate buffer at a concentration of 0.3-0.5%, which maintains the pH level of 7.2-7.8 is available, corresponding to the pH of the tear fluid of a healthy person. To create the desired osmotic pressure of the composition should be entered sodium chloride at a concentration of 0.5-0.7%.

The choice of a hydrating component (polymer moisture holding on conjunctiva) must be made with regard to the transparency requirements applicable to the drug. The model can serve as an isotonic solution of sodium chloride, containing what s the maximum concentration pgmg-GC. Polymers, physico-chemically compatible with saline pgmg-GC andproviding compositions, similar in viscosity to the lacrimal fluid (1,2-1,4), suitable for use in accordance with the invention. These are the dextran with a molecular mass of about KD (concentration 3-3,5%), kollidon (copolymer of vinylpyrrolidone/vinyl acetate in a molar ratio of 6:4, the concentration of 3-3,5%) and water-soluble methylcellulose with a molecular mass of about 20 kDa (concentration of 0.05-0.1%).

Thus, the purpose of the invention can be achieved by using ophthalmic drug in the form of droplets containing hexamethylenediamine were, phosphate saline buffer, hydrating component selected from the group consisting of dextran, a copolymer of vinylpyrrolidone/vinyl acetate and a water-soluble methyl cellulose, characterized in that the hexamethylenediamine were presented branched oligomers of the formula (I) in the form of a hydrochloride

where R representora n1n2and n3equal 1-3, a z is equal to 0.15-1,10 molecular weight distribution Mw/Mnfrom 5.4 to 9.3 when the mass-average molecular mass Mwin the range of from about 3800 to 6300 and srednetsenovoj molecular mass Mnin the range of from about 600 to 1100, and PR is parathas further comprises a copolymer based on N-vinylpyrrolidone General formula (II):

where Monomeric link M is the fragment of 2-methyl-5-vinyltetrazole (MW) or 2-methyl-5-vinylpyridine) - derivatives (IMP):

and the content of monomer units n is 25-50 mole.%, srednevozrastnoe molecular mass Mµthe copolymer depends on the nature of M: if M is MW, Mµ=30-50 kDa; if M is a profit center, then Mµ=15-40 kDa, with the following content of components (in wt.%):

The guanidine hydrochloride0,01-0,4
Copolymer based on N-vinylpyrrolidone0,01-0,05
Phosphate saline buffer containing
Sodium dihydrophosphate0,1-0,2
Phosphate sodiumof 0.2-0.3
Sodium chloride0,5-0,7
Hydrating componentof 0.05 to 3.5
Purified water to100,0

In the first preferred implementation of the ophthalmic drug in the form of droplets has with the Tav (in wt.%):

The guanidine hydrochloridethe 0.05-0.1
Copolymer based on N-vinylpyrrolidone0,01-0,03
Phosphate saline buffer containing
Sodium dihydrophosphate0,1-0,2
Phosphate sodiumof 0.2-0.3
Sodium chloride0,5
Hydrating component (dextran)of 3.0-3.5
Purified waterto 100.0

In the second preferred implementation of the ophthalmic drug in the form of droplets has a composition (in wt.%):

The guanidine hydrochloride0,1-0,2
Copolymer based on N-vinylpyrrolidone0,02-0,05
Phosphate saline buffer containing
Sodium dihydrophosphate0,1-0,2
Phosphate sodiumof 0.2-0.3
Sodium chloride0,5-0,7
Hydrating component (kollidon)of 3.0-3.5
Purified waterto 100.0

In the third preferred implementation of the ophthalmic drug in the form of droplets has a composition (in wt.%):

The guanidine hydrochloride0,1-0,2
Copolymer based on N-vinylpyrrolidone0,01-0,05
Phosphate saline buffer containing
Sodium dihydrophosphate0,1-0,2
Phosphate sodiumof 0.2-0.3
Sodium chloride0,5-0,7
Hydrating component (methylcellulose)0,05-0,15
Purified waterto 100.0

The solution in accordance with the invention is suitable for use within let, that was confirmed by comparison of physico-chemical and microbiological parameters obtained for vegetativnogo drug and drug after storage. The quality indicators that require monitoring (pH, surface tension, electrical resistivity and refractive index) for all drugs during storage statistically significantly (p<0,05)? did not differ from the original values.

The retention time of the drug on the cornea can be indirectly assessed by the severity of bacteriostatic or bactericidal action. Evaluation of retention time is the time after which growth of the microorganism colony at bacteriostatic concentrations (0.01 to 0.05%), or the time, to which there is no growth of colonies of the microorganism at bactericidal concentrations (0.1-0.4 percent) in the sowing sample of tear fluid on an appropriate nutrient medium. Studies have shown that the greatest retention time of the drug (up to 8 hours) is achieved with the use of water-soluble methyl cellulose. The product containing the copolymer of vinylpyrrolidone/vinyl acetate, held during 6-7 hours.

The achievement of the technical result of the invention will be further illustrated by the preferred examples of its implementation.

The implementation of the invention

Example 1. Capl is for the treatment of dry eye syndrome

Under aseptic conditions in a glass apparatus with a stirrer, thermometer and heated jacket is placed 45-55 ml of hot water and purified sequentially dissolve it required (in accordance with three preferred implementation of the invention), the amount of guanidine of the formula (I) in the form of the hydrochloride, of a copolymer of formula (II), sodium dihydrophosphate, sodium hydrogen phosphate, sodium chloride.

In the second similar apparatus in the remaining amount of water dissolve the appropriate amount of the selected hydrating agent. The solutions are mixed under aseptic capacity to work under pressure or under vacuum. After obtaining a clear solution is sterilized resulting solution by filtration through a membrane filter with shut-off capacity of 0.2 μm. The sterile solution is taken as the second aseptic tank, which create and maintain the required vacuum. Alternatively, the sterilization solution is carried out by keeping at a temperature of 120°C for 8-12 minutes.

After sterilization of the finished drug portions of 2 ml Packed in a sterile dropper polyethylene high-pressure supply screw-on lids and placed in boxes with the information necessary for the identification and application.

Example 2. Evaluation of retention time and smear istaricheskogo of action of the drug on the minimum bacteriostatic (overwhelming growth) concentration (MIC) in vitro

Spectrum bactericidal efficacy in the experience of in vitro characterized by suspension polymerization in accordance with the guidance of P 4.2.264 3-10 "Methods of laboratory research and testing of disinfectants to assess their effectiveness and safety. Explore 0.05% solution of hydrochloride, guanidine of the formula (I) (phmg-GC) and the drug is prepared in accordance with example 1 of the invention.

Minimum bacteriostatic (IPC) concentration is determined by micromethods serial twofold dilutions in medium Mueller-Hinton (Oxoid) in accordance with the normative document "guidelines for determining the sensitivity of microorganisms to antibiotics" (MUK 4.2 1890-04).

Preparations with a concentration of active ingredient 1000 μg/ml, prepared in pyrogen-free distilled water, diluted to 128 µg/ml of culture medium. Studies performed in 96-well tablets for immunological studies. Prepare a series of twofold dilutions of study drug in the environment II Mueller-Hinton (Oxoid) in a volume of 50 μl. For microorganisms, poorly growing on ordinary nutrient media, in the above medium was added 5% defibrinating sheep blood.

The inoculate bacterial cultures from isolated colonies are prepared in the form of a suspension according to the turbidity standard Macherla is Yes (0,5) in physiological solution. The suspension is diluted in the environment II Mueller-Hinton to a concentration of 108 CFU/ml of the Prepared suspension contribute to the wells of plates (50 μl/well) and prepare a dilution in the concentration range from 128 to 0,0003 mg/ml Inoculated tablets incubated for 18 hours at 37°C. the Lowest concentration of the study drug, at which no visible growth of microorganisms, is an estimate of the IPC.

To determine the IPC Candida albicans isolated from colonies of preparing a suspension in a nutrient medium Saburo standard turbidity of Mcfarland (0,5), which corresponds to 106 CFU/ml for fungal cultures. A series of twofold dilutions of the drugs are prepared in an environment Saburo in a volume of 100 ml After inoculation of yeast tablets incubated for 48 hours at 30°C.

The results of the action at the IPC series serial twofold dilutions are presented in table 1.

Table 1
The microorganism (Strain)Pgmg-GCMedication
Escherichia coli (ATSS 27952)24
Proteus mirabilis (5)11
Staphylococcus aureus (ATCC29213, feeling twiceler methicillin) 24
Staphylococcus aureus
ADS 43300 methicillin-resistant)
24
Candida albicans (ATSS 24433)48

The data obtained indicate that the proposed drug has a higher activity compared with the solution pgmg-GC.

Example 3. Treatment of dry eye syndrome in dogs

The effectiveness of the treatment of dry eye syndrome in dogs appreciate the stability of the tear film (sample for Norn (M.S. Norn, 1969). In accordance with the study Protocol in the lower conjunctival SAC instilliruut 1 drop of 0.2% fluorescein-sodium, and then determine the time from the last blink to the appearance in tinted tear film break in the form of black spots or cracks on the surface of the cornea. The time of the destruction of the tear film is an important indicator of its stability.

The results were evaluated as follows:

more than 10 secondsNorma
5-10 secondsless than normal
less than 5 secondssharp red eye reduction is the stability of the tear film

An alternative way to determine the function of the lacrimal glands is common in the world of the Schirmer test, which establishes the total tear production. To do this, use special strips of filter paper. The strip is bent on the marked end at an angle of 40-45° and placed in the lower conjunctival fornix in the outer third of the eye slits: the inflection point must lie on the edge of the century, and the bent portion of the strip should not touch the conjunctiva. The animal closes his eyes, and after 1 minute I get the strip and take into account the result, measuring the length of the wetted area of the fold line.

Dogs with a diagnosis of keratoconjunctivitis", "dry eye syndrome" was treated with the composition prepared in accordance with example 1. The solution was instillirovti 4 times a day for 2 weeks. Siteproduct was determined by the method Schirmer. The results are presented in table 2.

Table 2
AnimalsThe length of the wetted area, mm
Before the treatmentAfter 2 weeks
Poodle610
Poodle8 15
Spaniel1017
Pekingese720
Pekingese910

Thus, 2 weeks after treatment was eliminated purulent conjunctivitis, animals disappeared painful spasm of the eyelids and photophobia. Selection tears almost normalized (>15 mm).

1. Ophthalmic drug in the form of droplets containing polyhexamethylene guanidine, phosphate saline buffer, hydrating component selected from the group consisting of dextran, a copolymer of vinylpyrrolidone/vinyl acetate and a water-soluble methylcellulose, wherein the polyhexamethylene guanidine presents branched oligomers of the formula (I) in the form of a hydrochloride

where R representsora n1n2and n3equal 1-3, a z is equal to 0.15-1,10 molecular weight distribution Mw/Mnfrom 5.4 to 9.3 when the mass-average molecular mass Mwin the range of from about 3800 to 6300 and srednetsenovoj molecular mass Mnin the range of from about 600 to 1100, the preparation further comprises a copolymer based on N-vinylpyrrolidone General formula (II):

where Monomeric link M is the fragment of 2-methyl-5-vinyltetrazole (MW) or 2-methyl-5-vinylpyridine) - derivatives (IMP):
,
and the content of monomer units n is 25-50 mole.%, srednevozrastnoe molecular mass Mµthe copolymer depends on the nature of M: if M is MW, Mµ=30-50 kDa; if M is a profit center, then Mµ=15-40 kDa, with the following content of components (in wt.%):

The guanidine hydrochloride0,01-0,4
Copolymer based on N-vinylpyrrolidone0,01-0,05
Phosphate saline buffer containing
Sodium dihydrophosphate0,1-0,2
Phosphate sodiumof 0.2-0.3
Sodium chloride0,5-0,7
Hydrating componentof 0.05 to 3.5
Purified waterto 100.0

2. Ophthalmic preparation according to claim 1, characterized in that it has stood the (in wt.%):

The guanidine hydrochloridethe 0.05-0.1
Copolymer based on N-vinylpyrrolidone0,01-0,03
Phosphate saline buffer containing
Sodium dihydrophosphate0,1-0,2
Phosphate sodiumof 0.2-0.3
Sodium chloride0,5
Hydrating component (dextran)of 3.0-3.5
Purified waterto 100.0

3. Ophthalmic preparation according to claim 1, characterized in that it has a composition (in wt.%):

The guanidine hydrochloride0,1-0,2
Copolymer based on N-vinylpyrrolidone0,02-0,05
Phosphate saline buffer containing
Sodium dihydrophosphate0,1-0,2
Phosphate sodiumof 0.2-0.3
Sodium chloride0,5-0,7
Hydrating component (kollidon)of 3.0-3.5
Purified waterto 100.0

4. Ophthalmic preparation according to claim 1, characterized in that it has a composition (in wt.%):

The guanidine hydrochloride0,1-0,2
Copolymer based on N-vinylpyrrolidone0,01-0,05
Phosphate saline buffer containing
Sodium dihydrophosphate0,1-0,2
Phosphate sodiumof 0.2-0.3
Sodium chloride0,5-0,7
Hydrating component (methylcellulose)0,05-0,15
Purified waterto 100.0



 

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Eye drops // 2504372

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to eye drops that contain 1-3 wt % of taurine, 0.01-0.1 wt % of dexamethasone, 0.4-0.6 wt % of boric acid, 0.4-0.6 wt % of hydroxypropyl methyl cellulose and water. The eye drops aim at treating various eye diseases related to metabolic disturbance in eye tissues, and inflammatory injury of an eye surface.

EFFECT: higher therapeutic efficacy of the eye drops.

3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents pharmaceutical composition for treating gastroesophageal reflux disease, containing at least one proton pump inhibitor and at least one probiotic, wherein the proton pump inhibitor is taken in the amount of 0.05-25 wt % in the composition; and the probiotic is taken in the amount of 10-95 wt %; additive agents up to 100 wt %.

EFFECT: provided preventing Hpylori translocation, avoiding the necessity of Hpylori detection and antibacterial course of eradication, higher safety of the prolonged therapy with the proton pump inhibitors and avoided gastric mucosa atrophy, and a risk of gastric cancer.

5 cl, 10 tbl

FIELD: medicine.

SUBSTANCE: invention refers to veterinary medicine, and may be used for increasing milk producing ability and improving milk quality in the cows kept in the heavy metal contaminated territories. For the purpose of increasing the milk producing ability, the cows are fed up with the probiotic EM-Vita 9.5-10.5 ml/head once a day for 9-11 days, every 6-8 days; the regimen is repeated for three times and added with 2.5-3% chitosan 1.9-2.1 ml/kg of body weight 2 times a day for 9-11 days every 6-8 days. The invention provides increasing a daily average milk yield by 19.2, casein - by 18.82, total protein - by 16.52, fat - by 12.13 and lactose - by 23.16%, and improves the ruminal digestion values: pH increase by 3.92%, volatile fatty acids by 33.64%, infusoria count by 80.71%.

EFFECT: economical effectiveness of the method makes 9,31 roubles to one rouble of the expenses.

1 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to pharmacology and clinical medicine, and describes a pharmaceutical composition in the form of tablets containing a S1P receptor modulator representing 2-amino-2-[2-(4-octylphenyl)ethyl]propane-1,3-diol and/or a pharmaceutically acceptable salt thereof, and additive substances: microcrystalline cellulose, sodium carboxymethyl starch, calcium stearate or magnesium stearate in the following proportions.

EFFECT: composition is more stable and has less side effects.

3 cl, 4 ex

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