Disulfiram and taurine-containing ophthalmological medication in form of eye drops

FIELD: medicine.

SUBSTANCE: invention relates to field of ophthalmology. Ophthalmological medication in form of eye drops, contains 0.2-0.5 wt % of disulfiram, dissolved in pharmaceutically acceptable water-based carrier, 0.5-2.0 wt % of hydroxypropyl cyclodextrin, 2.0-5.0 wt % of taurine; agent, which ensures required resin condition, containing sodium chloride, sodium monohydrophosphate and dihydrophosphate, and methylparaben (nipagin) as a preservative.

EFFECT: invention ensures effective treatment of pathological conditions of eyes, such as cataract, glaucoma, ophthalmological hypertension and traumatic injuries of cornea, extends arsenal of existing preparations in form of eye drops.

6 cl, 5 tbl, 2 dwg, 5 ex

 

The invention relates to pharmacology and ophthalmology, and can be used when creating a product for the treatment of pathological conditions of the eye selected from cataract, glaucoma, ophthalmoparesis and traumatic injuries of the cornea in patients of different ages.

Information about prior art

In its broadest sense, the term "cataract" determine any change in optical homogeneity or decrease the transparency of the eye lens. In the etiology of cataract involved many factors, such as heredity, aging, diabetes, Smoking, nutrition, the cumulative effect of x-ray and UV radiation, and the endocrine and/or enzymatic equilibrium in the body.

The most significant among the chemical compounds that cause cataracts are oxygen radical particles, for example, formed under the action of UV radiation present in the spectrum of sunlight. Such particles disturb the homeostasis of the lens by increasing the level of ions of CA2+in the lens, which, in particular, activates calciseptine protease, for example, calpain. This leads to the destruction of proteins in the crystalline lens, such as crystalline, and, ultimately, to its dimness.

The proposed mechanism is not the only, but allows you to choose the target DL the drugs and to develop treatment strategies. In particular, one of the famous and very safe antioxidants linking hydroxyl, peroxide, peroxynitrite radicals, is disulfiram - dimer of diethyldithiocarbamate, which itself also able to resolve the action of hydroxyl radicals and to inhibit lipid peroxidation. However, the low solubility of disulfiram in water, stable in neutral aqueous media and the inability to penetrate through the cornea are significant obstacles to its use in ophthalmology.

In the application EP 2238978 (publ. 13.10.2010) disclosed a pharmaceutical composition comprising an inclusion complex of disulfiram and cyclodextrin, optionally containing uncomplexed disulfiram and one or more pharmaceutically acceptable carriers. In embodiments of the invention disclosed liquid parenteral, preformed oral and palletirovaniya subcutaneous form of the drug for treatment of addiction to alcohol and cocaine, containing 15-80 wt.% complex disulfiram.

Article N. Nagai et al. "Delay in ICR/f Rat Lens Opacification by the Instillation of Eye Drops Containing Disulfiram and Hydroxypropyl-β-cyclodextrin Inclusion Complex" (Biol. Pharm. Bull. Vol.30(8) (2007). P.1529-1534, publ. 05.06.2007) in rat models ICR/f (line with cataracts inherited in recessive type) shows the following. To 77 day life of animals in the groups treated with eye drops containing di is ulyram, the lens opacity was 35-45% less expressed than in animals of the control group treated with isotonic saline solution, which is already 75 day life emerged clearly observed cataract. Experimental animals since the 30 days, twice a day was administered in the left eye 50 µl drops containing 0.25-to 0.50% of disulfiram, 3,0-5,0% 2-hydroxypropyl-β-cyclodextrin and 0.1% hydroxypropylmethylcellulose.

In article Nagai N., Ito Y., Takeuchi N. "Effect of Disulfiram Eye Drops on Lipid Peroxide Formation via Excessive Nitric Oxide in Lenses of Hereditary Cataract ICR/f Rats" (Biol. Pharm. Bull. Vol.31 (5) (2008). P.981-985, publ. 13.02.2008) shows that the introduction of droplets containing 0.25-to 0.50% of disulfiram, 3,0-5,0% 2-hydroxypropyl-β-cyclodextrin and 0.1% hydroxypropyl-methylcellulose to 77 day life of animals in 1,5-2 times pixel increases the level of transparency of the lens and in the same proportion reduces the content of ions of CA2+in the lens. In the lens 1.5 times reduced the concentration of NO and 2 times reduced the content of lipid peroxides.

The authors consider the results disclosed in both articles as the basis for further studies of such drugs disulfiram as a potential anti-cataract drugs, due to aging.

In article Nagai N., Ito Y., Takeuchi N. "Pharmacokinetic and Pharmacodynamic Evaluation of the Anti-cataract Effect of Eye Drops Containing Disulfiram and Low-Substituted Methylcellulose Using ICR/f Rat Lens as a Hereditary Catarat Model" (Biol. Pharm. Bull. Vol.35 (2) (2012). P. 239-245, publ. 24.11.2011) in rat models ICR/f shows that the introduction of eye drops containing 0.5% of disulfiram, 5% 2-hydroxy-propyl-β-cyclodextrin, 0.1% hydroxypropyl-methylcellulose, and 2.0% methylcellulose allows the time interval from 77 84-day life of a male model animals to maintain a pixel index of lens transparency, greater than 2-3 times the rate in the control group. It was also found that a preparation containing methylcellulose in the clinical concentration (2,0%), more effective than a similar product described in previous articles. The authors explain this fact by gelation with increasing temperature up to the temperature of the eye (about 35°C), which increases the retention time of eye drops on the surface of the cornea.

The prior art various ophthalmic preparations containing taurine. In the application EP 0778021 (publ. 11.06.1997) revealed eye drops to accelerate the regeneration of the cornea after injury, containing 0.5 to 3.0% taurine, sodium chloride, potassium chloride and sodium bicarbonate having a pH of from 5.5 to 8.0 and the osmotic pressure of from 250 to 450 mOsm.

In the patent RU 2127099 (publ. 10.03.1999) revealed eye drops containing (in wt.%):

sodium succinate shestibalny1,91
sodium citrate 5.5-water0,40
sorbitol0,80
sodium chloride0,31
L-glutamic acid0,015
Riboflavin is mononucleotides0,02
benzalkonium chloride0,014
glucose0,30
taurine4 g
distilled water for injectionthe rest of it.

The use of drops can improve energy metabolism in the cells of the anterior, posterior epithelium of the cornea and keratoplastic under any process that violates this exchange.

In the patent RU 2404768 (publ. 10.03.1999) revealed eye drops for the prevention and treatment of cataract, containing, g:

taurineof 1.5-1.9
carnosineof 1.5-1.9
glutathionenot less than 0.01
d is xtran low-molecular-weight
microdispersionsof 10.5 to 15.0
benzalkonium chloride0,005-0,02
purified waterto 100 ml

A disadvantage of the known preparations containing taurine, is the presence of benzalkonium salts, which can cause allergic reactions. There is therefore a need for new effective and safe drugs for the treatment of cataract.

On the market of ophthalmic preparations of the Russian Federation there are eye drops "Tulong" (CJSC "Institute of pharmaceutical technology")containing 3 wt.% taurine, as well as, g:

nicotinamide (Niacin, vitamin PP)4
dextran30
methyl parahydroxybenzoate (methylparaben, nipagin)1
sodium chloride4,5
potassium monophosphate10
sodium dibasic phosphate8,5
water for injection to 1000 ml

At present a unified view of the causes and mechanisms of development of glaucoma are missing. Moreover, sometimes difficulties arise when attempting to define the term "glaucoma". Specialists comprise about 60 diseases of the eye, which has the following General features: continuous or periodic individually exceeded tolerance level of IOP, glaucomatous optic neuropathy, resulting in its final stages to atrophy of the optic nerve and is typical for glaucoma disorders of visual functions.

In the context of the invention, the term "glaucoma" refers to a chronic eye disease characterized by continuous or periodic increase in intraocular pressure (IOP) with the development of trophic disorders in the ways of outflow of aqueous fluid in the retina and in the optic nerve that causes the development of regional excavation of the optic disc and the appearance of typical defects in the field of view.

In the article, Ito Y., Nagai N., Shimomura Y. "Reduction in Intraocular Pressure by the Instillation of Eye Drops Containing Disulfiram Included with 2-Hydroxypropyl-β-cyclodextrin in Rabbit" (Biol. Pharm. Bull. Vol.33 (9) (2010). P.1574-1578, publ. 08.06.2010) on the model of ocular hypertension in rabbits caused by a rapid infusion of 5% solution of glucse shown that the introduction of eye drops containing 0.1-0.5% of disulfiram, 1,1-5,0% 2-hydroxypropyl-β-cyclodextrin and 0.1% hydroxyprop the Il-methylcellulose in the period of time from 5 to 30 minutes after induction of ocular hypertension, allows 10-30% reduction in IOP. The authors believe that the results give reason to believe investigated drugs are the basis for the development of antiglaucoma funds.

Article V. Ermakova. "The effectiveness of combination taufona with antiadrainergicakimi drugs in primary open-angle glaucoma" (Ross. the oft. Journe. No. 2 (2008). P.12-17) have shown that a combined application of taufona with timolol, practolol, proxophelinum and proccacia for a long time (up to 1 year) can only slightly reduce IOP, but sufficiently improves the outflow of aqueous humor.

Ocular hypertension is not a disease as such, but is a pathological condition of elevated intraocular pressure, which normally is within 10-21 mm Od. Persistent or recurrent ocular hypertension can cause not only the development of glaucoma, but also lead to other injuries of the eye, leading to vision loss, such as occlusion of the retinal vein and nglaucomatous the destruction layer of the optic nerve fibers [D.S. Minckler "Histology of optic nerve damage in ocular hypertension and early glaucoma". Surv. Ophthalmol. Vol.33 (April 1989). P.401-411].

In article Bunin YA, Yartseva H., Kolesnikova Y.A., Yermakova VN, Yakovlev A.A., Berdnikovoy T.A., Komleva N.A. "the Effect of taurine on intraocular pressure and blood-ophtalmic the ski barrier (experimental study [Matters. the oft. No. 1 (1978). S-24] on the model of prostaglandin hypertension in rabbits have shown that instillation of 4% solution of taurine delay time increased IOP and statistically reduces 2-5 mm Hg IOP experienced eyes during the whole experiment. Similar results were obtained in models of salt hypertension in the eyes of rhesus monkeys. Thus, taurine has a hypotensive effect on the intraocular pressure, which may be due to inhibition of secretion of aqueous humor.

However, there is a need for ophthalmic drugs with greater pharmacological activity.

Brief description of drawings

Figure 1 presents the dependence of intraocular pressure (IOP) over time for a model of acute glaucoma in rabbits.

Figure 2 presents the dependence of intraocular pressure (IOP) over time for a model of chronic glaucoma in rabbits.

Description of the invention

The authors of the present invention have conducted extensive studies and found that there is a possibility of creating a stable liquid pharmaceutical composition containing 0.2-0.5 wt.% disulfiram. Thus, the present invention is aimed at expanding Arsenal of medicines, provides ophthalmic drug in the form of eye drops containing disulfiram and taurine, designed the config for the treatment of pathological conditions of the eye, selected from cataract, glaucoma, ophthalmoparesis and traumatic injuries of the cornea, characterized in that it contains 0.2 to 0.5 wt.% disulfiram dissolved in the pharmaceutically acceptable carrier is water-based due to the formation of inclusion complex with hydroxypropylcellulose present in the amount of 0.5-2.0 wt.%, 2.0 to 5.0 wt.% taurine, the agent providing the desired osmollnosti containing sodium chloride, monohydratefast and phosphate buffer, and methylparaben (nipagin) as preservative.

The term "treatment" in the context of the invention should be understood in the broad sense in which it means an improvement of the disease, slowing the progression of the disease, partial or complete restoration of function of the eyes or elimination of pathological conditions, as well as the separation of undesirable consequences caused by the pathological condition.

The method of calculation of the composition of the agent providing the desired osmollnosti, depending on the set values of osmotic pressure and pH of the pharmaceutical composition is in the competence of a person skilled in this field. The content of the preservative (methylparaben) must not exceed the value set by current regulations for funds local application.

The achievement of the technical result of the invention, mentioned is the student in improving the flow of cataracts or glaucoma, and in the long-term reduction of intraocular pressure shown in the respective adequate models in vivo.

A comparative study of known drug "Taufon, eye drops 4%, and the drug in accordance with the invention in a model of traumatic cataract in rabbits authors showed that the best results are characterized by a minimum size and intensity of turbidity damaged portion of the lens, was observed in rabbits receiving the proposed drug (table 2).

A comparative study of known drug "Taufon, eye drops 4%, and the drug in accordance with the invention in a model of acute glaucoma in rabbits authors showed that the best results are characterized by a more pronounced decrease in IOP was observed in rabbits receiving the proposed drug (figure 1).

A comparative study of known drug "Taufon, eye drops 4%, and the drug in accordance with the invention in a model of chronic glaucoma in rabbits authors showed that the best results are characterized by a significantly greater reduction in IOP was observed in rabbits receiving the proposed drug (figure 2).

During all studies found no any side effects, as well as signs of intolerance allergizirujushchego steps of the proposed drug.

Thus, the authors evidence confirm the achievement of the claimed technical result of the present invention.

The implementation of the invention

Hereinafter the invention will be illustrated by examples of its implementation.

Example 1. General method of preparation of eye drops

Separately prepare a solution of the agent providing the desired osmollnosti. To do this in sterile distilled water taken in an amount of 10% by volume of the finished product, is dissolved with stirring sodium dihydrophosphate and sodium chloride.

In sterile distilled water taken in an amount of 70% by volume of the finished product, with stirring, dissolve the methylparaben (nipagin)add disulfiram, and then hydroxypropylcellulose (GPCD). The mixture is stirred in the absence of light to obtain the solution (approximately 20 hours), then add taurine and the prepared solution of the agent providing the desired osmollnosti. Spend sterilizing filtration through a filter with pore size 0.2 μm, aseptically Packed in vials of 10 ml, which is then sealed and provided with labels.

Mass content (g/100 g of solution and in wt.%) solid substances in preparations prepared in accordance with example 1, are presented in table 1.

Table 1
ComponentThe drug 1The product 2
Mass, gWt.%Mass, gWt.%
Disulfiram0,20,20,50,5
GPCD0,50,52,02,0
Taurine2,02,05,05,0
Sodium dihydrophosphate0,260,260,250,25
Phosphate sodium0,10,10,10,1
Sodium chloride0,80,80,850,85
Methylparaben1,01,01,01,0

Example 2. The study of therapeutic action on the model of traumatic cataract in rabbits

The study was conducted on 24 rabbits breed "Chinchilla" average weight of 3.5 kg age 3.5-4 months with a model of traumatic cataract.

Modeling of traumatic cataract performed on the right eye of all animals in the following way. After medical Misa called twice instillation in the conjunctival cavity 1%solution of pilocarpine hydrochloride with an interval of 15 minutes, to produce laser coagulation of the pigment portion of the pupil localization coagulates 1,5-2,0 mm outwards from the optical center of the lens in the Meridian 8-10 hours On the iris of each eye put 15-40 coagulates. The parameters of laser radiation pulse energy of 1.6 to 2.2 W, pulse duration of 0.6 seconds. Delivery of laser radiation carried through the head binocular Ophthalmoscope.

In accordance with the objectives of the study all animals are divided into 3 groups (table 2).

Table 2
GroupThe drug and dosage The number of animals (eyes)
1Preparation 2 according to the invention; 1 mg/kg rabbit 1 time per day subkonyunktivalno within 10 days.6 (6)
2"Taufon, eye drops 4%"; 1 mg/kg rabbit 1 time per day subkonyunktivalno within 10 days.6 (6)
3Water for injection of 0.3 ml rabbit 1 time per day subkonyunktivalno within 10 days.6 (6)

In the first week biomicroscopy of the eye lens and the study of its transparency spend every day, and in the future - weekly in transmitted light using a slit lamp SL-2B and head binocular microscope (NBO-2) using the Ophthalmoscope lenses of different optical power.

In addition, all rabbits immediately after cataract simulation, as well as after 1 and 2 months of therapy compared drugs are photography nature of cataract using the apparatus "Retcam-2" (production of Massive Research, USA). The results of dynamic monitoring of rabbits entered in a special registration card.

After 30 minutes of laser treatment of pigmented rim La CCA in the ground causing the laser coagulates acquires a milky white color. On the second day of the experiment, the pupil acquires former size and exposes the Department of the lens subjected to laser radiation. It is an area of intensive clouding of the capsule and anterior cortical lens layers in a u shape (projection pigmented rims constricted pupil at the time of laser irradiation). This thin plot of turbidity, follow the contour of the edge of the pupil, surrounded by a halo subcapsular vacuoles and sites growing dimness, not extending more than 1.5 mm from the basic "outline" of the dimness.

Starting from the third or fourth day the turbidity of the considered sections of the lens reaches the maximum intensity, depth and area, and is stabilized. The trend to reverse (very minor) traumatic cataract development gains since the 30th day of the experiment. However, even after 60 days of treatment of the studied drugs in any case not showed complete regression of cataract.

Size of the lens opacity is determined using a micrometer grid imposed on the full-sized image of the lens performed using apparatus "Retcam-2", according to the formula:

S=N+n/2,

where S is the area of opacity mm2; N is the number of millimeter squares, fully "employed" clouding; n - the number is about a millimeter squares, partially "employed" by the dimness.

The severity of lens opacity assessed on a four point scale: 0 for full transparency of the lens; "1" - a gentle blackvideo turbidity; "2" - pronounced turbidity, for which, however, could be weakened by the fundus of the eye reflex; "3" - intense dense cataract in the absence in his projection of the fundus of the eye reflex. Due to the fact that cataract heterogeneous, calculate the average coefficient of turbidity by multiplying the intensity of the turbidity in each plot on its area, followed by summing and dividing by the total area of the dimness.

The results of dynamic monitoring of rabbits in groups shown in table 1, are presented in table 3.

Table 3
nThe monitoring phase
Group
PA
30 days60 day
Size, mm2SeveritySize, mm2Severity
165,3±0,52,5±0,34,5±0,52,0±0,2
265,8±0,52,7±0,25,0±0,52,1±0,2
366,1±0,62,8±0,25,8±0,52,6±0,2

In the study of the effectiveness of animal therapy found that both the investigational product have a significant positive impact on the clinical course of experimental traumatic cataract. So, after 1 month of treatment in all animals receiving the compared drugs, has been a steady trend towards the reduction of the size and intensity of cataract. While the changes primarily affect areas vacuolization and "secondary" opacities in the anterior and anterior subcapsular cortical layers of the lens.

The drug in accordance with the invention according to a survey on the 30th day of the experiment was slightly, but statistically significantly more effective is h, what is the drug "Taufon, eye drops 4%". In the control group 3 size, depth and intensity of turbidity remained more stable than in animals treated with therapy.

According to the results of further observations of rabbits, conducted in the period from 30 on the 60th day of the experiment, has more than a slight tendency to reverse the development of pathological changes in the lens (area, depth and intensity of turbidity), especially in group 1 treated with drug therapy in accordance with the invention.

Example 3. The study of therapeutic action in a model of acute glaucoma in rabbits

Studies conducted on rabbits breed "Chinchilla" weighing from 1.5 to 2.1 kg Intraocular pressure (IOP) is measured contactless automatic TonoVet tonometer (Jorgen Kruuse, Denmark) and for further research are selected animals with basal IOP 12-16 mm Hg, forming 3 groups of 4 individuals of both sexes in each.

Rabbits in the right (control) eye, injected pharmaceutical carrier, left (experienced) eyes - a solution of the product 2. 15 minutes after instillation of medication into the back of the ear vein of the rabbits injected with 5% dextrose (15 ml/kg). Measure IOP every 5 minutes until reaching values close to normal. The measurement results are averaged over the groups shown in figure 1.

Example 4. The study is uchebnogo actions on the model of chronic glaucoma in rabbits

Studies conducted on rabbits breed "Chinchilla" weighing from 1.5 to 2.1 kg Animal intravenous diazepam (1 mg/kg) and ketamine (25 mg/kg). In the rear chamber through the cannula impose a freshly prepared solution of α-chemotrypsin (50 Units in 0.1 ml sterile saline). Intraocular pressure (IOP) is measured contactless automatic TonoVet tonometer (Jorgen Kruuse, Denmark) and for further research are selected animals with stable ocular hypertension, forming 3 groups of 4 individuals of both sexes in each.

Rabbits in the right (control) eye, injected pharmaceutical carrier and measure IOP in the source point in time. In the left (experienced) eyes - a solution of the drug 1. Measurement of IOP is produced in the initial moment of time, and then at 15, 30, 45, 60, 120 and 180 days of the experiment. The measurement results are averaged over the groups shown in figure 2.

Example 5. The study of reparative actions on the model of extensive epithelial defects of the cornea in rabbits

Experimental studies conducted on 16 male rabbits breed "White giant" (32 eyes) with a mass of 2.8-3.0 kg, contained in standard vivarium conditions. As an experimental model using the model of extensive epithelial defects of the cornea, which is applied on both eyes of each animal as follows. After epibulbar anesthesia in what ocaina in the center of the cornea treponem for layer-by-layer transplant cornea form a wound damage with a diameter of 5 mm and a depth of 0.5 mm, why stop pin on trapane set to the appropriate position. The injury area stained with 1% solution of sodium salt of fluorescein. Remove blind drive, including the epithelium, boninovo the membrane and the surface layer of the stroma, within fluorescein labels produce special curved spatula. Then the defect re-paint the same solution and washed with sterile saline. All manipulations should be carried out under standard total intravenous anesthesia.

After conducting standard transactions animals are divided into two groups of eight animals in each group. In the postoperative period, the animals of the first group in one eye every 2-3 drops 2 times a day will intelliroute the drug in accordance with the invention, the animals of the second group is a drug comparison Taufon, eye drops 4%". The second eye serves as a control. In the control eyes intelliroute sterile saline solution.

The efficiency of wound healing evaluated by the results of clinical studies eye and time to complete epithelialization of the operating injuries using the following methods:

1) inspection in the focal and side lighting,

2) biomicroscopy anterior segment of the eye using a handheld slit lamp Heine HSL 150 state assessment to junctive, its injectionist vessels, presence of hemorrhage and edema. Also assess the condition of the cornea of the subject area, the nature and depth of the lesion, presence and nature (diffuse, local swelling, the degree of infiltration of the cornea, the presence of superficial and deep vascularization of cornea, as well as determine the nature and type formed scars.

3) fluorescing test staining of the cornea, which perform sterile disposable strips fluorescine (production Haag-Streit AG) to evaluate the dynamics of epithelization of the cornea and determine the time epithelialization.

All survey data are entered in a special report forms and supply photos.

The final step carried out morphological studies of enucleated eyes of rabbits, dead by the method of air embolism, on the 25th day after the start of the experiment. After enucleation, the eyes intended for research, fixed in 10% formalin solution and sent to a certified veterinary the anatomic laboratory.

Research methods 1)to 3) for the drug in accordance with the invention and known drug "Taufon, eye drops 4%" obtained pooled estimates in table 4. For obtaining this evaluation came from all indicators of the condition of the cornea, considering experienced and entry checkpoints for important locations the e eyes with the same epithelialization.

Table 4
Best epithelialization eyes:
experienced (eye/%)control (eye/%)
Group 1 (preparation 2)24.065/62,5%0/0,0%
29.065/62,5%1/12,5%
06. 076/75,0%1/12,5%
Group 2 (Taufon, 4%)24.061/12,5%0/0,0%
29.063/37,5%2/25,0%
06.074/50,0%2/25,0%

The results of morphological studies experienced eye control for the following histological criteria for assessment of wound healing:

1) the degree and the presence of corneal edema,

2) the presence of vascularization of the cornea,

3) the presence of fibrosis or abnormal granulation of the cornea

4) CTE is Yan inflammation,

5) the degree of corneal ulceration,

6) epithelial hyperplasia cornea

by degrees from normal (0)to severe (4) are summarized in table 5.

Table 5
The use of the drug:
Now (animals/%)Ineffective (animals/%)Equivalent (animals/%)
Group 1 (preparation 2)5/62,5%3/37,5%0/0,0%
Group 2 (Taufon, 4%)4/50,0%3/37,5%1/12,5%

Obtained in examples data demonstrate achievement of stated technical results when implementing the present invention in accordance with variants of the drug containing various amounts of the active ingredients of the complex formed by disulfiram and cyclodextrin, and taurine.

1. Ophthalmic drug in the form of eye drops containing disulfiram and taurine, intended for the treatment of pathological conditions of the eye selected from cataract, glaucoma, oft is lipohypertrophy and traumatic injuries of the cornea, characterized in that it contains 0.2-0.5 wt.% disulfiram dissolved in the pharmaceutically acceptable carrier is water-based due to the formation of inclusion complex with hydroxypropylcellulose present in the amount of 0.5-2.0 wt.%, 2.0 to 5.0 wt.% taurine, the agent providing the desired osmollnosti, where the specified agent contains sodium chloride, monohydratefast and sodium dihydrophosphate and methylparaben (nipagin) as preservative.

2. Ophthalmic preparation according to claim 1, characterized in that it contains 0.2 wt.% disulfiram dissolved in the pharmaceutically acceptable carrier is water-based due to the formation of inclusion complex with hydroxypropylcellulose present in the amount of 0.5 wt.%, and 2.0 wt.% taurine.

3. Ophthalmic preparation according to claim 1, characterized in that it contains 0.5 wt.% disulfiram dissolved in the pharmaceutically acceptable carrier is water-based due to the formation of inclusion complex with hydroxypropylcellulose present in the amount of 2.0 wt.%, and 5.0 wt.% taurine.

4. Ophthalmic preparation according to claim 3, characterized in that it is designed for the treatment of cataract.

5. Ophthalmic preparation according to claim 1 to 3, characterized in that it is designed for the treatment of glaucoma and/or ophthalmoparesis.

6. Ophthalmic preparation according to claim 3, the tives such as those what it is intended for the treatment of traumatic injuries of the cornea.



 

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18 cl, 5 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to field of medicine, in particular to ophthalmology. Medicinal compositions for intravitreal injections and methods of treating ophthalmological disorders are disclosed. Medicinal compositions represent suspensions on the basis of low-soluble medication, such as triamcinolone acetonide. Compositions of suspensions have relatively low viscosity and are easily extracted via needle of 27- or 30-gauge needle, but are highly flocculated and can be easily redispersed.

EFFECT: group of inventions ensures improvement of vitreos body visualisation in the course of vitrectomy, treatment of ophthalmological disorders.

20 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: group of inventions relates to field of ophthalmology. Described is application of compositions for reduction of intraocular pressure, which contain antocyanoside or including it extract, proantocyanidine or including it extract or their combinations.

EFFECT: group of inventions ensures effective application of compositions for reduction of intraocular pressure in patient.

30 cl, 1 tbl

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to ophthalmology and can be used for treatment of post-LASIK keratectasia. For this purpose in space under epithelial-stromal corneal flap round recess is made from periphery to optic zone (in central zone of cornea), into which hypotonic riboflavin solution is introduced. When thickness of cornea 400 mcm and more is reached, space is filled with 0.1% riboflavin solution on 20% solution of dextran T 500 until cornea is saturated with riboflavin. After that, ultrasonic irradiation of cornea is carried out with wavelength 365 nm with intensity 3 mW/cm2 for 30 min fractionally - 6 cycles 5 each 5 minutes long. During irradiation of cornea with ultrasonic waves riboflavin solution is instilled on cornea each 2-3 minutes, additionally riboflavin solution is introduced into recess under epithelial-stromal corneal flap each 5 minutes for constant support of riboflavin solution volume in intrastromal space.

EFFECT: method ensures increase of cornea thickness to required level due to creation of conditions for fast saturation of cornea with riboflavin solution, acceleration of healing process with reduction of risk of postoperative complications development to minimum.

1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a method of intraocular pressure reduction and to a method of pain control involving the administration of a therapeutic compound representing , or its tautomer or stereoisomer forms wherein X represents NH; n is equal to 2 or 3; Ra, Rb, Rc and Rd represent stable functional groups independently consisting of: 0 to 4 carbon atoms, 1 to 9 hydrogen atoms; and Re represents H or C1-4alkyl. Furthermore, the invention refers to a compound represented by formula , or to its tautomer or stereoisomer form.

EFFECT: new compound is prepared; besides, the known compounds to be applied in pain and glaucoma control are studied.

8 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to food and pharmaceutical industry, namely the production of biologically active additives used for prevention of the conditions caused by vitamin and mineral deficiency, i.e. a powder for solution. The vitamin-mineral product contains a prebiotic (either sorbitol, or isomalt, or lactulose, or inulin), citric acid, a flavour, vitamins and minerals - retinol palmitate, alpha-tocopherol acetate, ascorbic acid, colecalciferol, nicotinamide, zinc, iodine, iron, selenium. The product represents a powder of weight 2.0±0.3 g.

EFFECT: vitamin-mineral product according to the invention is characterised by dosage uniformity, storage stability, bioavailability and neutral taste.

4 cl, 8 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: claimed is application of levodopa and carbidopa for preparation of medication, intended for treatment of Parkinson's disease; or for treatment of sleep malfunction in patients with Parkinson's disease, for treatment of motive activity malfunction in patients with Parkinson's disease (versions), where medication contains levodopa and carbidopa in pharmaceutically effective quantity for continuous introduction into intestine for time period, which constitutes 24 h per day or more than one day. Sleep rating scale of patients with Parkinson's disease increased by 130% on the second night after starting twenty-four-hour introduction and remained within two following years.

EFFECT: twenty-four-hour introduction of medication replaces frequent per oral intake of medications, makes it possible to reach claimed prescriptions, with preservation of stable response to on medication introduction, which is not accompanied by development of clinically significant tolerance or side effects.

17 cl, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to veterinary, namely to veterinary mycology, bacteriology and parasitology. Complex medication for treating dogs and cats with cutaneous mycoses, bacterioses and acaroses includes as active and auxiliary components (wt %): chlorhexidine digluconate - 0.05-0.075; cypermethrin - 10.0-15.0; tetramethrin - 1.5-2.25; pyperonyl butoxide - 10.0-15.0; dimethyl sulfoxide - 15.0-22.5; polyethylene glycol M-200 or M 400 - 10.0-15.0; glycerol - 10.0-15.0, 1,2-propylene glycol - the remaining part.

EFFECT: medication has complex effect, without staining skin and its derivatives, is easily washed away with water, is efficient at temperature from minus 30 to plus 30°C and higher, has 2-year long storage term.

9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, particularly to therapeutic preparations of mumiyo. The therapeutic preparation which contains purified mumiyo, grapefruit citrosept, edible glycerol, ethanol and water at specific proportions.

EFFECT: preparation has a prolonged shelf life.

8 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed are: application of silibinin component of general formula (I) for obtaining medication for parenteral introduction for trweatment of viral hepatitis, with medication optionally containing cyclodextrin and/or phospholipid, and set of similar purpose, which includes said silibinin component and other medication, representing one or several pharmaceutical agents from: arginine, glutamate, silymarin, citiolone, epodemiol, ornithine oxoglurate, tidiacic arginine, myoinosite, methionine and N-acetyl methionine, choline, ornithine aspartate, cyanidanol, thiopronin, betaine, cyanocobalamin, leucine, levolose, acyclovir, idoxuridine, vidarabine, ribavirin, ganciclovir, famciclovir, valaciclovir, cidofovir, penciclovir, valganciclovir, brivudin, interferon. Medication preferably does not contain silidianin, and/or silicristin, and/or isosilibinin.

EFFECT: reduction of viral strain and reactivation of patients after parenteral introduction of claimed silibinin component.

21 cl, 12 dwg, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to pharmaceutical industry, namely to stable water calcium gluconate solution for injections. Said stable water calcium gluconate solution for injections contains 0.5-1 wt % of succinic acid as stabiliser, content of calcium gluconate constituting 10 wt %.

EFFECT: increased stability of calcium gluconate solution, increased term of its storage, increased resistance to low temperatures and mechanical impact.

4 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of medicine and deals with pharmaceutical composition of anti-tumor action, its obtaining and perfusion solution. Essence of invention lies in the following: solution contains taxane derivatives in surface-active layer. Said solutions are used for preparation of perfusion solutions. Method of solution obtaining lies in dissolution of active substance in ethanol and introduction of surface-active substance.

EFFECT: invention makes it possible to reduce dose of active substance, reduce ethanol concentration.

8 cl, 1 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of biotechnology and immunology. Claimed is medication for treatment and prevention of TNF-dependent disorder, which contains molecule of TNF-binding nanobody, lyoprotector, surface-active substance and buffer, method of such medication obtaining, method of lyophilised preparation reduction and method of analysis of medication-manufacturing process, as well as method and set for treatment or prevention of TNF-dependent disorder.

EFFECT: invention ensures obtaining stable pharmaceutical preparations of TNF-binding nanobodies and can be applied in therapy of TNF-dependent diseases.

30 cl, 12 ex, 3 tbl, 32 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to pharmacology, and concerns creating a drug preparation of an active substance of rifabutin by parenteral administration for treating human and animal infectious when administered parenterally. The parenteral drug preparation of rifabutin for therapy for the human and animal infectious diseases containing the active substance of rifabutin, excipients and water for injections, with the excipients presented by sodium metabisulphite and disodium edetate in the following ratio, g per 1 litre of water for injections: rifabutin 20-40, sodium metabisulphite, 0.7-0.9; 0.1-0.3 disodium edetate, water for injections - 1 litre.

EFFECT: invention provides a high therapeutic effect and high stability of the drug preparation, reduces the gastrointestinal toxicity of rifabutin, well tolerated, does not cause allergies and other side effects.

2 ex

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine and are intended for treating urinary bladder cancer. Apaziquone is applied. Medication is introduced intravesically during 6 hours after transurethral resection.

EFFECT: invention makes it possible to achieve re-epithelisation after TUR in patients with absence of systemic side effects.

15 cl, 4 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to medicine, namely to therapeutic agents used for treating ischemic cardiac disorders, and describes a combined medicine as a thrombocyte aggregation inhibitor containing an agent presented by a combination of clopidogrel or a pharmaceutically acceptable salt thereof, acetyl salicylic acid and magnesium hydroxide and additives.

EFFECT: invention provides enlarging the list of medicines and preparing the new combination of the agents possessing activity on platelet aggregation and the property to protect the gastric mucosa, as well as enhancing the clinical effectiveness of the medicine and prolonging its action.

13 cl, 3 tbl, 1 ex

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