EA041403B1 - PHARMACEUTICAL FOR THE TREATMENT OF ARTHROLOGICAL DISEASES - Google Patents

Description

The invention relates to the field of medicine, in particular to medicines for the treatment of arthrological diseases.

State of the art

According to the World Health Organization, diseases of the musculoskeletal system are the leading factor in disability worldwide. Such diseases limit mobility and motor skills, leading to premature termination of labor activity, reducing the ability to perform social functions.

Most of the diseases of the musculoskeletal system are disorders that affect the joints. These include osteoarthritis, rheumatoid arthritis, psoriatic arthritis, gout, ankylosing spondylitis, etc.

A characteristic feature of these diseases is the destruction of cartilage and changes in the structure of bones. Most often, diseases of the joints are affected by people over forty years old, but today they are increasingly common in the younger generation.

The basis for maintaining joint function is chondromodulating therapy, in which preparations based on the sodium salt of chondroitin sulfate, a mucopolysaccharide obtained from animal tissues, are widely used today. The drug effectively affects the metabolic processes in the patient's connective tissue, including cartilage, stimulating and normalizing the biosynthesis of glycosaminoglycans.

Chondroitin sulfate (hereinafter also CS) is a high molecular weight heteropolysaccharide that belongs to the group of glycosaminoglycans, linear unbranched polymers.

The structure of the cholesterol molecule determines its polyanionic properties and participation in the processes of transport of water, amino acids and lipids in the avascular areas of the cartilage. Long chains of cholesterol, which are part of the extracellular matrix, determine the most important biomechanical properties of cartilage tissue. Chondroitin sulfate is a structural modulator that is not only synthesized by the body, but also, after administration, integrates into the structures of cartilage tissue, stimulating its synthesis and inhibiting destruction. Its timely appointment and regular use provide inhibition, stabilization and prevention of the development of destructive processes in the joint. The main function of chondroitin sulfate in the body is to retain water and nutrients in the cartilage and ensure the movement of molecules through the cartilage tissue. This is the most important property, since there is no blood in the cartilage, which provides metabolic exchange. Chondroitin sulfate is also a chondroprotector. The water it retains in the thickness of the cartilage creates good cushioning and absorbs shocks, which ultimately increases the strength of the connective tissue.

Chondroitin sulfate is a natural component of articular cartilage, which plays an important role in maintaining the necessary osmotic pressure, due to which the matrix and collagen strands are stretched. This substance has anti-inflammatory activity, acting mainly on the cellular component of inflammation, stimulates the synthesis of hyaluronic acid and proteoglycans and inhibits the action of proteolytic enzymes. Chondroitin sulfate is the main part of articular cartilage. It is formed from repeating disaccharide units of glucuronic acid and N-acetyl-O-galactosamine. In the degenerative-dystrophic process, the amount of chondroitin decreases sharply, which leads to cartilage degradation [Builova T.V. An open randomized study of the efficacy and safety of Chondroxid® in the complex treatment of patients with chronic vertebrogenic lumbar ischialgia//BC. 2010. No. 17. S. 1678-1686].

Today, chondroitin sulfate medicines are presented on the market in injectable and non-injectable forms.

Non-injectable forms are represented by tablets and capsules.

The drug Artra is a film-coated tablet, 500 mg + 500 mg: 30, 60, 100 or 120 pcs. Active ingredients: chondroitin sulfate sodium (Chondroitin sulfate sodium), glucosamine (Glucosamine). 1 tab. contains chondroitin sulfate sodium - 500 mg, glucosamine hydrochloride - 500 mg. Excipients: disubstituted calcium sulfate - 230 mg, microcrystalline cellulose - 185 mg, croscarmellose sodium - 80 mg, stearic acid - 70 mg, magnesium stearate 10 mg.

Shell composition: hydroxypropyl methylcellulose - 35 mg, titanium dioxide (E171) - 8.2 mg, triacetin - 6.8 mg.

Capsules based on cholesterol are represented by Structum, Teraflex advance, Teraflex, Chondroitin AKOS, Chondroitin, Kondronova.

All of the above drugs have the active ingredient: chondroitin sulfate sodium (Chondroitin sulfate sodium).

Gelatin capsules have excipients, such as talc, stearic acid, magnesium stearate, manganese sulfate.

Typically, the composition of the capsule shell includes titanium dioxide and gelatin.

Gels based on cholesterol are known, for example, the drug Chondroitin (Chondroitine, VERTEKS AO (Russia) gel for external use 5% g: tubes 30 g or 50 g, cans 30 g. Active ingredient: chondroitin sulfate sodium (Chondroitin sulfate sodium ) Gel for external use 5% - 1 g. Composition: chondroitin sulfate - 50 mg. Excipients are added to the gel: dimethyl sulfoxide; propylene glycol; carbomer; trolamine; macrogol; edetate; methylparaben; nipagin; neroli and lavender oils; purified water.

Ointments based on cholesterol are represented by the following preparations: Mukosat ointment 5%, Artrafik ointment 5%, Chondroitin AKOS ointment 5%. Ointments contain sodium chondroitin sulfate and excipients: lactose, calcium stearate.

Injection forms are represented by lyophilizates and solutions.

Known solutions for intramuscular injection in ampoules: Drastop, Chondrogard, Injectran, Atravir-Incamfarm, Artogistan.

An example of a lyophilizate is Chondrolon, which is a lyophilized form of an injectable preparation based on the substance of the sodium salt of chondroitin sulfate.

All of the above drugs based on chondroitin sulfate (CS), whether injectable forms, gels, ointments, tablets or capsules for oral administration, having a chondroprotective effect, anti-inflammatory activity, acting mainly on inflammatory mediators, stimulate the synthesis of hyaluronic acid and proteoglycans and inhibit the action proteolytic enzymes.

CS drugs have a chondrostimulating, regenerating, anti-inflammatory and analgesic effect, have chondroprotective properties, enhance metabolic processes in hyaline and fibrous cartilage, subchondria bone; inhibit enzymes that cause degradation (destruction) of articular cartilage; CS stimulates the production of proteoglycans by chondrocytes, helps to reduce the release of inflammatory mediators and pain factors into the synovial fluid, inhibits the secretion of leukotrienes and prostaglandins, slows down bone tissue resorption and reduces calcium loss, accelerates the processes of bone tissue restoration, slows down the progression of osteoarthrosis and osteochondrosis, helps to restore the articular bag and cartilaginous surfaces of the joints, prevents the collapse of the connective tissue, normalizes the production of joint fluid.

From the above data, it can be seen that cholesterol drugs in various forms are actively used for the treatment of arthrological diseases.

The problem of known drugs is the low bioavailability of chondroitin sulfate, which varies depending on the form of the drug and leads to low efficiency.

Studies show that the effectiveness of the use of chondroitin preparations occurs only with long-term constant use of their course for 3, 6 or 9 months, which leads to an increased risk of side effects due to the duration of use.

Such a long course is often accompanied by the following side effects: allergic reactions, swelling, redness and even inflammation at the injection site due to repeated administration.

Disclosure of invention

The subject of the present invention is an agent for the treatment of arthrological diseases, comprising an effective amount of sodium chondroitin sulfate and at least one excipient or carrier, characterized in that it additionally contains molybdenum in a relative amount of 0.1 to 15 mg/kg, calculated on the mass of the active substances - chondroitin sulfate sodium.

The technical result of the present invention is to increase the bioavailability of chondroitin sulfate preparations in various forms, achieved through its use in combination with molybdenum, to reduce the course of treatment and reduce negative side effects.

The use of the agent according to the invention also leads to the normalization of metabolic processes, the acceleration of the removal of edema in case of injuries and/or injections, and a faster regeneration process.

It was found that the introduction of certain (relatively small) doses of molybdenum into compositions containing chondoitin sulfate as an active ingredient significantly increases the therapeutic efficacy of the composition.

This effect of the combination of molybdenum and chondroitin sulfate in the composition is unexpected, although it is known that molybdenum is part of such enzymes as aldehyde hydroxidase, sulfite oxidase.

Sulfite oxidase is necessary for the normal course of protein metabolism in the body. Molybdenoenzymes perform complex catalytic reactions in the metabolism; anabolic reactions in the body are impossible without their participation.

Molybdenum activates the enzyme xanthine oxidase involved in nitrogen metabolism.

The trace element takes an active part in the processes of hematopoiesis. Without molybdenum, the synthesis of red blood cells is impossible, it is responsible for the metabolism of iron in the body, its use to build hemoglobin.

Molybdenum affects the formation of sulfur-containing amino acids and their further use in the work of the higher nervous system.

Another important function of molybdenum in the body is the protection of vitamins and biologically active substances.

- 2 041403 substances from premature destruction. The element activates the antioxidant effect of ascorbic acid.

Molybdenum also affects the condition of bone and dental tissue. Under its influence, the body loses fluoride from tooth enamel more slowly, and teeth are less susceptible to caries.

According to known studies, there is no noticeable accumulation of molybdenum in the human body. Soluble molybdenum compounds are excreted from the body with urine and feces.

The daily norm of molybdenum is 2 mcg / kg, i.e. for an adult, the daily requirement is about 150 micrograms. A dose of 5 mg of molybdenum is toxic to humans, and 50 mg is lethal.

With an excess content of molybdenum in food, the formation of purine bases, which are included in nucleic acids, increases. If the kidneys cannot cope with their excretion, then excess uric acid accumulates in the body, which, being deposited in the cartilage and tendons, causes the development of gout.

As a rule, known means of molybdenum are vitamin complexes or dietary supplements.

Thus, a vitamin-mineral complex is known that contains vitamins B1, B2, B3 (nicotinamide), B5 (calcium pantothenate), B6, B9 (folic acid), B12, A, C, D3, E and minerals magnesium, copper, iodine, iron, molybdenum, selenium, calcium, chromium, divided taking into account their mutual influence into two solid preparative forms taken at different times, characterized in that it additionally contains lycopene and β-carotene, minerals zinc, phosphorus and manganese as vitamins. The first solid formulation contains B1, B2, B3 (nicotinamide), B5 (calcium pantothenate), B6, B9 (folic acid), B12 and minerals iodine, magnesium, copper, iron, molybdenum (see RU 2275192).

Known means for the maintenance therapy of diseases of the cardiovascular system, characterized in that it contains as active ingredients vitamins, bioflavonoids, micro- and macroelements, extracts of medicinal plants, a complex of red grape polyphenols, broccoli concentrate, borage oil, L-cysteine, L -glutathione, DL-methionine and targeted additives cellulose, silicon dioxide, stearic acid, magnesium stearate, hydroxypropyl methylcellulose. The agent is made in the form of a tablet containing, among other components, molybdenum in the amount of 40.5-49.5 μg (see RU 2292901).

Known composition with antioxidant activity, containing from 10 to 90 wt.% gel from the leaves of aloe vera; from 5 to 50 wt.% grape juice; from 0.1 to 5 wt.% green tea extract; from 0.01 to 0.2 wt.% of a vitamin mixture containing vitamin B1, vitamin B9 (folic acid), vitamin B12 and vitamin E; from 0.01 to 0.1 wt.% chlorophyll; from 0.05 to 0.15 wt.% coenzyme Q10; from 0.01 to 0.1 wt.% choline; from 0.005 to 0.015 wt.% selenium; and from 0.005 to 0.1 wt.% of an extract from a node of wheat containing 10% resveratrol. The complex in a specific embodiment also contains trace elements: selenium (Se), chromium (Cr), cobalt (Co), iron (Fe), iodine (I), copper (Cu), manganese (Mn), molybdenum (Mo) and zinc ( Zn) (see RU 2630579).

Means, according to the stated purpose, containing molybdenum in their composition, have not been identified from the prior art.

As will be shown in the examples below, the independent use of molybdenum in the indicated concentrations does not lead to the manifestation of a significantly significant effect. Molybdenum does not have independent therapeutic activity in relation to arthrological diseases.

As part of this drug, molybdenum helps to increase the bioavailability of chondroitin sulfate and significantly increases the effectiveness of the latter through the use of the composition.

As part of the product according to the invention, molybdenum is used in the form of a chelate.

The choice of a specific molybdenum chelate is determined by the specific dosage form.

So, for adding to preparations in the form of tablets, capsules, ointments and creams, various chelated forms of molybdenum can be used, for example, Country Life, Molybdenum, chelated [https://zavitaminom.ru/product/country-life-molibden-helatnyj-150- mkg-100-tabletok] or molybdenum amino acid chelates [https://ru.luckyvitamin.com/p-353556-kal-molybdenum-amino-acid-chelate-250-mcg-100micro-tablets].

For use in injectable forms, substances containing molybdenum are required, which are completely soluble in water. These include, for example, crystals of ammonium molybdate. They are suitable for use in lyophilized powder and for solution preparation.

Crystals of ammonium molybdate in aqueous solutions undergo complete hydrolysis. For this reason, this substance is the most convenient means for the preparation of injection solutions.

Molybdates of alkali and alkaline earth metals, such as, for example, potassium, sodium, calcium, magnesium molybdate, can also be used in the context of the present invention.

The agent of the present invention includes molybdenum chelate in a relative amount of 0.1 to 15 mg/kg, calculated on the weight of the active substance - chondroitin sulfate.

In a particular embodiment, in a relative amount of from 0.2 to 10 mg/kg, and also from 0.3 to 8 mg/kg, calculated on the weight of the active substance.

- 3 041403

In a private variant, in a relative amount of 0.4 to 6 mg/kg, and also from 0.5 to 4 mg/kg, and also from 0.2 to 2 mg/kg, and also from 0.15 to 2 mg/kg kg, as well as from 7 to 10 mg/kg, as well as from 4 to 8 mg/kg, calculated on the weight of the active substance.

In a particular variant, in a relative amount from 1 to 8 mg/kg, and also from 2 to 8 mg/kg, and also from 3 to 8 mg/kg, and also from 4 to 8 mg/kg, and also from 5 to 8 mg/kg in terms of the mass of the active substance.

In a private variant, in a relative amount from 0.1 to 0.8 mg/kg, and also from 0.2 to 0.8 mg/kg, and also from 3 to 0.8 mg/kg, and also from 4 to 0 .8 mg / kg, as well as from 5 to 0.8 mg / kg, calculated on the mass of the active substance.

In a particular variant, in a relative amount of from 1 to 6 mg/kg, and also from 2 to 6 mg/kg, and also from 3 to 6 mg/kg, and also from 4 to 6 mg/kg, calculated on the weight of the active substance.

In a particular variant, in a relative amount of from 1 to 5 mg/kg, and also from 2 to 5 mg/kg, and also from 3 to 5 mg/kg, calculated on the weight of the active substance.

In a particular variant, in a relative amount of 2 to 10 mg/kg, as well as from 3 to 10 mg/kg, as well as from 4 to 10 mg/kg, as well as from 5 to 10 mg/kg, from 6 to 10 mg/kg kg, as well as from 8 to 10 mg/kg in terms of the mass of the active substance.

In a private variant, in a relative amount of 2 to 12 mg/kg, as well as from 3 to 12 mg/kg, as well as from 4 to 12 mg/kg, as well as from 5 to 12 mg/kg, from 6 to 12 mg/kg kg, as well as from 8 to 12 mg/kg in terms of the mass of the active substance.

In a particular variant, in a relative amount of 2 to 15 mg/kg, and also from 3 to 15 mg/kg, and also from 4 to 15 mg/kg, and also from 5 to 15 mg/kg, from 6 to 15 mg/kg kg, as well as from 8 to 15 mg/kg in terms of the mass of the active substance.

The proposed concentrations of molybdenum chelate turned out to be optimal for solving the problem.

The amount of chondroitin sulfate sodium in the product can be from 50 to 2500 mg.

The amount of chondroitin sulfate sodium in the product can be from 2000 to 2500 mg.

The amount of chondroitin sulfate sodium in the product can be from 1500 to 2500 mg.

The amount of chondroitin sulfate sodium in the product can be from 1000 to 2500 mg.

The amount of chondroitin sulfate sodium in the product can be from 100 to 2000 mg.

The amount of chondroitin sulfate sodium in the product can be from 1500 to 2000 mg.

The amount of chondroitin sulfate sodium in the product can be from 1000 to 2000 mg.

The amount of chondroitin sulfate sodium in the product can be from 500 to 2000 mg.

The amount of chondroitin sulfate sodium in the product can be from 300 to 1500 mg.

The amount of chondroitin sulfate sodium in the product can be from 1000 to 1500 mg.

The amount of chondroitin sulfate sodium in the product can be from 500 to 1500 mg.

The amount of chondroitin sulfate sodium in the product can be from 800 to 1500 mg.

The amount of chondroitin sulfate sodium in the product can be from 500 to 1200 mg.

The amount of chondroitin sulfate sodium in the product can be from 50 to 250 mg.

The amount of chondroitin sulfate sodium in the product can be from 50 to 100 mg.

The amount of chondroitin sulfate sodium in the product can be from 50 to 150 mg.

The amount of chondroitin sulfate sodium in the product can be from 50 to 300 mg.

The amount of chondroitin sulfate sodium in the product can be from 50 to 350 mg.

The amount of chondroitin sulfate sodium in the product can be from 100 to 400 mg.

The amount of chondroitin sulfate sodium in the product can be from 150 to 450 mg.

The amount of chondroitin sulfate sodium in the product can be from 250 to 1000 mg.

The mass ratio of sodium chondroitin sulfate to molybdenum can be 1:1x10'7 1:1x10'5.

The agent of the present invention may be in liquid or solid form.

The tool can be used for oral, injection or topical application.

Forms intended for topical use include creams, gels and ointments.

Oral forms include tablets and capsules.

Injectable forms include lyophilisates and injectable solutions.

Auxiliary components are selected depending on the form of manufacture.

The tool, made in the form of a cream, gel or ointment, may contain one or more excipients selected from the group of dimethyl sulfoxide; propylene glycol; carbomer; trolamine; macrogol; edetat; neroli and lavender oils; lanolin; petrolatum.

The tool, made in the form of a tablet, may additionally contain glucosamine hydrochloride.

In a private embodiment, the ratio of chondroitin sulfate sodium and glucosamine hydrochloride in a tablet is 1:1.

The tablet may additionally contain the following excipients, taken in relation to sodium chondroitin sulfate: disubstituted calcium sulfate - 1:0.46, microcrystalline cellulose - 1:0.37, croscarmellose sodium - 1:0.16, stearic acid - 1:0.14, magnesium stearate 1:0.02.

In a private embodiment, the tablet can be film-coated, in which case the tablet shell has the following composition, taken in relation to sodium chondroitin sulfate: hydroxypropyl methylcellulose - 1: 0.07, titanium dioxide (E171) - 1: 0.016, triacetin - 1: 0.014.

The agent, made in the form of a capsule, may additionally contain excipients selected from the group of talc, stearic acid, magnesium stearate, manganese sulfate.

The composition of the capsule shell may include titanium dioxide and gelatin.

The tool, made in the form of a solution, contains water in its composition.

More specifically, the product contains distilled or pyrogen-free water.

The finished product may include in its composition a certain amount of preservatives, such as benzyl alcohol and sodium benzoate or the like.

The specific ratios of the components are determined by the form of manufacture and the severity of the disease.

The claimed agent is intended for the treatment of arthrological diseases.

Such diseases include degenerative-dystrophic diseases of the joints and spine: osteoarthritis of peripheral joints; intervertebral osteochondrosis and osteoarthritis, rheumatoid arthritis, gout, reactive arthritis, spondyloarthropathies, arthritis in systemic lupus erythematosus, dermatomyositis and other systemic diseases, psoriatic arthritis, post-traumatic damage to articular cartilage, ligaments, menisci.

List of figures

Fig. 1 - X-ray of the knee joints of rabbits of groups I and V;

fig. 2 - radiograph of the knee joints of rabbits treated intraarticularly in the right (R) joint with papain and preparations A and B. The left (L) joint is intact;

fig. 3 - X-ray of the knee joints of rabbits of group IV, treated intra-articularly with papain and the control drug (comparison) in the right (R) joint;

fig. 4 - articular cartilage of the knee joint of a rabbit of group I;

fig. 5 - synovial membrane of the right knee joint of a rabbit of group I;

fig. 6 - articular cartilage of the rabbit knee joint after intramuscular injection of preparation A, preparation B, saline (C).

Implementation of the invention

Below are examples of the preparation of various drugs based on the claimed means of chondroitin sulfate.

Example 1

A gel preparation containing sodium chondroitin sulfate, purified water, which additionally contains molybdenum chelate from 0.10 to 15 mg/kg, can be obtained using various excipients.

1. The preparation in the form of a gel is obtained by first forming solution A, mixing purified water and carbomer, which is taken in a volume of 3% of the total mass. Then solution B is formed by dissolving methyl parahydroxybenzoate in ethanol, where ethanol and methyl parahydroxybenzoate are taken in a volume of 10% and 0.1% of the total mass, respectively. To obtain solution B, 2 g of chondroitin sulfate, dimethyl sulfoxide - 7.5; propylene glycol - 7.5; trolamine (triethanolamine) - 3; macrogol glycerylhydroxystearate - 0.4; disodium edetate - 0.1. After that, solutions A, B, C are constantly stirred for several hours until a gel mass is formed, adding ammonium molybdate 0.0005% of the total mass. If necessary, add flavors (wt./vol.%): lavender oil - 0.1; orange blossom oil (neroli oil) - 0.05. The resulting finished composition of the drug in the form of a gel contains (wt./vol.%): chondroitin sulfate - 5; ethanol - 10; dimethyl sulfoxide - 7.5; propylene glycol - 7.5; carbomer - 3; trolamine (triethanolamine) - 3; macrogol glycerylhydroxystearate - 0.4; disodium edetate - 0.1; methyl parahydroxybenzoate (methylparaben, nipagin) 0.1; lavender oil - 0.1; orange blossom oil (neroli oil) - 0.05; ammonium molybdate - 0.0005; purified water - the rest up to 100.

2. Solution A is obtained by adding 10 g of carbomer to 120 ml of purified water, followed by stirring. To obtain solution B, 0.2 g of methyl parahydroxybenzoate is dissolved in 60 g of ethanol. Solution B is prepared by stirring with heating to a temperature of 70°C in 181.6 ml of purified water, 2 g of chondroitin sulfate, 2 g of glucosamine sulfate, 4 g of methylsulfonylmethane, 0.04 g of sodium metabisulphite, 20 g of propylene glycol. After that, solutions A, B, C are constantly stirred for several hours until a gel mass is formed, adding ammonium molybdate 0.0002% of the total mass. If necessary, add a fragrance in the amount of 0.2 g. glucosamine sulfate - 0.5; methylsulfonylmethane - 1.0; sodium metabisulphite - 0.01; methyl parahydroxybenzoate - 0.05; propylene glycol - 5.0; ethanol - 15.0; carbomer - 2.5; fragrance - 0.05; ammonium molybdate - 0.0002; purified water - the rest up to

- 5 041403

100.

Example 2

The preparation in the form of an ointment, including sodium chondroitin sulfate, purified water, which additionally contains molybdenum from 0.1 to 15 mg/kg, can also be obtained using various excipients.

1. Medical vaseline in an amount of 37 wt.%, anhydrous lanolin in an amount of 15 wt.%, stearic acid in an amount of 3 wt.%, pentol in an amount of 5 wt.% are melted at a temperature of (70 ± 2) ° C, mixed, then cooled to a temperature of (55±2)°C (ointment base). Chondroitin sulfate in an amount of 5 wt.% is dissolved in 20 wt.% distilled water. Diclofenac sodium in an amount of 5 wt.% is dissolved in 10 wt.% dimethyl sulfoxide. Ammonium molybdate 0.00005% of the total mass is added to solutions of sodium diclofenac in dimethyl sulfoxide and chondroitin sulfate in water with stirring, the resulting substance is added to the ointment base, homogenized, and then transferred to packaging. Get the finished ointment having the composition (wt./vol.%): chondroitin sulfate sodium (in terms of dry matter) - 5; dimethyl sulfoxide - 10; diclofenac sodium - 5; lanolin - 0.15; vaseline 0.5; ammonium molybdate - 0.00005; purified water - the rest up to 100.

2. Medical vaseline in the amount of 37 wt.%, anhydrous lanolin in the amount of 15 wt.%, stearic acid in the amount of 3 wt.%, pentol in the amount of 5 wt.% are melted at a temperature of (70 ± 2) ° C, mixed, then cooled to a temperature of (55±2)°C (ointment base). Chondroitin sulfate in an amount of 5 wt.% is dissolved in 20 wt.% distilled water. Diclofenac sodium in an amount of 5 wt.% is dissolved in 10 wt.% dimethyl sulfoxide. Ammonium molybdate is added to solutions of sodium diclofenac in dimethyl sulfoxide and chondroitin sulfate in water with stirring to 0.0002% of the total mass, the resulting substance is added to the ointment base, homogenized, and then transferred to packaging. Get the finished ointment having the composition (wt./vol.%): chondroitin sulfate sodium (in terms of dry matter) - 5; dimethyl sulfoxide - 10; diclofenac sodium - 5; lanolin - 0.15; vaseline 0.5; ammonium molybdate - 0.0002; purified water - the rest up to 100.

Example 3

The drug contains 95-120 mg of lyophilized powder of Na-salt of chondroitin sulfate, which is obtained from the sodium salt of chondroitin sulfate dissolved in pyrogen-free injection water.

The injection solution prepared from the said lyophilizate using pyrogen-free water contains Na-salt of chondroitin sulfate in a therapeutic dosage of 9.0-11.5 wt.%.

The preparation can be obtained, for example, in the following way.

A substance with a sodium salt content of chondroitin sulfate of 96.2-97.1% is dissolved in 1000 ml of pyrogen-free injection water, the pH is set from 6.0 to 7.5 with sodium hydroxide solution, after which the mixture is saturated with ammonium molybdate to the level 0.01-1.0 mg/l of the mixture, then sterilizing filtration is carried out, poured into 1 ml ampoules and sublimation is carried out in a known manner, the ampoules with the lyophilized drug are sealed.

1. 104 g of a substance containing 96.2% sodium salt of chondroitin sulfate is dissolved in 1000 ml of pyrogen-free injection water, pH is adjusted from 6.0 to 7.5 with sodium hydroxide solution. Then, in relation to the resulting mixture, the process of saturation with ammonium molybdate to a level of 0.10 mg/l of the mixture is carried out. Then the process of sterilizing filtration is carried out, poured into 1 ml ampoules and sublimation is carried out in a known manner. Ampoules with lyophilized drug are sealed. 103 mg of lyophilized powder is obtained in 1 ampoule, which corresponds to 99.7 mg of the sodium salt of chondroitin sulfate, the residual moisture is the rest, which, when dissolved in 1 ml of injection water, will give a solution with an active substance content of 9.97%.

2. 103 g of a substance containing 96.2% sodium salt of chondroitin sulfate is dissolved in 1000 ml of pyrogen-free injection water, the pH is adjusted from 6.0 to 7.5 with sodium hydroxide solution. Then, in relation to the resulting mixture, the process of saturation with ammonium molybdate to a level of 0.50 mg/l of the mixture is carried out. Then the process of sterilizing filtration is carried out, poured into 1 ml ampoules and sublimation is carried out in a known manner. Ampoules with lyophilized drug are sealed. 102 mg of lyophilized powder is obtained in 1 ampoule, which corresponds to 99.7 mg of the sodium salt of chondroitin sulfate, the residual moisture is the rest, which, when dissolved in 1 ml of injection water, will give a solution with an active substance content of 9.97%.

Example 4

Tablet containing chondroitin sulfate. The composition in the form of a tablet can be prepared as follows: weighed chondroitin sulfate sodium, glucosamine hydrochloride in a ratio of 1:1, molybdenum chelate from 0.10 to 10 mg/kg are mixed in a drum-type mixer. The resulting mixture is molded and pressed, then dried to the required residual moisture and calibrated. Then they are enclosed in a hard shell, which may have a composition taken in relation to sodium chondroitin sulfate: hydroxypropyl methylcellulose - 1: 0.07, titanium dioxide (E171) - 1: 0.016, triacetin - 1: 0.014 mg. Also, the tablet may additionally contain excipients taken in relation to

- 6 041403 chondroitin sulfate sodium: disubstituted calcium sulfate - 1:0.46, microcrystalline cellulose - 1:0.37 mg, croscarmellose sodium - 1:0.16, stearic acid - 1:0.14, magnesium stearate - 1: 0.02.

1. Tablet containing chondroitin sulfate. The composition in the form of a tablet can be prepared as follows: weighed chondroitin sulfate sodium - 250 mg, sodium molybdate - 0.6 mg/kg; calcium stearate - 1:0.019; crospovidone - 1:0.05; povidone K30 - 1:0.04; microcrystalline cellulose 1:0.38; magnesium bicarbonate pentahydrate - 1:0.429 is mixed in a drum mixer. The resulting mixture is molded and pressed, then dried to the required residual moisture and calibrated.

2. Tablet containing chondroitin sulfate and glucosamine hydrochloride. The composition in the form of a coated tablet can be prepared as follows: sodium chondroitin sulfate, glucosamine hydrochloride in a ratio of 1:1.25; sodium molybdate - 0.2 mg/kg; methylsulfonylmethane 1:0.75. Cellulose can also be added - 1:0.50; calcium hydrophosphate dihydrate - 1:0.3; stearic acid - 1:0.18; croscarmellose sodium - 1:0.125; magnesium stearate - 1:0.025; colloidal silicon dioxide - 1:0.01. The resulting mixture is molded and pressed, then dried to the required residual moisture and calibrated. Then they are enclosed in a shell, which may have the following composition, taken in relation to the amount of chondroitin sulfate: hypromellose - 1:0.04; polydextrose - 1:0.02; titanium dioxide - 1:0.0001; talc - 1:0.02; maltodextrin - 1:0.0117; triglycerides - 1:0.0015; E110 - 1:0.0023.

The above examples show that the preparation of preparations can be implemented using various excipients that do not affect the final result, since the functional role of the agent for the treatment of arthrological diseases and the achievement of the claimed technical result is determined by the active substance based on sodium chondroitin sulfate, to which molybdenum is additionally added from 0.1 to 10 mg/kg.

Microbiological control of contamination in solid form was carried out. In particular, after 6 months and 12 months of storage of the finished form, no significant changes were detected.

Example 5

The effectiveness of chondroitin sulfate preparations.

1. The effectiveness of products in the form of a gel or ointment, including sodium cholesterol, purified water, molybdenum chelate from 0.1 to 10 mg/kg, was tested on rabbits.

The studied samples were applied to animals several times. The activity was assessed on the model of destruction, which was caused by 6 injections of papain with an interval of 5 days into the cavity of the right knee joint at a dose of 50 mg per injection (1 ml of a 5% solution) - I, II, III, IV, V groups of 10 rabbits in each.

Experimental animals were applied to the knee joint with light rubbing daily for 15 days for groups I and II - the studied samples of ointment (ammonium molybdate concentration 0.04 mg/l) and gel (ammonium molybdate concentration 0.1 mg/l), respectively, for Group III - chondroitin sulfate ointment, not containing molybdenum, for group IV - ammonium molybdate solution 0.1 mg/l, for control group V - isotonic sodium chloride solution.

The severity of edema was assessed by measuring its thickness before and after administration of papain.

When applied on the skin in groups I, II, III after 15 days, there was a decrease in the severity of swelling of the knee joint in comparison with the control groups by 1.9 times.

A pronounced anti-inflammatory effect from the use of the agents studied according to the invention (ointment and gel) and an ointment that does not contain molybdenum was observed in groups I, II, III and did not appear in control groups IV, V.

With a longer observation, it was noted that groups I and II showed more active regeneration than group III.

In particular, out of 10 rabbits of each of groups I, II, III, in 9 out of 10 in group I, in 8 out of 10 in group II, complete regeneration of bone tissue was recorded after 35 days, and in group III, only 6 out of 10.

2. The effectiveness of injection forms.

The effectiveness of injectable similar forms of cholesterol containing molybdenum was studied and compared with the effect of injections of a cholesterol preparation that did not contain molybdenum.

Namely, they used

A) an agent for the treatment of arthrological diseases, which is a preparation in the form of a lyophilized powder of Na-salt of chondroitin sulfate and residual moisture, containing ammonium molybdate 0.1 mg/ml,

B) an agent for the treatment of arthrological diseases, which is a preparation in the form of a solution for intramuscular injection, including Na-salt of chondroitin sulfate, purified water, containing ammonium molybdate 0.2 mg / ml,

B) control preparation: an agent for the treatment of arthrological diseases, which is a preparation in the form of a solution for intramuscular injection, including Na-salt of chondroitin sulfate, purified water.

- 7 041403

At the same time, the tested injection solution was prepared once, stored under standard conditions, and administered, including after storage. Thus, the drug was administered after 12 and 25 weeks of storage. At the same time, according to the results of a biochemical study of connective tissue components by spectrophotometry, no difference was found in the use of the drug immediately after its manufacture and after its storage (under standard conditions for 12 and 25 weeks). Standard control methods were used.

The study of preparations A and B was tested on 70 white rats of different sexes and an initial weight of 250-300 g. The animals were divided into 5 groups of 14 animals each.

The drug according to A and B variants of the invention was administered intramuscularly at doses of 0.25 and 0.5 g/kg and intravenously at doses of 0.1 and 0.25 g/kg.

Experimental batches of the dosage form of the drug were used. According to option A, the solution for administration was prepared on the basis of a lyophilized powder obtained according to the claimed invention.

Control animals received the reference drug at the same doses intravenously and intramuscularly.

The effect of the drug on the course of the inflammatory process was assessed by the change in the magnitude of the inflammatory edema of the limb (oncometrically), by the content of leukocytes and eosinophils in the blood.

The strength of the skin scar in rats was assessed by two indicators - the force that causes the rupture of the scar, and the relative elongation at break, which characterizes the elasticity of the tissue.

The effect of drugs on wound healing was studied on a model of a flat-bone skin wound.

Pathological and histochemical studies of the joints were performed randomly.

The material (synovium, articular cartilage of the knee joint) was fixed, embedded in paraffin, stained with hematoxylin-eosin, and total GAGs were determined with safranin-T. For separate detection of cholesterol, alcian blue staining was used on acetate buffer (pH 5.8) with different contents of MgCl ₂ (0.4M MgCl ₂ when reacting to cholesterol).

The GAG content was assessed visually in points. Thus, the absence of staining with safranin was considered as subthreshold (minimum) for this dye (-). The content of GAGs is focal, light red staining, as a low content of GAGs (+), diffuse light red, as moderate (++), diffuse bright red, pronounced (+++). No alcian blue staining (-), pale blue staining as low (+), blue as moderate (++), bright blue as significant (+++).

Destruction was caused by 6 injections of papain.

Rats of I, II, III, IV groups were intravenously injected with papain at 10 mg/kg (1% solution) - 4 injections with an interval of 3-4 days.

Animals of the V (control) group received physiological saline at the same time.

A day after the last injection of papain, the rats of group II began to receive intramuscular injection of preparation A, 0.5 ml daily for a month.

Rats of group III received intramuscularly preparation B at the same time, 0.5 ml. Rats of group IV received intramuscularly at the same time a control preparation of 0.5 ml.

At the end of the experiment, the rats were killed. The costal cartilages were separated, cleaned of soft tissues, dried with acetone, and the total GAG content was determined in them according to the method of D.V. Kosyagin. [Kosyagin D.V. Issues of medical chemistry, 1982, 28, 4, 68-71 pp.].

The results of the studies have shown that the GAG content in the costal cartilage of rats decreases slightly after the administration of papain. According to the norm, it is equal to 14.25±2.7 mg of uronic acid per 1 g of dry tissue; in untreated rats of group I, the decrease in GAG was 15% (12.11±2.4 mg/g).

With the introduction of drug B, the content of GAG increased and was above the norm to the level of 17.98±3.16 mg/g.

In rats treated with drug A, the GAG content was also higher than in control animals (18.54±3.01 mg/g).

In rats treated with the control preparation, the content of GAGs also turned out to be higher than in control animals (17.20±3.12 mg/g).

Thus, the results of experiments on rats showed that drug A and drug B have a chondroprotective effect in case of damage to cartilage tissue by papain, simulating the accumulation of GAG in the costal cartilages of rats better than the control drug.

Evaluation of the effect of drugs on destructive changes in the joint in rabbits.

In the experiments, 35 male chinchilla rabbits weighing 2.1-2.6 kg were used. Destruction was caused by 6 injections of papain with an interval of 5 days into the cavity of the right knee joint at a dose of 50 mg per injection (1 ml of a 5% solution) - groups I, II, III, IV, 7 rabbits each. Group V rabbits received intra-articular injection of 1.0 ml of saline, after which a natural increase in the circumference of the joint was recorded, intra-articular injection of 1.0 ml of saline - group V (7 rabbits).

Within 2 months, rabbits of group I were injected with saline, group II - preparation A

- 8 041403, 1.0 ml 3 times a week, group III - preparation B, 1.0 ml 3 times a week, group IV (control) - 1.0 ml of the reference preparation.

The drugs were administered intramuscularly. Thus, the chondroprotective effect of preparations A and B and the control preparation were studied in order to evaluate the therapeutic effect of the influence of the molybdenum + complex.

cholesterol and compare it with a cholesterol-based drug (Mukosat), which has also proven effective.

The circumference of the joint edema increased after papain injections. By the end of the second month of the experiment, the joint circumference in rabbits of group I (without treatment) was significantly increased (more than 18 mm). In groups II, III, who received drugs A and B, the edema was slightly less - 6.4±1.3 mm and 6.2±1.1 mm, respectively, compared with group IV, which received the reference drug (8, 2 ± 1.5).

In rabbits of group I, who received only papain, by the end of 2 months, the GAG content was 13.01 mg/ml, which indicated the destruction of cartilage tissue. In animals treated with drugs A, B and control, the level of GAG was 6.72 mg/ml, 7.04 mg/ml and 7.86 mg/ml, respectively, from which it was concluded that destructive processes were less pronounced. The condition of group V was expressed within the increment of 3.08 mg/ml.

Pathological changes in the joints of rabbits of group I (without treatment) were recorded during X-ray examination.

In FIG. 1 shows a radiograph of the knee joints of rabbits of groups I and V (two months of experience). Injections into the right (R) joint. Left (L) intact.

A - rabbit No. 1 - group V. XS solution. Both joints are unchanged.

B - rabbit No. 2 - group I without treatment (intra-articular papain); P - signs of arthritis-arthrosis, destructive changes in the condyles of the femur; L - no change.

B - rabbit No. 3 - group I without treatment (papain intra-articular); P - synovitis; L - no change.

In FIG. Figure 2 shows a radiograph of the knee joints of rabbits treated intraarticularly with papain and preparations A and B in the right (R) joint. The left (L) joint is intact. Experience 2 months.

A - rabbit number 4 - group II. Both joints are unchanged.

B - rabbit No. 5 - IV group. Both joints are unchanged.

In FIG. 3 shows a radiograph of the knee joints of rabbits of group IV, which received intra-articular papain and the control drug (comparison) in the right (R) joint. The left joint (L) is intact. Experience 2 months.

A - rabbit No. 6 - P - arthritis, osteoporosis; L - no change.

B - rabbit No. 7 - both joints unchanged.

General data on the results of observations by the end of 2 months are summarized in the table.

Type of destruction The number of rabbits in which destruction was revealed by the end of the experiments I group II group III group IV group Arthritis 2 0 1 2 Arthrosis 3 0 0 0 Synovitis 2 0 0 0 Osteoporosis 3 0 0 2

It can be seen from them that in group I, destructive changes persisted by the 2nd month in each rabbit. Most of the rabbits in this group had pronounced complex signs of arthritis-arthrosis and arthritis-osteoporosis.

In groups II and III, treated with preparations A and B, only 1 rabbit from group III showed signs of arthritis. In group IV rabbits treated intraarticularly with papain and intramuscularly, a good therapeutic effect was also observed, and only 2 rabbits had arthritis and osteoporosis at the same time. All other rabbits of groups II, III, IV showed no changes in the joints.

According to the results of the study, it can be concluded that the introduction of drugs A and B prevented the development of pathological changes in the joints, as well as the use of the control drug of comparison, but the effect of drugs A and B is more pronounced than that of the control based on cholesterol.

The positive effect of the action of drugs A and B was also confirmed by pathomorphological studies.

An autopsy of rabbits of group I showed that each of them had pronounced signs of destruction of the articular cartilage in the right joint (see Figs. 4 and 5).

In FIG. 4 shows the articular cartilage of the knee joint of a group I rabbit.

A. After intra-articular injection of papain solution. Usurs are visible, penetrating to the middle of the intermediate layer. Proliferation of chondrocytes alternates with areas of devastation. There is a decrease in GAG. Stained with safranin - T. 10x6.3.

B. Control. The histological structure of the cartilage is preserved. The amount of GAG is normal. Stained with safranin - T. 10x6.3.

- 9 041403

In FIG. 5 shows the synovial membrane of the right knee joint of a group I rabbit.

A - after intra-articular administration of papain. Severe hyperplasia of the synovial membrane, synoviocytes are large, located loosely, form 5-5 layers. In the subsynovial layer, the proliferation of histicites, fibroblasts and diffuse macrofocal plasmacytic infiltration are visible. Hem.eosin 25x6.3.

B - control - normal structure.

At autopsy of rabbits II, III (see Fig. 6), the surface of the articular cartilage was smooth and shiny.

In FIG. 6 shows the articular cartilage of the rabbit knee joint after intramuscular injection of preparation A, preparation B, saline (C).

A and B show increased proliferation of chondrocytes with a significant increase in GAG in the matrix.

B. The histological structure is preserved. Group V. Safranin - T 25x6.6.

In 2 rabbits of group IV, who received the control Mucosat simultaneously with papain intramuscularly, a small amount of serous exudate was found in the joint cavity. And all the rabbits of this group had a smooth and shiny surface of the articular cartilage.

These studies show that preparations A and B have the best effect on bone tissue regeneration, while biochemically and immunologically in these groups of animals, redness at the injection site, manifestations of allergic reactions and other side effects were not recorded. Studies on the used model can be used with known certainty to conclude on the effect on the human body.

Example 5. The effectiveness of chondroitin sulfate preparations.

Studies have been carried out on preparations in the form of a gel of the following composition:

preparation A: gel containing chondroitin sulfate -100 mg; ethanol - 1000 mg; dimethyl sulfoxide 75 mg; propylene glycol - 75 mg; carbomer - 300 mg; trolamine -300 mg; macrogol glycerylhydroxystearate - 40 mg; disodium edetate - 10 mg; methyl parahydroxybenzoate - 10 mg; lavender oil - 10 mg; orange blossom oil -5 mg; ammonium molybdate - 0.000015 mg; water up to 10000 mg;

drug B: gel containing chondroitin sulfate -100 mg; ethanol - 1000 mg; dimethyl sulfoxide 75 mg; propylene glycol - 75 mg; carbomer - 300 mg; trolamine -300 mg; macrogol glycerylhydroxystearate - 40 mg; disodium edetate - 10 mg; methyl parahydroxybenzoate - 10 mg; lavender oil - 10 mg; orange blossom oil -5 mg; ammonium molybdate - 0.00005 mg; water up to 10000 mg;

drug B: gel containing chondroitin sulfate -300 mg; ethanol - 1000 mg; dimethyl sulfoxide 75 mg; propylene glycol - 75 mg; carbomer - 300 mg; trolamine -300 mg; macrogol glycerylhydroxystearate - 40 mg; disodium edetate - 10 mg; methyl parahydroxybenzoate - 10 mg; lavender oil - 10 mg; orange blossom oil -5 mg; ammonium molybdate - 0.0003 mg; water up to 10000 mg;

drug D: gel containing chondroitin sulfate -500 mg; ethanol - 1000 mg; dimethyl sulfoxide 75 mg; propylene glycol - 75 mg; carbomer - 300 mg; trolamine -300 mg; macrogol glycerylhydroxystearate - 40 mg; disodium edetate - 10 mg; methyl parahydroxybenzoate - 10 mg; lavender oil - 10 mg; orange blossom oil -5 mg; ammonium molybdate - 0.001 mg; water up to 10000 mg;

reference drug A1: gel containing chondroitin sulfate - 100 mg; ethanol - 1000 mg; dimethyl sulfoxide - 75 mg; propylene glycol - 75 mg; carbomer -300 mg; trolamine - 300 mg; macrogol glycerylhydroxystearate - 40 mg; disodium edetate - 10 mg; methyl parahydroxybenzoate - 10 mg; lavender oil 10 mg; orange blossom oil - 5 mg; water up to 10000 mg;

reference drug B1: gel containing: chondroitin sulfate -100 mg; ethanol - 1000 mg; dimethyl sulfoxide - 75 mg; propylene glycol - 75 mg; carbomer - 300 mg; trolamine - 300 mg; macrogol glycerylhydroxystearate - 40 mg; disodium edetate - 10 mg; methyl parahydroxybenzoate - 10 mg; lavender oil 10 mg; orange blossom oil - 5 mg; water up to 10000 mg;

reference drug B1: gel containing chondroitin sulfate -300 mg; ethanol - 1000 mg; dimethyl sulfoxide - 75 mg; propylene glycol - 75 mg; carbomer -300 mg; trolamine - 300 mg; macrogol glycerylhydroxystearate - 40 mg; disodium edetate - 10 mg; methyl parahydroxybenzoate - 10 mg; lavender oil - 10 mg; orange blossom oil - 5 mg; water up to 10000 mg;

reference drug G1: gel containing chondroitin sulfate -500 mg; ethanol - 1000 mg; dimethyl sulfoxide - 75 mg; propylene glycol - 75 mg; carbomer - 300 mg; trolamine - 300 mg; macrogol glycerylhydroxystearate - 40 mg; disodium edetate - 10 mg; methyl parahydroxybenzoate - 10 mg; lavender oil 10 mg; orange blossom oil - 5 mg; water up to 10000 mg;

preparation D: ammonium molybdate solution 0.1 mg/l.

The effectiveness was tested on rabbits.

The total number of animals is 80. The animals were divided into 4 groups of 20 rabbits.

Group No. 1 compared the regenerative activity of preparations A and A1.

Group No. 2 compared the regenerative activity of preparations B and B1.

Group No. 3 compared the regenerative activity of preparations B and B1.

Group No. 4 compared the regenerative activity of preparations G and G1.

- 10 041403

In turn, the groups were divided into 4 subgroups. The same study design was used for all groups.

For group number 1.

Subgroup I received study drug A.

Subgroup II received the reference drug A1.

Subgroup III received drug D.

Subgroup IV received isotonic sodium chloride solution.

For group number 2.

Subgroup I received study drug B.

Subgroup II received the comparator B1.

Subgroup III received drug D.

Subgroup IV received isotonic sodium chloride solution.

For group number 3.

Subgroup I received study drug B.

Subgroup II received the comparator B1.

Subgroup III received drug D.

Subgroup IV received isotonic sodium chloride solution.

For group number 4.

Subgroup I received study drug D.

Subgroup II received the reference drug G1.

Subgroup III received drug D.

Subgroup IV received isotonic sodium chloride solution.

The activity was assessed on a model of destruction, which was caused by 6 injections of papain with an interval of 5 days into the cavity of the right knee joint at a dose of 50 mg per injection (1 ml of a 5% solution). One day after the last administration of papain, the rabbits were started to apply the test preparations and reference preparations skin-wise to the area of the knee joint.

The severity of edema was assessed by measuring its thickness before and after administration of papain for 25 days.

When applied on the skin in subgroups I and II of each group, after 15 days, there was a decrease in the severity of edema of the knee joint in comparison with III and IV subgroups. The average value is 2.3 times.

Thus, the anti-inflammatory effect from the use of the preparations according to the invention was observed in subgroups I and II and did not appear in III and IV. A similar effect was observed in all study groups. It was also noted that in subgroup I of all groups, the anti-inflammatory effect was more pronounced.

Additionally, the regenerative activity of preparations A, B, C, D was compared. It was found that the regenerative activity depends on the content of cholesterol and ammonium molybdate in the preparation. The higher this content, the more pronounced the regenerative effect.

The effectiveness of analogous forms of cholesterol containing and not containing molybdenum intended for injection was studied.

Namely, the following drugs were studied:

preparation A. Solution for intramuscular injection containing chondroitin sulfate - 100 mg; benzyl alcohol - 9 mg; magnesium molybdate - 0.000015 mg; water for injection - up to 1 ml;

drug A1. Solution for intramuscular injection containing chondroitin sulfate - 100 mg; benzyl alcohol - 9 mg; water for injection - up to 1 ml;

drug B. Solution for intramuscular injection containing chondroitin sulfate - 150 mg; benzyl alcohol - 9 mg; magnesium molybdate - 0.000075 mg; water for injection - up to 1 ml;

drug B1. Solution for intramuscular injection containing chondroitin sulfate - 150 mg; benzyl alcohol - 9 mg; water for injection - up to 1 ml;

drug B. Solution for intramuscular injection containing chondroitin sulfate - 200 mg; benzyl alcohol - 9 mg; magnesium molybdate - 0.0002 mg; water for injection - up to 1 ml;

drug B1. Solution for intramuscular injection containing chondroitin sulfate - 200 mg; benzyl alcohol - 9 mg; water for injection - up to 1 ml;

drug G. Solution for intramuscular injection containing chondroitin sulfate - 200 mg; benzyl alcohol - 9 mg; magnesium molybdate - 0.0004 mg; water for injection - up to 1 ml;

drug G1. Solution for intramuscular injection containing chondroitin sulfate - 200 mg; benzyl alcohol - 9 mg; water for injection - up to 1 ml.

At the same time, the tested injection solution was prepared once, stored under standard conditions, and administered, including after storage.

The study of the preparations was tested on 80 white rats of different sexes and with an initial weight of 250300 g. The animals were divided into 4 groups of 20 animals each.

Group No. 1 - preparations A and A1 were studied.

- 11 041403

Group No. 2 - preparations B and B1 were studied.

Group No. 3 - preparations B and B1 were studied.

Group No. 4 - preparations G and G1 were studied.

Experimental batches of the dosage form of the drug were used.

The effect of the drug on the course of the inflammatory process was assessed by the change in the magnitude of the inflammatory edema of the limb (oncometrically), by the content of leukocytes and eosinophils in the blood.

The strength of the skin scar in rats was evaluated by two indicators - the force that causes the scar to break, and the relative elongation at break, which characterizes the elasticity of the tissue.

The effect of drugs on wound healing was studied on a model of a flat-bone skin wound.

Pathological and histochemical studies of the joints were performed randomly.

The material (synovial membrane, articular cartilage of the knee joint) was fixed, embedded in paraffin, stained with hematoxylin-eosin, total GAGs were determined with safranin-T, for separate detection of cholesterol, alcian blue staining in acetate buffer (pH 5.8) with different contents of MgCl ₂ was used. (0.4M MgCl ₂ when reacting to cholesterol).

The GAG content was assessed visually in points. Thus, the absence of staining with safranin was considered as subthreshold (minimum) for this dye (-). The content of GAGs is focal, light red staining, as a low content of GAGs (+), diffuse light red, as moderate (++), diffuse bright red - pronounced (+++). No alcian blue staining (-), pale blue staining as low (+), blue as moderate (++), bright blue as significant (+++).

Destruction was caused by papain. By intravenous administration of 0.5 ml (1% solution) - 4 injections with an interval of 3-4 days.

For a comparative analysis of the effectiveness of the study drugs, each group was divided into 4 subgroups.

For group number 1.

Subgroup I received papain.

Subgroup II received papain and study drug A.

Subgroup III received papain and comparator A1.

Subgroup IV received saline.

For group number 2.

Subgroup I received papain.

Subgroup II received papain and study drug B.

Subgroup III received papain and comparator B1.

Subgroup IV received saline.

For group number 3.

Subgroup I received papain.

Subgroup II received papain and study drug B.

Subgroup III received papain and comparator B1.

Subgroup IV received saline.

For group number 4.

Subgroup I received papain.

Subgroup II received papain and study drug G.

Subgroup III received papain and the reference drug G1.

Subgroup IV received saline.

The studied preparations and reference preparations were administered intramuscularly in doses of 0.25 ml a day after the end of papain injections.

At the end of the experiment, the rats were killed. The costal cartilages were separated, cleaned of soft tissues, dried with acetone, and the total GAG content was determined in them according to the method of D.V. Kosyagin. [Kosyagin D.V. Issues of medical chemistry, 1982, 28, 4, 68-71 pp.].

The results of the studies showed that the GAG content in the costal cartilages of rats decreases with the introduction of papain.

According to the norm, it is equal to 14.25 ± 2.7 mg of uronic acid per 1 g of dry tissue.

The following results were obtained for the groups.

- 12 041403

Group number 1.

Subgroup I II III IV GAG content 11.03±2.1 15.01±2.5 14.68±1.8 14.23±2.3 (mg/g) Group #2 Subgroup I II III IV GAG content 11.08±2.2 15.98±2.1 14.72±1.8 14.22±2.3 (mg/g) Group #3 Subgroup I II III IV GAG content 11.23±2.4 16.03±3.1 14.37±1.3 14.23±2.2 (mg/g) Group #4 Subgroup I II III IV GAG content 11.03±2.1 16.23±2.5 16.35±2.1 14.23±2.3

(mg/g)

According to the results of the experiment, it was found that preparations containing magnesium molybdate showed greater efficiency than preparations with only chondroitin sulfate. Also, the level of effectiveness is dependent on the content of chondroitin sulfate and magnesium molybdate.

Studies were conducted on the following drugs in the form of a tablet dosage form.

Preparation A. An agent for the treatment of arthrological diseases of the following composition:

Chondroitin sulfate - 500 mg;

Calcium stearate - 9.5 mg;

Crospovidone - 2.5 mg;

Povidone KZO - 2 mg;

Cellulose microcrystalline - 190 mg;

Metal molybdenum - 0.000075 mg.

drug A1. Means for the treatment of arthrological diseases of the following composition:

Chondroitin sulfate - 500 mg;

Calcium stearate - 9.5 mg;

Crospovidone - 2.5 mg;

Povidone KZO - 2 mg;

Cellulose microcrystalline - 190 mg.

Preparation B. An agent for the treatment of arthrological diseases of the following composition:

Chondroitin sulfate - 1000 mg;

Calcium stearate - 10.5 mg;

Crospovidone - 3.5 mg;

Povidone KZO - 2.8 mg;

Cellulose microcrystalline - 220 mg;

Metal molybdenum - 0.00015 mg.

Preparation B1. Means for the treatment of arthrological diseases of the following composition:

- 13 041403

Chondroitin sulfate - 1000 mg;

Calcium stearate - 10.5 mg;

Crospovidone - 3.5 mg;

Povidone KZ 0 - 2.8 mg;

Cellulose microcrystalline - 220 mg;

Preparation B. An agent for the treatment of arthrological diseases of the following composition:

Chondroitin sulfate - 1000 mg;

Calcium stearate - 11.5 mg;

Crospovidone - 4.5 mg;

Povidone KZ0 - 3.2 mg;

Cellulose microcrystalline - 260 mg;

Metal molybdenum - 0.001 mg

drug B1. Means for the treatment of arthrological diseases of the following composition:

Chondroitin sulfate - 1000 mg;

Calcium stearate - 11.5 mg;

Crospovidone - 4.5 mg;

Povidone KZ0 - 3.2 mg;

Cellulose microcrystalline - 260 mg.

Preparation G. Means for the treatment of arthrological diseases of the following composition:

Chondroitin sulfate - 1800 mg;

Calcium stearate - 11.5 mg;

Crospovidone - 4.5 mg;

Povidone KZ0 - 3.2 mg;

Cellulose microcrystalline - 260 mg;

Metal molybdenum - 0.0036 mg.

Preparation G1. Means for the treatment of arthrological diseases of the following composition:

Chondroitin sulfate - 1800 mg;

Calcium stearate - 11.5 mg;

Crospovidone - 4.5 mg;

Povidone KZ0 - 3.2 mg;

Cellulose microcrystalline - 260 mg.

Experimental batches of the dosage form of the drug were used.

The study of drugs was tested on 80 white rats of different sexes and an initial weight of 250300 g.

The rats were divided into 4 groups of 20 animals each.

Group No. 1 - trials of preparation A and reference preparation A1.

Group No. 2 - trials of preparation B and comparison preparation B1.

Group 3 - trials of preparation B and reference preparation B1.

Each group was divided into 4 subgroups.

The effect of the drug on the course of the inflammatory process was assessed by the change in the magnitude of the inflammatory edema of the limb (oncometrically), by the content of leukocytes and eosinophils in the blood.

The strength of the skin scar in rats was evaluated by two indicators - the force that causes the scar to break, and the relative elongation at break, which characterizes the elasticity of the tissue.

The effect of drugs on wound healing was studied on a model of a flat-bone skin wound.

Pathological and histochemical studies of the joints were performed randomly.

The material (synovium, articular cartilage of the knee joint) was fixed, embedded in paraffin, stained with hematoxylin-eosin, and total GAGs were determined with safranin-T. For separate detection of cholesterol, alcian blue staining was used on acetate buffer (pH 5.8) with different contents of MgCl2 (0.4M MgCl2 in the reaction for cholesterol).

The GAG content was assessed visually in points. Thus, the absence of staining with safranin was considered as subthreshold (minimum) for this dye (-). The content of GAGs is focal, light red staining, as a low content of GAGs (+), diffuse light red, as moderate (++), diffuse bright red - pronounced (+++). No alcian blue staining (-), pale blue staining as low (+), blue as moderate (++), bright blue as significant (+++).

Cartilage tissue destruction was caused by 1% papain solution by intravenous administration of 4 injections with an interval of 3-4 days.

The studies were carried out according to a single scheme for all three groups.

Subgroup I of each group received only papain.

Subgroup II of each group received, respectively, drug A (for group No. 1), drug B (for group No. 2), drug C (for group No. 3).

Subgroup III, by analogy, received preparations A1, B1 and C1: preparation A1 (for group No. 1), preparation B1 (for group No. 2), preparation B1 (for group No. 3).

Subgroup IV received saline.

Rats of I, II and III subgroups were intravenously injected with papain at 10 mg/kg (1% solution) - 4 injections with an interval of 3-4 days.

Animals of the IV (control) subgroup received physiological saline at the same time.

The preparations were administered to experimental animals in crushed form together with food 1 time per day one day after the last injection of papain for 30 days in the following doses:

group No. 1 - 3.02 mg each, group No. 2 - 5.3 mg each, group No. 3 - 8.9 mg each.

At the end of the experiment, the rats were killed. The costal cartilages were separated, cleaned of soft tissues, dried with acetone, and the total GAG content was determined in them according to the method of D.V. Kosyagin. [Kosyagin D.V. Issues of medical chemistry, 1982, 28, 4, 68-71 pp.].

According to the results of the study, it was found that with the introduction of papain, the content of GAG in the costal cartilage of rats decreases. Normally, it is equal to 14.25±2.7 mg of uronic acid per 1 g of dry tissue.

After the end of the experiment, the following results were obtained by groups.

Group number 1.

Subgroup I II III IV Content GAG (mg/g) 11.15±2.6 14.32±2.8 13.02±2.3 14.21±2.5

Group number 2.

Subgroup I II III IV GAG content (mg/g) 11.13±2.2 14.38±2.1 13.61±2.2 14.21±2.5

Group number 3.

Subgroup I II III IV GAG content (mg/g) 11.35±2.9 14.69±2.2 13.93±2.2 14.21±2.5

Group number 4.

Subgroup I II III IV GAG content (mg/g) 11.39±2.2 14.93±2.2 14.01±2.2 14.21±2.5

The results of the experiment on rats showed that the presence of metal molybdenum sodium sulfate in the preparations of chondroitin sulfate provides a more pronounced chondroprotective effect in case of damage to cartilage tissue by papain, the accumulation of GAGs in the costal cartilage of rats is stimulated to a large extent than when using preparations with one chondroitin sulfate.

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Claims (28)

CLAIM 1. An agent for the treatment of arthrological diseases, comprising an effective amount of sodium chondroitin sulfate and at least one auxiliary substance or carrier, characterized in that it additionally contains molybdenum in a relative amount of from 0.1 to 15 mg/kg, calculated on the weight of sodium chondroitin sulfate . 2. The agent according to claim 1, which contains molybdenum in a relative amount of 0.2 to 12 mg/kg, calculated on the weight of sodium chondroitin sulfate. 3. The agent according to claim 1, which contains molybdenum in a relative amount of 0.3 to 10 mg/kg, calculated on the weight of sodium chondroitin sulfate. 4. The agent according to claim 1, which contains molybdenum in a relative amount of 0.4 to 8 mg/kg, calculated on the weight of sodium chondroitin sulfate. 5. The agent according to claim 1, which contains molybdenum in a relative amount of 0.5 to 6 mg/kg, calculated on the weight of sodium chondroitin sulfate. 6. The agent according to claim 1, which contains molybdenum in a relative amount of 0.2 to 4 mg/kg, calculated on the weight of sodium chondroitin sulfate. 7. The agent according to claim 1, which contains molybdenum in a relative amount of 0.15 to 2 mg/kg, calculated on the weight of sodium chondroitin sulfate. 8. The agent according to claim 1, which contains molybdenum in a relative amount of 7 to 10 mg/kg, calculated on the weight of sodium chondroitin sulfate. 9. The agent according to claim 1, which contains molybdenum in a relative amount of 4 to 8 mg/kg, calculated on the weight of sodium chondroitin sulfate. 10. The agent according to claims 1 to 9, wherein the molybdenum is a molybdenum chelate. 11. An agent according to claim 10 wherein the molybdenum chelate is selected from the group of ammonium molybdate or sodium molybdate. 12. An agent according to claims 1 to 9, in which the amount of chondroitin sodium sulfate is from 50 to 2500 mg. 13. An agent according to claims 1 to 9, wherein the amount of chondroitin sodium sulfate is from 100 to 2000 mg. 14. An agent according to claims 1 to 9, in which the amount of chondroitin sodium sulfate is from 300 to 1500 mg. 15. An agent according to claims 1 to 9, in which the amount of chondroitin sodium sulfate is from 500 to 1200 mg. 16. An agent according to claims 1 to 9, in which the amount of chondroitin sodium sulfate is from 50 to 250 mg. 17. An agent according to claims 1 to 9, in which the amount of chondroitin sodium sulfate is from 250 to 1000 mg. 18. The agent according to claim 1, in which the mass ratio of chondroitin sodium sulfate to molybdenum is 1:(1x10' ⁷ - 1x10'5). 19. The agent according to claim 1, characterized in that it is in the form of an ointment, gel or cream. 20. Means according to claim 1, characterized in that the excipient is selected from the group of dimethyl sulfoxide; propylene glycol; carbomer; trolamine; macrogol; edetat; neroli and lavender oils; lanolin; petrolatum. 21. The agent according to claim 1, characterized in that it is in the form of a tablet or capsule. 22. An agent according to claim 21, characterized in that it is in the form of a film-coated tablet. 23. The agent according to claim 21, characterized in that the tablet additionally contains auxiliary substances taken in relation to sodium chondroitin sulfate, disubstituted calcium sulfate 1:0.46, microcrystalline cellulose - 1:0.37, croscarmellose sodium - 1:0 ,16, stearic acid 1:0.14, magnesium stearate - 1:0.02. 24. The agent according to claim 21, characterized in that the tablet additionally contains glucosamine hydrochloride, and the composition of the tablet is selected in such a way that the ratio of chondroitin sodium sulfate to glucosamine hydrochloride is 1:1. 25. The agent according to claim 22, characterized in that the tablet shell has a composition taken in relation to sodium chondroitin sulfate, hydroxypropyl methylcellulose - 1: 0.07, titanium dioxide (E171) 1: 0.016, triacetin - 1: 0.014. 26. An agent according to claim 21, characterized in that the composition of the capsule shell consists of titanium dioxide and gelatin. 27. The agent according to claim 21, characterized in that the capsule contains one or more of the excipients: talc, stearic acid, magnesium stearate, manganese sulfate. 28. The agent according to claim 1, characterized in that it is in the form of a lyophilisate. -