RU2739747C9 - Pharmaceutical agent for arthritic diseases treatment - Google Patents

Abstract

FIELD: medicine; pharmaceuticals.

SUBSTANCE: invention refers to pharmaceutical industry, namely to an agent for treating arthritic diseases. Agent for treating arthritic diseases comprising 50 mg to 2500 mg of chondroitin sodium sulphate and at least one excipient or carrier, and also contains metallic or colloidal silver in relative amount from 0.2 mg/kg to 8 mg/kg in terms of weight of chondroitin sodium sulphate.

EFFECT: agent described above improves stability of the agent for a long period of time regardless of the form of the preparation containing said agent.

28 cl, 6 ex, 1 tbl, 6 dwg

Description

The invention relates to 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 restrict mobility and motor skills, leading to premature termination of work, reducing the ability to perform social functions.

Most of the diseases of the musculoskeletal system are related to disorders affecting 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 bone structure. Most often, joint diseases are affected by people over forty, but today it is increasingly common among the younger generation.

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

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

The structure of the CS molecule determines its polyanionic properties and participation in the transport of water, amino acids and lipids in the avascular regions of the cartilage. Long CS chains, 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 the 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 to enable the movement of molecules through the cartilage tissue. This is an important property, since there is no blood in the cartilage that provides metabolite metabolism. Chondroitin sulfate is also a chondroprotective agent. The water retained by it in the thickness of the cartilage creates good shock absorption and absorbs shocks, which ultimately increases the strength of the connective tissue.

Chondroitin sulfate is a natural component of articular cartilage that plays an important role in maintaining the required osmotic pressure, due to which the matrix and collagen filaments 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 major part of articular cartilage. It is formed from repeating disaccharide units of glucuronic acid and N-acetyl-D-galactosamine. In a degenerative-dystrophic process, the amount of chondroitin decreases sharply, which leads to cartilage degradation [Builova T.V. Open randomized study of the efficacy and safety of the drug Chondroxide® in the complex treatment of patients with chronic vertebrogenic lumboishalgia // BC. 2010. No. 17. S. 1678-1686.].

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

Non-injection forms are presented in 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 sodium sulfate - 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.

CS-based capsules are represented by Structum, Teraflex Advance, Teraflex, Chondroitin AKOS, Chondroitin, Kondronova.

All of the above drugs have an active ingredient: Chondroitin sulfate sodium.

Capsules are gelatinous, have auxiliary substances, for example: talc, stearic acid, magnesium stearate, manganese sulfate.

Typically, the capsule shell includes titanium dioxide and gelatin.

Known gels based on CS, for example, the drug Chondroitin (Chondroitine, VERTEX AO (Russia) - gel for external use 5% g: tubes 30 g or 50 g, cans 30 g. Active ingredient: 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 CS are represented by the following preparations: Mucosat ointment 5%, Artrafic ointment 5%, Chondroitin AKOS ointment 5%. Ointments contain chondroitin sodium sulfate and excipients: lactose, calcium stearate.

Injection forms are represented by lyophilisates and solutions.

Known solutions for intramuscular injection in ampoules: Drastop, Hondroguard, Inektran, Atravir-Inkampharm, Artogistan.

An example of a lyophilisate is Chondrolone, 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, possessing chondroprotective action, anti-inflammatory activity, acting mainly on inflammatory mediators, stimulate the synthesis of hyaluronic acid and proteoglycans and inhibit the action proteolytic enzymes.

In more detail, cholesterol preparations have a chondrostimulating, regenerating, anti-inflammatory and analgesic effect, have chondroprotective properties, enhance metabolic processes in hyaline and fibrous cartilage, subchondrial bone; inhibits enzymes that cause degradation (destruction) of articular cartilage; stimulates the production of proteoglycans by chondrocytes, helps to reduce the release of inflammatory mediators and pain factors into the synovial fluid, suppresses the secretion of leukotrienes and prostaglandins, slows down bone resorption and reduces calcium losses, accelerates the processes of bone tissue recovery, slows down the progression of osteoarthritis and osteochondrosis, promotes the restoration of the joint capsule and cartilage surfaces of joints, prevent the collapse of connective tissue, normalize the production of articular fluid.

It can be seen from the above data that cholesterol drugs in various forms are actively used to treat arthrological diseases.

At the same time, a number of common technical problems are characteristic of all of the above-described drugs for the treatment of arthrological diseases based on CS.

Microbial contamination is one such problem. The reasons for the contamination of medicinal products are, in particular, inadequate conditions for obtaining, storing or transporting the medicinal product or components intended for its preparation. Raw materials of animal origin are among the most contaminated.

Also, increased contamination can be associated with prolonged and / or improper storage of the drug. That is, there is a problem of reducing the shelf life of the drug, which in turn reduces the possibility of its effective use and requires additional efforts to dispose of the unused drug with an early expired shelf life.

Contamination leads not only to a decrease up to the complete absence of the necessary therapeutic effect, but to the occurrence of inflammatory processes and the risk of infectious diseases during operation. Taking into account the fact that drug treatment involves its long-term and repeated use - such risks can be very significant.

A separate problem of preparations based on natural organic raw materials is their potential allergenicity. The likelihood of allergic diseases with prolonged use of the drug also increases significantly.

As a rule, to combat pathogenic microorganisms in preparations of this kind, preservatives are used, which are various derivatives of benzene.

For example, the drug Mucosat, which is a solution for injection, includes the sodium salt of chondroitin sulfate (8-12%), as a preservative - benzyl alcohol - 0.8-1.2% and pyrogen-free water - the rest, the pH of the drug solution is 6.5 -7.5.

This medicine contains benzyl alcohol as a preservative. However, this substance does not completely eliminate contamination, but only slightly suppresses and thus slows down the growth of microorganisms, including microbes and fungi. And also dictates high requirements for the temperature storage regime, failure to comply with which entails a significant decrease in the activity of the active substance. Thus, the problem with long-term storage persists.

In addition, benzyl alcohol in some cases (as side effects) exhibits the following toxic effects: respiratory failure, vasodilation, hypotension, convulsions and paralysis. He is also responsible for the development of "gasping syndrome" in children, characterized by respiratory failure, changes in motor functions, hypotension, renal failure, thrombocytopenia. Obviously, with the systematic and long-term use of the drug, which is typical for arthrological diseases, the risk of these negative consequences objectively increases.

Thus, the problem of creating preparations of chondroitin sulfate that are stable during storage and retain their therapeutic efficacy during long-term storage and / or operation, while not showing negative side effects associated with the presence of a relatively large amount of preservative, remains unresolved at present.

The present invention is based on the technical problem of creating a product that is stable during storage and operation due to effective control of the natural level of contamination and minimizing the risk of allergic reactions in the treatment of arthrological diseases.

Also, the present invention is based on the task of minimizing the content of the preservative, that is, to achieve the stability of the agent when included in its composition the minimum amount of a preservative, for example, benzyl alcohol or sodium benzoate.

Disclosure of invention

The authors of the invention solve this problem by creating an agent for the treatment of arthrological diseases, which includes a pharmaceutically effective amount of an active substance - chondroitin sulfate and metallic or colloidal silver in a relative amount from 0.1 mg / kg to 10 mg / kg based on the weight of the active substance - chondroitin sulfate.

In a particular embodiment, in a relative amount from 0.2 mg / kg to 8 mg / kg, as well as from 0.3 mg / kg to 6 mg / kg, based on the weight of the active substance.

In a particular version, in a relative amount from 0.4 mg / kg to 5 mg / kg, as well as from 0.5 mg / kg to 4 mg / kg, as well as from 0.2 mg / kg to 3 mg / kg, and also from 0.15 mg / kg to 2 mg / kg, as well as from 7 mg / kg to 10 mg / kg, as well as from 4 mg / kg to 8 mg / kg, based on the weight of the active substance.

At the same time, the proposed agent, depending on the concentration of silver introduced into the composition, can either be free from a preservative (benzyl alcohol, sodium benzoate or others with similar properties), or, if necessary, include it in a smaller amount.

The technical result manifested when using the invention is the stability of the agent for a long time and / or during operation due to the absence of microbial contamination, the preservation of its effectiveness and safety. It is important that this effect is manifested for various forms of the drug containing this agent, which is of great importance not only for injectable forms (solution, lyophilisate), but also for storage of oral (tablet, capsule) and topical forms for the first opening of the package (ointment , gel).

It is also important that when using the claimed agent, there are no negative effects associated with the presence of a relatively large amount of preservative, including benzene derivatives. The risk of allergic reactions is reduced, which is due to both the elimination or minimization of the preservative, and the stabilization of the active principle with silver in the stated concentrations.

It has been found that the addition of silver to the composition of the product in the specified amount provides maximum suppression of negative effects and avoids possible risks. These negative effects and risks include allergic reactions, as well as toxic accumulation of silver in the organs and tissues of the body.

Thus, the proposed silver concentrations are unexpectedly optimal for solving the problem.

Today silver is actively used in the food, cosmetic and therapeutic industries. The popularity of silver compounds is due to their high antifungal, antibacterial and anti-inflammatory properties.

In medicine, such compounds are usually used as an independent active substance.

For example, RF patent 2268074 (published: 01.20.2006) describes a method for treating rheumatoid arthritis by drug electrophoresis on the area of the affected joints using a transverse technique. According to the invention, electrophoresis of a 1-2% solution of silver nitrate is carried out daily in a number of procedures of at least 7, while the first procedure is carried out with a duration of 15 minutes, and the following - 20 minutes. When electrophoresis is carried out with a 1-2% solution of silver nitrate, a "depot" (accumulation) of silver ions is formed in the upper layers of the skin over the affected joints, which provides a prolonged effect at the site of exposure. The concentration of the silver nitrate solution was selected empirically and, as shown by observations, is optimal for solving the problem. At a concentration of less than 1%, an insignificant effect is observed, and at a concentration of more than 2%, side reactions occur in the form of itching.

This method has shown effectiveness in rheumatoid arthritis and ankylosing spondylitis in terms of a significant reduction in pain, stiffness in the joints and spine, reduction of swelling in the joints, positive dynamics of laboratory parameters of inflammation.

However, the use of silver for medicinal purposes has several limitations.

So, for example, the disadvantage of the above method is the possibility of itching as a side effect due to the penetration of the drug through the skin.

When administered internally, silver nitrate (AgNO3) decomposes into pure silver, nitrogen dioxide and oxygen:

2AgNO3 → 2Ag + 2NO2 + O2, where pure silver itself is accumulated by the body and excreted only through the digestive tract.

The mass fraction of silver in silver nitrate AgNO3 is 63.5%, a 2% solution of silver nitrate contains 1.27% pure silver.

When electrophoresis is usually used 20-30 ml of a solution containing 254-381 mg of pure silver.

As mentioned above, the clinical effect of the drug is manifested when a 1-2% solution of silver nitrate is used, in which the minimum dose of silver entering the body is 127 mg.

It is known that the toxic dose of silver for humans is 50-60 μg / l.

Consequently, the internal administration of the drug in the form of a solution of silver nitrate is fraught not only with allergic reactions, but also with toxic accumulation of silver, exceeding the daily dose, which can cause argyrosis.

It is known that leukocytes absorb silver and deliver it to the site of infection. And under the action of silver, inflammation is removed: metal and proteins form special compounds that can neutralize the action of most pathogenic microbes. Moreover, these compounds are capable of exerting a regenerating effect on tissues. Actually, this explains the beneficial effect of silver in any inflammation.

The active healing element of silver is its ions - Ag +. Silver ions easily interact with other ions, forming, as a rule, insoluble or poorly soluble compounds, which prevents the penetration of silver into a living organism. For example, silver ions easily bind with chlorine anions, resulting in the formation of poorly soluble silver chloride.

However, in aqueous solution, silver ions retain their activity due to their stable stabilization in the form of hydrated silver. This is due to the property of a bipolar water molecule to form hydrogen bonds, as a result of which water molecules in the form of a "shell" can shield anions and cations from mutual action.

In fact, the fragments of the water molecule form a rather stable shell around the silver ion, keeping this ion in a free and active state. Therefore, even when it enters the intestines, the stabilized hydrated silver is not significantly affected by chlorine ions and safely enters the body.

Just as easily, under the protection of water molecules, silver ions penetrate into skin tissues. Circulating in the bloodstream and tissue fluids, hydrated silver ions freely penetrate pathogenic microbes, viruses and fungi through their outer shell, and then combine with a respiratory enzyme and, blocking the respiratory function, lead to their death. At the same time, pathogenic microorganisms cannot develop resistance to the destructive action of silver ions, as they do in relation to antibiotics.

Known drug "Colloidal silver" in the form of an ionized solution in a bottle of 60 ml, which consists of an active component: colloidal silver in the form of an ionized solution, intended for internal and external administration (Latin name: Silver colloidal, active ingredient: Colloidal silver (Silver colloidal) , manufacturer: Nittany Pharmaceuticals / Vitaline, Nature's Sunshine Products (USA), Coral club (Germany) It is used for rheumatoid arthritis.

During treatment with the drug, the development of allergic reactions is also possible.

According to the World Health Organization, the ability to guaranteedly kill certain bacteria is observed at concentrations of silver ions above 150 μg / L, and at a lower concentration, they only inhibit the growth of bacteria.

Therefore, the use of colloidal silver also has a clinical effect only when the toxic dose of silver is exceeded in 50-60 μg / l.

The least toxic metallic silver. Poorly soluble silver salts (for example, chloride) have low toxicity, but they are also inactive in terms of bactericidal activity.

These data allow us to conclude that preparations containing silver can exhibit antibacterial activity, but also have technical problems: the complexity of delivery without toxicity of the body as a whole.

The authors of the present invention have created an agent containing an effective amount of chondroitin sulfate and silver, allowing to provide the desired therapeutic effect, to avoid microbial contamination during manufacture, storage and use, while minimizing the negative effects associated with the presence of silver in the composition.

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

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

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

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

The amount of chondroitin sodium sulfate in the agent can range from 50 mg to 250 mg.

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

The agent according to the present invention comprises metallic or colloidal silver in a relative amount of 0.1 mg / kg to 10 mg / kg, based on the weight of the active substance, chondroitin sulfate.

In a particular embodiment, silver is contained in a relative amount from 0.2 mg / kg to 8 mg / kg, as well as from 0.3 mg / kg to 6 mg / kg, based on the weight of the active substance.

In a particular version, silver is contained in a relative amount from 0.4 mg / kg to 5 mg / kg, as well as from 0.5 mg / kg to 4 mg / kg, and also from 0.2 mg / kg to 3 mg / kg and also from 0.15 mg / kg to 2 mg / kg in terms of the weight of the active substance.

The mass ratio of sodium chondroitin sulfate to metallic or colloidal silver can be 1: 1 × 10 ⁷ -1: 1 × 10 ⁵ .

As part of the product, metallic or colloidal silver can be used.

More specifically, silver gels or sols can be used in the agent.

The size of the silver particles used can be 1-100 μm - 1-100 nm.

Colloidal silver can be used, for example, AgBion-2 colloidal nanosilver concentrate [http://rps61.ru/good/65] or KND-S colloidal silver concentrates [http://ultrasilver.ru]

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

The agent can be used for oral, injection or topical administration.

Topical forms include creams, gels, and ointments.

Oral forms include tablets and capsules.

Injectable forms include lyophilisates and injection solutions.

Auxiliary components are selected depending on the form of manufacture.

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

The tablet formulation may additionally contain glucosamine hydrochloride.

In a particular embodiment, the ratio of chondroitin sodium sulfate to glucosamine hydrochloride in the 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 mg, 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 this case the tablet shell has the following composition, taken with respect to sodium chondroitin sulfate: hydroxypropyl methylcellulose - 1: 0.07, titanium dioxide (E171) - 1: 0.016, triacetin - 1: 0.014 mg.

The tool, made in the form of a capsule, may additionally contain auxiliary substances selected from the group: talc, stearic acid, magnesium stearate, manganese sulfate

The capsule shell composition may include titanium dioxide and gelatin.

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

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

The finished product may contain 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 the 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 images:

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

Fig. 2: X-ray of the knee joints of rabbits receiving intra-articular papain in the right (P) joint and preparations A and B. The left (L) joint is intact;

FIG. 3: shows a radiograph of the knee joints of rabbits of group IV, which received intra-articular papain and a control preparation (comparison) in the right (P) joint;

FIG. 4: articular cartilage of the knee joint of a rabbit group I;

FIG. 5: synovium of the right knee joint of a rabbit of group I;

FIG. 6 shows the articular cartilage of the knee joint of a rabbit after the intramuscular administration of Preparation A, Preparation B, saline (C).

Implementation of the invention

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

Example 1

A preparation in the form of a gel, including chondroitin sodium sulfate, purified water, and which additionally contains metallic or colloidal silver from 0.10 mg / kg to 10 mg / kg, can be obtained using various auxiliary substances.

1. A preparation in the form of a gel is obtained by first forming a solution A: by 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, mix with heating to a temperature of 65-75 ° C in purified water (w / v%): 2 g of chondroitin sulfate, dimethyl sulfoxide - 7.5; propylene glycol - 7.5; trolamine (triethanolamine) - 3; macrogol glyceryl hydroxystearate - 0.4; disodium edetate - 0.1. Then solutions A, B, C are constantly stirred for several hours until the formation of a helium mass, adding metallic or colloidal silver 0.0005% of the total mass of the total mass. If necessary, add flavorings (w / v%): lavender oil - 0.1; orange blossom oil (neroli oil) - 0.05. The resulting finished composition of the preparation in the form of a gel contains (w / v%): chondroitin sulfate - 5; ethanol - 10; dimethyl sulfoxide - 7.5; propylene glycol - 7.5; carbomer - 3; trolamine (triethanolamine) - 3; macrogol glyceryl hydroxystearate - 0.4; disodium edetate - 0.1; methyl parahydroxybenzoate (methylparaben, nipagin) - 0.1; lavender oil - 0.1; orange blossom oil (neroli oil) - 0.05; metallic or colloidal silver - 0.0005; purified water - the rest is up to 100.

2. Solution A is prepared 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 while heating to 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 metabisulfite, 20 g of propylene glycol. Then solutions A, B, C are constantly stirred for several hours until the formation of a helium mass, adding metallic or colloidal silver 0.0002% of the total mass. If necessary, add perfume in an amount of 0.2 g. The resulting finished composition of the preparation in the form of a gel contains (w / v%): chondroitin sulfate - 5; glucosamine sulfate - 0.5; methylsulfonylmethane - 1.0; sodium metabisulfite - 0.01; methyl parahydroxybenzoate - 0.05; propylene glycol - 5.0; ethanol 15.0; carbomer - 2.5; perfume - 0.05; metallic or colloidal silver - 0.0002; purified water - the rest is up to 100.

Example 2

A preparation in the form of an ointment, including chondroitin sodium sulfate, purified water, and which additionally contains metallic or colloidal silver from 0.1 mg / kg to 10 mg / kg, can also be obtained using various auxiliary substances.

1. Vaseline medical 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. % is melted at a temperature of (70 ± 2) ° С, stirred, then cooled to a temperature of (55 ± 2) ° С (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. In solutions of diclofenac sodium in dimethyl sulfoxide and chondroitin sulfate in water with stirring, adding metallic or colloidal silver 0.00005% of the total mass, the resulting substance is added to the ointment base, homogenized, and then transferred to packaging. Get a ready-made ointment, having the composition (wt./vol.%): Chondroitin sodium sulfate (in terms of dry matter) - 5; dimethyl sulfoxide - 10; lanolin - 0.15; petroleum jelly - 0.5; metallic or colloidal silver - 0.00005; purified water - the rest is up to 100.

2. Vaseline medical 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. % is melted at a temperature of (70 ± 2) ° С, stirred, then cooled to a temperature of (55 ± 2) ° С (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. In solutions of diclofenac sodium in dimethyl sulfoxide and chondroitin sulfate in water with stirring, adding metallic or colloidal silver to 0.0002% of the total mass, the resulting substance is added to the ointment base, homogenized, and then transferred to packaging. Get a ready-made ointment, having the composition (wt./vol.%): Chondroitin sodium sulfate (in terms of dry matter) - 5; dimethyl sulfoxide - 10; lanolin - 0.15; petroleum jelly - 0.5; metallic or colloidal silver - 0.0002; purified water - the rest is up to 100.

Example 3

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

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

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

The substance containing the sodium salt of chondroitin sulfate 96.2-97.1% is dissolved in 1000 ml of pyrogen-free injection water, the pH is adjusted from 6.0 to 7.5 with a sodium hydroxide solution, after which the resulting mixture is subjected to ionization with Ag + ions until the level of 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 way, ampoules with lyophilized drug are sealed.

1. 104 g of a substance with a sodium salt of chondroitin sulfate of 96.2% 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 ionization process is carried out with silver ions Ag + to a level of 0.10 mg / l of the mixture. 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 a lyophilized drug are sealed. Get 103 mg of lyophilized powder in 1 ampoule, which corresponds to 99.7 mg of sodium salt of chondroitin sulfate, residual moisture - 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 with a sodium salt of chondroitin sulfate of 96.2% is dissolved in 1000 ml of pyrogen-free injection water, the pH is adjusted from 6.0 to 7.5 with sodium hydroxide solution. After that, in relation to the resulting mixture, the process of ionization with silver ions Ag + to the 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 a lyophilized drug are sealed. Get 103 mg of lyophilized powder in 1 ampoule, which corresponds to 99.7 mg of sodium salt of chondroitin sulfate, residual moisture - 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

A tablet containing chondroitin sulfate. The composition in the form of a tablet can be made as follows: suspended chondroitin sodium sulfate, glucosamine hydrochloride in a 1: 1 ratio, colloidal silver from 0.10 mg / kg to 10 mg / kg are mixed in a drum mixer. The resulting mixture is molded and pressed, then dried to the required residual moisture content and calibrated. Then they are enclosed in a hard shell, which may have a composition taken in relation to chondroitin sodium sulfate: hydroxypropyl methylcellulose - 1: 0.07, titanium dioxide (E171) - 1: 0.016, triacetin - 1: 0.014 mg. Also, the tablet may additionally contain auxiliary substances taken in relation to chondroitin sodium sulfate: calcium sulfate disubstituted - 1: 0.46, microcrystalline cellulose - 1: 0.37 mg, sodium croscarmellose - 1: 0.16, stearic acid - 1: 0.14, magnesium stearate - 1: 0.02.

1. A tablet containing chondroitin sulfate. The composition in the form of a tablet can be made as follows: suspended chondroitin sodium sulfate 250 mg, colloidal silver - 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 content and calibrated.

2. A tablet containing chondroitin sulfate and glucosamine hydrochloride. The composition in the form of a coated tablet can be prepared as follows: chondroitin sodium sulfate, glucosamine hydrochloride in a ratio of 1: 1.25; colloidal silver - 0.2 mg / kg; methylsulfonyl methane 1: 0.75. Can also be added: cellulose - 1: 0.50; calcium hydrogen phosphate 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 content 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 examples presented above show that the preparation of preparations can be carried out 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 chondroitin sodium sulfate to which metal or colloidal silver from 0.1 mg / kg 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 revealed.

Example 5

Assessment of resistance to microbial contamination.

1. Cream, gel, ointment

The effect was revealed on the bacteria Staphylococcus aureus and E. Coli.

When growing Staphylococcus aureus, a nutrient medium based on yolk-salt agar and growth stimulants was used.

The growth of E. coli biomass was carried out in a nutrient medium at 37 ° C and 150 rpm for 24 hours.

In ointments and gels based on CS and silver, obtained according to the invention (Examples 1, 2), the obtained cultures of Staphylococcus aureus and E. Coli were inoculated separately.

Ointments and gels of a similar composition containing silver at concentrations of 0.040 mg / kg and 0.070 mg / kg were used as comparison drugs.

The growth of bacterial colonies was not observed for several hours in ointments and gels with the content of colloidal silver in it from 0.20 mg / kg and above.

With a decrease in the level of colloidal silver (reference preparations), the growth of bacterial colonies began immediately and had a progressive effect.

2. Solution

The effect was revealed on the bacteria Staphylococcus aureus and E. Coli.

When growing Staphylococcus aureus, a nutrient medium based on yolk-salt agar and growth stimulants was used.

The growth of E. coli biomass was carried out in a nutrient medium at 37 ° C and 150 rpm for 24 hours.

In solutions based on CS and silver, obtained according to the invention (Example 3), the obtained cultures of Staphylococcus aureus and E. Coli were inoculated separately.

CS solutions of a similar composition containing silver at concentrations of 0.040 mg / kg and 0.070 mg / kg were used as reference drugs.

The growth of bacterial colonies was not observed for several hours in solutions saturated with silver ions Ag + from 0.20 mg / kg and above. With a decrease in the level of silver ions, the growth of bacterial colonies began immediately and had a progressive effect.

Example 6

The effectiveness of chondroitin sulfate preparations.

1. The effectiveness of agents in the form of a gel or ointment, including sodium cholesterol, purified water, metallic or colloidal silver from 0.1 mg / kg 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-fold 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 5% solution) - groups I, II, III, IV, V groups of 10 rabbits in each.

Experimental animals applied to the knee joint with gentle rubbing daily for 15 days:

for groups I and II - studied samples of ointment (concentration of colloidal silver 0.04 mg / l) and gel (concentration of colloidal silver 0.1 mg / l), respectively,

for group III - chondroitin sulfate ointment, which does not contain metallic or colloidal silver, containing benzyl alcohol in its composition.

for the control group IV - isotonic sodium chloride solution.

In another control group V, nothing was applied.

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

When applied to the skin in groups I, II, III after 15 days, a decrease in the severity of knee swelling was noted in comparison with the control groups by 2.1 times.

The severity of the anti-inflammatory effect of the investigated agents (ointment and gel) according to the invention and the ointment that does not contain silver was observed and did not manifest itself in control groups IV, V.

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

In particular, out of 10 rabbits of each of I, II, III groups in 9 out of 10 in groups I, II after 35 days, complete regeneration of bone tissue was recorded, and in group III only 7 out of 10.

Thus, the claimed agents according to the invention showed anti-inflammatory activity, normalization of metabolic processes, as well as more effective regeneration of bone tissues than the CS ointment, which does not contain silver.

The presence of allergic reactions in animals was determined visually. In 7 rabbits from group II and 6 rabbits from group II, reddening at the injection site and itching were observed. In group III, redness was observed in one animal, itching was not observed.

2. The effectiveness of injection forms

The efficacy of similar forms of cholesterol containing silver intended for injection, and their comparison with the effect of injections of a cholesterol preparation containing benzyl alcohol and not containing silver, was investigated.

Namely, they used the means:

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 silver ions Ag + 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 administration, including Na-salt of chondroitin sulfate from 4 to 12 wt. %, purified water containing silver ions Ag + 0.2 mg / ml.

B) Control drug: An agent for the treatment of arthrological diseases, which is a preparation in the form of a solution for intramuscular administration, including Na-salt of chondroitin sulfate from 4 to 12 wt. %, benzyl alcohol, purified water.

In this case, the tested injection solution was prepared once, stored under standard conditions, and introduced, including after storage. So the drug was administered after 12 and 25 weeks of storage. At the same time, according to the results of a biochemical study of the components of connective tissue by means of spectrophotometry, no difference was established when using 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 preparation 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 series of the drug dosage form was used. According to option A, the solution for administration was prepared on the basis of the lyophilized powder obtained according to the claimed invention.

Control animals received the comparison drug in 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 amount of inflammatory edema of the extremity (oncometric), by the content of leukocytes and eosinophils in the blood.

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

The effect of drugs on wound healing was studied using a model of a squamous skin wound.

Pathomorphological and histochemical studies of the joints were performed at random.

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

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

Destruction was caused by 6-fold papain injections.

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

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

One day after the last injection of papain, rats of group II were injected intramuscularly with drug A, 0.5 ml daily for a month. The rats of group III received 0.5 ml of preparation B intramuscularly at the same time. The rats of the IV group at the same time received an intramuscular injection of a control preparation, 0.5 ml.

At the end of the experiment, the rats were sacrificed. The costal cartilage was separated, cleaned from soft tissues, dried with acetone, and the total GAG content was determined in them by the method of D.V. Kosyagin. [Kosyagin D.V. - "Questions of medicinal chemistry", 1982, 28, 4, 68-71 p.].

The results of the studies showed that after the introduction of papain, the content of GAG in the rib cartilage of rats decreases slightly. Normally, it is equal to 14.25 ± 2.7 mg uronic acid per g of dry tissue, while in untreated rats of group I, the decrease in GAG was 15% (12.11 ± 2.4 mg / g).

With the introduction of Preparation B, the GAG content increased and was above the norm to the level of 18.03 ± 2.23 mg / g.

In rats treated with Preparation A, the GAG content was also higher than in control animals (18.72 ± 2.11 mg / g).

In the rats receiving the control drug, the GAG content was also higher than in the control animals (17.14 ± 2.08 mg / g).

Thus, the results of experiments on rats showed that Preparation A and Preparation B have a chondroprotective effect on papain damage to cartilage tissue, simulating the accumulation of GAG in the rib cartilage of rats slightly better than the control preparation.

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

The experiments used 35 male chinchilla rabbits weighing 2.1-2.6 kg. Destruction was caused by 6-fold 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 5% solution) - groups I, II, III, IV, 7 rabbits each. The group of rabbits, in relation to which the natural increase in the circumference of the joint edema was recorded, was injected intra-articularly with 1.0 ml of saline - group V (7 rabbits).

Within 2 months, rabbits of group I were injected with saline, group II - Drug A, 1.0 ml 3 times a week, group III - Drug B, 1.0 ml 3 times a week, group IV (control) - 1 each, 0 ml of the reference drug.

The drugs were injected intramuscularly. Thus, we studied the chondro-protective effect of Preparations A and B and the control drug in order to assess the therapeutic effect of the silver + CS complex and compare it with the CS-based drug (Mucosat), which also proved 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 Preparations A and B, the edema was slightly less - 6.2 ± 1.1 mm and 6.3 ± 1.2 mm, respectively, compared with group IV, which received the reference drug (8, 1 ± 1.3).

In rabbits of group I, who received only papain, by the end of 2 months, the GAG content increased to 12.6 mg / ml, which indicated the destruction of cartilage tissue. In animals treated with Preparations A, B and control, the GAG level was significantly lower (6.56 mg / ml, 6.88 mg / ml and 7.73 mg / ml, respectively), from which it was concluded that the destructive processes were to a lesser extent. The state of the V group was expressed within the increase of 3.02 mg / ml.

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

FIG. 1 shows a radiograph of the knee joints of rabbits of groups I and V (two-month experience). Injections into the right (R) joint. The left (L) is intact.

A - Rabbit number 1 - group V. Cholesterol 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 changes.

B - Rabbit No. 3 - Group I without treatment (intra-articular papain); P - synovitis; L - no changes.

FIG. 2 shows a radiograph of the knee joints of rabbits that received papain and preparations A and B intra-articularly into the right (R) joint. The left (L) joint is intact. Experience 2 months.

A. rabbit No. 4 - group II. Both joints are unchanged.

B. Rabbit number 5 - IV group. Both joints are unchanged.

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

A. Rabbit No. 6 - II - arthritis, osteoporosis; L - no changes.

B. Rabbit # 7 - both joints unchanged.

General data on the results of observations by the end of 2 months are summarized in Table 1.

It can be seen from them that in group I, destructive changes persisted up to 2 months 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, who received Preparations A and B, only 1 rabbit from group III showed signs of arthritis. In rabbits of group IV, who received intra-articular papain and intramuscularly the drug, 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 did not reveal changes in the joints.

According to the results of the study, it can be concluded that the introduction of Preparations A and B prevented the development of pathological changes in the joints, as well as the use of the control comparison drug, but the preventive effect of Preparations A and B is slightly better than that of the control based on CS.

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

Autopsy of rabbits of group I showed the presence of distinct signs of destruction of articular cartilage in each of them in the right joint (see Fig. 4 and Fig. 5).

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

A. After intra-articular administration of papain solution. Uzurs can be seen penetrating to the middle of the intermediate layer. Proliferation of chondrocytes alternates with areas of emptying. There is a decrease in GAG. Safranin staining - Т.10 × 6.3.

B. Control. The histological structure of the cartilage is preserved. The amount of GAG is normal. Safranin staining - Т.10 × 6.3.

FIG. 5 shows the synovium of the right knee joint of a group I rabbit.

A - after intra-articular administration of papain. Pronounced hyperplasia of the sinoium membrane, synoviocytes are large, loosely located, form 5-5 layers. In the subsynovial layer, the proliferation of hissticites, fibroblasts and diffuse large focal plasmacytic infiltration are visible. Heme.-eosin 25 × 6.3.

B - control - normal structure.

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

FIG. 7 shows the articular cartilage of the knee joint of a rabbit after intramuscular administration of Preparation A, Preparation B, saline solution (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 25 × 6.6.

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

The research data show that preparations A and B have the best effect on the regeneration of bone tissues, while biochemically and immunologically, there were no manifestations of allergic reactions in these groups of animals.

Claims (28)

1. An agent for the treatment of arthrological diseases, comprising from 50 mg to 2500 mg of chondroitin sodium sulfate and at least one excipient or carrier, characterized in that it additionally contains metallic or colloidal silver in a relative amount of 0.2 mg / kg up to 8 mg / kg based on the weight of sodium chondroitin sulfate. 2. The agent according to claim 1, which contains silver in a relative amount from 0.3 mg / kg to 6 mg / kg, based on the weight of sodium chondroitin sulfate. 3. The agent according to claim 1, which contains silver in a relative amount of from 0.4 mg / kg to 5 mg / kg, based on the weight of sodium chondroitin sulfate. 4. The agent according to claim 1, which contains silver in a relative amount of from 0.5 mg / kg to 4 mg / kg in terms of the weight of chondroitin sodium sulfate. 5. The agent according to claim 1, which contains silver in a relative amount of 0.2 mg / kg to 3 mg / kg, based on the weight of chondroitin sodium sulfate. 6. The agent according to claim 1, which contains silver in a relative amount of 4 mg / kg to 8 mg / kg, based on the weight of chondroitin sodium sulfate. 7. The agent according to claims 1-6, in which the colloidal silver is a concentrate of colloidal nanosilver AgBion-2. 8. The agent according to claims 1-6, in which the colloidal silver is a concentrate of colloidal silver KND-S. 9. An agent according to claims 1-6, wherein the amount of chondroitin sodium sulfate is from 100 mg to 2000 mg. 10. An agent according to claims 1-6, in which the amount of chondroitin sodium sulfate is from 300 mg to 1500 mg. 11. The agent according to claims 1-6, in which the amount of chondroitin sodium sulfate is from 500 mg to 1200 mg. 12. The agent according to claims 1-6, in which the amount of chondroitin sodium sulfate is from 50 mg to 250 mg. 13. The agent according to claims 1-6, in which the amount of chondroitin sodium sulfate is from 250 mg to 1000 mg. 14. The agent according to claim 1, in which the mass ratio of chondroitin sodium sulfate to metallic or colloidal silver is 1: (1 × 10 ^-7 - 1 × 10 ^-5 ). 15. The agent according to claim 1, characterized in that it is in the form of an ointment, gel or cream. 16. The agent according to claim 1, characterized in that the auxiliary substance is selected from the group: dimethyl sulfoxide; propylene glycol; carbomer; trolamine; macrogol; edetat; neroli and lavender oils; lanolin; petrolatum. 17. The agent according to claim 1, characterized in that it is in the form of a tablet or capsule. 18. An agent according to claim 17, characterized in that it is in the form of a film-coated tablet. 19. The agent according to claim 17, characterized in that the tablet additionally contains auxiliary substances taken in relation to chondroitin sodium 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. 20. The agent according to claim 17, 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. 21. The agent according to claim 18, characterized in that the tablet shell has a composition taken with respect to sodium sulfate chondroitin: hydroxypropyl methylcellulose - 1: 0.07, titanium dioxide (E171) - 1: 0.016, triacetin - 1: 0.014. 22. An agent according to claim 17, wherein the composition of the capsule shell consists of titanium dioxide and gelatin. 23. The agent according to claim 17, characterized in that the capsule contains one or more of the auxiliary substances: talc, stearic acid, magnesium stearate, manganese sulfate. 24. The agent according to claim 1, characterized in that it is in the form of a lyophilisate. 25. An agent according to claim 1, characterized in that it is in the form of a solution. 26. The agent according to claim 1, characterized in that the solution is prepared by dissolving the lyophilisate according to claim 24. 27. The agent according to claim 1, characterized in that it additionally contains a preservative. 28. The agent according to claim 27, characterized in that benzyl alcohol or sodium benzoate is used as a preservative.

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