Pharmaceutical agent for treating joint diseases

Abstract

An agent for treating joint diseases, containing an effective amount of sodium chondroitin sulphate and at least one adjuvant or carrier, is characterized in that it further contains copper in a relative amount of from 1 mg / kg to 20 mg / kg, calculated on the basis of the mass of the active ingredient, sodium chondroitin sulphate.

Description

[0001] A PHARMACEUTICAL PRODUCT FOR THE TREATMENT OF ARTHROLOGICAL DISEASES

[0002] The invention relates to the field of medicine, in particular to medicinal products for the treatment of arthrological diseases.

[0003] State of the art

[0004] Diseases of the musculoskeletal system

[0005] The musculoskeletal system is the most extensive system in the human body. It includes the skeleton, muscles, tendons, and ligaments—everything that allows the body to move and perform any movement. Treatment of the musculoskeletal system is covered by such medical fields as orthopedics, traumatology, neurology, and others. The danger of such diseases lies in the fact that they affect not only a person's motor activity but can also impact the health of internal organs, heart rate, well-being, and overall quality of life.

[0006] The most common arthrological diseases are osteoarthritis of the peripheral joints and intervertebral osteochondrosis and osteoarthritis. The knee joint is most frequently affected.

[0007] The treatment of arthrological joint diseases is based on chondromodulatory therapy, which currently widely uses medications based on sodium chondroitin sulfate, a mucopolysaccharide derived from animal tissue. This medication effectively influences metabolic processes in the patient's connective tissue, including cartilage, stimulating and normalizing the biosynthesis of glycosaminoglycans.

[0008] Chondroitin sulfate (CS) is a high-molecular heteropolysaccharide that belongs to the group of glycosaminoglycans, linear unbranched polymers.

[0009] The structure of the chondroitin sulfate molecule determines its polyanionic properties and its role in transporting water, amino acids, and lipids in avascular areas of cartilage. Long chains of chondroitin sulfate, 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 cartilage structures, stimulating synthesis and inhibiting destruction. Its timely administration and regular use ensure the inhibition, stabilization, and prevention of destructive processes in the joint. The main function of chondroitin sulfate in the body is to retain water and nutrients in cartilage and facilitate the movement of molecules through it. This is a crucial property because cartilage lacks blood to support metabolism. Chondroitin sulfate also acts as a chondroprotector.The water it retains within the cartilage provides good cushioning and absorbs shock, which ultimately increases the strength of the connective tissue.

[0010] Chondroitin sulfate is a natural component of articular cartilage, playing a vital role in maintaining the necessary osmotic pressure, which allows the matrix and collagen fibers to stretch. This substance has anti-inflammatory activity, primarily affecting the cellular component of inflammation, stimulating the synthesis of hyaluronic acid and proteoglycans and inhibiting the action of proteolytic enzymes.

[0011] Chondroitin sulfate preparations

[0012] There are currently a significant number of chondroitin sulfate products on the market. They are divided into three main groups:

[0013] 1 Topical agents.

[0014] 2 Oral agents.

[0015] 3 Parenteral agents.

[0016] Topical agents include ointments and gels. These medications are relatively easy to use, but have low bioavailability and, consequently, low efficacy. Topical agents are often used in combination therapy with parenteral agents.

[0017] Oral medications come in the form of tablets and capsules. This group also has low bioavailability. Furthermore, these medications are primarily used for prophylaxis and require long-term treatment. These medications are also primarily dietary supplements.

[0018] The most effective are parenteral agents (solutions and lyophilisates).

[0019] These products are represented by a fairly large group of drugs:

[0020] Chondroitin-Apex solution for intramuscular injection. Administer intramuscularly, 1 ml every other day. If well tolerated, the dose is increased to 2 ml, starting with the 4th injection. The course of treatment is 25-30 injections. If necessary, a repeat course of treatment can be administered after 6 months. The duration of repeat courses is determined by the physician. For callus formation, the course of treatment is 3-4 weeks (10-14 injections every other day).

[0021] Artogystan solution for intramuscular injection. Administered intramuscularly, 100 mg every other day. If well tolerated, the dose is increased to 200 mg, starting with the fourth injection. A course of treatment consists of 25-35 injections. If necessary, a repeat course of treatment can be administered after 6 months.

[0022] Chondrogard solution for intramuscular and intra-articular administration. Administer intramuscularly, 100 mg every other day. If well tolerated, the dose is increased to 200 mg, starting with the fourth injection. The course of treatment consists of 25-30 injections. If necessary, a repeat course of treatment can be administered after 6 months. For osteoarthritis of large joints, a combination of intra-articular and intramuscular administration is possible. Up to 5 intra-articular injections of 200 mg are administered with a 3-day interval between injections, and 16 intramuscular injections of 200 mg are administered with a 1-day interval between injections (every other day). Depending on the joint size, up to 2 ml of Chondrogard can be injected into the joint cavity.

[0023] Injectran solution for intramuscular and intra-articular administration. Administer intramuscularly, 1 ml every other day. If well tolerated, the dose is increased to 2 ml, starting with the fourth injection. The course of treatment consists of 25-30 injections. If necessary, a repeat course of treatment can be administered after 6 months. For osteoarthritis of large joints, a combination of intra-articular and intramuscular administration is possible. Up to 5 intra-articular injections of 2 ml are administered with a 3-day interval between injections, and 16 intramuscular injections of 2 mg are administered with a 1-day interval between injections (every other day). Depending on the joint size, up to 2 ml of Injectran can be injected into the joint cavity.

[0024] Mucosat solution for intramuscular and intra-articular administration. The drug is administered intramuscularly at a dose of 100 mg (1 ml) every other day. If well-tolerated, the dose is increased to 200 mg (2 ml), beginning with the fourth injection. A course of treatment consists of 25-30 injections. If necessary, repeat courses can be administered after 6 months.

[0025] To form bone callus, the course of treatment is 3-4 weeks (10-14 injections every other day).

[0026] For osteoarthritis of large joints, a combination of intra-articular and intramuscular administration is possible. Up to 5 intra-articular injections of 200 mg are administered with a 3-day interval between injections, and 16 intramuscular injections of 200 mg are administered with a 1-day interval between injections (every other day).

[0027] Intra-articular administration is performed under aseptic conditions by a specialist trained in intra-articular injection technique. Depending on the joint size, up to 2 ml of Mucosat can be injected into the joint cavity.

[0028] After intra-articular injection of the drug, the puncture site is lubricated with an alcohol wipe and a bactericidal plaster is applied.

[0029] Chondroitin-B solution for intramuscular injection. Administer intramuscularly, 100 mg (1 ml) every other day. If well tolerated, the dose is increased to 200 mg (2 ml), beginning with the fourth injection. A course of treatment consists of 25-35 injections. If necessary, a repeat course of treatment can be administered after 6 months. The duration of repeat courses is determined by the physician. For callus formation, a course of treatment is 3-4 weeks (10-14 injections every other day).

[0030] Chondroitin-Binergia solution for intramuscular and intra-articular administration. The drug is administered intramuscularly at a dose of 100 mg (1 ml) every other day. If well-tolerated, the dose is increased to 200 mg (2 ml), starting with the fourth injection.

[0031] The treatment course consists of 25-35 injections. If necessary, a repeat course of treatment can be administered after 6 months.

[0032] For osteoarthritis of large joints, a combination of intra-articular and intramuscular administration is possible. Up to 5 joint injections of 2 ml each are administered with a 3-day interval between injections, and 16 intramuscular injections of 2 ml each are administered with a 1-day interval between injections (every other day).

[0033] Intra-articular injection of the drug is performed under aseptic conditions by a specialist trained in intra-articular injection technique. Depending on the joint size, up to 2 ml of the drug can be injected into the joint cavity.

[0034] After intra-articular injection of the drug, the puncture site is lubricated with an alcohol wipe and a bactericidal plaster is applied.

[0035] To form bone callus, the course of treatment is 3-4 weeks (10-14 intramuscular injections every other day).

[0036] Khonsat solution for intramuscular injection. The drug is administered intramuscularly at a dose of 1 ml (100 mg) every other day. If well tolerated, the dose is increased to 2 ml (200 mg), beginning with the fourth injection. A course of treatment consists of 25-30 injections. If necessary, repeat courses can be administered after 6 months. For callus formation, a course of treatment is 3-4 weeks (10-14 injections every other day).

[0037] Chondroitin sulfate solution for intramuscular injection. The drug is administered intramuscularly at a dose of 100 mg (1 ml) every other day. If well tolerated, the dose is increased to 200 mg (2 ml), beginning with the fourth injection. A course of treatment consists of 25-30 injections. If necessary, repeat courses can be administered after 6 months.

[0038] To form bone callus, the course of treatment is 3-4 weeks (10-14 injections every other day).

[0039] Chondrofast solution for intramuscular injection. The drug is administered intramuscularly at a dose of 100 mg (1 ml) every other day. If well tolerated, the dose is increased to 200 mg (2 ml), beginning with the fourth injection. A course of treatment consists of 25-30 injections. If necessary, repeat courses can be administered after 6 months.

[0040] To accelerate the formation of bone callus, the course of treatment is 3-4 weeks (10-14 injections every other day).

[0041] Chondromed-Lekpharm solution for intramuscular injection. The drug is administered intramuscularly at a dose of 100 mg (1 ml) every other day. If well tolerated, the dose is increased to 200 mg (2 ml), beginning with the fourth injection. The course of treatment consists of 25-35 injections. If necessary, a repeat course of treatment can be administered after 6 months.

[0042] AR TRAVIR-TRIVIUM solution for intramuscular injection. Administer 100 mg (1 ml) intramuscularly every other day. If well tolerated, the dose is increased to 200 mg (2 ml), beginning with the fourth injection.

[0043] The course of treatment consists of 25-30 injections. If necessary, repeat courses can be administered after 6 months.

[0044] The effectiveness of parenteral agents is also due to their high bioavailability. Following an intramuscular injection, sodium chondroitin sulfate is detectable in synovial fluid within 15 minutes. It then enters the joint, where it reaches its peak concentration within 48 hours.

[0045] However, these medications have side effects, including allergic reactions (itching, erythema, urticaria, dermatitis, swelling), and hemorrhages at the injection site. Since these medications require a long course of treatment (at least 25 injections), this inevitably leads to an increase in these side effects. Furthermore, long courses are inconvenient for patients, as they require at least 25 days of treatment in the treatment room, and not all medical professionals are trained in administering these injections, especially intra-articular ones. This leads to patients not completing full courses of treatment, reducing the effectiveness of the treatment. Furthermore, all of these medications require repeat courses at least six times a year, which further complicates treatment for patients.

[0046] Use of copper in medicine The function of copper in the body

[0047] Copper (Cu) is an essential trace element necessary for the normal functioning of the human body. It is a component of enzymes and plays a role in all processes:

[0048] - metabolism;

[0049] - in tissue respiration;

[0050] - together with iron, it participates in the creation of red blood cells and hemoglobin;

[0051] - maintaining the normal structure of bones, cartilage, tendons, elasticity of the walls of blood vessels and skin;

[0052] - formation of skin and hair pigments;

[0053] - normal functioning of the thyroid gland and cardiovascular system;

[0054] - in the assimilation of proteins and carbohydrates;

[0055] - functioning of the immune system;

[0056] - production of female sex hormones;

[0057] - strengthening the vestibular apparatus.

[0058] The highest copper concentrations are found in the liver, kidneys, and brain. The body's physiological requirement for copper is 2-3 mg / day. The toxic threshold for humans is 200 mg / day. Copper enters the body through food. In some cases, copper supplements are necessary. Most existing medications perform this function.

[0059] Preparations containing copper

[0060] Asparaginase Medac contains the copper-containing enzyme asparaginase. It is effective in the treatment of lymphoblastic leukemia. Turamin Copper, 90 capsules, 0.2 g (copper citrate) - prevents copper deficiency.

[0061] Copper gluconate GLS, 400 mg capsules, 60 pcs. (Copper gluconate 14.5 mg, including copper 2 mg) - prevention of copper deficiency.

[0062] The drug Tetralab copper chelate, 90 pcs., tablets weighing 100 mg (copper chelate (copper bisglycinate) - as a biologically active food supplement - an additional source of copper.

[0063] The drug Vitamir copper chelate, 60 tablets weighing 100 mg (copper chelate (copper bisglycinate) - prevention of copper deficiency.

[0064] Disclosure of invention

[0065] The objective of the present invention is to develop a product with sodium chondroitin sulfate in the form of lyophilized and liquid injection forms for the treatment of arthrological diseases, containing copper and having significantly higher efficiency compared to products containing only sodium chondroitin sulfate, which makes it possible to significantly reduce the duration of the course of treatment.

[0066] It has been found that the introduction of certain doses of copper into compositions containing sodium chondroitin sulfate as an active substance significantly reduces the duration of treatment with the same or greater therapeutic efficacy and a low level of side effects.

[0067] These effects of the combination of copper and sodium chondroitin sulfate are unexpected.

[0068] The subject of the present invention is a means for treating arthrological diseases, comprising an effective amount of sodium chondroitin sulfate and at least one auxiliary substance or carrier, characterized in that it additionally contains copper in a relative amount of 1 mg / kg to 20 mg / kg based on the weight of the active substance - sodium chondroitin sulfate.

[0069] The technical result of the present invention is a significant reduction in the course of treatment due to the increased therapeutic efficacy of sodium chondroitin sulfate in a copper-containing composition and a low level of side effects. Use of the inventive agent also leads to the normalization of metabolic processes, accelerated reduction of swelling following injuries and / or injections, a more rapid regeneration process, and improved tissue blood flow.

[0070] No products containing copper in their composition have been identified from the prior art according to their stated purpose.

[0071] Description of the invention

[0072] In this preparation, copper helps increase the therapeutic activity of sodium chondroitin sulfate and improves the overall effectiveness of the composition.

[0073] The composition of the product according to the invention uses copper in the form of various chemical compounds.

[0074] The choice of a specific compound is determined by the production method and dosage forms.

[0075] Copper sulfate, copper chloride, copper gluconate, and chelated forms of copper may be used in the context of the present invention. This list is not exhaustive.

[0076] The agent according to the present invention includes copper in a relative amount of 1 mg / kg to 20 mg / kg based on the weight of the active substance - sodium chondroitin sulfate.

[0077] In a particular embodiment, in a relative quantity from 2 mg / kg to 9 mg / kg, as well as from 1 mg / kg to 8 mg / kg based on the mass of the active substance.

[0078] In a particular embodiment, in a relative quantity of 1 mg / kg to 6 mg / kg, as well as 3 mg / kg to 10 mg / kg, as well as 2 mg / kg to 2 mg / kg, as well as 1 mg / kg to 5 mg / kg, as well as 7 mg / kg to 10 mg / kg, as well as 4 mg / kg to 8 mg / kg based on the mass of the active substance.

[0079] The amount of sodium chondroitin sulfate in the product can range from 50 mg to 2500 mg.

[0080] The amount of sodium chondroitin sulfate in the product can range from 100 mg to 2000 mg.

[0081] The amount of sodium chondroitin sulfate in the product can range from 300 mg to 1500 mg.

[0082] The amount of sodium chondroitin sulfate in the product can range from 500 mg to 1200 mg.

[0083] The amount of sodium chondroitin sulfate in the product can range from 50 mg to 250 mg.

[0084] The amount of sodium chondroitin sulfate in the product can range from 250 mg to

[0085] 1000 mg. The mass ratio of sodium chondroitin sulfate to copper can be 1: 1 x 10-7 - 1: 1 x 10-5.

[0086] Forms of release of the invention

[0087] The agent according to the present invention can be produced in liquid and lyophilized form.

[0088] The product can be used for injection.

[0089] Injectable forms include injection solutions and lyophilisates.

[0090] Auxiliary components are selected depending on the form of manufacture.

[0091] The product, which is made in the form of a solution, contains water.

[0092] More specifically, the product contains distilled water.

[0093] The finished parenteral product may contain a certain amount of preservatives such as benzyl alcohol, sodium benzoate, sodium metabisulfite, sodium bisulfite, methyl parahydroxybenzoate or similar.

[0094] The specific ratios of components are determined by the production technology and the requirements for use and storage.

[0095] Therapeutic efficacy

[0096] The claimed product is intended for the treatment of arthrological diseases.

[0097] These diseases include degenerative-dystrophic diseases of the joints and spine: osteoarthrosis of the peripheral joints; intervertebral osteochondrosis and osteoarthrosis, rheumatoid arthritis, gout, reactive arthritis, spondyloarthropathies, arthritis in systemic lupus erythematosus, dermatomyositis and other systemic diseases, psoriatic arthritis, post-traumatic injuries of articular cartilage, ligaments, menisci.

[0098] Implementation of the invention

[0099] Examples of the preparation of various forms of compositions containing sodium chondroitin sulfate and copper, which are not exhaustive.

[0100] Example 1. Preparation of a solution A preparation in the form of a solution, including sodium chondroitin sulfate, purified water, and which additionally contains copper from 1 mg / kg to 20 mg / kg based on the weight of sodium chondroitin sulfate, can be obtained in the following ways.

[0101] Option 1: Preparation of solution "A". Dissolve 100 g of sodium chondroitin sulfate (based on dry matter content) in 500 ml of injection water heated to 50°C. After complete dissolution, cool the sodium chondroitin sulfate solution to a temperature no higher than 35°C. Preparation of solution "B". Add 150 ml of injection water to 9.0 g of benzyl alcohol and stir until benzyl alcohol is completely dissolved. Add 0.002 g of copper gluconate (containing 3 mg of copper per 1 kg of sodium chondroitin sulfate). Preparation of solution "G". Add 230 ml of solution "B" to solution "A" with constant stirring, along with a 0.1 M NaOH solution to pH 6-6.5 and injection water to a volume of 1 liter. Analyze the content of the main substances and the pH of the solution; adjust the solution if necessary. Solution "G" is sterilized and filtered into a sterile container. The solution is dispensed into 1.0 ml ampoules and sealed.

[0102] A ready-made solution is obtained with the following composition (wt / vol%):

[0103] 1 Chondroitin sodium sulfate - 10;

[0104] 2 Benzyl alcohol - 1 ;

[0105] 3 Copper gluconate - 0.0002;

[0106] 4 Water up to 100.

[0107] Option 2:

[0108] A pre-prepared reactor is loaded with 15 liters of water for injection at a temperature of 24°C. The water is bubbled with sterile nitrogen at an excess pressure of 0.2 ± 0.1 bar (0.02 ± 0.01 MPa) for at least 10 minutes (then the process is carried out with constant bubbling of the solution with nitrogen).

[0109] With the stirrer running (200-300 rpm), add 40 g of sodium disulfite to the reactor and stir for at least 10 minutes until completely dissolved. Then, add 2 kg (based on the main ingredient) of sodium chondroitin sulfate to the reactor in portions and stir for at least 60 minutes until completely dissolved.

[0110] Next, 10 g of methyl parahydroxybenzoate is added to the reactor, stirred for at least 20 minutes, and a sample is taken. The pH of the resulting solution is measured and, if necessary, adjusted to 6.8 with 1 M sodium hydroxide solution. The solution is stirred for at least 10 minutes. Then, while stirring, 0.4 g of 10% copper chelate in the form of copper glycinate amino acid chelate (containing 20 mg of copper per 1 kg of sodium chondroitin sulfate) is added. The solution is then brought to the calculated volume (20 L) with water for injection and stirred for at least 15 minutes.

[0111] After analysis and adjustment (if necessary), the solution is subjected to sterilizing filtration and poured into 1 ml ampoules.

[0112] A ready-made solution is obtained with the following composition (wt / vol%):

[0113] 1 Chondroitin sodium sulfate - 10;

[0114] 2 Sodium disulfite - 0.2;

[0115] 3 Methyl parahydroxybenzoate - 0.05;

[0116] 4 Copper chelate 10% (in the form of amino acid chelate copper glycinate) - 0.002;

[0117] 5 Water up to 100.

[0118] Option 3:

[0119] Preparation of solution "A": Dissolve 1 kg of sodium chondroitin sulfate (calculated as dry substance) in 4 liters of water for injection heated to 50°C. After the sodium chondroitin sulfate is completely dissolved, cool the solution to room temperature, bring the volume to 5 liters with water for injection, and sterilize-filter.

[0120] Preparation of solution "B": Add 1.5 liters of injection water to 90 g of benzyl alcohol and stir until the benzyl alcohol is completely dissolved. Then, while stirring, add 90 mg of 10% copper chelate as copper bisglycinate (containing 9 mg of copper per 1 kg of sodium chondroitin sulfate).

[0121] Preparation of solution "B". Dissolve 0.05 g of sodium hydroxide in 500 ml of water for injection.

[0122] Preparation of solution "G." Add 500 ml of solution "B" to sterile solution "A" while stirring constantly. Then, 15-20 minutes after adding solution "B," continue stirring and then sterile filter 1.5 L of solution "B." Continue stirring for 15-20 minutes after adding solution "B."

[0123] Preparation of the drug. The remaining amount (up to 10 liters) of water for injection is added to the sterile container containing solution "G" through a sterilizing filter.

[0124] Filling the solution. The solution is poured into 1 ml ampoules. The ampoules are sealed.

[0125] A ready-made solution is obtained with the following composition (wt / vol%):

[0126] 1 Chondroitin sodium sulfate - 10;

[0127] 2 Benzyl alcohol - 1 ;

[0128] 3 Sodium disulfite - 0.1; and 4 Copper chelate 10% (as copper bisglycinate) - 0.0009;

[0129] 5 Water up to 100.

[0130] Example 2. Preparation of lyophilisate

[0131] The drug contains 95-120 mg of lyophilized powder of Na-salt of chondroitin sulfate, which is obtained from sodium salt of chondroitin sulfate dissolved in apyrogenic injection water and copper from 1 mg / kg to 20 mg / kg based on the mass of sodium chondroitin sulfate.

[0132] The injection solution prepared from the said lyophilisate using apyrogenic water contains Na-salt of chondroitin sulfate in a therapeutic dosage of 9.0-11.5 wt%.

[0133] The drug can be obtained, for example, in the following way:

[0134] Option 1: 101 mg of a substance containing 90-115% sodium chondroitin sulfate is dissolved in 0.9 ml of pyrogen-free water for injection. The pH is adjusted from 6.0 to 7.5 with sodium hydroxide solution, after which 0.0014 mg of copper gluconate is added (containing 2 mg of copper per 1 kg of sodium chondroitin sulfate). Sterilizing filtration is carried out, the mixture is poured into 1 ml ampoules and sublimated in a known manner, the ampoules with the lyophilized drug are sealed. A preparation is obtained containing at least 98.7 mg of sodium chondroitin sulfate; 0.0014 mg of copper gluconate per 1 ml of an aqueous solution obtained by dissolution in pyrogen-free water for injection.

[0135] Option 2: Dissolve 104 g of a substance containing 90-115% sodium chondroitin sulfate in 800 ml of pyrogen-free water for injection, and add 0.3 g of sodium disulfite with stirring. Adjust the pH to 6.0 to 7.5 with sodium hydroxide solution, then add 11.44 mg of 10% copper chelate as copper bisglycinate (containing 11 mg of copper per 1 kg of sodium chondroitin sulfate). Perform sterilizing filtration, dispense into 1 ml ampoules, and sublimate using a known method. The ampoules containing the lyophilized drug are sealed. A preparation is obtained containing at least 99.6 g of sodium chondroitin sulfate, 11.44 mg of 10% copper chelate in the form of copper bisglycinate, 0.3 g of sodium disulfite per 1 liter of aqueous solution obtained by dissolution in apyrogenic injection water.

[0136] Option 3: 515 g of a substance containing 90-115% sodium chondroitin sulfate are dissolved in 4.5 liters of pyrogen-free water for injection. The pH is adjusted from 6.0 to 7.5 with sodium hydroxide solution, after which 63.06 mg of copper gluconate is added (containing 18 mg of copper per 1 kg of sodium chondroitin sulfate). Sterilizing filtration is carried out, poured into 1 ml ampoules and sublimated in a known manner, the ampoules with the lyophilized drug are sealed. A preparation is obtained containing at least 99.7 mg of sodium chondroitin sulfate, 63 mg of copper gluconate per 5 liters of an aqueous solution obtained by dissolution in pyrogen-free water for injection,

[0137] The examples presented above demonstrate that the preparation of drugs can be implemented in various dosage forms using various methods and 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 stated technical result is determined by the active substance based on sodium chondroitin sulfate with the addition of copper from 1 mg to 20 mg per 1 kg of sodium chondroitin sulfate.

[0138] Research

[0139] Animal studies were conducted to evaluate the therapeutic efficacy and safety of the inventive agents. These parameters were assessed in animals for each formulation of the invention, manufactured using different variants. Comparative agents were similar formulations of the inventive agents, differing in composition by the absence of copper. Furthermore, the comparators are also analogs of drugs available on the pharmaceutical market.

[0140] Effectiveness study

[0141] To evaluate efficacy, a 50-day simulation of arthrosis was conducted in 110 rabbits. Following diagnostic testing (blood and synovial fluid parameters, behavioral characteristics, and external signs of joint damage), rabbits with the most severe arthrosis were selected. The selected rabbits were divided into groups of 10 depending on the dosage form, manufacturing method, and drug type (invented agents or comparators). Following this, a standard course of 25 intramuscular injections was administered with the inventive agents and comparators. During this course, blood and synovial fluid parameters were regularly analyzed, behavioral responses were monitored, and radiography was performed. For each group, parameters were monitored before the start of the simulation (baseline), after the simulation, and before the start of the injection course, as well as the recovery period to baseline values.

[0142] Drugs participating in the study

[0143] The list of drugs studied is given in Table 1.

[0144] Table 1

[0145] Dosage, duration of course, method of administration

[0146] In accordance with guidelines for studying the overall effectiveness of pharmacological agents, the minimum dose when studying side effects should be close to the therapeutic dose.

[0147] Based on therapeutic dose and metabolic coefficient data for each study drug and comparator drugs, a daily dose of 32 mg was established, administered every other day. The course duration was 51 days.

[0148] Experimental groups

[0149] To conduct the research, the drugs and animals were divided into 10 groups:

[0150] Table 2

[0151]

[0152] Preparation of animals for research

[0153] The experiments were performed on Soviet Chinchilla rabbits aged 14–16 months, weighing 2.5 ± 0.5 kg.

[0154] The criteria for selecting animals for research were the absence of external signs of disease and homogeneity of groups by body weight (±10%).

[0155] All animals were quarantined for 14 days. During this period, each animal was examined daily for behavior and general condition, and the animals were observed twice daily in their cages for morbidity and mortality. Animals that did not meet the criteria were excluded from the study during the quarantine period.

[0156] Animal keeping

[0157] The animals were kept in accordance with the requirements of GOST R 53434-2009 from 02.12.2009 "Principles of Good Laboratory Practice (GLP)". The animals were kept in ventilated cages "Rair Iso System", in groups of 5 animals. Sterile wood sawdust from non-coniferous trees was used as bedding. The feed was standard granulated complete feed for laboratory animals (extruded) PK-120 GOST R 51849-2001 R.5. Animals were fed according to the standards corresponding to the animal species. Purified tap water was given to all animals ad libitum in standard drinkers. The animals were kept in controlled environmental conditions: air temperature 22-24°C and relative humidity 60-70%. Lighting in the rooms was natural and artificial. A 12-hour lighting cycle was maintained in the animal keeping rooms.

[0158] Observation period and recorded indicators

[0159] The observation period was 103 days.

[0160] All animals underwent modeling of arthrosis 50 days before the start of the study by intra-articular administration of dexamethasone at a dose of 5 mg / kg.

[0161] To confirm the development of arthrosis at the end of the arthrosis simulation period, X-ray images were analyzed. The animals' behavioral responses were also monitored throughout the simulation period.

[0162] Before and after the simulation, as well as on the 1st, 3rd, 5th, 7th, 9th, 13th, 17th, 21st, 25th, 30th, 35th, 40th, 45th, 50th and 51st days of the experiment, blood and synovial fluid parameters were recorded.

[0163] To evaluate the research results, a comprehensive analysis of X-ray images, blood parameters, synovial fluid parameters, and behavioral responses was conducted.

[0164] Methods of performance evaluation

[0165] Blood parameters and synovial fluid parameters were recorded in tables before and after the start of the arthrosis simulation, as well as on the 1st, 3rd, 5th, 7th, 9th, 13th, 17th, 21st, 25th, 30th, 35th, 40th, 45th, 50th, and 51st days of the study. After completing the course of intramuscular injections, the time to achieve the parameters before the start of the simulation was analyzed, indicating a cure for arthrosis. Normalization of the morphofunctional state of the joint (swelling, thickening) undergoing the simulation was also monitored, as were radiographs for cartilage surface restoration, and behavioral responses.

[0166] Results of the analysis of blood and synovial fluid parameters Group 1

[0167] The results for group No. 1 are shown in Table 3 (blood parameters) and Table 4 (synovial fluid parameters).

[0168] Table 4

[0169] Group 2

[0170] The results for group No. 2 are shown in Table 4 (blood parameters) and Table 5

[0171] (synovial fluid parameters).

[0172] Table 4

[0173] *-l - before modeling starts

[0174] **0 - after modeling

[0175] Table 5

[0176] *-l - before modeling starts

[0177] **0 - after modeling

[0178] Group 3

[0179] The results for group No. 3 are shown in Table 6 (blood parameters) and Table 7 (synovial fluid parameters).

[0180] Table 7

[0181] *-l - before modeling starts

[0182] **0 - after modeling

[0183] Group 4

[0184] The results for group No. 4 are shown in Table 8 (blood parameters) and Table 9 (synovial fluid parameters).

[0185] Table 8

[0186] *-l - before modeling starts

[0187] **0 - after modeling

[0188] Table 9

[0189] Synovial fluid parameters in rabbits

[0190] *-1 - before the start of modeling

[0191] **0 - after modeling

[0192] Group 5

[0193] The results for group No. 5 are shown in Table 10 (blood parameters) and Table 11

[0194] (synovial fluid parameters).

[0195] Table 10

[0196]

[0197] Table 11

[0198] *-l - before modeling starts

[0199] **0 - after modeling

[0200] Group 6

[0201] The results for group No. 6 are shown in Table 12 (blood parameters) and Table 13 (synovial fluid parameters).

[0202] Table 12

[0203]

[0204] *-l - before modeling starts

[0205] **0 - after modeling

[0206] Group 7

[0207] The results for group No. 7 are shown in Table 14 (blood parameters) and Table 15

[0208] (synovial fluid parameters).

[0209] Table 14

[0210] *-l - before modeling starts

[0211] **0 - after modeling

[0212] Table 15

[0213] *-l - before modeling starts

[0214] **0 - after modeling

[0215] Group 8

[0216] The results for group No. 8 are shown in Table 16 (blood parameters) and Table 17 (synovial fluid parameters).

[0217] Table 17

[0218] *-l - before modeling starts

[0219] **0 - after modeling

[0220] Results of monitoring behavioral reactions, morphofunctional state of animals and evaluation of radiographs

[0221] Behavioral responses and morphofunctional status were assessed based on animal mobility, traumatic manifestations (lameness, limb retraction), knee joint enlargement, increased local temperature of the affected joint, and pain. These manifestations peaked in almost all animals after the arthrosis simulation and before the injection course. Throughout the course of intramuscular injections, the severity of the aforementioned effects was assessed, and the point at which they declined was recorded for all groups.

[0222] The results obtained are shown in Table 18.

[0223] Radiographs were used to assess both the extent of joint damage during the arthrosis simulation and the degree of joint recovery during the course of intramuscular injections. After the arthrosis simulation, almost all animals showed uneven narrowing of the joint space, the presence of osteophytes, and osteosclerosis of the articular surfaces. During the course of intramuscular injections, radiographic analysis revealed that significant improvement in joint condition by day almost coincided with the days indicated in Table 18. Conclusion on the efficacy study

[0224] Summary data from the efficacy studies are presented in Table 19. For each group, the time (in days) to maximum joint recovery was assessed based on blood and synovial fluid analysis data, behavioral assessment, morphofunctional state of the joints, and radiography.

[0225] The presented data allow us to draw a clear conclusion about the significantly greater effectiveness of the inventive treatments. In fact, the course of treatment can be shortened by a factor of three.

[0226] Safety research

[0227] A safety study was conducted in animals to assess the severity of adverse effects over the full course of therapy. Adverse effects for injectable forms of sodium chondroitin sulfate, according to the instructions for use, include swelling and hemorrhage at the injection site. To assess safety, all animals received a full course of injections, during which time they were observed and the number of animals experiencing adverse effects was counted. Drugs involved in the study

[0228] The list of drugs studied is given in Table 6.

[0229] Dosage, duration of course, method of administration

[0230] In accordance with guidelines for studying the overall effectiveness of pharmacological agents, the minimum dose when studying side effects should be close to the therapeutic dose.

[0231] Based on therapeutic dose and metabolic coefficient data for each study drug and comparator drugs, a daily dose of 32 mg was established, administered every other day. The course duration was 50 days.

[0232] Experimental groups

[0233] To conduct the studies, the drugs and animals were divided into 8 groups: Table 7.

[0234] Animals for research

[0235] The determination of the indicators was carried out on rabbits.

[0236] The experiments were performed on Chinchilla rabbits aged 14–16 months, weighing 2.4 ± 0.5 kg.

[0237] A randomization method was used to assign animals to groups. The absence of external signs of disease and homogeneity of body weight across groups (±10%) were considered criteria for randomization eligibility.

[0238] Quarantine

[0239] All animals were quarantined for 14 days. During this period, each animal was examined daily for behavior and general condition, and the animals were observed twice daily in their cages for morbidity and mortality. Before the study began, animals meeting the inclusion criteria were randomly assigned to groups. Animals that did not meet the criteria were excluded from the study during the quarantine period.

[0240] Animal keeping

[0241] The animals were kept in accordance with the requirements of GOST R 53434-2009 from 02.12.2009 "Principles of Good Laboratory Practice (GLP)". The animals were kept in ventilated cages "Rair Iso System", in groups of 5 animals. Sterile wood sawdust from non-coniferous trees was used as bedding. The feed was standard granulated complete feed for laboratory animals (extruded) PK-120 GOST R 51849-2001 R.5. The animals were fed according to the standards corresponding to the animal species. Purified tap water was given to all animals ad libitum in standard drinkers. The animals were kept in controlled environmental conditions: air temperature 22-24°C and relative humidity 60-70%. The lighting in the rooms was natural and artificial. A 12-hour lighting cycle was maintained in the animal keeping rooms.

[0242] Observation period and recorded indicators

[0243] The observation period was 50 days.

[0244] Upon completion of the course of administration, animals of all groups were euthanized by an overdose of ether and sent for autopsy.

[0245] The animals' general condition was assessed daily. Weighing, rectal temperature measurements, and water and food intake were performed once every two weeks and after the end of the experiment.

[0246] Every 5 days, animals with severe hemorrhages and swelling at the injection site were counted.

[0247] Safety assessment methods

[0248] Safety assessment was conducted over a 50-day period. The severity of hemorrhagic manifestations and swelling at the injection site were assessed every 5 days.

[0249] Data processing

[0250] During the study, data on the number of animals experiencing side effects was entered into a comparative table. The resulting data were then summarized and compared between the inventive agents and the comparator drugs.

[0251] Results of the study on side effects

[0252] Solution for intramuscular administration

[0253] The results of the study of solutions for intramuscular administration are presented in Table 8.

[0254]

[0255] Lyophilisate for intramuscular administration

[0256] The results of the study of solutions for intramuscular administration are presented in Table 9. Safety Study Conclusion

[0257] The results of the safety study are presented in Table 10.

[0258] The study confirmed the high safety profile of the inventive agents. The number of animals with identified adverse effects for the inventive agents was minimal and similar to that of the comparison drugs.

[0259] Conclusion on the research

[0260] Efficacy and safety studies clearly demonstrate that the inventive agents are highly effective, allowing the treatment course to be more than halved compared to standard treatment with injectables containing sodium chondroitin sulfate. A standard course of treatment is 50 days (25 injections), while the inventive agents achieve the same results in 10-16 days (5-8 injections). Studies also confirmed the high safety profile of the inventive agents. During the standard course of treatment, the incidence and severity of side effects did not exceed those of injectables containing sodium chondroitin sulfate.

Claims

CLAUSES OF THE INVENTION An agent for the treatment of arthrological diseases, comprising an effective amount of sodium chondroitin sulfate and at least one auxiliary substance and / or carrier, characterized in that it additionally contains copper in a relative amount of 1 mg / kg to 20 mg / kg based on the weight of the active substance - sodium chondroitin sulfate.

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