Use of an agent for treating joint diseases

Abstract

The invention relates to the field of medicine, and more particularly to the use of chondroitin sulphate medicinal agents for treating joint diseases. The invention discloses the use of a medicinal agent containing, as active ingredient, chondroitin sodium sulphate for treating joint diseases selected from the group of osteoarthritis of the peripheral joints, intervertebral osteochondrosis and osteoarthritis, which includes administering a course of the medicinal agent, wherein the course comprises not more than 20 intramuscular injections of 200 mg of chondroitin sodium sulphate administered every other day. The invention provides a reduction in the time to therapeutic onset, with the same or greater treatment efficacy and also greater safety by comparison with a standard course of 25-30 injections, and obviates the need for initial test injections that lead to an increase in the length of a course of treatment and a decrease in the efficacy thereof.

Description

[0001] APPLICATION OF THE REMEDY FOR THE TREATMENT OF ARTHROLOGICAL DISEASES

[0002] FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0003] The invention relates to the field of medicine, in particular to the use of chondroitin sulfate medicinal products for the treatment of arthrological diseases.

[0004] LEVEL OF TECHNOLOGY

[0005] Degenerative joint disease, or osteoarthritis (OA), is the most common form of joint disease, with the knee joint most frequently affected. Each year, more than four million new patients seek medical attention due to knee pain. An estimated 10% of the population over 55 years of age exhibit signs of knee deterioration, with approximately 25% of these patients experiencing significant problems that impact their quality of life. According to the WHO Global Disease Burden Report, knee OA is a leading cause of disability: the fourth leading cause among women and the eighth leading cause among men. Osteoarthritis can affect anyone, regardless of gender, age, race, or skin color. The primary manifestations of OA include disruption of articular cartilage structure, subchondral bone remodeling, and osteophyte formation (joint ossification).The disease has a chronic, progressive course, with exacerbations most often occurring under the influence of mechanical factors, and destructive changes progressively worsening. OA occurs not only in the elderly but also in the working-age population, often leading to decreased mobility and even disability, the socioeconomic cost of which is very high. The onset of OA is closely linked to age: under 50, the disease is more common in men, while after 50, it is more common in men.

[0006] - in women, resulting from a lack of estrogen during menopause. The incidence of the disease in women and men becomes equal around age 80.

[0007] An equally dangerous disease is osteochondrosis of the spine.

[0008] - the basis of the human musculoskeletal system. The spinal column is subject to significant static-dynamic loads, which lead to the relatively early development of degenerative-dystrophic processes in the spinal joints. Treatment principles

[0009] Treatment of these diseases is complex and includes a number of preventive and therapeutic measures:

[0010] 1. Therapy aimed at relieving pain in the form of parenteral or oral administration of analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) and opiates;

[0011] 2. Local therapy - topical steroids, H11VP and capsaicin in gels and creams;

[0012] 3. Intra-articular injections of corticosteroids and hyaluronic acid;

[0013] 4. Non-drug methods - physiotherapy, aerobics, stretching exercises, transcutaneous electrical nerve stimulation, orthopedic insoles;

[0014] 5. Surgical methods - joint replacement, arthroscopic debridement of affected joints.

[0015] Frequent side effects and low efficacy limit the use of many non-surgical therapies.

[0016] In recent years, chondroitin, glucosamine, avocado and soybean unsaponifiables, and diacerein have been proposed as new treatments for osteoarthritis.

[0017] According to the latest guidelines from the American College of Rheumatology and the European League Against Rheumatism, medications for the treatment of osteoarthritis are classified as symptom-modifying and structure-modifying, depending on their ability to influence disease progression. Accumulated evidence allows chondroitin (sodium chondroitin sulfate (SS)) to be classified as a symptom-modifying agent, as it primarily relieves pain and improves joint function. One of the main advantages of chondroitin sulfate is its safety profile.

[0018] Sodium chondroitin sulfate belongs to the family of heteropolysaccharides called glycosaminoglycans. Chondroitin sulfate is found in human cartilage, bone tissue, cornea, skin, and arterial walls. One of the main mechanisms of action of chondroitin sulfate is believed to be the restoration of the extracellular matrix of cartilage tissue, preventing cartilage degradation, and replenishing the deficiency of sulfur-containing amino acids, which are essential building blocks for the assembly of cartilage extracellular matrix molecules. Many patients with osteoarthritis in Russia and around the world already use chondroitin. Medications

[0019] Groups

[0020] The pharmaceutical market offers the following groups of drugs with the active ingredient sodium chondroitin sulfate:

[0021] 1. Topical agents are primarily used as part of combination therapy due to their low bioavailability, which is related to the fact that the active ingredient in ointments or gels must cross the tissue barrier to exert a therapeutic effect. According to Russian and European clinical guidelines, topical formulations are most often used in conjunction with parenteral agents.

[0022] 2. Oral medications also have low bioavailability. According to various literature sources, it ranges from 8% to 13%. These medications are primarily dietary supplements. They also often contain low-quality ingredients. These medications are recommended for prophylactic use.

[0023] 3. Parenteral medications containing sodium chondroitin sulfate are the most effective. This is due to its high bioavailability. After an intramuscular injection, sodium chondroitin sulfate is detectable in the synovial fluid within 15 minutes. It then enters the joint, where it reaches its peak concentration within 48 hours.

[0024] 4. Products containing sodium chondroitin sulfate in general and products for parenteral administration in particular are characterized by a long course of therapy.

[0025] Commercially available drugs

[0026] Artogistan solution for intramuscular injection is a well-known medication. It is 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.

[0027] A well-known medication is "Drastop solution for intramuscular injection." It is administered intramuscularly at a dose of 1 ml (100 mg sodium chondroitin sulfate) every other day. If well-tolerated, the dose is increased to 2 ml (200 mg sodium chondroitin sulfate), starting with the fourth injection. A course of treatment consists of 25-30 injections. If necessary, a repeat course of treatment can be administered after 6 months.

[0028] Chondrogard solution for intramuscular and intra-articular administration is a well-known drug. It is administered intramuscularly, 100 mg every other day. If well tolerated, the dose is increased to 200 mg, beginning with the fourth injection. The treatment course 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.

[0029] Injectran solution for intramuscular and intra-articular administration is a well-known medication. It is administered intramuscularly, 1 ml every other day. If well-tolerated, the dose is increased to 2 ml, beginning with the fourth injection. A 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.

[0030] Mucosat solution for intramuscular and intra-articular administration is a well-known drug. The drug is administered intramuscularly at 100 mg (1 ml) every other day. If well tolerated, the dose is increased to 200 mg (2 ml), starting with the fourth injection. The course of treatment consists of 25-30 injections. If necessary, repeat courses 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).

[0031] 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.

[0032] After intra-articular injection of the drug, the puncture site is lubricated with an alcohol wipe and a bactericidal plaster is applied.

[0033] A well-known drug is "Chondroitin-Apex solution for intramuscular injection." 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 is 25-30 injections. If necessary, a repeat course of treatment can be carried out after 6 months. The duration of repeat courses of treatment is determined by the doctor. A well-known drug is "Chondroitin-B solution for intramuscular injection." Intramuscularly, 100 mg (1 ml) every other day. If well tolerated, the dose is increased to 200 mg (2 ml), starting with the fourth injection. The course of treatment is 25-35 injections. If necessary, a repeat course of treatment can be carried out after 6 months. The duration of repeat courses of treatment is determined by the doctor.

[0034] Chondroitin-Binergia solution for intramuscular and intra-articular administration is a well-known drug. The drug is administered intramuscularly at 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. For osteoarthritis of large joints, a combination of intra-articular and intramuscular administration is possible. Up to 5 joint injections of 2 ml are administered with a 3-day interval between injections, and 16 intramuscular injections of 2 ml are administered with a 1-day interval between injections (every other day).

[0035] 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.

[0036] After intra-articular injection of the drug, the puncture site is lubricated with an alcohol wipe and a bactericidal plaster is applied.

[0037] Chondroitin sulfate solution for intramuscular injection is a well-known medication. It 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] Chondrofast solution for intramuscular injection is a well-known medication. It 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.

[0039] A well-known medication is "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), starting with the fourth injection. A course of treatment consists of 25-30 injections. If necessary, repeat courses can be administered after 6 months.

[0040] A well-known medication is "Chondromed-Lekpharm solution for intramuscular injection." The medication 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. A course of treatment consists of 25-35 injections. If necessary, a repeat course of treatment can be administered after 6 months.

[0041] ARTRAVIR-TRIVIUM solution for intramuscular injection is a well-known medication. It 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.

[0042] All of the above medications have similar side effects: allergic reactions (itching, erythema, urticaria, dermatitis, swelling), hemorrhages at the injection site, and pain associated with prolonged administration. Long-term treatment (at least 25 injections) with the above medications 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, and not all medical professionals are trained in administering these injections. This leads to patients not completing full treatment courses, reducing treatment effectiveness or achieving no improvement at all. The need for three trial injections also reduces treatment effectiveness. These injections prolong treatment time and reduce its effectiveness.

[0043] Thus, the problem of effective treatment of arthrological diseases has not been solved to date.

[0044] DISCLOSURE OF THE ESSENCE OF THE INVENTION

[0045] The present invention addresses the aforementioned problems of known solutions. The objective of the present invention is to develop a strategy for the effective treatment of arthrological diseases that is comparable in effectiveness to or superior to known solutions, while providing greater safety and treatment compliance than known strategies.

[0046] The stated problem is solved by using a medicinal product with the active substance sodium chondroitin sulfate for the treatment of arthrological diseases selected from the group of osteoarthrosis of peripheral joints, intervertebral osteochondrosis and osteoarthrosis, including a course of administration of the medicinal product, where the course contains no more than 20 intramuscular injections of 200 mg of sodium chondroitin sulfate every other day.

[0047] The connective tissue polysaccharide hyaluronan is found in serum at concentrations <100 μg / L (average 30-40 μg / L in middle-aged individuals). High concentrations of hyaluronic acid (HA) in synovial fluid provide essential lubrication for moving joint parts and act as a shock absorber, reducing friction between moving bones and joint wear. In joint diseases, HA is destroyed, reducing the viscosity of the synovial fluid and weakening its shock-absorbing and lubricating properties. This limits joint mobility, and any movement is accompanied by pain.

[0048] The clinical activity of osteoarthritis (OA) depends on pathological changes in the parameters of the synovial fluid. It has been noted that in OA, the enzymatic activity of hyaluronidase (an enzyme that breaks down HA) increases by 3.7 times; accordingly, the concentration of hyaluronic acid decreases by 3.7 times, and the content of glucuronic acid increases by 2.3 times. Against the background of a decrease in hyaluronic acid in the synovial fluid and in the joint itself, the concentration of HA in the blood of such patients increases, as is believed, as a result of its leaching from the joints [Laurent T.S. et al. Serum hyaluronan as a disease marker. Ann Med 1996 Jun; 28 (3): 241-53]. When creating an artificial deficiency of hyaluronidase and exoglycosidase in mice, accumulation of hyaluronic acid and chondroitin sulfate was noted. Experiments have shown that under the influence of chondromodulating therapy there is a reliable increase in the concentration of hyaluronic acid already three months after the start of therapy, by an average of 2.6 times [Ryabkov A.B.Abstract of a dissertation on medicine “Biochemical parameters of synovial fluid in clinical and laboratory evaluation of the effectiveness of chondromodulating therapy for osteoarthritis”, St. Petersburg, 2005, 28 C].

[0049] The generally accepted therapeutic dose of chondroitin sulfate is 800 mg.

[0050] It is also well known that OA is characterized by persistent inflammation in joint tissues, leading to the development of chondritis, osteitis, and synovitis. Inflammation not only causes pain, stiffness, and limited mobility in the affected joint, but also contributes to a chronic, progressive course. Therefore, the advisability of anti-inflammatory therapy is clear. NSAIDs are the cornerstone of symptom-modifying therapy for OA and an integral part of comprehensive treatment. Most standard NSAIDs are considered to accelerate cartilage degeneration by inhibiting the metabolic activity of chondroblasts and suppressing the synthesis of proteoglycans by chondrocytes, as well as other macromolecules that ensure the normal functioning of hyaline cartilage.Studies in experimental models have shown that NSAIDs can have a negative effect on hyaline cartilage metabolism; the nature and strength of this effect is determined by the drug's mechanism of action, depending on the stage of OA development and the duration of treatment. Indomethacin is known to negatively affect articular cartilage in both the early and advanced stages of the disease, while diclofenac and naproxen primarily affect it in the advanced stages [Badokin V.V. Nonsteroidal anti-inflammatory drugs in the treatment of osteoarthritis. Modern rheumatology. Pharmacotherapy. No. 1, Vol. 9, pp. 73-77].

[0051] The negative effect of NSAIDs on articular cartilage has given grounds to recommend only short-term use of NSAIDs for OA and only in cases of exacerbation of the disease or severe joint pain and the ineffectiveness of simple analgesics, which causes significant difficulties given the duration and painfulness of the course.

[0052] The authors of the present invention have developed a treatment strategy that involves the use of sodium chondroitin sulfate medications in a shorter course of treatment than the standard one, which allows for the minimization or elimination of the use of NSAIDs for therapy while maintaining or enhancing the therapeutic effect.

[0053] This application provides a shorter time to achieve a therapeutic effect, equal or greater treatment effectiveness, and greater safety compared to a standard course of 25-30 injections. It eliminates the need for initial test injections, which can lead to an extended treatment course, increased pain, and decreased effectiveness. The present invention relates to the use of a medicinal product containing the active ingredient sodium chondroitin sulfate for the treatment of arthrological diseases selected from the group of peripheral joint osteoarthritis, intervertebral osteochondrosis, and osteoarthrosis, comprising a course of medicinal product administration consisting of no more than 20 intramuscular injections of 200 mg of sodium chondroitin sulfate every other day.

[0054] The present invention also relates to a method for treating arthrological diseases selected from the group of osteoarthrosis of peripheral joints, intervertebral osteochondrosis and osteoarthrosis, comprising a course of administration of a medicinal product with the active substance sodium chondroitin sulfate, wherein the course contains no more than 20 intramuscular injections of 200 mg of sodium chondroitin sulfate every other day.

[0055] According to a particular embodiment of the invention, the course may include no more than 20, 19, 18, 17, 16 or 15 intramuscular injections.

[0056] According to a particular embodiment of the invention, the course may include no more than

[0057] 15 intramuscular injections.

[0058] According to a particular embodiment of the invention, the course may include 15 - 20,

[0059] 16-20, 17-20, 15-16, 15-17, 15-19, 16-18, 16-19 intramuscular injections.

[0060] IMPLEMENTATION OF THE INVENTION

[0061] Examples of preparation of injection forms with sodium chondroitin sulfate, which are not exhaustive

[0062] Example #1

[0063] Preparation of solution "A": Dissolve 10 kg of sodium chondroitin sulfate (calculated as absolutely dry substance) in 40 liters of injection water heated to 50°C. After the sodium chondroitin sulfate is completely dissolved, cool the solution to room temperature, bring the volume to 40 liters with injection water, and sterilize-filter.

[0064] Preparation of solution "B": Add 25 liters of injection water to 1000 g of benzyl alcohol and stir until the benzyl alcohol is completely dissolved. Then, while stirring, add 1111.11 mg of iron gluconate dihydrate (containing 8 mg of elemental iron per 1 kg of sodium chondroitin sulfate. Manufacturer: Pfizer Inc., Germany).

[0065] Preparation of solution "B". Dissolve 0.05 g of sodium hydroxide in 24 l of water for injection.

[0066] Preparation of solution "G." Sterilely filter 50 L of solution "B" into sterile solution "A" while constantly stirring. Then, 15-20 minutes after adding solution "B," while continuing to stir, sterilely filter 25 L of solution "B." Stirring is continued for 15-20 minutes after adding solution "B."

[0067] Preparation of the drug. The required amount (up to 100 liters) of water for injection is added to the sterile container containing solution "G" through a sterilizing filter.

[0068] Filling the solution. The solution is poured into 2 ml ampoules. The ampoules are sealed.

[0069] Example #2

[0070] A pre-prepared reactor is loaded with 90.7 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).

[0071] With the stirrer running (200-300 rpm), add 181.41 g of sodium disulfite to the reactor and stir for at least 10 minutes until completely dissolved. Then, add 9.07 kg (based on the main substance) of sodium chondroitin sulfate to the reactor in portions and stir for at least 60 minutes until completely dissolved. Next, add 45.35 g of methyl parahydroxybenzoate to the reactor, stir for at least 20 minutes, and collect a sample. The pH of the resulting solution is measured and, if necessary, its value is adjusted to 6.8 using 1 M sodium hydroxide solution. The solution is stirred for at least 10 minutes. Then, while stirring, 1763.32 mg of iron gluconate dihydrate is added (based on containing 14 mg of elemental iron per 1 kg of sodium chondroitin sulfate. Manufacturer of the substance: Pfizer Inc., Germany). The solution is then brought to the calculated volume (20 l) with water for injection and stirred for at least 15 minutes.

[0072] After analysis and adjustment (if necessary), the solution is subjected to sterilizing filtration and poured into 2 ml ampoules.

[0073] Example #3

[0074] Preparation of solution "A": Dissolve 10.42 kg of sodium chondroitin sulfate (based on the active ingredient content) in 52.08 L of water for injection, heated to 50°C. After the chondroitin sulfate is completely dissolved, cool the solution to a temperature no higher than 35°C.

[0075] Preparation of solution "B": Add 36.46 liters of water for injection to 937.5 g of benzyl alcohol and stir until the benzyl alcohol is completely dissolved. Add 104.17 g of sodium disulfite and 578.7 mg of ferrous gluconate dihydrate (containing 4 mg of elemental iron per 1 kg of sodium chondroitin sulfate. Manufacturer: Novartis AG, Switzerland).

[0076] Preparation of solution "G". Add 35 liters of solution "B" to solution "A" with constant stirring, along with 0.1 M NaOH to a pH of 6-6.5 and water for injection to bring the volume to 100 liters. The solution is analyzed for the content of the essential substances and its pH, and adjusted if necessary. Solution "G" is sterilized and filtered into a sterile container. The solution is dispensed into 2 ml ampoules and sealed.

[0077] CLINICAL STUDIES

[0078] The study involved 74 individuals diagnosed with stage 1-3 osteoarthritis, aged 18 to 65 years, including 49 women and 15 men. The patients were divided into three groups: two groups of 27 individuals each, and a control group of 10 patients. All patients had a stable clinical picture of the disease with pain of at least 40 mm on a 100 mm visual analogue scale (VAS).

[0079] The first group received Mucosat according to the standard regimen: the first three injections at a subtherapeutic dose of 100 mg intramuscularly every other day, beginning with the fourth injection of 200 mg every other day, for a total of 30 injections. Nonsteroidal anti-inflammatory drugs (NSAIDs) were prescribed as needed for pain relief.

[0080] The second group received Mucosat according to the regimen of 200 mg intramuscularly every other day, a total of 30 injections, H11VP were prescribed on demand to relieve pain.

[0081] The third group received standard H11VP therapy for pain relief on demand.

[0082] The assessment of pain parameters was carried out at 4 visits.

[0083] Visit 1 corresponded to the first visit to the clinic and reflected the indicators before the start of therapy,

[0084] Visit 2 corresponded to a period of 14 (±5 days) after the start of treatment,

[0085] Visit 3 - 30 (±5 days),

[0086] Visit 4 60 (±5 days).

[0087] At all visits, adverse events were assessed and their connection with the drug intake was established; if an adverse reaction was detected, the patient was continued to be observed until it resolved.

[0088] The distribution characteristics of the VAS score across visits are presented in Table 1.

[0089] Table 1. Characteristics of the distribution of the VAS indicator by visits

[0090] Table 2. Characteristics of adverse events (AE) and their relationship with drug intake

[0091] At all visits, adverse events were recorded and the relationship of the reaction to drug administration was assessed.

[0092] A total of five adverse events were recorded during the observation period. In all cases, a definite relationship with the medication was established, meaning all events were caused by the medication and were considered adverse reactions. In the first group, at the second visit, one subject developed a urticarial rash, which was successfully managed without discontinuing the study medication by administering systemic and topical desensitizing agents.

[0093] In the third group, which received N11VP, the highest number of adverse reactions was observed: at Visit 1, one patient reported nausea, which was relieved by changing the nonsteroidal agent and prescribing a proton pump inhibitor. At Visit 3, one patient in Group 3 noted an increase in blood pressure over the past week to 135 / 85 mmHg (previously, pressure did not rise above 125 / 80 mmHg), which was relieved by prescribing an antihypertensive drug. At Visit 4, one of the observed patients noted increasing insomnia over the past 2 weeks, accompanied by periodic headaches and dizziness. Since the observation period had ended by this point, the drug was discontinued, which was followed by normalization and stabilization of the condition.

[0094] At the end of treatment, the overall VAS pain score was found to be the lowest in the second group, with 26% of patients reporting no pain and 74% reporting mild pain. Seven percent of patients in the first group, who received the first three injections of chondroitin sulfate at a reduced dose, continued to experience moderate pain by the end of treatment, while 78% reported mild pain. In the control group, 10% continued to experience severe pain by the end of treatment, while 80% reported mild or moderate pain.

[0095] The use of chondroitin sulfate at a dose of 200 mg from the first injection allowed 55% of patients to stop taking NSAIDs after 2 weeks, 90% after a month of therapy, and by the end of treatment, all patients stopped taking NSAIDs; in the control group, this figure was only 60%, and in the first group, 93%.

[0096] All patients had their venous blood samples collected weekly.

[0097] The blood was centrifuged for 5 minutes and the serum was collected. Hyaluronidase activity in the serum was determined by the fluorimetric Morgan-Elson method modified by T. Takahashi et al. under conditions of 3-hour hydrolysis at 37 °C for the end product N-acetylglucosamine. The activity of the accompanying exohydrolases was inhibited by 0.02 M mucic acid added to the mixture. Fluorescence was measured at an excitation wavelength of 545 nm and an emission wavelength of 602 nm (Fluorate-2M, LUMEX, St. Petersburg, Russia). The amount of enzyme required under the given reaction conditions to form 1 micromole of terminal glucosamine in 1 min was taken as a unit of hyaluronidase activity [DZGOEVS.G.DOTROV I.N. HYALURONIDASE ACTIVITY OF BLOOD SERUM FROM PATIENTS WITH RHEUMATOID ARTHRITIS. No. 56-12, 2019, pp. 53-55; Takahashi T. et al. A fluorimetric Morgan-Elson assay method for hyaluronidase activity. No. 322, Vol. 15, 2003, pp. 257-263].

[0098] The results of the study of hyaluronidase activity by groups (mU / ml) are presented in Table 3.

[0099] Table 3. Results of the study of hyaluronidase activity by groups (mU / ml)

[0100] In patients of the second group, a gradual decrease in the activity of serum hyaluronidase was observed; in the first group, against the background of the first three injections at a dose of 100 mg, an increase in the activity of serum hyaluronidase was noted, and then, after increasing the dose of chondroitin sulfate to 200 mg, a gradual decrease in activity, which, however, did not reach the indicators of the 2nd group.

[0101] The data in the 3 groups remained unchanged throughout the entire course of therapy.

[0102] Thus, chondroitin sulfate at a subtherapeutic dose of 100 mg causes a temporary increase in serum hyaluronidase activity, which negatively impacts the results of chondroitin sulfate therapy, as hyaluronidase is an agent that degrades the administered substance. Dynamic monitoring of pain assessment using the VAS scale showed that the best results in reducing the pain index were achieved with the administration of chondroitin sulfate at a dose of 200 mg from the first day of therapy. All patients either had no pain or reported mild pain at the end of treatment. In the control group receiving N11VP monotherapy, 40% of patients reported severe or moderate pain at the end of treatment, while only 10% reported no pain.In the first group, which received the first three injections of chondroitin sulfate at a reduced dose of 100 mg, only 15% of patients reported pain relief at the end of therapy, compared to 26% in the second group. Moderate pain was experienced by 7%, and no patients in the second subgroup experienced moderate pain at the end of the course. It should also be noted that by the final visit, 100% of patients in the second group had discontinued their pain medications (NSAIDs).

[0103] The second group, which received chondroitin sulfate at a dose of 200 mg from the first day of therapy, demonstrated the best efficacy-to-safety ratio: it demonstrated the greatest reduction in pain score, the lowest serum hyaluronidase activity, and the highest safety profile. In the first group, which received the first three injections of chondroitin sulfate at a subtherapeutic dose, the efficacy was significantly lower, and serum hyaluronidase, an antagonist of chondroitin sulfate, was elevated.

[0104] Course duration

[0105] The study included 72 women and 51 men aged 50 to 75 years (mean 63.0 ± 7.4 years) with a diagnosis of knee OA of radiographic stages II and III that did not require surgical treatment. Patients were divided into six groups of 19–22 patients each.

[0106] All patients were examined at visit 1 (inclusion in the study, start of observation and therapy).

[0107] The examination was then carried out: Visit 2 after 15 days ± 3 days;

[0108] Visit 3 after 30 days±3 days;

[0109] Visit 4 after 35 days±3 days;

[0110] Visit 5 after 40 days±3 days;

[0111] Visit 6 after 50 days±3 days;

[0112] Visit 7, 3 months after the end of therapy, the date of the visit was calculated individually depending on the duration of the course;

[0113] Visit 8, 6 months after the end of therapy (telephone notification);

[0114] Visit 9 with open date.

[0115] All patients received H11VP therapy in standard therapeutic doses and injectable chondroitin sulfate (CS) according to the following regimen:

[0116] Group 1 - 1 ml intramuscularly every other day for the first 3 days, then 2 ml intramuscularly every other day, a total of 25 injections;

[0117] Group 2 – 2 ml intramuscularly every other day, 25 injections;

[0118] Group 3 – 2 ml intramuscularly every other day, 20 injections;

[0119] Group 4 – 2 ml intramuscularly every other day, 18 injections;

[0120] Group 5 – 2 ml intramuscularly every other day, 15 injections;

[0121] Group 6 - H11VP.

[0122] Visit 1 (beginning of therapy).

[0123] Table 4. Visit 1 Visit 2

[0124] By visit 2, patients in the first group received 3 injections of 1.0 ml and 5 injections of 2.0 ml; in groups 2–5, all patients received 8 injections of 2.0 ml; group 6 did not receive chondroitin sulfate.

[0125] Table 5. Visit 2

[0126] The reduction in pain and mobility indices by the second visit (after 2 weeks of therapy) was most pronounced in groups No. 2, 3, 4, and 5. In groups No. 1 and 6, positive dynamics were also noted, but its severity was significantly less.

[0127] Visit 3

[0128] By visit 3, group No. 5 had completed therapy (15 injections).

[0129] Table 6. Visit 3 The reduction in pain and mobility indices continued by the third visit (after 30 days of therapy) and was most pronounced in groups 2, 3, 4, and 5. Positive dynamics were also observed in groups 1 and 6, but to a significantly lesser extent. Group 5 completed the full course of therapy—15 injections—by visit 3. Thereafter, patients were monitored and received only N11VP if pain developed or worsened.

[0130] Visit 4

[0131] By visit 4, group #4 had completed therapy (18 injections).

[0132] Table 7. Visit 4

[0133] Visible improvements in pain and mobility scores were observed from Visit 3 to Visit 4 in Groups 2, 3, and 4. Group 4 completed the full course of therapy—18 injections—by Visit 4. Thereafter, patients were monitored and received only N11VP if pain developed or worsened. None of the patients in Group 5 who completed CS therapy reported increased pain, and no NSAIDs were required.

[0134] Visit 5

[0135] By visit 5, group #3 had completed therapy (20 injections).

[0136] Table 8. Visit 5

[0137] The most pronounced reduction in pain and mobility scores was observed between visits 4 and 5 in groups 2 and 3. Group 3 completed the full course of therapy (20 injections) by visit 4. Patients were then monitored and received only N11VP if pain developed or worsened. In group 5, which completed CS therapy, despite the overall positive dynamics of the group, one patient reported an increase in pain, necessitating the use of N11VP.

[0138] Visit 6

[0139] By visit 6, groups No. 6, No. 1 and No. 2 had completed therapy.

[0140] Table 9. Visit 6

[0141] A decrease in pain and mobility indices was observed from Visit 4 to Visit 5 in Groups 1, 2, and 3. Group 4 showed no changes in these indices. In Group 5, which completed CS therapy, despite the overall improvement in the group, one patient reported pain, which necessitated the use of N11VP. In Group 3, persistent remission with further improvement in pain and mobility indices was observed. Positive dynamics were also observed in Groups 1 and 2, but Group 1's indices significantly lagged behind those of Group 2. Group 6 demonstrated the worst dynamics at all visits. In Group 1, one patient developed a urticaria-like rash with severe itching. Despite desensitizing therapy, itching could not be completely relieved; therapy with chondroitin sulfate was discontinued early.In Group 2, two patients developed extensive hemorrhages at the injection site at Visit 6, and local therapy was prescribed. Due to the end of HS therapy, no further measures were taken.

[0142] Visit 7

[0143] 3 months after the end of therapy.

[0144] Table 10. Visit 7

[0145] All patients were examined 3 months after completion of therapy. The worst results were observed in Group 6, among patients taking NSAIDs. After discontinuing the drug, all parameters practically returned to pre-study levels: almost all patients reported increased pain and decreased mobility after discontinuing therapy. A worsening of these parameters was also observed in Group 5. Although all patients reported a decrease in pain and improved mobility during HS therapy, 4 patients required NSAIDs 3 months after completion of therapy, and all parameters showed some negative dynamics. Patients in Group 4 showed positive dynamics in all parameters during therapy, and no negative dynamics were observed 3 months after completion of therapy; all patients experienced stable remission.

[0146] In groups 1 and 2, which received the maximum number of injections, the best results were observed in patients who received 2.0 ml of HS from the first injection. The reduction in indices in group 1, in patients who received a subtherapeutic dose of 1.0 ml of HS during the first week of therapy, was less pronounced at the end of therapy and 3 months later.

[0147] The best results were observed in Group 3. All patients showed positive dynamics; none of them required additional NSAIDs by the end of therapy. Three months after the end of therapy, a further decrease in the indices and the absence of the need for NSAIDs were noted.

[0148] In groups №№ 2, 3, 4, and 5, higher efficacy was noted due to the initiation of therapy with a dose of 2.0 ml of CS versus the standard therapy of 1.0 ml for the first three injections and then 2.0 ml up to 25 CS administrations in group № 1. Groups №№ 2 and 3, where patients received 2.0 ml of CS for 20 and 25 injections, respectively, demonstrated comparable dynamics 3 months after the end of therapy; however, one adverse reaction in the form of urticaria was recorded in group № 1, and two cases of hemorrhage at the injection site were recorded in group № 2. Given the identified negative impact of long-term therapy on the safety profile and the lack of effect on the positive dynamics of the indices, it can be considered that administering an additional 5 injections is inappropriate.

[0149] Following treatment, patients were surveyed to determine whether they were willing to undergo the next course.

[0150] According to experts, long-term adherence to any treatment, regardless of the disease, is low and does not exceed 50%, especially in the treatment of chronic diseases, since they require long-term, often lifelong, use of medications and compliance with a number of medical recommendations. Lack of adherence to prescribed therapy can cause insufficient therapeutic effect, be accompanied by an exacerbation or progression of the disease, lead to hospitalization and / or disability of the patient [Hughes, C. M. Medication non-adherence in the elderly: how big is the problem? / CM Hughes / / Drugs Aging. - 2004. - Vol. 21, N 12. - P. 793-811.].In osteoarthritis, low adherence to drug therapy is recorded, however, to achieve the maximum effect, patients must follow medication recommendations, it is especially important to avoid skipping or changing the regimen of intramuscular administration of symptom-modifying therapy drugs, including chondroitin sulfate. In this case, the determining factors are not only the proven efficacy and good tolerability of drugs (LM), but also high patient adherence to therapy. Currently, poor adherence is another proven risk factor for any disease, which reduces the effectiveness and increases the costs of treatment, increases the risk of developing various complications, and worsens the prognosis of the disease and life [Chowdhury R, ​​Khan H, Heydon E, et al. Adherence to cardiovascular therapy: a meta-analysis of prevalence and clinical consequences. Eur Heart J 2013; 34: 2940-8. Ho PM, Bryson CL, Rumsfeld JS. Medication adherence.Its importance in cardiovascular outcomes. Education 2009; 119: 3028-35].

[0151] To assess patients' willingness to comply with physician recommendations, treatment adherence was assessed in all treatment groups using the KOP-25 questionnaire, which was developed in 2008 to assess treatment adherence in patients with arterial hypertension but was subsequently updated for universal use. In this study, the version for patients with chronic diseases was used [https: / / clinpharm-journal.ru / articles / 2018-l / rossijskij-universalnyj-oprosnik-kolichestvennoj-otsenki-priverzhennosti-k-lecheniyu-kop-25 / ]. Each technical indicator is a simple sum of points obtained from answers to the corresponding questions. The minimum possible value for each technical indicator is 5 points, the maximum is 30 points.

[0152] A compliance rate of <50% was considered low, from 51 to 75% as average, and >75% as high [Nikolaev N.A. Guide to Clinical Research in Internal Medicine (scientific monograph). Moscow, 2015, 74 p.].

[0153] Table 11

[0154] Visit 1

[0155] By the time of inclusion in therapy, all groups demonstrated comparable rates of treatment adherence: the average level predominated, i.e., the greatest number of patients were willing to follow medical recommendations and actions based on them. Table 12

[0156] Visit 7

[0157] All subjects were interviewed 3 months after the end of therapy; the date of the visit was calculated individually, depending on the end date of the course of therapy.

[0158] The lowest adherence rate was demonstrated by observation group No. 6, which is likely due to the fact that virtually all patients reported low treatment efficacy due to increased pain and decreased mobility after discontinuing N11VP. Fifty-seven percent of patients indicated that they did not consider it necessary to follow medical recommendations and related actions.

[0159] Group 5 also demonstrated decreased adherence to therapy. Although all patients reported pain reduction and improved mobility during HS therapy, 4 patients required N11VP therapy three months after completion of therapy. All indices demonstrated some negative dynamics, which affected the dynamics of the observed patients' expectations: the number of patients with low adherence to treatment more than doubled, while the number of patients with a high degree of readiness to follow doctors' recommendations decreased by 1.5 times.

[0160] In group No. 4, no significant dynamics of the indicators were observed; a slight decrease in the number of patients with high and moderate adherence and an increase in the number of patients with low readiness to follow recommendations were recorded.

[0161] In groups No. 1 and No. 2, an increase in the number of patients with low adherence to treatment was also noted, which was probably caused by the development of adverse reactions in the form of urticaria and hemorrhages.

[0162] The best results were obtained in group No. 3, which is probably due to the recorded positive dynamics in all patients who received therapy and the absence of the need for additional intake of NSAIDs; 97% of respondents demonstrated a willingness to follow doctors' recommendations.

[0163] Table 13

[0164] After Visit 7, all patients in Groups 1, 2, 3, 4, and 5 received standard recommendations regarding the need for regular courses of chondroitin sulfate therapy at semiannual intervals to maintain remission. After six months, all previously observed patients were notified by telephone to schedule follow-up care. The message included information about the need to return for a follow-up appointment with a doctor to continue therapy.

[0165] All patients in group No. 6 at the 7th visit were prescribed chondroitin sulfate therapy at 2.0 ml every other day, a total of 20 injections, due to pronounced unsatisfactory dynamics and for ethical reasons; NSAID intake was maintained in the “on demand” regimen.

[0166] Based on the results of the telephone alert, attendance at doctor's consultations was distributed among groups as follows.

[0167] Table 14 Group 3 demonstrated the highest attendance and adherence to therapy, with only 5% of patients not returning for treatment. Group 5 had the worst results, with 14% of patients not returning for treatment. Reasons cited for not continuing therapy in both groups included duration and inconvenience of use, adverse reactions, and treatment ineffectiveness.

[0168] Based on the above, the best and optimal balance of efficacy, safety, and compliance was demonstrated by Group 3's regimen: 2 ml intramuscularly every other day, 20 injections. Increasing the number of injections did not result in the expected linear increase in effect and instead contributed to the development of adverse reactions amid a plateau in efficacy. A small number of injections reduced pain and increased joint mobility but failed to achieve sustained and long-term remission. The use of low doses of chondroitin sulfate at the start of therapy not only failed to demonstrate the expected positive effect on the efficacy and safety profile, but also demonstrated a negative impact associated with the effect of low doses of chondroitin sulfate on the activation of serum hyaluronidase (an agent that destroys chondroitin), which was recorded as stagnation in pain and mobility indices and adverse reactions to chondroitin sulfate administration.NSAIDs as a drug of choice for long-term treatment of pain in OA have not shown any effect on the establishment of long-term remission and its maintenance.

Claims

1. CLAUSES OF THE INVENTION 1. The use of a medicinal product with the active substance sodium chondroitin sulfate for the treatment of arthrological diseases selected from the group of osteoarthrosis of the peripheral joints, intervertebral osteochondrosis and osteoarthrosis, including a course of administration of the medicinal product, where the course contains no more than 20 intramuscular injections of 200 mg of sodium chondroitin sulfate every other day.

2. Use according to paragraph 1, where the course contains no more than 18 intramuscular injections.

3. Use according to paragraph 1, where the course contains no more than 16 intramuscular injections.

4. Use according to I.1, where the course contains no more than 15 intramuscular injections.

5. Use according to points 1-4, where the course contains at least 15 intramuscular injections.

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