RU2777213C1 - Method for treatment of joint diseases - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to the field of medicine. The method for local therapy of osteoarthritis of the knee joint includes a once a week, for six weeks in a row, intra-articular injection to a patient in need of a drug obtained by mixing the contents of ampoules A and B containing glucosamine sulfate sodium chloride, trometamol, lidocaine hydrochloride, diethanolamine and water for injection at a component ratio, wt. %: ampoule A (preparation), ampoule B (solvent).

EFFECT: claimed method provides an increase in the effectiveness of therapy for osteoarthritis of the knee joint in patients who need it.

1 cl, 7 tbl

Description

The invention relates to the field of medicine.

Osteoarthritis (hereinafter - OA) ranks first in prevalence among other rheumatic diseases. Thus, in the United States, in people over the age of 30, symptomatic OA of the knee occurs in approximately 6%, and symptomatic OA of the hip joint occurs in approximately 3% of the population [ Leeb BF, Schweitzer H, Montag K, Smolen JS. A meta-analysis of chondroitin sulfate in the treatment of osteoarthritis. J Rheumatol 2000;27:205-11 ]. In population studies, the frequency and prevalence of the disease increases 2-10 times in the age range from 30 to 65 years and continues to increase with age. OA develops mainly in middle and old age, at a young age it can occur after joint injuries, inflammatory processes, in patients with congenital pathology of the musculoskeletal system. So, if at the age of up to 29 years 8.4 people per 1000 of the population are sick, at 30-39 years old - 42.1; 40-49 years old - 191.9; 50-59 years - 297.2; then at 60-69 years old - 879.7 per 1000 people. Radiographic evidence of OA occurs in most people over 65 years of age and in about 80% of people over 75 years of age. 11% of people over 60 years of age have symptomatic (with clinical manifestations) knee OA. In addition to the increase in the incidence of osteoarthritis with age, gender differences are also evident. So, before the age of 50, the prevalence of OA in most cases is higher in men than in women (in most studies, OA of the hip joint, coxarthrosis, is more than 2 times more common in men), after 50 years of OA of the knee joints (gonarthrosis ), joints of the hand and foot are more common in women [ McAlindon TE, LaValley MP, Felson DT. Glucosamine and chondroitin for treatment of osteoarthritis: a systematic quality assessment and meta-analysis. JAMA 2000;283:1469-75. ].

It has been proven that osteoarthritis is both the result of the action of mechanical and biological factors that disrupt the synchronous processes of biodegradation and the formation of articular cartilage cells, as well as subchondral bone. Although osteoarthritis can be initiated by many factors, including genetic, evolutionary, metabolic, and traumatic, the disease affects all synovial joint tissues. As a result, osteoarthritis is manifested by morphological, biochemical, molecular and biomechanical changes in the cells and matrix, which lead to softening, fibrillation, ulceration and a decrease in the thickness of the articular cartilage, as well as to osteosclerosis with a sharp thickening and compaction of the cortical layer of the subchondral bone, the formation of osteophytes and the development subchondral cysts. Clinically, osteoarthritis is manifested by arthralgia, pain and limited movement, crepitations, periodic effusion in the joint cavity, and an inflammatory process of varying severity without systemic manifestations. The early stage of OA (swelling and disintegration of the collagen scaffold, increased synthesis of proteoglycans and matrix proteases) is usually clinically asymptomatic. Further, degradation processes occur in the cartilage with the destruction of proteoglycans by proteases, thinning and softening of the cartilage, its fragmentation, the appearance of areas of osteosclerosis, subchondral cysts, and the appearance of osteophytes. It is still unclear whether the damage to the cartilage is primary or whether the processes occurring in the subchondral bone are primary. Thus, a patient with OA needs not only analgesic therapy, but long-term (for months and years) treatment aimed at improving the function of the main tissues and structures of the joint, which can also lead to a persistent analgesic effect.

Obviously, the immediate goal of such treatment is to reduce pain and improve the function of the affected joint. Pharmacological agents in OA can have a rapid symptomatic effect (paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs)) or a slow analgesic effect (the so-called basic or "chondroprotective" drugs). However, the assessment of the impact on the progression of OA is complex and requires many years of treatment with a standardized assessment of the radiographic manifestations of the disease. In addition, among patients with OA, elderly patients prevail, often having concomitant cardiovascular, gastrointestinal, respiratory, and other pathologies, that is, risk factors for intolerance to NSAIDs. According to current WHO recommendations, patients with OA should begin analgesic therapy with paracetamol, and if it is ineffective, with NSAIDs that selectively inhibit COX-2. Selective COX-2 inhibitors are significantly less likely to cause damage to the gastrointestinal mucosa, do not have a negative effect on cartilage characteristic of non-selective drugs (indomethacin, piroxicam), however, these drugs are indicated only in the presence of synovitis and do not solve the problem of patient pain relief for other causes of pain syndrome.

The problem solved when creating the claimed invention was to develop a safe and tolerable method of therapy, while the technical result achieved in solving this problem was to increase the effectiveness of the treatment of osteoarthritis of the knee joint in patients in need of it.

To achieve the set result, a method for local therapy of osteoarthritis of the knee joint is proposed, including once a week, for six weeks in a row, intra-articular injection to a patient in need of it, a drug obtained by mixing the contents of ampoules A and B, containing glucosamine sulfate sodium chloride, trometamol, lidocaine hydrochloride, diethanolamine and water for injection in the following ratio, wt.%:

Ampoule A (preparation):

glucosamine sulfate sodium chloride - 25;

trometamol - up to pH 2.0 ÷ 3.0;

lidocaine hydrochloride - 0.5;

water for injection - 74;

Ampoule B (solvent):

diethanolamine - 2.4;

water for injection - 97.6.

, является активным компонентом вышеуказанного препарата (далее - Препарат). При производстве перепарата может быть использован глюкозамина сульфат от компании «Биоиберика С.А.У.», Испания. Глюкозамина сульфат обладает противовоспалительным и обезболивающим действием, восполняет эндогенный дефицит глюкозамина, стимулирует синтез протеогликанов и гиалуроновой кислоты синовиальной жидкости; способствует фиксации серы в процессе синтеза хондроитинсерной кислоты, тормозит развитие дегенеративных процессов в суставах, восстанавливает их функцию, способствует предотвращению процессов разрушения хряща, стимулирует восстановление хрящевой ткани, улучшает подвижность суставов, уменьшает потребность в нестероидных противовоспалительных препаратах. Glucosamine sulfate having the structural formula

, is the active component of the above preparation (hereinafter referred to as the Preparation). Glucosamine sulfate from Bioiberica S.A.U., Spain can be used in the preparation of the preparation. Glucosamine sulfate has an anti-inflammatory and analgesic effect, replenishes the endogenous deficiency of glucosamine, stimulates the synthesis of proteoglycans and hyaluronic acid in the synovial fluid; contributes to the fixation of sulfur in the process of synthesis of chondroitin sulfuric acid, inhibits the development of degenerative processes in the joints, restores their function, helps prevent the processes of cartilage destruction, stimulates the restoration of cartilage tissue, improves joint mobility, reduces the need for non-steroidal anti-inflammatory drugs.

The superiority of intra-articular therapy with the drug in terms of higher efficacy at the primary end point in patients with osteoarthritis of the knee, as well as its safety and tolerability, were studied in a group of 231 men and women aged 50 to 80 years diagnosed with gonarthrosis according to the Altman R criteria. , one or both joints, X-ray stage II-III according to Kellgren, with pain intensity after walking 15 m on a flat surface according to VAS more than 40 mm but less than 90 mm, with an average body weight of about 80 kg. and a height of 1.66 m, on the basis of Clinical Hospital No. 3 (Yaroslavl, Mayakovsky St., 61), Ivanovo Clinical Hospital named after Kuvaevs (Ivanovo, Ermaka St., 52/2) and Clinical Hospital No. 2 (Yaroslavl, Suzdal highway, 39).

As part of the ongoing studies, the Preparation was prepared immediately before each injection according to the following method:

the components were mixed Ampoule A (preparation) + Ampoule B (solvent), where the content of the components was in the following values (mg. or wt.% equivalent):

Ampoule A (drug)

glucosamine sulfate sodium chloride - 502.5 mg - 25.125%

(corresponds to the content of glucosamine sulfate - 400.0 mg (20.0%) and sodium chloride - 102.5 mg (5.125%));

trometamol - up to pH 2.0 - 3.0;

lidocaine hydrochloride - 10.0 mg (0.5%);

water for injection - up to 2 ml (74.375%)

Ampoule B (solvent)

diethanolamine - 24.0 mg (2.4%)

water for injection - up to 1 ml (97.6%).

The study protocol is presented in Table 1.

Table 1

Method of administration Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Intra-articular administration of the Drug once a week for six weeks (main group) X X X X X X Intramuscular administration of the Drug three times a week for six weeks (control group 1) X X X X X X Intra-articular administration of the reference drug ^* once a week for five weeks (control group 2) X X X X X

^* As a comparison drug, a solution for intra-articular injection of Hyalgan® Fidia manufactured by Phidia Pharmaceutical S.p.A., Italy (the active ingredient is sodium hyaluronate) was used.

The breakdown of patients into treatment groups was performed randomly, the results of the breakdown are presented in table 2.

table 2

Main group Control group 1 Control group 2 85 85 61

The general scheme of the research procedure is presented in Table 3.

Table 3

Actions Visit one 2 3 four 5 Research Day one fourteen 28 42 63 Start of therapy X Assessment of the intensity of pain in the target joint according to the visual analogue scale (VAS) X X X X X Lequesne index X X X X WOMAC Index X X X X Monitoring of adverse events (AEs) X X X X X Evaluation of the effectiveness of therapy by the patient X X Evaluation of the effectiveness of therapy by a doctor X X

The main end points for evaluating the effectiveness of the claimed method were the proportion of patients who responded to therapy after 6 weeks compared to baseline (before the study), where the response to therapy was considered to be a decrease in the Algofunctional Lequesne index by at least 3 points, subject to a positive overall impression of effectiveness, according to the investigator, as well as the change in the subscale "pain" of the WOMAC index (Western Ontario and McMaster Universities osteoarthritis Index) after 6 weeks of therapy compared with baseline. Secondary endpoints confirming the effectiveness of the method were the assessment of the severity of pain according to the VAS, the assessment of the function of the joints according to WOMAC after 6 and 9 weeks from the start of the study, the assessment of the severity of gonarthrosis according to the Lequesne index after 9 weeks from the start of the study, as well as the overall clinical impression scale /Patient's impressions to evaluate the improvement of the condition after 6 and 9 weeks from the start of the study.

The results of the distribution of the effectiveness of therapy carried out using the Drug among patients who responded to therapy after 6 weeks in comparison with the baseline are presented in Table 3.

Table 3

Group Main
Group Control group 1 Control group 2 Index Result N % N % N % The patient responded to the therapy Not
Yes 19
66 22.4%
77.6% 34
51 40.0%
60.0% 21
40 34.4%
65.6%

The statistics of the scores of the subscale "pain" of the WOMAC index after 6 weeks of therapy in comparison with the baseline are presented in Table 4.

Table 4

Index Group Average N Std.Off Median Min Max scope YOUR_joint_1 Main 62.6 85 10.45 am 63 45 88 43 Control 1 61.1 85 9.21 60 38 81 43 Control 2 in / with 60.7 61 12.34 58 41 87 46 YOUR_joint_4 Main 27.8 85 14.25 28 2 63 61 Control 1 27.0 85 16.48 25 0 76 76 Control 2 in / with 27.5 61 15.6 24 5 76 71 YOUR_joint_
rev_4 Main -34.8 85 14.97 -36 -74 2 76 Control 1 -34.1 85 13.76 -37 -62 -four 58 Control 2 in / with -33.2 61 11.77 -34 -70 -9 61

Statistics of pain intensity scores in the target joint according to VAS and their changes by visits and treatment groups are presented in Table 5.

Table 5

Index Group Average N Std.Off Median Min Max scope YOUR_joint_1 Main 62.6 85 10.45 am 63 45 88 43 Control 1 61.1 85 9.21 60 38 81 43 Control 2 60.7 61 12.34 58 41 87 46 YOUR_joint_2 Main 48.6 85 12.24 48 25 72 47 Control 1 48.2 85 12.53 47 24 81 57 Control 2 50.3 61 13.31 49 28 86 58 YOUR_joint_3 Main 38 85 14.8 40 6 70 64 Control 1 37.8 85 fifteen 36 12 80 68 Control 2 38.1 61 15.12 37 fourteen 75 61 YOUR_joint_4 Main 27.8 85 14.25 28 2 63 61 Control 1 27 85 16.48 25 0 76 76 Control 2 27.5 61 15.6 24 5 76 71 YOUR_joint_5 Main 23.8 85 15.17 23 0 62 62 Control 1 22.5 85 16.41 19 0 73 73 Control 2 22.5 61 15.97 twenty 2 68 66 YOUR_joint_change_
2 Main -14.1 85 10.14 -12 -41 3 44 Control 1 -12.9 85 9.23 -12 -33 2 35 Control 2 -10.4 61 7.2 -ten -35 3 38 YOUR_joint_change_
3 Main -24.7 85 15.06 -23 -66 four 70 Control 1 -23.2 85 12.2 -23 -46 0 46 Control 2 -22.6 61 10.4 -22 -52 0 52 YOUR_joint_change_
four Main -34.8 85 14.97 -36 -74 2 76 Control 1 -34.1 85 13.76 -37 -62 -four 58 Control 2 -33.2 61 11.77 -34 -70 -9 61 YOUR_joint_change_
5 Main -38.9 85 16.38 -39 -78 0 78 Control 1 -38.6 85 14.39 -41 -61 -one 60 Control 2 -38.2 61 14.37 -39 -74 -ten 64

The statistics of the total amount of the WOMAC index by visits and treatment groups are presented in Table 6.

Table 6

Index Group Average N Std.Off Median Min Max scope WOMAC_Amount_1 Main 42.2 85 14.37 45 ten 76 66 Control 1 38.3 85 16.56 37 ten 74 64 Control 2 41.0 61 16.21 43 eleven 72 61 WOMAC_Amount_3 Main 29.5 85 12.16 28 four 52 48 Control 1 29.6 85 15.77 27 6 69 63 Control 2 31.0 61 14.4 thirty eight 60 52 WOMAC_Amount_4 Main 21.8 85 10.36 22 four 52 48 Control 1 22.5 85 14.46 21 2 59 57 Control 2 23.2 61 11.89 22 5 56 51 WOMAC_Amount_5 Main 18.7 85 10.59 19 2 53 51 Control 1 19.5 85 13.08 17 one 57 56 Control 2 19.6 61 10.58 twenty 2 45 43 WOMAC_Sum_change_
3 Main -12.7 85 10.44 -ten -47 3 fifty Control 1 -8.8 85 7.81 -eight -24 31 55 Control 2 -10.0 61 6.68 -9 -26 one 27 WOMAC_Sum_change_
four Main -20.4 85 12.39 -twenty -53 one 54 Control 1 -15.8 85 11.34 -fourteen -44 31 75 Control 2 -17.8 61 8.32 -eighteen -35 -2 33 WOMAC_Sum_change_
5 Main -23.5 85 14.12 -22 -55 -one 54 Control 1 -18.8 85 12.62 -eighteen -44 31 75 Control 2 -21.4 61 10.21 -twenty -43 -2 41

The number and proportion of patients with AE by treatment group during the study are presented in Table 6.

Table 6

Group Main group Control group 1 Control group 2 Total There are AEs N % N % N % N % Not
Yes 81
four 95.3%
4.7% 75
ten 88.2%
11.8% 56
5 91.8%
8.2% 212
19 91.8%
8.2%

The results of the assessment of the overall clinical impression by visit and treatment group are presented in Table 7.

Table 7

Group Main group Control group 1 Control group 2 Visit Result % % % Visit 4 Marked improvement 34.1% 23.5% 21.3% Significant improvement 56.5% 52.9% 65.6% Minor improvement 8.2% 22.4% 13.1% Without changes 1.2% 1.2% 0.0% Visit 5 Marked improvement 40.0% 31.8% 34.4% Significant improvement 50.6% 52.9% 57.4% Minor improvement 5.9% 14.1% 8.2% Without changes 3.5% 1.2% 0.0%

Thus, the research results show that the claimed method, within the scope of the claims, is an effective and safe method of local (intra-articular) treatment of osteoarthritis of the knee joint (gonarthrosis according to Altman R. criteria, one or both joints, II-III X-ray stage according to Kellgren.

Claims (9)

A method for local therapy of osteoarthritis of the knee joint, including once a week, for six weeks in a row, intra-articular injection to a patient in need of it, a drug obtained by mixing the contents of ampoules A and B containing glucosamine sulfate sodium chloride, trometamol, lidocaine hydrochloride, diethanolamine and water for injection at the following ratio of components, wt.%: ampoule A (preparation): glucosamine sulfate sodium chloride - 25; trometamol - up to pH 2.0 ÷ 3.0; lidocaine hydrochloride - 0.5; water for injection - 74; ampoule B (solvent): diethanolamine - 2.4; water for injection - 97.6.