RU2827073C1 - Agent for treating arthrological diseases in lyophilized form for injections - Google Patents

Abstract

FIELD: medicine; chemistry; pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry and medicine, specifically to preparations with chondroprotective action, which can be useful in articular pathology, such as osteoarthrosis. Pharmaceutical preparation in the form of a lyophilisate for preparing a solution for intramuscular administration contains a combination of active substances from sodium chondroitin sulphate, glucosamine sulphate sodium chloride and dalargin and auxiliary substances, including sodium disulphite, mannitol, sorbitol, trometamol, phenol, with certain content of components.

EFFECT: what is presented is a preparation with chondroprotective action.

1 cl, 4 ex

Description

The invention relates to the field of chemical-pharmaceutical industry and medicine, specifically to drugs with chondroprotective action, which can be useful in joint pathology, such as osteoarthritis.

Diseases of the joints and periarticular tissues are one of the most common causes of limited ability to work and mobility, even to the point of disability. Up to 80% of the population suffers from joint diseases. Most diseases are characterized by a chronic progressive course and worsening of symptoms over time.

Among joint diseases, osteoarthritis (OA) is a significant problem, which is primarily due to the constant increase in incidence (Alekseeva LI, Basic therapy of osteoarthritis: a modern view on the use of glucosamine and chondroitin drugs. Modern rheumatology. 2021; 15 (2): 112-119). The prevalence of OA is increasing worldwide as the population ages and risk factors such as obesity and sedentary lifestyle increase, which leads to a serious public health problem. However, OA is not an exclusive prerogative of the elderly and also affects young people, especially those with risk factors such as overweight, metabolic syndrome or joint injuries. Knee joint lesions account for approximately 85% of OA cases worldwide. The pathophysiology of the disease is complex and includes interactions between mechanical, genetic, metabolic and inflammatory mechanisms at various levels. Anatomically, OA is characterized by destruction of articular cartilage, remodeling of subchondral bone, and low-grade inflammation of the synovial membrane.

To date, there is no clearly effective disease-modifying therapy for the treatment of osteoarthritis, which can be attributed to a lack of understanding of the pathogenesis and the absence of a sufficiently sensitive biomarker to allow the diagnosis of OA in the early asymptomatic phase.

The choice of treatment for osteoarthritis and other arthrological diseases depends on the cause of the pathology, the severity of symptoms, diagnostic results, as well as the individual characteristics of the patient's body.

In the treatment of joint pathologies, drugs for stopping the inflammatory process and relieving pain syndrome come to the forefront. At the same time, drugs are prescribed that stimulate regeneration processes or slow down the destruction of cartilage.

The most well-known group of drugs used to treat and improve the functions of damaged joints are chondroprotectors. Chondroprotective drugs reduce pain, increase joint functionality and slow down degenerative changes. In arthrosis, they reduce discomfort caused by wear of articular cartilage, improve the structure of the intra-articular coating, and slow down further destruction. Chondroprotectors stimulate the regeneration of cartilage cells, increase resistance to oxidation, and inhibit enzymes that destroy cartilage.

A number of drugs based on such chondroprotectors, which are common in rheumatological practice, as chondroitin, glucosamine, hyaluronic acid, and their various combinations are known from the state of the art.

Russian Federation Patent 2275190, published 27.04.2006, relates to agents for the treatment of joint diseases in the form of injection solutions, which contain saccharides - chondroitin sulfate (0.5÷20.0 wt.%) and glucosamine salt (1.0÷25.0 wt.%), a preservative (0.1÷2.0 wt.%), a non-ionic surfactant, in particular a monoester of oleic acid and polyoxyethylated sorbitan (1.0÷5.0 wt.%) and water (the rest).

Eurasian patent EA 025549, published 2017.01.30, discloses a pharmaceutical composition for the prevention and treatment of diseases of the joints and spine, including the peptides Lys-Asp-Glu, Ala-Asp-Glu, Asp-Glu-Gly in an effective amount and a pharmaceutically acceptable carrier, a mixture of chondroitin or its salts and glucosamine or its salts.

Russian Federation Patent 2290922, published 10.01.2007, pertains to the field of chemical and pharmaceutical industry, namely for the creation of agents used in the treatment of joint diseases. The agent is a lyophilisate containing glucosamine salt, chondroitin sulfate and trisamine in a certain ratio of components.

The closest analogue may be Sustalong® (https://medi.ru/instrukciya/sustalong_27142/). Composition of the drug per 1 ampoule:

Glucosamine sulfate sodium chloride 251.25 mg Chondroitin Sulfate Sodium 50.00 mg Trometamol to pH 3.0-5.0

Solvent composition (per 1 ml)

Lidocaine hydrochloride monohydrate (in terms of lidocaine hydrochloride) 20.0 mg Sodium chloride 6.0 mg Sodium hydroxide to pH 5.0-7.0

Despite their advantages, known drugs are not always effective in later stages of the disease and require long-term use.

Thus, there remains a need to find new means for the treatment of arthrological diseases.

The objective of the present invention is to create a new effective means for the treatment of arthrological diseases.

The problem is solved by a combined composition of a pharmaceutical preparation in the form of a lyophilisate for the preparation of a solution for intramuscular administration.

The proposed product contains a combination of active ingredients of Chondroitin Sodium Sulfate, Glucosamine Sodium Chloride Sulfate and Dalargin and excipients including sodium disulfite, mannitol, sorbitol, trometamol, phenol, with the following component content, mg:

Chondroitin Sulfate Sodium 20.0-60.0 Glucosamine sulfate sodium chloride 200,0-300 Dalargin 0.5-1.5 Sodium disulfite 0.5-5.0 Mannitol 5-15 Sorbitol 7-20 Trometamol to pH 3.0-5.0 Phenol 0.1-0.6

Technical result: development of a composition of a pharmaceutical preparation in the form of a lyophilisate for the preparation of a solution for intramuscular administration, aimed at reducing side effects and maintaining stability throughout the shelf life of the preparation.

The method for obtaining a pharmaceutical composition in the form of an easily reconstituted lyophilisate consists of ensuring complete dissolution of the components during the preparation process to form a true solution for further lyophilization.

To obtain a solution for intramuscular administration, the lyophilisate is reconstituted with water for injection to 1 ml.

Chondroitin sulfate is a high-molecular polysaccharide obtained as sodium salt from cartilaginous tissue of cattle. Raw materials from animals from farms that do not have bacterial, mycoplasmal, viral and prion pathologies pathogenic for humans are used.

Chondroitin sulfate (CS), like dermatan sulfate, keratan sulfate, heparan sulfate, and heparan, are compounds classified as glycosaminoglycans. CS is formed primarily from the association of alternating sulfated and/or unsulfated glucuronic acid residues and N-acetylgalactosamine residues into polysaccharide chains.

Chondroitin maintains the required viscosity of synovial fluid in the joint cavities by stimulating the function of synovial cells that produce it; stimulates the function of chondrocytes - minifactories for the production of components of joint tissues that produce collagen and proteoglycans to create new cartilage tissue; blocks the action of certain enzymes that have been found in the synovial fluid of people with joint diseases (rheumatoid arthritis) and may be responsible for the destruction of joint tissue; helps increase the number of chondrocytes.

Glucosamine (GK), formed in the body as glucosamine 6-phosphate (GK6-P), is a fundamental building block required for the biosynthesis of compounds such as glycolipids, glycoproteins, glycosaminoglycans, hyaluronate, and proteoglycans. As such, GK is a component of cell membranes and cell surface proteins, as well as intermediate structural molecules that connect cells. Directly or indirectly, glucosamine plays a role in the formation of articular surfaces, tendons, ligaments, synovial fluid, skin, bone tissue, nails, heart valves, blood vessels, and mucous secretions of the digestive, respiratory, and urinary tracts.

One of the most important physiological functions of glucosamine is stimulation of the synthesis of substances necessary for proper joint function. Experimental studies have shown that glucosamine stimulates proteoglycan synthesis, inhibits proteoglycan degradation and stimulates cartilage regeneration after experimentally induced damage. Glucosamine does not inhibit cyclooxygenase and proteolytic enzymes involved in the inflammatory response. Unlike NSAIDs, which act by inhibiting cyclooxygenase and modifying prostaglandin synthesis, the mechanism of action of GC is associated with its ability to stimulate the synthesis of proteoglycans necessary for stabilizing the cell membrane and increasing the intracellular substance.

In the proposed composition it is used in the form of a stable double salt of glucosamine sulfate-sodium chloride.

Dalargin (Tyrosyl-D-alanyl-glycyl-phenylalanyl-leucyl-arginine diacetate) is a synthetic hexapeptide, an analogue of leucine enkephalin, is a drug of predominantly peripheral action, its effect is realized at the tissue level. It practically does not penetrate the blood-brain barrier. The most active "acceptors" of dalargin and its metabolites are the tissues of the kidneys, liver and lungs. At the same time, the tissues of the stomach and spleen are close to them in the number of resynthesized products.

There is evidence that opioid receptors are found on osteoblast-like tumor cells and that bone-forming cellular structures, in addition to mature osteoblasts and osteoclasts, are capable of synthesizing opioids.

One of the experiments examined the effect of dalargin itself on the regeneration of bone tissue and bone marrow. The experiment was conducted on tubular bones. It was found that dalargin accelerated the regeneration of bone marrow and bone tissue, and also increased the volume of bone marrow regeneration.

Dalargin at a concentration of 100 μg/l, acting through opioid 6-receptors, stimulated proliferation in vitro in a culture of multipotent mesenchymal stromal cells, increasing their growth by the 3rd day by 19-34%. In addition, dalargin at an optimal concentration of 100 μg/l had a pronounced antiproliferative effect on osteosarcoma cells of the HOS line, reducing their growth by the 3rd day by 22-34%.

The proposed complex of dalargin, chondroitin sulfate and glucosamine sulfate sodium chloride in specified quantitative intervals allows to increase the effectiveness of treatment of arthrological diseases.

Chondroitin sulfate and glucosamine sulfate have a chondroprotective effect, inhibit the development of degenerative processes in the joints, stimulate regenerative processes, restore the function of damaged joints, and reduce joint pain. Dalargin unexpectedly enhances the effects of this combination. At the same time, it has an analgesic and mebranoprotective effect, and also stimulates the antioxidant system under metabolic stress, thus neutralizing the imbalance between anabolic and catabolic processes, including in hyaline cartilage. When administered intra-articularly, dalargin has an analgesic, anti-inflammatory effect.

Sodium disulfite is a direct antioxidant that destroys hydroperoxides. It does not stop the chain oxidation process, but by reducing the rate of chain branching, it slows down oxidation reactions. The inhibitory effect of such oxidizers is stronger, the higher the reaction rate of these substances with hydroperoxides.

Mannitol, due to its ability to crystallize during freezing and maintain the macroscopic structure of the lyophilisate in a wide range of temperatures, is an exocellular cryoprotector. It binds extracellular water and, when frozen, slows the growth of extracellular ice crystals, envelops cells and prevents the impact of already formed crystals on them. Mannitol is chemically indifferent, ensures the manifestation of the proper pharmacological action of the drug, taking into account its pharmacokinetics, is biologically harmless and biocompatible with body tissues, does not have an allergenic or toxic effect and does not adversely affect the organoleptic properties of drugs.

Sorbitol is a natural sweetener. It is a white crystalline powder, odorless, with a pleasant cooling sweet taste. It has been assigned the status of a food product by the Scientific Committee of Experts on Food Additives of the European Community. Sorbitol is characterized as a moisture-retaining agent, complexing agent, texturizer and emulsifier.

The use of the combination of the said sugar alcohols in the stated quantities in the present invention made it possible not only to stabilize all active substances, but also to improve the pharmacokinetics of the combination.

Trometamol is a white crystalline powder. It is easily soluble in water. The aqueous solution has an alkaline reaction.

Phenol is the simplest representative of the phenol class. Colorless needle-shaped crystals that turn pink in the air due to oxidation, leading to the formation of colored substances. They have a specific gouache smell. Soluble in water, in solutions of alkalis in alcohol, in benzene, in acetone. 5% solution in water is an antiseptic, widely used in medicine.

The possibility of implementing the invention can be demonstrated by the following examples:

Example 1

Composition of the drug:

1 ampoule contains:

Active ingredients:

Chondroitin Sulfate Sodium 20 mg Glucosamine sulfate sodium chloride 300 mg Dalargin 0.5 mg

Excipients:

Sodium disulfite 2.0 mg Mannitol 15.0 mg Sorbitol 7.0 mg Trometamol to pH 4.0 Phenol 0.6 mg

The method for obtaining the pharmaceutical composition consists in dissolving sodium disulfite, mannitol, sorbitol and phenol in water for injection. Then sodium chondroitin sulfate, sodium glucosamine sulfate and dalargin are introduced and mixed thoroughly. The pH of the solution is adjusted using a trometamol solution to a value from 3.0 to 5.0. Then the solution undergoes sterilizing filtration through 0.22 μm sterilizing filters and is poured into ampoules. The ampoules with the solution are loaded into a lyophilization unit, where the lyophilization process takes place, under the lyophilization drying mode of the drug: freezing at -80°C and drying in a vacuum at room temperature. After that, the ampoules with the lyophilisate are sealed in a nitrogen stream.

The drug is a white with a creamy tint amorphous powder or a porous mass compacted into a tablet.

During a shelf life of 3 years at room temperature, no significant changes in the composition of the drug were observed.

The preparation meets the following requirements: the number of visually invisible particles according to the counting-photometric method of size: ≥10 µm no more than 6000 particles/amp; ≥25 µm no more than 600 particles/amp.

Impurities were determined by HPLC: single impurity no more than 0.5%, total impurities no more than 2.0%. The preparation is sterile. Endotoxins - no more than 80.5 EU per 1 ml of the resulting solution.

Example 2

Composition of the drug:

1 ampoule contains:

Active ingredients:

Chondroitin Sulfate Sodium 60 mg Glucosamine sulfate sodium chloride 240 mg Dalargin 1.5 mg

Excipients:

Sodium disulfite 5.0 mg Mannitol 5 mg Sorbitol 20 mg Trometamol to pH 3.0 Phenol 0.1 mg

Obtained in a similar manner to the method in example 1.

Example 3

Pharmacological activity

Osteoarthritis was induced in rabbits by injecting 0.2 ml of 2% formalin solution into the knee joint cavity. The experiment involved male rabbits aged about 2.2-3.1 months and weighing 2.7-3.2 kg. After 3 days, the animals developed symptoms of acute arthritis, on which the anti-inflammatory and analgesic effects of the drugs could be tested. Each experimental group included 5 animals. The test drug according to Example 1 was injected into the knee joint cavity daily for 5 days, starting from the 3rd day after the injection of formalin into the joint.

Comparisons were made with the administration of individual drugs chondroitin sulfate and glucosamine sulfate.

It was shown that the combined drug had anti-inflammatory and analgesic effects, and also contributed to the restoration of functional activity of the joints. In the control group, severe osteoarthritis developed. In the chondroitin sulfate and glucosamine groups, the effects were less pronounced.

Thus, the complex of dalargin, chondroitin sulfate and glucosamine sulfate sodium chloride mutually complements the action of all components and can be effective in the treatment of degenerative joint diseases.

Example 4

Patients and methods:

The active control study involved 42 volunteer patients with osteoarthritis of one or both knee joints. According to the scheme, the patients were divided into 3 groups, where patients of the first group received the intramuscular study combination drug Sustalong® (Group 1), the second group - the claimed drug, and the third - Chondrolon. The duration of therapy was 6 weeks. Efficacy assessments also included the dynamics of the Lequesne index and the WOMAC index throughout the study; the overall impression of the patient and the physician-investigator about the treatment results; the need for additional intake of NSAIDs (Ibuprofen).

Results: It was demonstrated that 81.6% of patients responded to therapy in Group 1, 84.4% of patients in Group 2, and 57.9% of patients in Group 3. ANOVA analysis of variance with repeated measures showed statistically significant dynamics (decrease) in the mean values (p<0.001) of the total Lequesne index and the total WOMAC index during the study; a more pronounced decrease was observed in Group 2.

The overall impression of the treatment results according to patients' assessments in the first and second groups was "Marked improvement". However, in the second group, supplementation with ibuprofen tablets after the 4th visit was practically not required, unlike in the other two groups.

These data confirm that the drug provides the necessary pharmacological effects and, therefore, can be used in pharmaceutical practice.

Claims (2)

A pharmaceutical preparation for the treatment of arthrological diseases in the form of a lyophilisate for the preparation of a solution for intramuscular administration, characterized in that it contains a combination of active substances from Chondroitin sodium sulfate, Glucosamine sulfate sodium chloride and Dalargin and excipients including sodium disulfite, mannitol, sorbitol, trometamol, phenol, with the following content of components, mg: Chondroitin Sulfate Sodium 20.0-60.0 Glucosamine sulfate sodium chloride 200,0-300 Dalargin 0.5-1.5 Sodium disulfite 0.5-5.0 Mannitol 5-15 Sorbitol 7-20 Trometamol to pH 3.0-5.0 Phenol 0.1-0.6