RU2711624C2 - Combined agent based on nsiad, muscle relaxant and vitamin - Google Patents

Abstract

FIELD: chemistry; pharmaceutics.

SUBSTANCE: group of inventions relates to the chemical-pharmaceutical industry and is an agent for use in hypertension and spasm of striated muscle, comprising: aceclofenac in amount of 30 to 200 mg; tolperisone 25 to 300 mg; vitamin B₁₂ from 0.1 to 1 mg. Inventions include use of said agent in hypertension and spasm of striated musculature, as well as use of vitamin B₁₂ for making the agent for hypertension and spasm of striated musculature.

EFFECT: group of inventions enables to achieve synergetic effect of aceclofenac and tolperisone with vitamin B₁₂ treatment of hypertonus and spasms of striated musculature.

16 cl, 6 ex

Description

FIELD OF TECHNOLOGY

The present invention relates to a combination agent based on aceclofenac, tolperisone and vitamin B ₁₂ for oral and intramuscular administration with hypertonicity and spasm of striated muscles resulting from organic diseases of the central nervous system (including pyramidal lesions, multiple sclerosis, stroke, myelopathy, ence ), musculoskeletal system (including spondylosis, spondylarthrosis, cervical and lumbar syndromes, arthrosis of large joints); during rehabilitation treatment after orthopedic and traumatological operations.

BACKGROUND

Aceclofenac (CAS 89796-99-6) is a non-steroidal anti-inflammatory drug from the group of phenylacetic acid derivatives, has anti-inflammatory, analgesic and antipyretic effects associated with the indiscriminate suppression of COX-1 and COX-2, regulating the synthesis of prostaglandins. After oral administration, it has a high degree of absorption. C _{max is} reached within 1.25-3 hours. It penetrates into the synovial fluid, where its concentration reaches 57% of the plasma concentration and the time to reach C _max is 2-4 hours later than in plasma. Binding to plasma proteins (albumin) is about 99%. Aceclofenac circulates mainly unchanged, its main metabolite is 4'-hydroxyaceclofenac. T _1/2 is 4 hours. It is excreted by the kidneys, mainly in the form of hydroxy derivatives (about 2/3 of the administered dose).

Tolperisone (CAS 728-88-1) is a centrally acting muscle relaxant. It reduces the pathologically increased skeletal muscle tone, due to the ability of tolperisone to suppress spinal polysynaptic reflexes and a depressing effect on the caudal part of the reticular formation. It has central n-anticholinergic properties. It does not significantly affect the peripheral parts of the nervous system. It has a weak antispasmodic and vasodilator effect.

Vitamin B ₁₂ is the general name for a group of cobalt-containing biologically active substances called cobalamins: cyanocobalamin (CAS 68-19-9), hydroxocobalamin (CAS 13422-51-0) and two coenzyme forms methylcobalamin (CAS 13422-55-4) and cobamamide ( synonyms: adenosylcobalamin, dibencoside; CAS 13870-90-1). Sometimes in a narrower sense, vitamin B ₁₂ is called cyanocobalamin, since it is in this form that the main amount of vitamin B ₁₂ enters the human body, without losing sight of the fact that it is not synonymous with B ₁₂ . It has a high biological activity. It is necessary for normal blood formation, promotes the maturation of red blood cells. Participates in the processes of transmethylation, hydrogen transfer, the formation of methionine, nucleic acids, choline, creatine. Promotes the accumulation of compounds containing sulfhydryl groups in red blood cells. It has a beneficial effect on the function of the liver and nervous system. Participates in the synthesis of the myelin sheath, stimulates hematopoiesis, reduces pain associated with damage to the peripheral nervous system, and stimulates nucleic acid metabolism via activation of folic acid. It activates the blood coagulation system, in high doses causes an increase in the activity of thromboplastin and prothrombin. After oral administration, cyanocobalamin is absorbed from the digestive tract. It is metabolized in tissues, turning into a coenzyme form - adenosylcobalamin, which is an active form of cyanocobalamin. It is excreted in the bile and urine.

WO 1995031194 A1 (publ. 11/23/1995) discloses a method for treating a chronic inflammatory disease resulting from a hypoxic / reperfusion injury, comprising systemically administering a composition comprising (1) a therapeutically effective amount of an active water-soluble compound having a molecular weight of from about 100 up to about 1400 daltons, or a pharmaceutically acceptable salt, amide, ester derivative thereof, (2) optionally an effective amount of at least one coagent, selected one of the group consisting of (a) an antioxidant, a compound for removing free radicals, a chemical having indirect antioxidant properties, a vitamin, a chemical mating agent, and / or (b) a non-absorbable polyamine substance, (3) at least one drug in an amount effective to treat a chronic inflammatory disease. Such substances / additional substances may be aceclofenac and vitamin B ₁₂ .

Eurasian patent EA 018536 B1 (published August 30, 2013) discloses an anhydrous topical pharmaceutical preparation containing tolperisone or its pharmaceutically acceptable salts or tolperisone and a non-steroidal anti-inflammatory drug or their pharmaceutically acceptable salts, a gelling macromolecule and a solvent. The non-steroidal anti-inflammatory acid preparation may be aceclofenac. The objective of the development of the invention was to investigate the anti-inflammatory and anti-hyperalgesic effects of pharmaceutical compositions containing tolperisone or tolperisone combined with non-steroidal anti-inflammatory drugs. In addition, the task of the inventors was to develop a pharmaceutical product for external use in which gelation does not require the addition of water and does not depend on temperature and pH conditions, providing a promising approach to the preparation of very sensitive tolperisone. The experiments of the inventors focused on the development of anhydrous gel preparations, which, unlike traditional gel systems, contain a high amount of organic solvent as a hydrophilic medium, and the method of their manufacture is independent of temperature or pH conditions. Pharmaceutically and cosmetically acceptable organic solvents were used, such as dimethyl sulfoxide, propylene glycol, diethylene glycol monoethyl ether, propylene carbonate, polyethylene glycols with a molecular weight ranging from 200 to 900 Da, or a mixture thereof. Semi-synthetic and synthetic macromolecules, for example, cellulose derivatives and poly (acrylic acid) derivatives, were used to develop an anhydrous gel structure. During the experiments, the authors unexpectedly discovered that the solvents used and their mixture also functioned as plasticizers, therefore, the gel structure was formed without additional plasticizer or the need to change the temperature or pH conditions of the system. The authors found that in gel formulations, tolperisone showed suitable stability even under accelerated testing conditions.

In the application of the Russian Federation RU 2015121239 A (published on December 27, 2016), a stable pharmaceutical composition for the treatment of pain syndromes is disclosed, comprising a non-steroidal anti-inflammatory drug from the group of acetic acid derivatives, an analgesic and antipyretic from the group of anilides and muscle relaxant. A non-steroidal anti-inflammatory drug from the group of acetic acid derivatives may be aceclofenac. A muscle relaxant may be aceclofenac.

In the prior art there is no information on a combination agent based on aceclofenac, tolperisone and vitamin B ₁₂ for oral and intramuscular use with hypertonicity and spasm of striated muscles resulting from organic diseases of the central nervous system (including pyramidal lesions, multiple sclerosis, stroke, myelopathy , encephalomyelitis), musculoskeletal system (including spondylosis, spondylitis, cervical and lumbar syndromes, arthrosis of large joints); rehabilitation treatment after orthopedic and traumatological operations.

The combined tool according to the invention due to the components included in its composition, has the following actions:

- anti-inflammatory, analgesic and antipyretic;

- antispasmodic and vasodilator;

- analgesic, repair effect due to participation in the synthesis of the myelin sheath, stimulation of nucleic acid metabolism through activation of folic acid (effect of vitamin B12).

- synergistic action of the active substances included in the tool.

SUMMARY OF THE INVENTION

The present invention relates to a new tool for use in hypertonicity and spasm of striated muscles resulting from organic diseases of the central nervous system, including damage to the pyramidal tract, multiple sclerosis, stroke, myelopathy, encephalomyelitis; musculoskeletal system, including spondylosis, spondylarthrosis, cervical and lumbar syndromes, arthrosis of large joints; during rehabilitation treatment after orthopedic and traumatological operations, containing aceclofenac, tolperisone and vitamin B ₁₂ .

In one embodiment, the agent of the invention may comprise:

Aceclofenac from about 30 to about 200 mg;

Tolperisone from about 25 to about 300 mg;

Vitamin B ₁₂ from about 0.1 to about 1 mg.

In one embodiment, the agent of the invention may be a solution for intramuscular administration.

In one embodiment, the agent of the invention may further comprise adjuvants. Excipients may be lidocaine hydrochloride, methyl parahydroxybenzoate, diethylene glycol monoethyl ether and / or water for injection.

In one particular embodiment, the agent according to the invention may contain: aceclofenac - 100 mg, tolperisone - 100 mg, vitamin B ₁₂ - 1 mg.

In one embodiment, the agent of the invention may be a tablet. The tablet may be coated.

In one embodiment, the agent of the invention may further comprise adjuvants. Excipients may be citric acid monohydrate, colloidal silicon dioxide, stearic acid, talc, microcrystalline cellulose, corn starch and / or lactose monohydrate.

In one particular embodiment, the agent according to the invention may contain: aceclofenac - 100 mg, tolperisone - 50 mg, vitamin B ₁₂ - 240 mcg.

In one particular embodiment, the agent according to the invention may contain: aceclofenac - 100 mg, tolperisone - 150 mg, vitamin B ₁₂ - 240 mcg.

In addition, the present invention also relates to a new use of an agent containing aceclofenac, tolperisone and vitamin B ₁₂ for hypertonicity and spasm of striated muscles resulting from organic diseases of the central nervous system, including pyramidal lesions, multiple sclerosis, stroke, myelopathy, encephalomyelitis; musculoskeletal system, including spondylosis, spondylarthrosis, cervical and lumbar syndromes, arthrosis of large joints; during rehabilitation treatment after orthopedic and traumatological operations.

In addition, the present invention also relates to a new use of vitamin B ₁₂ for the manufacture of an agent containing aceclofenac, tolperisone and vitamin B ₁₂ for use in hypertonicity and spasm of striated muscles resulting from organic diseases of the central nervous system, including pyramidal lesions, multiple sclerosis, stroke myelopathy, encephalomyelitis; musculoskeletal system, including spondylosis, spondylarthrosis, cervical and lumbar syndromes, arthrosis of large joints; rehabilitation treatment after orthopedic and traumatological operations.

DETAILED DESCRIPTION OF THE INVENTION

There is a need in the art to provide alternatives to commercially available oral and intramuscular administration agents. The expansion of the arsenal of such funds at the expense of the claimed funds will overcome the existing difficulties known to specialists in this field of technology, and to reach a new level of treatment.

Osteoarthrosis (osteoarthritis) is a degenerative joint disease caused by damage to the cartilage of the articular surfaces. The term “osteoarthrosis” unites a group of diseases of various etiologies, but with similar biological, morphological and clinical outcomes, in which not only articular cartilage is involved in the pathological process, but also the entire joint, including subchondral bone, ligaments, capsule, synovial membrane and periarticular muscles. The main clinical symptoms of osteoarthritis are pain and deformation of the joints, leading to functional failure. The basis of degenerative dystrophic changes in arthrosis is primary damage to the cartilage, followed by an inflammatory reaction, which is why arthrosis is often called arthrosis-arthritis. Arthrosis is always associated with bone deformity, which is why it is also called osteoarthritis or deforming arthrosis.

Osteoarthritis is the most common form of joint damage and one of the main causes of disability, causing a deterioration in the quality of life and significant financial costs, especially in older people. Most often, osteoarthritis affects the joints of the hand, the first metatarsophalangeal joint of the foot, the joints of the cervical and lumbar spine, knee and hip joints. However, according to the severity of dysfunction of the musculoskeletal system, the first place is occupied by the hip, knee and ankle joints, as well as the shoulder joint.

Osteoarthrosis is a consequence of mechanical and biological causes that disrupt the formation of cells of the articular cartilage and subchondral bone. It can be triggered by many causes, including hereditary, evolutionary, metabolic and traumatic. Osteoarthrosis affects all tissues of the joints. The disease is manifested by morphological, biochemical, molecular and biomechanical changes in the cells and matrix, which lead to softening, saping, ulceration and a decrease in the thickness of the articular cartilage, as well as osteosclerosis with a sharp thickening and compaction of the subchondral bone cortical layer, the formation of osteophytes and the formation of osteophytes. Clinically, osteoarthritis is manifested by arthralgia, soreness and limited movement, recurrent synovitis, local inflammation in various tissues of the joint.

Osteoarthrosis is primary and secondary. If the cause of the disease is not established, then such arthrosis is usually called primary, or idiopathic. Secondary osteoarthritis has an obvious reason: it develops after an injury, with metabolic disorders, endocrine diseases, as the outcome of a degenerative necrotic process (aseptic necrosis of the femoral head, dissecting osteochondritis (Koenig disease), Perthes disease), as the outcome of the inflammatory process (purulent joint inflammation , rheumatoid arthritis, arthritis with systemic lupus erythematosus, with tuberculosis).

Risk factors for primary osteoarthritis are: hereditary predisposition, overweight, old age, specific professions. In addition, the incidence of osteoarthritis depends on gender and racial / ethnicity. Genetic factors include: hereditary disorders and mutations of type II collagen, other hereditary diseases of bones and joints, congenital disorders of joint development (dysplasia). Non-genetic (non-inherited) multiple factors, such as: age, osteoporosis, leave an imprint on the development and progression of osteoarthritis. overweight; violation of the endocrine balance of the body, including a decrease in estrogen secretion (postmenopausal period); metabolic disorders in the body; deficiency in the body of trace elements; developmental impairment (dysplasia) and acquired diseases of bones and joints; neurodystrophic manifestations of the pathological process in the lumbosacral (lumbar-iliac muscle syndrome), or in the cervical spine (shoulder-scapular periarthritis); inflammatory process in the joint.

The following risk factors for osteoarthritis are environmental factors: hypothermia; violation of ecological balance; the effect of chemical toxins; joint trauma, repeated microtrauma; joint surgery (e.g., meniscectomy); occupation and physical activity at work.

Regardless of the cause, there are 3 stages of arthrosis. At the first or initial stage of arthrosis, there are no pronounced morphological disorders of joint tissues. Changes relate only to the function of the synovial membrane, to the biochemical composition of the synovial fluid, which, through diffusion, nourishes the cartilage and menisci of the joint. The joint loses its ability to withstand the usual load for it, and joint overload is accompanied by inflammation and pain.

In the second stage of the disease, we see the beginning destruction of articular cartilage and menisci. The bone responds to the load of the articular area with marginal growths - osteophytes.

The second stage inevitably passes into the third - the stage of severe arthrosis. Its signs are pronounced bone deformation of the supporting area of the joint, which changes the axis of the limb. Failure, shortening of the ligaments of the joint leads to pathological mobility of the joint or, in combination with the stiffness of the joint bag, to a sharp restriction of natural movements - contractures. Chronic inflammation and chronic pain usually accompany stage 2 and 3.

In the initial stage of the disease, the muscles that carry out movements in the joint are weakened, but, in general, are not changed. In the second stage, a violation of muscle function due to a violation of reflex neurotrophic regulation is observed. In the third stage of the disease, joint loading and motor activity are severely impaired, due to contractures and violation of the limb axis, the amplitude of muscle contraction changes, normal attachment points of the muscular-tendon complex change. This is accompanied by a shortening or stretching of the muscle, a decrease in the ability to fully contract. Trophic disorders in joint disease affect not only the muscles, but also all tissues of the limb.

The pathogenesis of this disease is based on a violation of the function and structure of the cartilage of the joint. Articular cartilage is a highly specialized tissue consisting of a matrix and chondrocytes immersed in it. The matrix contains two major macromolecules, glycosamines (proteoglycans) and collagen. The high concentration of proteoglycans in the cartilage keeps the collagen network energized, thus contributing to an even distribution of the load that acts on the cartilage, and ensuring the restoration of shape after the termination of the load. With the loss of even a small amount of glycosamine, the resistance of the cartilage matrix to the effects of physical activity decreases, and the surface of the cartilage becomes sensitive to damage. In the very early stages of arthrosis, the cartilage becomes thicker than normal, but with progression it becomes thinner. The cartilage becomes soft and friable, deep ulcers appear on it, usually only in the most loaded part of the joint.

Normally, during periodic loads, for example when walking, the cartilaginous plate is deformed and returns to its previous shape, acting as a kind of pump, which provides the expulsion of decay products and the “absorption” of nutrients and building material. Compression and shape restoration during loading is the main condition for the regeneration of damaged cartilage tissue. However, excessive or prolonged loading of the joint adversely affects the function of the articular cartilage and aggravates the course of arthrosis.

The nutrition of the cartilage and menisci of the joint is carried out only due to synovial fluid. The "health" of the sliding and shock-absorbing joint structures depends on how much and in what quality the fluid is secreted by the synovial membrane.

The synovial membrane performs an important function of filtering the building material of cartilage - hyaluronic acid, it prevents the leaching of the latter from the joint cavity. Violation of the biochemical composition of synovial fluid during trauma or inflammation of the joint actually leads to the development of a disease called osteoarthritis.

The effectiveness of the circulation and diffusion of synovial fluid is directly related to movement in the joint and joint loading. Movement in the joint is necessary for metabolism in the cartilage. In itself, a prolonged restriction of movements in the joint leads to a deterioration in the nutrition of cartilage.

With arthrosis, the balance between the formation of a new building material for the restoration of cartilage and its destruction is disturbed. Cartilage from a strong, elastic structure turns into a dry, thin with a rough surface. The underlying bone becomes thicker and grows to the sides of the cartilage, which limits movement and causes joint deformation. The joint capsule is compacted - fibrosed, and also inflamed. The joint is filled with inflammatory fluid that stretches the capsule and ligaments of the joint. Pain, and subsequently deformation of the articular surfaces during arthrosis, leads to joint stiffness and joint contractures. Morning and starting pain, as well as stiffness in the joint in patients with deforming arthrosis, is actually due to the low elasticity of the cartilage and the need for starting movements to restore sufficient cartilage elasticity. This creates a feeling of pain and stiffness.

With inflammation, the joint assumes a resting position or physiological position. In this position, the maximum expansion of the ligaments and capsules of the joint is ensured. In this position, pain in the joint is minimal. A great influence on the course of the pathological process is exerted by the condition of the so-called muscle corset of the joint, that is, the muscle system, which not only carries out movement in the joint, but also stabilizes the joint, absorbing powerful inertial pulses during movement. Thus, the internal broad muscle in the quadriceps of the thigh protects the knee joint from lateral instability at the time of landing on the heel when walking, and the middle gluteus muscle on the side of the supporting leg limits the inclination of the pelvis at the time of transfer, which protects the hip joint from overload.

The outcome of arthrosis is the complete destruction of the joint with the formation of ankylosis - complete immobility of the joint or neoarthrosis with unnatural mobility. This is accompanied by severe limb dysfunction. Recently, without waiting for the outcome of the disease, special operations are increasingly being used to replace the joint with a prosthesis - joint replacement. The figure shows the varus deformity of the knee typical for the terminal stage of arthrosis of the knee joint in combination with lateral pathological instability of the knee joint. Osteoarthritis of a block or spherical joint, such as a hip, results in ankylosis. In this case, joint closure usually occurs in the non-physiological (vicious) position of the limb. In this case, we see the hip in the position of flexion and adduction, in which the leg is shortened, and the axis of the limb and the biomechanics of the musculoskeletal system are significantly disturbed. [URL: https://ru.wikipedia.org/wiki/Osteoarthrosis]

Osteochondrosis is a complex of dystrophic disorders in the articular cartilage. It can develop in almost any joint, but most often the intervertebral discs are affected. Depending on the localization, cervical, thoracic and lumbar osteochondrosis is distinguished.

The root cause of osteochondrosis is upright posture. In the process of growing up in humans, the vascular bed in the intervertebral discs is physiologically reduced, so their nutrition occurs diffusely. This complicates the restoration of intervertebral discs after injuries and loads. Inadequate diet aggravates osteochondrotic processes. Cartilage loses its elasticity and strength; its shape and consistency change.

Irrational and asymmetric work of the muscles of the spine adversely affect the disks, namely: with improper habitual postures, with insufficient warm-up, when carrying bags on the shoulder, when using soft pillows and mattresses. Flat-footedness can act as a stimulator of pathological processes. If the foot does not provide adequate amortization of the interactions with the support, the latter has to be done with the spinal column. Obesity also contributes to osteochondrosis of the spine. Excess fatty tissue, deposited in different places, complicates the maintenance of balance and overloads the intervertebral joints. Complications of osteochondrosis include diseases such as: protrusion, disc herniation (intervertebral hernia, spinal hernia), kyphosis, radiculitis.

The causes of changes in the intervertebral discs are not fully understood. People begin to feel manifestations of osteochondrosis most often after 35 years. The development and exacerbation of this ailment is facilitated by various back injuries, static and dynamic overloads, as well as vibration. The older the person, the more manifestations he has. But in recent years, more and more people aged 18 to 30 have been complaining of back pain. The reasons for the early manifestation of the disease are many: poor physical fitness, impaired posture and curvature of the spine, flat feet and being overweight. The main reasons: hereditary (genetic) predisposition; metabolic disorders in the body, infection, intoxication; overweight; improper nutrition (lack of trace elements and fluids); age-related changes; spinal injuries (bruises, fractures); violation of posture, curvature of the spine, hypermobility (instability) of the segments of the spinal column, flat feet; adverse environmental conditions; sedentary lifestyle; work related to lifting weights, frequent changes in the position of the body (turns, flexion and extension, jerking movements); prolonged exposure to uncomfortable postures in a standing, sitting, lying position, when lifting and carrying heavy loads, when performing other work, which increases the pressure in the disks and the load on the spine as a whole; excessive physical exertion, unevenly developed musculoskeletal system; spinal overload associated with diseases of the foot, as well as the result of wearing uncomfortable shoes, high heels and pregnancy in women; abrupt cessation of regular training by professional athletes; nervous strain, stressful situations; smoking.

Patients suffering from osteochondrosis complain of constant aching back pain, which is often joined by numbness and a feeling of aching in the limbs. In the absence of adequate treatment, weight loss and atrophy of the extremities occur. The main symptoms: persistent aching back pain, numbness and aching in the limbs; increased pain during sudden movements, physical exertion, weight lifting, coughing and sneezing; decrease in range of motion, muscle spasms; with osteochondrosis of the cervical spine: pain in the arms, shoulders, headaches; possible development of the so-called vertebral artery syndrome, which consists of the following complaints: a noise in the head, dizziness, flickering of "flies", colored spots in front of the eyes in combination with a burning throbbing headache. The cause of the vertebral artery syndrome may be its spasm in response to both the direct irritation of its sympathetic plexus due to bone growths, disc herniation, arthrosis of the intervertebral joint, and a reflex reaction due to irritation of any spine receptors. The presence of vertebral artery syndrome can aggravate the course of coronary or cardio-muscular pathology, if any; with osteochondrosis of the thoracic spine: pain in the chest (as a "count" in the chest), in the region of the heart and other internal organs; with osteochondrosis of the lumbosacral spine: lower back pain radiating to the sacrum, lower limbs, sometimes to the pelvic organs; damage to nerve roots (with hernias of the intervertebral discs, bone growths, spondylolisthesis, spondylarthrosis): shooting pain and impaired sensitivity, hypotrophy, hypotension, weakness in innervated muscles, decreased reflexes.

A preliminary diagnosis is made during the initial examination of the patient. The examination is usually carried out by a neurologist in connection with the patient's complaints of local changes that may manifest as pain, deformation or limitation of mobility. The spine is examined in the position of the patient standing, sitting and lying, both at rest and in motion. The level of damage to the spine is determined by counting the number of vertebrae from certain anatomical landmarks or according to a special scheme. When examining the back, they pay attention to posture, structural features of the trunk, mark the line of the spinous processes (median groove of the back), the lower corners of the shoulder blades, the crests of the ilium, the lateral contours of the waist and neck, the position of the shoulder girdles, the deviation of the intergluteal groove from the vertical, reveal protrusion of the spinous pay attention to the relief of the muscles located near the spine. Palpation of the spine allows you to supplement the examination data (presence or absence of deformation), to determine the localization, degree and nature of pain. When feeling, also note the tension of the muscles located near the spine, because most injuries and diseases of the spine are accompanied by an increase in muscle tone. Spinal flexion is used to determine the range of motion in different parts of the spine. The main role in the study of the spine is assigned to radiography, computed tomography and magnetic resonance imaging, with which the level of damage is determined, the diagnosis is specified and specified, and hidden pathologies are revealed. Diagnostic data allow the attending physician to determine treatment tactics and choose the most effective treatment methods. [URL: https://ru.wikipedia.org/wiki/Osteochondrosis]

Spondylarthrosis is a particular form of osteoarthrosis, which is a heterogeneous form of diseases that are different in clinical presentation and outcomes, which are based on the defeat of all the constituent elements of the joint - cartilage, subchondral bone, ligaments, capsules and periarticular muscles. The most common localization of osteoarthritis is arthrosis of the knee and hip joints, as well as the spine. In the latter case, both the joints between the vertebral bodies and the arcuate (facet) joints of the vertebral segments are affected.

Spondylarthrosis is a disease not only of advanced age, although in the latter case it is observed in 85-90%. In young people, arthritic changes in the spine can develop after 25-30 years, which is facilitated by congenital anomalies of the spine, hypermobility of the vertebral segments and, of course, trauma.

A) The early occurrence of arthrosis is promoted by such anomalies as the presence of transitional lumbosacral vertebrae; lumbarization, i.e. the presence of the 6th lumbar vertebra due to the superior sacral segment or, conversely, sacralization, i.e. fusion of the 5th lumbar vertebra with the sacrum. An important role (in the appearance of recurrent back pain) is played by a violation of articular tropism, i.e. asymmetric arrangement of the arched joints.

The linear arrangement of facet joints deserves special attention. In the cervical region, the facets are located horizontally (transversely), with a very small posterior-lower deviation. In the thoracic region, the facet joints are located at a lower level (relative to the vertebral body) and can be compared with the location of the nerve root (horizontal on the neck and going down - on the thoracic). In the lumbar region, the facet joints are located sagittally in the first and second vertebrae and almost coronary (i.e. parallel to the coronal suture or - trying to occupy a perpendicular position to the lateral surface of the vertebral body) in the 3-5th vertebrae. Sometimes the facet joint is on the one hand in the sagittal plane, and on the other hand, in the coronary. Such anomalies of "tropism" are found in many people and are considered a predisposing factor for additional rotational load on them.

Small anomalies are so widespread that they can be detected in almost every second person.

“Transient vertebra” - in addition to facet tropism anomalies, a change in the number of mobile vertebrae at the lumbar level is the most significant among the causes of pain. Lumbarization of the first sacral vertebra increases the “shoulder of the lever” for the lower back and causes an increased load on the lumbosacral joint. Sacralization of the fifth lumbar vertebra is unlikely to cause pain if the vertebra is firmly connected to the sacrum. However, if sacralization is one-sided, the load on the vertebra becomes abnormal. The most common form of sacralization is when one transverse process of the fifth lumbar vertebra is enlarged and connected by a joint to the sacrum. The axis of movement on the connection side shifts from the sagittal plane of such a joint and excursion on the opposite side of the vertebra increases. This can cause tension on the side opposite to sacralization.

Two anomalies - the sixth lumbar vertebra and the sacralization of the fifth vertebra are clinically significant, may be contraindications to certain professions. The diagnosis is easily established radiologically.

"Spina bifida occulta" - refers to the non-closure of the arches of the lumbar vertebrae. An anomaly is so common that it can be considered as a variant of the anatomical norm.

B) Injury is a very common cause of lower back pain. Often, it contributes to the lack of physical condition of the individual. Most muscle sprains and lumbar pain can be prevented by controlling body weight, daily exercise and regular sports activity (depending on age and physical condition). Athletes and young healthy people relatively rarely damage the lower back, because they are in good physical shape. However, most people after 30 years of age, reduce physical activity, gain weight and do not pay attention to exercise. When they have to deal with physical activity, it is often excessive for them. So, a person sitting at a desk five days a week cannot count on a successful game of tennis.

A traumatic subluxation of the facet joint is one of the very common causes of lower back pain. This pathology is best diagnosed and treated with chiropractic methods.

Spondylolysis and spondylolisthesis are among many related to stress fractures of the “isthmus” or “inter-articular region” of the vertebra. Spondylolysis isthmus defect, spondylolisthesis is a bilateral defect with anterior sliding of the body of the injured vertebra and the transverse processes of the underlying vertebra. Thus, with spondylolisthesis, the posterior vertebrae (spinous process and arches) remain in a normal position. The degree of slipping ranges from 1st to 4th degree. 1st degree - displacement from 0 to 25% and 4th - complete anterior displacement of the vertebra. The fifth lumbar vertebra most often suffers, followed by the fourth lumbar vertebra.

In an oblique x-ray projection, a normal vertebra looks like a "spaniel in profile." If such a "spaniel" has a "collar", we can talk about spondylolysis; if "the head of the dog is separated from the body" - there is spondylolisthesis.

Usually spondylolisthesis is not a very significant problem, with irregular, occasional lower back pain as the only symptom. However, for active teenagers the problem can be more serious, especially with the progression of spondylolisthesis. Further slippage can cause severe root compression and stabilization of the vertebral segments is required.

C) Vertebral instability - an independent nosological unit; the lumbar vertebra moves back or forward with respect to the lower lying vertebra. Usually occurs between the third and fourth and between the fourth and fifth lumbar vertebrae. Typically, the displacement is frontal and occurs when bending.

Easily diagnosed with functional x-rays. Surgery is usually not indicated, as there is often multiple instability.

The phenomenon of osteoarthrosis is characterized as “carry (tire) and cry”; it is associated with degenerative changes in articular cartilage. Facet joints are affected in the spinal column. Repeated injuries over a number of years (adolescence and young age) play a role, but cannot fully explain the occurrence of the disease. Heredity and increased weight contribute to the disease. An analogy is drawn with the use of a car - the more and longer it is used, the more often it starts to “junk”.

Under the influence of statodynamic loads, the elastic gelatinous nucleus of the intervertebral disc, which plays a cushioning role and provides flexibility of the spine, begins to lose its physiological properties due, first of all, to the depolarization of saccharides of the nucleus. In conditions of altered, increased mobility of the vertebral segment (instability), reactive changes occur in adjacent vertebral bodies and joints - spondylarthrosis concomitant with osteochondrosis develops.

The composition of the vertebral segment includes not only the cartilaginous disk between adjacent vertebrae and the arched joints, but also the ligaments and muscles connecting them - transverse, interspinous and rotator muscles. These muscles, under the influence of impulses from the affected vertebral segment, especially from the posterior longitudinal ligament, strain reflexively; their asymmetric tension causes curvature of the spine - scoliosis, which doctors often observe in patients with spondylarthrosis.

The main clinical manifestation of osteoarthritis is pain that occurs when moving, changing the position of the trunk and passing at rest; but, as the disease progresses, morning stiffness appears, lasting 20-60 minutes. In case of joint subluxation or spondylolisthesis, arthritic (inflammatory) processes and reflex muscular-tonic reactions develop, causing pain and limitation of spinal mobility, lasting several weeks or months.

A specific situation is diagnosed by clinical criteria and radiological, in particular, computed tomography data. [Gorbacheva F.E. Spondylarthrosis of the spine: diagnosis and treatment. M., 2007. 12 pp.]

The agent according to the invention can be used for the treatment of primary and secondary osteoarthritis, osteochondrosis, spondylarthrosis.

The present invention relates to a new agent or drug or composition or pharmaceutical composition or preparation for use in hypertonicity and spasm of striated muscles resulting from organic diseases of the central nervous system, including pyramidal lesions, multiple sclerosis, stroke, myelopathy, encephalomyelitis; musculoskeletal system, including spondylosis, spondylarthrosis, cervical and lumbar syndromes, arthrosis of large joints; during rehabilitation treatment after orthopedic and traumatological operations, containing aceclofenac, tolperisone and vitamin B ₁₂ .

The tool may contain:

Aceclofenac from about 30 to about 200 mg;

Tolperisone from about 25 to about 300 mg;

Vitamin B ₁₂ from about 0.1 to about 1 mg.

The agent may be a solution for intramuscular administration.

The tool may additionally contain auxiliary substances. Excipients may be lidocaine hydrochloride, methyl parahydroxybenzoate, diethylene glycol monoethyl ether and / or water for injection.

In particular, the tool may contain:

Aceclofenac - 100 mg;

Tolperisone - 100 mg;

Vitamin B ₁₂ - 1 mg.

The agent may be a tablet.

The agent may be a coated tablet.

The tool may additionally contain auxiliary substances. Excipients may be citric acid monohydrate, colloidal silicon dioxide, stearic acid, talc, microcrystalline cellulose, corn starch and / or lactose monohydrate.

In particular, the tool may contain:

Aceclofenac - 100 mg;

Tolperisone - 50 mg;

Vitamin B ₁₂ - 240 mcg.

In particular, the tool may contain:

Aceclofenac - 100 mg;

Tolperisone - 150 mg;

Vitamin B ₁₂ - 240 mcg.

In addition, the present invention also relates to a new use of the agent according to the invention for hypertonicity and spasm of striated muscles resulting from organic diseases of the central nervous system, including pyramidal lesions, multiple sclerosis, stroke, myelopathy, encephalomyelitis; musculoskeletal system, including spondylosis, spondylarthrosis, cervical and lumbar syndromes, arthrosis of large joints; during rehabilitation treatment after orthopedic and traumatological operations.

In addition, the present invention also relates to a new use of vitamin B ₁₂ for the manufacture of an agent of the invention for use in hypertonicity and spasm of striated muscles resulting from organic diseases of the central nervous system, including pyramidal lesions, multiple sclerosis, stroke, myelopathy, encephalomyelitis; musculoskeletal system, including spondylosis, spondylarthrosis, cervical and lumbar syndromes, arthrosis of large joints; rehabilitation treatment after orthopedic and traumatological operations.

The oral agent of the present invention may contain:

Aceclofenac from about 30 to about 200 mg;

Tolperisone from about 25 to about 300 mg;

Vitamin B ₁₂ from about 0.1 to about 1 mg.

In particular, the agent of the present invention may comprise:

Coated Tablets:

Composition 1:

Aceclofenac - 100 mg;

Tolperisone - 50 mg;

Vitamin B ₁₂ - 240 mcg.

Composition 2:

Aceclofenac - 100 mg;

Tolperisone - 150 mg;

Vitamin B ₁₂ - 240 mcg.

In particular, the agent of the present invention may further comprise one or more of:

Citric acid monohydrate - 0.73 mg;

Colloidal silicon dioxide - 0.8 mg;

Stearic acid - 1.7 mg;

Talcum - 4.5 mg;

Microcrystalline cellulose - 14 mg;

Corn starch - 29.77 mg,

Lactose Monohydrate - 48.5 mg.

The composition of the film coating of the tablet may further comprise one or more of:

Colloidal silicon dioxide - 0.045 mg;

Titanium dioxide (E171) - 0.244 mg;

Lactose monohydrate - 0.392 mg;

Macrogol 6000-0.392 mg;

Hypromellose - 3.927 mg.

The agent in the form for intramuscular administration of the present invention may contain:

Aceclofenac from about 30 to about 200 mg;

Tolperisone from about 25 to about 300 mg;

Vitamin B ₁₂ from about 0.1 to about 1 mg.

In particular, the agent of the present invention may comprise:

Aceclofenac - 100 mg;

Tolperisone -100 mg;

Vitamin B ₁₂ -1 mg.

In particular, the agent of the present invention may further comprise one or more of:

Lidocaine hydrochloride - 2.5 mg;

Methyl parahydroxybenzoate - 0.6 mg;

Diethylene glycol monoethyl ether - 0.3 ml;

Water for injection - up to 1 ml.

The targeted administration of vitamin B ₁₂ or its derivative into the composition for intramuscular administration containing aceclofenac and tolperisone or its salt is an inventive step in relation to the prior art and can significantly accelerate the cure, which is predetermined by the synergistic effect of the combination discovered by the authors.

The combined use of vitamin B ₁₂ in combination with aceclofenac and tolperisone or its salt leads to a cumulative, super-cumulative effect, not known and not explicitly from the prior art. At the same time, the introduction of vitamin B ₁₂ into the composition of aceclofenac and tolperisone or its salt increases the period of its suitability for medical use. The claimed tool based on a combination of aceclofenac, tolperisone or its salt and vitamin B ₁₂ allows you to expand the arsenal of available products on the market, reduce treatment time, increase the effectiveness of anti-inflammatory, anti-allergic, immunosuppressive, analgesic, antipyretic and reparative effects.

EXAMPLES

The examples included in this description are not limiting of the claimed invention and are given only for the purpose of illustration and confirmation of the achievement of the expected technical results. These examples are one of many experimental data obtained by the inventors, which confirm the effectiveness of oral and intramuscular administration agents that are within the scope of the invention.

Example 1. Obtaining funds according to the invention and means of comparison.

1. Prepare a film-coated tablet based on aceclofenac, tolperisone and vitamin B ₁₂ . Get tool And containing:

aceclofenac - 100 mg;

tolperisone - 50 mg;

Vitamin B ₁₂ - 240 mcg.

2. Prepare a film-coated tablet based on aceclofenac and tolperisone. Get tool In, containing:

aceclofenac - 100 mg;

tolperisone - 50 mg.

Example 2. The use of the means according to the invention and means of comparison.

Obtained in Example 1, the funds were used in the study of patients with rheumatoid arthritis.

24 patients with moderate or severe pain were examined. All patients underwent outpatient or inpatient treatment; the study was conducted in conditions of complete patient awareness. The age of patients is from 41 to 52 years. The duration of the exacerbation is about 1 month.

Patients included in the study were divided into 2 groups regardless of age, duration of the disease, current exacerbation, severity of symptoms, assessed using clinical scales. The control group # 1 (means B) included 12 patients, including 6 men and 6 women; the main group (agent A according to the invention) included 12 patients, of which 6 were men and 6 were women.

The effectiveness of the treatment was evaluated by changing the parameters ranked in points:

1) the intensity of pain at rest and during movement (subjectively);

2) examination by a doctor with an assessment.

Examination of patients was carried out before treatment and after each injection of the drug.

There was a decrease in pain and parameters at rest after administration of agent A by 37%, with movement - by 43%. There was a decrease in pain and parameters at rest after administration of means B by 28%, with movement - by 37%.

When studying the dynamics of the pain syndrome, it turned out that therapy with the inclusion of the agent according to the invention significantly reduced the severity of pain both at rest and during movement.

Example 3. Stability studies.

The funds obtained in Example 1 were examined for storage stability.

Studies of the stability of the compositions of the agents, conducted by a method traditional in the art, showed a decrease in storage stability of the composition without vitamin B ₁₂ compared with compositions containing vitamin B ₁₂ .

Example 4. Obtaining funds according to the invention and means of comparison.

1. Prepare an agent for intramuscular administration based on aceclofenac, tolperisone and vitamin B ₁₂ . Get tool And containing:

aceclofenac -100 mg;

tolperisone - 100 mg;

Vitamin B ₁₂ - 1 mcg.

2. Prepare a tool for intramuscular administration based on aceclofenac and tolperisone. Get tool In, containing:

aceclofenac - 100 mg;

tolperisone - 100 mg.

Example 5. The use of the means according to the invention and means of comparison.

Obtained in Example 4 funds were used in the study of patients with rheumatoid arthritis.

24 patients with moderate or severe pain syndrome were examined. The study was conducted in conditions of complete patient awareness. The age of patients is from 43 to 56 years. The duration of the exacerbation is about 1 month.

Patients included in the study were divided into 2 groups regardless of age, duration of the disease, current exacerbation, severity of symptoms, assessed using clinical scales. The control group # 1 (means B) included 12 patients, including 6 men and 6 women; the main group (agent A according to the invention) included 12 patients, including 7 men and 5 women.

The effectiveness of the treatment was evaluated by changing the parameters ranked in points:

1) the intensity of pain at rest and during movement (subjectively);

2) examination by a doctor with an assessment.

Examination of patients was carried out before treatment and after each injection of the drug.

There was a decrease in pain and parameters at rest after administration of agent A by 36%, with movement - by 48%. There was a decrease in pain and parameters at rest after administration of agent B by 30%, with movement by 40%.

When studying the dynamics of the pain syndrome, it turned out that therapy with the inclusion of the agent according to the invention significantly reduced the severity of pain both at rest and during movement.

Example 6. Stability studies.

The funds obtained in Example 4 were examined for storage stability. Studies of the stability of the compositions of the agents, conducted by a method traditional in the art, showed a decrease in storage stability of the composition without vitamin B ₁₂ compared with compositions containing vitamin B ₁₂ .

Claims (28)

1. A tool for use with hypertonicity and spasm of striated muscle, containing: Aceclofenac from about 30 to about 200 mg; Tolperisone from about 25 to about 300 mg; Vitamin B ₁₂ from about 0.1 to about 1 mg. 2. The tool according to claim 1, characterized in that the hypertonicity and spasm of the striated muscle occurs due to arthrosis of large joints. 3. The tool according to p. 1, characterized in that it is a solution for intramuscular administration. 4. The tool according to p. 3, characterized in that it further comprises auxiliary substances. 5. The tool according to claim 4, characterized in that the excipients are lidocaine hydrochloride, methyl parahydroxybenzoate, diethylene glycol monoethyl ether and / or water for injection. 6. The tool according to p. 3, characterized in that it contains: Aceclofenac - 100 mg; Tolperisone - 100 mg; Vitamin B ₁₂ - 1 mg. 7. The tool according to claim 1, characterized in that it is a tablet. 8. The tool according to claim 7, characterized in that it is a coated tablet. 9. The tool according to p. 7, characterized in that it further comprises auxiliary substances. 10. The tool according to p. 9, characterized in that the excipients are citric acid monohydrate, colloidal silicon dioxide, stearic acid, talc, microcrystalline cellulose, corn starch and / or lactose monohydrate. 11. The tool according to p. 7, characterized in that it contains: Aceclofenac - 100 mg; Tolperisone - 50 mg; Vitamin B ₁₂ - 240 mcg. 12. The tool according to p. 7, characterized in that it contains: Aceclofenac - 100 mg; Tolperisone - 150 mg; Vitamin B ₁₂ - 240 mcg. 13. The use of funds according to any one of paragraphs. 1-12 with hypertonicity and spasm of striated muscles. 14. The use of 13, characterized in that the hypertonicity and spasm of the striated muscle occurs due to arthrosis of large joints. 15. The use of vitamin B ₁₂ for the manufacture of funds according to any one of paragraphs. 1-12 for use in hypertonicity and spasm of striated muscles. 16. The use of 15, characterized in that the hypertonicity and spasm of the striated muscle occurs due to arthrosis of large joints.