WO2008120965A1 - Pharmaceutical composition comprising a combination of an anti-arthritic agent, a chondroprotective agent, and an anti-inflammatory agent - Google Patents

Abstract

The invention relates to a pharmaceutical composition consisting of the synergic combination of an anti-arthritic agent, such as the active ingredient chondroitin sulphate, a chondroprotective agent, such as the active ingredient glucosamine, and an anti-inflammatory agent, such as the active ingredient meloxicam. Said agents are formulated in a single dosage unit to be orally administered in the form of a powder contained in single-dose envelopes. Said agents are suitable for treating illnesses such as osteoarthritis, rheumatoid arthritis, arthrosis and any other related rheumatoid illness.

Description

 PHARMACEUTICAL COMPOSITION UNDERSTANDING THE COMBINATION OF AN ANTIARTHRITIC AGENT, A DRIVING AGENT AND AN ANTI-INFLAMMATORY AGENT.

FIELD OF THE INVENTION

The present invention is applied in the pharmaceutical industry and describes a pharmaceutical composition composed of the synergistic combination of an antiarthritic agent, such as: Chondroitin, - a chondroprotective agent, such as: Glucosamine and an anti-inflammatory agent, this being: Meloxicam, which are formulated in a single dosage unit, which is indicated for the prevention and / or treatment of osteoarthritis, rheumatoid arthritis, osteoarthritis and other related rheumatic diseases.

The combination of the aforementioned active ingredients produces a greater synergistic effect when they are administered together in a single dose unit unlike when they are administered independently, generating benefits such as: lower dosages, faster action and lower side effects. BACKGROUND OF THE INVENTION

At present, osteoarthritis is a disease that too often suffers a large part of the population of the western world, however, its distribution is universal, there are differences that are based on various factors such as: geographical area, patterns Genetic, environmental development and lifestyle.

The impact of the disease from an economic and social point of view is enormous since osteoarthritis is the most important cause of functional disability in regards to processes related to the musculoskeletal system and the second cause of permanent disability after cardiovascular diseases . People suffering from osteoarthritis are affected in their economic situation and in their lifestyle, since the expenses invested in treatment are very high and most likely the consequence of this disease is the loss of employment and salary, due to the disability caused by this disease. Among the effects related to lifestyle in people suffering from osteoarthritis are: Limitation in work performance, depression, despair, anxiety and loss of interest and motivation to perform the activities of daily living. Osteoarthritis is the most common type of arthritis and affects men and women of adulthood, especially the elderly, being frequent in men before they reach 45 years of age, while after 45 years , the disease is more common in women. • However, osteoarthritis is not typical of people with advanced age, as there are young people who suffer from this disease, which is caused by an injury or a blow to a joint. There are other causes that cause the appearance of osteoarthritis, among these may be: excess weight, muscle weakness; nerve damage that supplies the joint area; synovial disease and even hereditary factors. Osteoarthritis is a disease of the joints that primarily affects cartilage. In osteoarthritis, the joints are damaged due to deterioration of the cartilage, which is a firm tissue, elastic and slippery that covers the extreme parts of the bones.

Under normal conditions, the cartilage provides a smooth and slippery surface that facilitates the mobility of the joints and allows the bones to have movement by sliding from one over the other, in addition to having the function of acting as a cushion between the bones , absorbing the tension produced by daily physical activities.

In osteoarthritis, the surface of the cartilage that is present between the joints wears and breaks, causing the bones to move and cause friction against one another, causing symptoms such as pain, inflammation, deformity and difficulty use the joint, resulting in the loss of physical movement.

It is important to mention that in the process of osteoarthritis, in addition to the wear and tear that the cartilage suffers, there is another factor that plays a very important role for the appearance of the disease, such as the liquid found in the joint called: synovial fluid, which lubricates the joint and is mainly composed of a substance called hyaluronic acid. People who suffer from osteoarthritis may have more hyaluronic acid between the joints than normal, however, this could be diluted, causing this to decrease their protective function.

Osteoarthritis is a disease that affects only the joints, without causing any damage to other internal organs. When the body detects the damage that osteoarthritis causes in the cartilage, it responds by producing new cartilage; However, the construction of the new cartilage does not maintain the rate of production with respect to how quickly it is destroyed, triggering the development of the final stage of osteoarthritis.

With respect to Rheumatoid Arthritis (RA), this is a chronic disease of common prevalence and worldwide distribution that most commonly affects people between 25 and 55 years of age, with women being the most affected than men. It is characterized by severely affecting survival, functional capacity and quality of life of the individual suffering from it, as well as the ability to maintain a satisfactory job. Rheumatoid arthritis commonly affects the joints of both sides of the body equally, with the wrists, fingers, knees, feet and ankles being the most frequently affected parts of the body.

Rheumatoid arthritis (RA) is considered an autoimmune disease, of which the cause that causes it is unknown. The way in which this disease manifests itself is through the immune system, which in normal conditions fights foreign substances, such as viruses or bacteria, but in the case of this disease classified as autoimmune, the immunological system takes the healthy tissue confusing it with foreign substances, causing the body to attack itself.

Rheumatoid arthritis causes pain, stiffness, swelling and loss of function in the joints, and can also cause inflammation in other organs. The manifestation and severity of rheumatoid arthritis can vary considerably, and can be caused by: infection, inheritance (genes), activity hormonal, among others, being these factors that can contribute to its development. Mortality due to direct causes or complications derived from rheumatoid arthritis continues to be double what was observed in the control population, without changing this trend in the last four decades.

The economic impact derived from this pathology has been underestimated in Latin American countries. In the United States, rheumatoid arthritis is considered one of the main causes of disability pension and direct and indirect economic losses.

Osteoarthritis is the most frequent of joint diseases and its prevalence increases with age. It is estimated that the radiological signs of osteoarthritis are rare before 40 years of age (2%), appear in 30% of people aged between 45 and 65 years and in 68% of people over 65 years of age. age. Typical joint disorders of osteoarthritis begin in the second decade of life, affecting 90% of people over 40 years.

Osteoarthritis affects the neck, lumbar region, knees, hips and finger joints. Approximately 70% of people over 70 show radiological evidence of the disease, but only half of them develop symptoms. Osteoarthritis can also affect joints that have been previously damaged by excessive and prolonged use, infection or a previous rheumatic disease. Patients with osteoarthritis suffer pain and functional impairment.

Today there is a wide variety of pharmaceutical products useful for the treatment of these diseases; However, the active ingredients included in the formulation of these medications are administered independently causing the relief of the symptoms manifested by these conditions and properly by the presence of the disease itself, is slower and ineffective.

The pharmacological treatments that are currently applied to treat osteoarthritis, rheumatoid arthritis, osteoarthritis and rheumatic diseases in general, mainly consist of the administration of non-steroidal anti-inflammatory drugs (NSAIDs), which treat the symptoms but not They delay the progression of these diseases, and may even cause the patient to get worse faster.

SUMMARY OF THE INVENTION

In order to offer a pharmaceutical alternative that achieves a better quality of life in patients suffering from diseases such as: osteoarthritis, rheumatoid arthritis, osteoarthritis and other related rheumatic diseases, the development of the pharmaceutical composition that was followed describe.

At present, most of the medications found in the market for the treatment of osteoarthritis, rheumatoid arthritis, osteoarthritis and other related rheumatic diseases, are composed of active ingredients that are formulated independently, which comply with a therapeutic activity specifies; However, these medications only contemplate the treatment of the symptoms manifested by these diseases, but do not slow or stop their progression. For this reason, and in order to eliminate all the inconveniences that arise when the active ingredients are administered independently, it is that the development of the pharmaceutical composition object of the present invention was carried out, which is composed of the synergistic combination of an antiarthritic agent, a chondroprotective agent and an anti-inflammatory agent, which produce a satisfactory therapeutic effect when administered together in a single oral dosage unit unlike when they are administered independently, generating benefits such as They are: lower concentrations of the active ingredients formulated, lower doses administered, faster action, greater efficacy of the therapeutic effect and lower adverse effects.

DETAILED DESCRIPTION OF THE INVENTION. Chondroitin is an antiarthritic with specific therapeutic activity. It is formed by chains of repeated molecules called glycosaminoglycans (GAG), mainly composed of the combination of various sulfated and non-sulfated residues of glucoronic acid and n-acetyl-galactosamine, necessary for the formation of proteoglycans (which provides elasticity to the cartilage), which are large macromolecules composed of a protein core to which multiple chains of glycosaminoglycans and oligosaccharides adhere that are found in the articular cartilage, which has a very important structural function, since it retains water and various nutrients useful for the formation of a healthy joint matrix, in addition to allowing the passage of other molecules through it, this property being very important, since the cartilage receives no blood supply. Its main function is played as an antiarthritic agent in patients suffering from rheumatic diseases. At the time of the 60's it was when the extraction and purification of Chondroitin was carried out for the first time, this being a substance that is naturally present in the body, as the main constituent of cartilage. Chondroitin is currently obtained and manufactured from natural sources such as: shark and / or beef cartilage, as well as bovine trachea cartilage, and can also be obtained through synthetic processes It is used to improve symptoms and prevent progressive damage during the degenerative process that manifests itself in patients suffering from osteoarthritis. For many years, research experts stated that Chondroitin administered orally did not cause the desired effect, since the molecules that compose it are too large that doubted that they could be absorbed through the digestive tract. However, in 1995 the researchers ruled out the aforementioned, taking as a basis that there was evidence that up to 15% of the chondroitin administered orally is absorbed by the digestive tract intactly. Chondroitin is widely used in Europe for the treatment of osteoarthritis, since in addition to treating the symptoms manifested by this disease, it protects the joints from damage caused by its progression. Glucosamine is characterized by having a specific therapeutic activity as a chondroprotector. It consists mainly of glucose, the type of sugar that the body transforms into energy and a called amino acid: glutamine, which is the precursor of the generation of glycosaminoglycans and constitutes up to 50% of the composition of hyaluronic acid, which is the natural lubricant found in synovial fluid, which has the function of being a lubricant and buffer, to restore and maintain healthy functioning of joints and / or joints. Glucosamine inhibits some cartilage-destroying enzymes, such as collagenases and phospholipase A2 and the formation of other substances that damage tissues, such as: macrophage superoxide radicals.

Glucosamine also fulfills several functions as a component of cartilage, among which are the following:

• It is an essential part of proteoglycans and is essential for the production of glycosaminoglycans, which are cartilage proteins that accumulate water. • It acts as a stimulant on chondrocytes that are cells that synthesize and secrete the organic components of the extracellular matrix, such as: collagen, hyaluronic acid, proteoglycans and glycoproteins Glucosamine is the factor that determines the amount of proteoglycans that chondrocytes can synthesize.

• Glucosamine sulfate provides significant amounts of sulfur, which is an essential nutrient of the joints. In fact, individuals suffering from arthritis generally have deficiencies of said nutrient.

• Glucosamine stimulates the self-repair mechanisms of articular cartilage.

The primary role of Glucosamine in the arrest or retardation of joint degeneration seems to be directly due to its ability to act as an essential substrate and stimulate the synthesis of glycosaminoglycans and the structure of hyaluronic acid necessary for the formation of proteoglycans found in the structural matrix of the joints.

Glucosamine is the fundamental block necessary for the biosynthesis of several types of compounds, among which are included: glycolipids, glycoproteins, glycosaminoglycans (which were previously called: mucopolysaccharides), hyaluronate and proteoglycans. As a component of these macromolecules, glucosamine plays an essential role in the synthesis of cell membranes, connective tissue, joint surfaces, tendons, ligaments, synovial fluid, skin, nails, blood vessels, heart valves and bone matrix.

Glucosamine is a very water-soluble small molecule, which is very easily absorbed by intestinal cells through active transport; and when administered orally as glucosamine sulfate, about 90% of its absorption is carried out rapidly in the gastrointestinal tract. Glucosamine is eliminated in the urine for 48 hours after oral administration in a proportion of about 5% of the administered dose. The main amount of Glucosamine administered orally is metabolized in joint tissues and is removed as CO2 in the expired air.

Glucosamine is rapidly incorporated into articular cartilage, this being the tissue in which the highest concentrations of this compound are found. Glucosamine treatment is considered to normalize substrate biosynthesis. required to restore joint functional capabilities. Glucosamine shows no effects on the cardiocirculatory system, on respiratory function and on the central or vegetative nervous system.

A successful treatment for osteoarthritis should effectively control the pain and slow or reverse the progression of the disease. Biochemical and pharmacological data together with studies in animals and humans show that Glucosamine can satisfy both criteria.

Although treatment with Glucosamine does not produce a blunt reduction in pain, which is associated with the use of nonsteroidal anti-inflammatory drugs, its ability to reduce pain is consistent and progressive, resulting in a long-term improvement of Disease and pain relief.

Meloxicam is a non-steroidal anti-inflammatory that performs anti-inflammatory, analgesic and antipyretic functions. It is an enolcarboxyamide derivative that belongs to the enolic acid group (related to oxicans: piroxicam, tenoxicam, sudoxicam). It performs a potent inhibitory activity on cyclooxygenase-2 (COX-2), with a selectivity 75 times higher for COX-2 compared with COX-I, acting as an inhibitor in the synthesis of prostaglandins that have the function of being responsible mediators of inflammatory processes. The selective and specific blockade performed on cyclooxygenase-2 gives Meloxicam a double therapeutic benefit by achieving, on the one hand, a remarkable anti-inflammatory and analgesic activity in patients suffering from rheumatic diseases

(osteoarthritis, rheumatoid arthritis, osteoarthritis, osteoarthritis), and on the other hand, it has excellent tolerance with minimal gastrointestinal or ulcerogenic adverse effects, unlike those patients who are treated with other non-steroidal anti-inflammatory agents, such as indomethacin, naproxen or acetylsalicylic acid.

The effective intracellular access of Meloxicam is determined by its lipophilic and amphiphilic properties. The low water solubility of Meloxicam at an acidic pH and its amphiphilic protonation behavior are responsible for tissue kinetics which prevents the concentrations of this active substance in certain tissues from rising.

Meloxicam has a good digestive absorption and optimal bioavailability (89%), after having been administered a single dose by mouth. Some of the main pharmacokinetic characteristics are: its prolonged absorption, its sustained serum concentrations and its long elimination half-life (20 hours), which allows a single daily dose to be administered. Once its absorption in the digestive tract, Meloxicam easily diffuses into the blood and inflamed tissues, having a high adherence with plasma proteins (> 99%) and its metabolites are excreted both in the urine and feces .

Meloxicam is indicated for the treatment of diseases such as: osteoarthritis, rheumatoid arthritis, gouty arthritis, muscular and traumatic conditions, as well as in inflammatory processes of soft tissues, airways and gynecological conditions.

The antiarthritic agent used in the pharmaceutical composition object of the present invention is the active ingredient Sulfate of Chondroitin, which is present in the formulation in a concentration range from 1.0 gr. up to 1.5 gr., preferably a concentration of approximately 1.1 gr. to 1.3 gr. per dose unit. The chondroprotective agent that is formulated in the pharmaceutical composition object of the present invention is the active ingredient Glucosamine, which is present in a concentration range from 1.2 gr. up to 1.7 gr., preferably a concentration of approximately 1.4 gr. to 1.6 gr. per dose unit.

The anti-inflammatory agent contained in the pharmaceutical composition object of the present invention is the active ingredient Meloxicam, being present in the formulation in a concentration range from 6.5 mg. up to 17 mg, with a concentration of approximately 7.0 mg being preferably used, at 16.0 mg. per dose unit.

The pharmaceutical composition protected by the present invention is formulated to be administered orally in a single powder dosage unit for solution with single dose sachets, in which the drug is contained. synergistic combination of the active substances: Chondroitin Sulfate, Glucosamine and Meloxicam, as well as pharmaceutically acceptable excipients.

Said pharmaceutical composition has been developed with the purpose of providing a pharmaceutical alternative for the treatment of diseases such as: osteoarthritis, rheumatoid arthritis, osteoarthritis and other related rheumatic diseases, which offers significant advantages such as: lower concentrations of active principles contained in the formulation, the effective control of pain suffered by patients suffering from such diseases, in addition to slowing or reversing their progression.

Claims

NOVELTY OF THE INVENTION Having described the present invention, it is considered as novelty and, therefore, the content of the following claims is claimed as property 1.- Pharmaceutical composition composed of the synergistic combination of an antiarthritic agent, a chondroprotective agent and an anti-inflammatory agent, characterized in that the antiarthritic agent is the active substance: Chondroitin Sulfate, - the chondroprotective agent is the active substance: Glucosamine and the agent Anti-inflammatory is the active substance: Meloxicam; as well as pharmaceutically acceptable excipients, formulated in a single dosage unit to be administered orally, indicated for the treatment of osteoarthritis, rheumatoid arthritis, osteoarthritis and other related rheumatic diseases. 2. - Pharmaceutical composition according to claim 1, characterized in that the antiarthritic agent, as is the active ingredient: Sulfate Chondroitin is present in the formulation in a concentration range of 1.1 gr. at 1.3 gr., a concentration of 1.2 gr being preferably used in the formulation. per dose unit. 3. - Pharmaceutical composition according to claims 1 and 2, characterized in that the chondroprotective agent, as is the active ingredient: Glucosamine is present in the formulation in a concentration range of 1.4 gr. at 1.6 gr., a concentration of 1.5 gr being preferably used in the formulation. per dose unit. 4. - Pharmaceutical composition according to claims 1 to 3, characterized in that the anti-inflammatory agent, as is the active ingredient: Meloxicam is present in the formulation in a concentration range of 7.0 mg, to 16.0 mg., Being preferably used in the formulation a concentration of 7.5 and 15 mg. per dose unit. 5. Pharmaceutical composition according to claims 1 to 4, characterized in that it is formulated in a single dosage unit for oral administration in powder form for solution with presentation in single dose sachets. 6. - The use of the pharmaceutical composition according to claims 1 to 5, characterized in that it is indicated for the treatment of diseases such as: osteoarthritis, rheumatoid arthritis, osteoarthritis and any other related rheumatic disease.