RU2547572C2 - Pharmaceutical composition for treating joint and bone tissue diseases - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: pharmaceutical composition for treating joint and bone tissue diseases contains a combination of active substances consisting of the glucosamine sulphate salt, chondroitin sulphate sodium salt, ibuprofen as a non-steroidal anti-inflammatory agent, additives from excipients and processing additives, wherein the additives optionally contain vitamins and a calcium-containing excipient. The group of inventions also concerns a method for preparing the above pharmaceutical composition.

EFFECT: enhancing the therapeutic effect of the pharmaceutical composition in relation to the common knowledge without increasing the number and severity of its side effects.

8 cl, 1 ex, 1 tbl

Description

The invention relates to medicine, in particular to the pharmaceutical industry, and describes an oral pharmaceutical composition for treating degenerative joint diseases and disorders of bone metabolism.

Osteoarthrosis and osteoporosis are the most common age-related diseases. With increasing age, the proportion of people who may have a combination of these diseases increases, which requires studying the features of the provision of therapeutic and diagnostic assistance to this category of patients.

Osteoarthritis is a disease or group of diseases that affects all components of the joint: articular cartilage, in which the physiological processes of degradation and synthesis of chondrocytes are disrupted, subchondral bone, capsule and synovial membrane, ligaments and periarticular muscles.

Osteoporosis is a common systemic multifactorial disease of the skeleton, with a decrease in bone mass and a violation of the microarchitectonics of bone tissue. Its natural outcome is an increase in bone fragility, and fractures are a frequent complication.

So, osteoarthrosis accounts for more than 75% of all rheumatic diseases, it is observed in more than 50% of people 65 years and older, and more than 1/3 of them develop a violation of various types of physical activity. The prevalence of osteoporosis in Russia among patients aged 50 years and older is 30-33% among women and men, but is more often recorded in women, especially after menopause. So, osteoarthrosis is detected in every tenth woman aged 50 years, and by 75 years - already every second. One in three menopausal women and more than half of those aged 75-80 years old suffer from osteoporosis. The social significance of osteoporosis is determined by its consequences - fractures of the vertebrae and bones of the peripheral skeleton.

The number of patients with osteoarthritis and osteoporosis increases with age, therefore, the increase in life expectancy observed in recent decades in developed countries and, accordingly, an increase in the proportion of elderly people, especially women, leads to an increase in the frequency of these diseases, turning them into one of the most important health problems and pharmaceutical industry.

The pharmaceutical composition for oral administration is described in the prior art and is described in EA Application No.2010000810. This composition contains a salt of chondroitin sulfate, a salt of glucosamine sulfate, ibuprofen as a non-steroidal anti-inflammatory agent and excipients, with the following components (w / w%):

chondroitin sulfate salt 20-30 glucosamine sulfate salt 30-36 ibuprofen 10-15 Excipients In sufficient quantity

Also known from the prior art is the drug Teraflex Advance (registration certificate No. LS-002678, registration date 12/29/2006), made in the form of capsules weighing 800 mg and containing the following composition (mg):

Active substances

glucosamine sulfate 250 chondroitin sodium sulfate 200 ibuprofen one hundred

Excipients

microcrystalline cellulose 30.78 corn starch 19.69 pregelatinized starch 17.47 stearic acid 11.59 sodium carboxymethyl starch 10 crospovidone 10 magnesium stearate 3 silicon dioxide 4.05 povidone 2,382

Glucosamine sulfate and chondroitin sulfate are known to improve the health of synovial joints without potentially life-threatening side effects. Also, non-steroidal anti-inflammatory drugs (NSAIDs), in particular ibuprofen, are usually used to relieve pain and inflammation.

Glucosamine is produced naturally in the body and is part of the synovial fluid. This substance is the main structural element of proteoglycan, one of the most important components of articular cartilage. Glucosamine is also necessary for the production of lubricants and protective agents for joints.

As research on glucosamine sulfate expanded, scientists found that this compound stimulates the growth of chondrocytes, inhibits the destruction of proteoglycans, and restores cartilage destroyed by osteoarthritis.

Chondroitin sulfate also provides cartilage endurance and flexibility and is an important component of proteoglycan in cartilage of synovial compounds. Due to the fact that chondroitin sulfate promotes the production of proteoglycans, researchers believe that its mechanism of action is similar to that of glucosamine sulfate.

In addition, the combination of glucosamine sulfate and chondroitin sulfate is considered more effective than using each of the drugs separately. An additional benefit is the modifying effect of the combination of both drugs on osteoarthritis, which limits the progression of joint damage (Huskisson E.C. Glucosamine and Chondroitin for Osteoarthritis. Journal of International Medical Research 2008. 36 (6): 1161-1179).

The well-known compositions of glucosamine sulfate and chondroitin sulfate, both in combination of two substances and in combination with ibuprofen, are among the most effective drugs in the treatment of osteoarthritis, however, recent studies of the relationship of osteoarthrosis with the risk of concomitant diseases determine new approaches to the medical treatment of rheumatic diseases and bone metabolism disorders.

Until recently, osteoporosis and osteoarthrosis were considered as mutually exclusive diseases. However, data from promising studies indicate that in patients with osteoarthritis, despite an increase in bone mineral density, the risk of invertebral fractures is not reduced compared with the control group of patients without osteoarthritis (Jones G., Nguyen T., Sambrook PN et al. Osteoarthritis, bone density, postural stability, and osteoporotic fractures: a population based study. J. Rheumatol. 1995; 22: 921-925). In addition, with osteoarthritis, local development of periarticular osteoporosis of the bones was found. It is believed that the tendency to osteoporotic fracture in joint inflammation, despite the absence of a pronounced decrease in bone mineral density, is associated with impaired quality of both bone tissue and muscle mass (Karvonen RL, Miller PR, Nelson DA et al. Periarticular osteoporosis in osteoarthritis of osteoarthritis of osteoarthritis of the knee. J. Rheumatol. 1998; 25: 2187-2194).

These data are extremely important, since they indicate the need for measures to prevent osteoporetic skeletal bone fractures not only in patients with osteoarthritis with reduced, but also “normal”, and even “increased” bone mineral density.

The situation is further complicated by the fact that osteoarthritis and osteoporosis can coexist and each of the diseases worsens the prognosis for a particular patient. The presence of osteoarthritis in a patient with osteoparosis can mask the true state of bone mineral density and interfere with proper diagnosis and, most important, underestimation of the risk of a possible fracture. The state of bone metabolism of the subchondral bone in the early stages of osteoarthritis is very similar to the processes that occur in patients with osteoporosis. There are already experimental studies and clinical studies on the effectiveness of the use of anti-osteoporotic drugs in the treatment of early stages of osteoarthritis (Relationships between biochemical markers of bone and cartilage degradation with radiological progression in patients with knee osteoarthritis receiving risedronate: the Knee Osteoarthritis Structural Arthritis randomized clinical trial / P. Garnero [et al.] // Osteoarthritis Cartilage. - 2008. - Vol.16. - P.660-666 .; Strontium ranelate effect in postmenopausal women with different clinical levels of osteoarthritis / P. Alexandersen [et al.] // Climacteric . - 2011. - Vol.14, N 2. - P.236-243). However, at present, these medical technologies are not yet available in practical public health.

The aim of the present invention is to provide a pharmaceutical composition for the treatment of osteoarthritis, the prevention of osteoporosis, the normalization of bone and cartilage tissue metabolism, as well as reducing the risk of developing low-traumatic fractures. The technical result of the invention is to enhance the therapeutic effect of the pharmaceutical composition relative to the prior art without increasing the number and severity of side effects from its use.

The authors of the present invention know that the normal metabolism of bone and cartilage tissue directly depends on the presence of vitamin D. An insufficient level of vitamin D can adversely affect calcium metabolism, osteoblast activity, and matrix ossification, bone density and articular cartilage (Parfitt AM , Gallagher JC, Heaney RP, et al. Vitamin D and bone health in the elderly. Am J Clin Nutr 1982; 36: 1014-1031., Corvol MT, Dumontier MF, Tsagris L, et al. Cartilage and vitamin D in vitro (author's transl). Ann Endocrinol (Paris) 1981; 42: 482-487). Vitamin D has a direct effect on articular cartilage by stimulating proteoglycan synthesis by mature articular chondrocytes (Gerstenfeld LC, Kelly CM, Von Deck M, Lian JB. Effect of 1,25-dihydroxyvitamin D3 on induction of chondrocyte maturation in culture: extracellular matrix gene expression and morphology. Endocrinology 1990; 126: 1599-1609). Especially effective are combinations of vitamin D3 and calcium. Thus, adequate doses of vitamin D in combination with calcium preparations can slow the progress of osteoarthrosis and prevent its occurrence.

In addition, it has been reliably known and proven by numerous studies that a high incidence of osteoarthritis is observed in populations with low levels of folic acid (vitamin B9) (Kowsari B, Finnie SK, Carter RL, et al. Assessment of the diet of patients with rheumatoid arthritis and osteoarthritis. J Am Diet Assoc 1983; 82: 657-659). Vitamin B9 and B12 deficiency is also observed in older people (Hanger NS, Sainsbury R, Gilchrist NL, et al. A community study of vitamin B12 and folate levels in the elderly. J Am Geriatr Soc 1991; 39: 1155-1159). According to clinical studies, the combined use of folic acid and cobalamin in the treatment of osteoarthritis (cobalamin or cyancobalamin 20 μg (0.02 mg) and folic acid 6400 μg (6.4 mg) daily) has an effect comparable to the use of NSAIDs (anti-inflammatory drugs). In contrast to the use of NSAIDs, no side effects are observed with vitamins (Flynn MA, Irvin W, Krause G. The effect of folate and cobalamin on osteoarthritic hands. J Am Coil Nutr 1994; 13: 351-356).

According to the present invention, a solid pharmaceutical composition for oral administration has been developed which has the following composition:

- a combination of active substances, consisting of glucosamine sulfate, chondroitin sodium sulfate, ibuprofen;

- a combination of excipients, consisting of a group of fillers (microcrystalline cellulose, corn starch, sodium carboxymethyl starch) and technological additives (magnesium stearate, silicon dioxide, povidone);

- a combination of excipients, consisting of a group of vitamins (cholecalciferol, folic acid, cyancobalamin) and a calcium-containing agent (calcium hydrogen phosphate dihydrate), also acting as a filler.

A similar combination of drugs from the prior art could not be identified.

The inventive composition is found experimentally, it is optimal and allows to obtain a technical result that is appropriate for the task: a pharmaceutical composition for the treatment of osteoarthritis, prevention of osteoporosis, normalization of bone and cartilage tissue metabolism with enhanced therapeutic effect without increasing the number and severity of side effects from its use.

The combination of active active ingredients, in particular ibuprofen in combination with a combination of vitamins B9 (folic acid) and B12 (cyancobalamin), causes a synergism of their anti-inflammatory and analgesic effect, and the content of cholecalciferol (vitamin D3) and calcium hydrogen phosphate dihydrate as structure-forming agents effect on the metabolism of bone and cartilage tissue, normalizes the synthesis of matrix proteoglycans in chondrocytes and modulates the activity of metalloproteinases receiving often in the destruction of cartilage. In addition, the use of calcium and vitamin D also leads to a decrease in the synthesis of parathyroid hormone, which indirectly prevents the excessive deposition of calcium in the articular cartilage.

Most preferred is the following content of components in wt.%:

Components Mass% Active active ingredients 79-96 Glucosamine Sulfate Salt 40-46 Chondroitin Sodium Sulfate 26-32 Ibuprofen 13-18 Excipients 21-4 A group of fillers and processing aids (microcrystalline cellulose, corn starch, sodium carboxymethyl starch, magnesium stearate, silicon dioxide, povidone) 12-1 Group of vitamins and calcium-containing agent (cholecalciferol, folic acid, cyancobalamin, calcium hydrogen phosphate dihydrate) 9-3 Total: one hundred%

Table 1 shows a specific formulation of the claimed composition.

Table 1 Components Recipe mg % Glucosamine Sulfate Salt 314.0 44.85 Chondroitin Sodium Sulfate 200,0 28.57 Ibuprofen 100.0 14.28 Microcrystalline cellulose 10.0 1.43 Corn starch 10.0 1.43 Sodium carboxymethyl starch 10.0 1.43 Calcium hydrogen phosphate dihydrate 34.58 4.94 Cholecalciferol 4.0 0.57 Folic acid 6.4 0.91 Cyanobalamin 0.02 0.0028 Magnesium stearate 3.0 0.43 Silicon dioxide 4.0 0.57 Povidone 4.0 0.57 Weight: 700,0 one hundred

The inventive pharmaceutical composition for the treatment of diseases of the joints and bone tissue can be made as follows:

suspended glucosamine sulfate salt, chondroitin salt sodium sulfate, ibuprofen, microcrystalline cellulose, croscarmellose sodium, calcium hydrogen phosphate dihydrate, folic acid, silicon dioxide, magnesium stearate are mixed in a drum type mixer. The resulting mixture is granulated in the fluidized bed of a granulator dryer with an aqueous solution of povidone, cholecalciferol and cyancobalamin, then dried to the required residual moisture and calibrated. The resulting mixture is metered in a disk manner and enclosed in hard gelatin capsules.

So, the total content of active substances in the capsule is from 79% to 96% by weight. Microcrystalline cellulose, corn starch, which were most often used in the production of solid dosage forms, were selected as fillers, and, in order to achieve the technical result of the invention, calcium hydrogen phosphate dihydrate was used as filler. The introduction of colloidal dioxide and magnesium stearate into the composition of silicon, as antifriction substances, was undertaken with the aim of increasing the fluidity of the mixture and reducing friction between the product and the contacting surfaces of the equipment, thereby contributing to increased productivity and reduced wear of the latter. To improve the bioavailability of the active substances, a disintegrant, sodium carboxymethyl starch, was introduced. For a uniform distribution of substances over the entire volume of the mixture, the components were mixed and sieved in dry form. Then, in order to improve the flowability of the mixture and its dosage during encapsulation, to achieve the necessary antifriction properties, as well as to evenly distribute the substances in liquid form, the optimal method for the industrial production of the mixture was chosen for this preparation - wet granulation with an aqueous solution of povidone, cholecalciferol and cyanobalamin in dryers - granulators, followed by calibration and drying.

In production, standard hard gelatin capsules were usually used. The average weight of the contents of the capsule depends on the size of the capsule and the geometric parameters of the dosage disk.

Claims (8)

1. A pharmaceutical composition for the treatment of diseases of joints and bone tissues, containing a combination of active substances consisting of glucosamine sulfate salt, sodium chondroitin sulfate, ibuprofen as a non-steroidal anti-inflammatory agent, excipients from among excipients and processing aids, characterized in that it is additionally the composition of excipients includes vitamins and a calcium-containing filler agent, and the components are contained in the following ratio (wt./wt.%)
Glucosamine Sulfate Salt 40-46 Chondroitin Sodium Sulfate 26-32 Ibuprofen 13-18 Excipients: 21-4
fillers and technological
additives 12-1
vitamins and calcium
bulking agent 9-3 2. The pharmaceutical composition according to claim 1, where the total amount of active substances is from 79 to 96% of the total mass 3. The pharmaceutical composition according to claim 1, wherein said excipients from the group of fillers and processing aids contain microcrystalline cellulose, corn starch, sodium carboxymethyl starch, magnesium stearate, silicon dioxide, povidone. 4. The pharmaceutical composition according to claim 1, wherein one of the substances from the group of vitamins and a calcium-containing excipient is cholecalciferol. 5. The pharmaceutical composition according to claim 1, wherein one of the substances from the group of vitamins and a calcium-containing excipient is folic acid. 6. The pharmaceutical composition according to claim 1, wherein one of the substances from the group of vitamins and a calcium-containing excipient is cyancobalamin. 7. The pharmaceutical composition according to claim 1, wherein one of the substances from the group of vitamins and a calcium-containing excipient is a calcium-containing agent and is calcium hydrogen phosphate dihydrate. 8. The method of obtaining the pharmaceutical composition according to claim 1, wherein the suspended salt of glucosamine sulfate, chondroitin salt of sodium sulfate, ibuprofen, microcrystalline cellulose, croscarmellose sodium, calcium hydrogen phosphate dihydrate, folic acid, silicon dioxide, magnesium stearate are mixed in a drum type mixer, then the resulting mixture is granulated in a fluidized bed dryer-granulator with an aqueous solution of povidone, cholecalciferol and cyancobalamin, then dried to the required residual moisture and calibrated, and obtained with the mixture is metered in a disk manner and enclosed in hard gelatin capsules.