Composition for the prophylaxis and treatment of calcium deficiency and osteoporosis

Abstract

The invention relates to the pharmaceutical industry and can be used for creating a medicinal preparation or dietary supplement for the prophylaxis and treatment of calcium deficiency and osteoporosis. The essence of the invention consists in a composition for the prophylaxis and treatment of calcium deficiency and osteoporosis which contains tribasic calcium phosphate, magnesium hydroxide, cholecalciferol, pyridoxine hydrochloride, resveratrol, astragaloside IV, sodium selenate, zinc oxide and sodium borate. The technical result of the invention lies in more effective prophylaxis and treatment of calcium deficiency and osteoporosis, together with increased calcium absorption into bone tissue, as well as in a tailored medical effect which consists in preventing loss of bone mass in postmenopausal women with no obvious symptoms of osteoporosis.

Description

[0001] Composition for the prevention and treatment of calcium deficiency and osteoporosis

[0002] The invention relates to the pharmaceutical industry and can be used to create a medicinal product or a biologically active supplement for the prevention and treatment of calcium deficiency and osteoporosis, including with a personalized medical effect of preventing bone loss in postmenopausal women without obvious osteoporosis and a positive medical effect in restoring the musculoskeletal system in both bone injuries and joint injuries.

[0003] Osteoporosis is a disease in which bones lose strength, become more brittle, and can easily break. Bone loss occurs gradually and is often diagnosed only after a complication has already occurred, such as a spinal or hip fracture.

[0004] Osteoporosis is classified as primary (including type I and type II) and secondary. Primary osteoporosis occurs in postmenopausal women, as well as in men and women over 70 due to aging. Secondary osteoporosis develops as a result of serious underlying medical conditions or medication use. Conditions that cause secondary osteoporosis include systemic diseases, endocrine disorders, and malignancies. Other causes of osteoporosis include chronic glucocorticoid use, unhealthy lifestyles, unhealthy habits, and severe depression.

[0005] The accepted standards of treatment for osteoporosis are the following, divided into categories:

[0006] — agents that suppress bone resorption (antiresorptive therapy), which include: bisphosphonates, denosumab, estrogen therapy, SERM (drugs of group No. 1);

[0007] — dual mechanism agents, which include strontium renelate (drugs of group No. 2);

[0008] — drugs that increase bone formation (anabolic therapy), which include teriparatide (drugs of group No. 3).

[0009] The accepted standards for the prevention of calcium deficiency, primary prevention of osteoporosis and additional therapy with drugs of groups No. 1, No. 2 and No. 3 are calcium-containing drugs and biologically active supplements that are used as an addition to therapy with drugs of groups No. 1, No. 2, No. 3, and are also used for the prevention and treatment of calcium deficiency and as a primary link in preventing the development of osteoporosis, and contain calcium and vitamin D3 (drugs of group No. 4).

[0010] Drugs in groups 1, 2 and 3 share several problems: the occurrence of side effects, expensive and lengthy therapy, failure to achieve the expected positive effect, the possibility of use only in the stage of active osteoporosis, the inability to use as a preventative measure for calcium deficiency and to prevent osteoporosis before it occurs.

[0011] The occurrence of side effects during therapy sometimes leads to the patient's inability to continue therapy.

[0012] One of the most popular bisphosphonates, “FOSAMAX,” is known from the prior art [https: / / dailymed.nlm.nih.gov / dailymed / druglnfo.cfm?setid=14e931fd-2c5f-4d90-b7db-5980706f4a56&audience=professional].

[0013] Side effects of this drug include stomach upset, esophagitis, osteonecrosis of the jaw, bone, joint, and muscle pain, and atrial fibrillation. In some cases, an unusual femur fracture has been reported.

[0014] Denosumab "Prolia" is well known [Medical review by Philip Thornton, Deeppharm. Denosumab drug instructions, Amgen USA. https: / / www.drugs.com / sfx / denosumab-side-effects.html].

[0015] Side effects of this medication include: back pain, blistering, crusting, irritation, itching, rash (including crusty, flaky, or oozing rash) or redness of the skin, bloody or cloudy urine, cracked, dry, or flaking skin, difficulty, burning, or painful urination, frequent urge to urinate, muscle or bone pain, pain in the arms or legs, swelling.

[0016] The estrogen therapy drugs "Raloxifene" and "Tamoxifen" are known [Instructions for the drugs "Raloxifene" and "Tamoxifen", https: / / www.rlsnet.ru / active-substance / raloksifen-2272, https: / / www.rlsnet.ru / active-substance / tamoksifen-293].

[0017] Side effects from the use of these drugs are: deep vein thrombosis, thromboembolism, pulmonary embolism and retinal vein thrombosis, vasodilation in the first 6 months of treatment, hot flashes, painful spasms of the calves

[0018] SUBSTITUTE SHEET (RULE 26) muscles, peripheral edema, hypercalcemia, hyperlipidemia, cataracts or visual impairment.

[0019] The drug teriparatide “Forsteo” is known [Instructions for the drug Forsteo, https: / / www.rlsnet.ru / drugs / forsteo-25529].

[0020] Side effects from using this drug include: pain in the limbs, nausea, headache and dizziness, anemia, hypercholesterolemia, depression, vertigo, palpitations, decreased blood pressure, shortness of breath, hiatal hernia, and increased sweating.

[0021] The drug “Strometta” (“Strontium ranelate”) is known [Instructions for the drug “Strontium ranelat”: https: / / www.rlsnet.ru / active-substance / stronciya-ranelat-2714].

[0022] Side effects of this drug include headache, nausea, diarrhea, loose stools, dermatitis, eczema, allergic reactions, musculoskeletal pain, muscle spasm, myalgia, ossalgia, arthralgia and pain in the extremities.

[0023] Thus, therapy with drugs from groups No. 1, No. 2 and No. 3, used in the advanced stage of osteoporosis, is associated with the risk of serious side effects, due to which in some cases patients are forced to abandon therapy.

[0024] Calcium-containing medicinal products and biologically active supplements of group No. 4 are used to treat calcium deficiency and as a supplement to therapy with drugs of group No. 1, No. 2, No. 3 listed above, and as a primary link in preventing the development of calcium deficiency and osteoporosis.

[0025] These drugs similarly cause side effects and are also associated with insufficient effectiveness in the absorption of calcium into bone tissue.

[0026] The most popular calcium salts in combination with vitamin D3 and other macro- and micronutrients used in Group 4 medications and dietary supplements are calcium carbonate, calcium citrate, and calcium chelate. Other common calcium salts include calcium gluconate, calcium hydroxyapatite, calcium hydrogen phosphates, calcium orthophosphate, calcium lactogluconate, and calcium malate.

[0027] A well-known calcium-containing drug is Calcium D3 Classic. Pharmacological group: bone and cartilage metabolism correctors in combination. Dosage form: chewable tablets (apple flavor), chewable tablets (orange flavor). Composition: 1 chewable tablet (apple flavor) contains: active ingredient: Calcium carbonate - 1250 mg, in terms of calcium - 500 mg; Vitamin D3 dry 100 GFP substance-granules 100,000 IU / g - 2.2 mg in terms of cholecalciferol - 5 mcg (200 IU) [composition of the substance-

[0028] SUBSTITUTE SHEET (RULE 26) of granules: active substance: cholecalciferol; excipients: B,L-alpha-tocopherol, medium-chain triglycerides, sucrose, acacia gum, corn starch, calcium phosphate, water; excipients: mannitol, lactitol, dextrates, sodium saccharinate (sodium saccharin), magnesium stearate, apple flavoring (maltodextrin, dextrin, glyceride triacetate, 1,2-propylene glycol, flavoring agents).1 chewable tablet (orange flavor) contains: active ingredient: Calcium carbonate - 1250 mg, in terms of calcium - 500 mg; Vitamin D3 dry 100 GFP, granule substance 100,000 IU / g - 4.4 mg in terms of cholecalciferol - 10 mcg (400 IU) [composition of the granule substance: active ingredient: cholecalciferol; excipients: B, E-alpha-tocopherol, medium-chain triglycerides, sucrose, acacia gum, corn starch, calcium phosphate, water]; Excipients: mannitol, lactitol, dextrates, sodium saccharinate (sodium saccharin), magnesium stearate, orange flavor (maltodextrin, gum arabic, butylhydroxyanisole, flavoring agents). Pharmacokinetics: vitamin D3 is absorbed in the small intestine. Calcium is absorbed in ionized form in the proximal small intestine via an active D3-vitamin-dependent transport mechanism [Registration Certificate: RU No. LSR-005425 / 10].

[0029] The disadvantages of this medication include inadequate calcium absorption in bone tissue, the occurrence of side effects, and a limited vitamin and mineral composition, with only calcium carbonate and vitamin D3 as the active ingredients. Magnesium is known to play a key role in regulating calcium absorption. Magnesium prevents calcification in soft tissues and regulates vascular and muscle tone. A lack of magnesium disrupts a crucial aspect of bone mineral metabolism—the Mg:Ca ratio. An imbalanced Mg:Ca ratio slows bone metabolism, reduces calcium absorption, and improperly stimulates the hormone calcitonin, leading to inadequate bone structure maintenance and inadequate regulation of blood calcium.The ionized form of calcium carbonate dissolves quickly in the acidic environment of the stomach, and the bulk of the calcium ion is absorbed by the stomach walls and excreted into depots in the vascular walls, where it is excreted into the kidneys, joints, tendons, and intervertebral discs, becoming less readily available for normal bone metabolism. A small portion of the remaining ionized calcium binds with food components (glucose, fatty acids, phosphorus, and oxalates) in the gastrointestinal tract, forming complexes that are also precipitated and excreted from the body, with virtually no absorption into bone tissue. The stated digestibility of calcium carbonate (18-20%) refers to absorption in the stomach and does not correlate with the calcium's role in bone metabolism. In other words, when calcium is absorbed in the stomach, calcium absorption in bone tissue is minimal.Rapid dissolution of ionized calcium also results in irritation of the gastrointestinal mucosa, manifesting as bloating, gastritis, and esophagitis. Another side effect is calcium deposition in organs and tissues, causing vascular calcification and kidney stone formation. Calcium leaching into the joints complicates musculoskeletal recovery in arthritis and arthrosis. Low calcium absorption in bone tissue, along with the resulting side effects, makes calcium deficiency treatment and osteoporosis prevention and treatment insufficient and fails to prevent further calcium loss. Low calcium absorption necessitates the use of 2 to 4 tablets daily, resulting in significant costs for a monthly course of treatment.

[0030] A well-known dietary supplement is "Calcium-Magnesium-Citrate Complex." Available in 669 mg capsules. Ingredients: calcium citrate (in a capsule - 84 mg, in a daily dose of 3 capsules - 252 mg), magnesium citrate (in a capsule - 21 mg, in a daily dose - 63 mg), zinc D-gluconate (in a capsule - 3.5 mg, in a daily dose - 10.5 mg), manganese-P-gluconate (in a capsule - 0.9 mg, in a daily dose - 2.7 mg), copper citrate (in a capsule - 0.3 mg, in a daily dose - 1 mg), vitamin B3 / cholecalciferol (in a capsule - 1 mcg, in a daily dose - 3 mcg), vitamin K1 / phylloquinone (in a capsule - 10 mcg, in a daily dose - 30 mcg), hydroxypropyl methylcellulose (capsule shell). Indications: As a dietary supplement to maintain adequate levels of micronutrients related to the skeletal system. As an additional source of vitamins D and K, calcium, magnesium, zinc, copper, and manganese. Directions: Adults: 3 capsules daily.Duration of treatment: 1 month. The course can be repeated if necessary. Contraindications: individual intolerance to any of the product's components, pregnancy, and breastfeeding. [State Registration Certificate: AM.01.07.01.003.R.000107.05.20 dated May 26, 2020].

[0031] The advantage of this well-known dietary supplement is its enhanced magnesium, zinc, manganese, copper, and vitamin K1 content. However, this supplementation with these components does not address the issue of inadequate calcium absorption, side effects, and the potential for calcium "leaching" from the body, which is a drawback of this dietary supplement. The stated digestibility of calcium citrate (44%, 2.5 times higher than that of calcium carbonate) is similar to that of calcium carbonate, but relates to absorption in the stomach and is not correlated with calcium's role in bone metabolism. This is because the ionized form of calcium citrate, like ionized carbonate, dissolves rapidly in the acidic environment of the stomach. Furthermore, the rapid dissolution of ionized calcium citrate, like that of calcium carbonate, results in gastrointestinal side effects and the formation of secondary deposits.Low absorption of calcium necessitates taking 3 capsules per day, which results in significant costs for a monthly course of treatment.

[0032] A biologically active supplement for the prevention of osteoporosis was selected as a prototype, including calcium and magnesium salts, vitamin D3, as well as boron and zinc salts. Calcium phosphate - from 400 to 4000 mg; Vitamin D3 - from 300 to 1000 IU; Magnesium phosphate - from 100 to 800 mg; Soluble boron salt in terms of B +3 - from 0.003 to 0.005 mg; Soluble zinc salt in terms of Zn +2 - from 2 to 20 mg; Soluble selenium salt in terms of Se +6 - from 0.0005 to 0.003 mg; Vitamin B6 - from 0.001 to 0.005 mg [RU2527042, publication date: 08 / 27 / 2014].

[0033] The advantage of the prototype over the known drug is the increased absorption of calcium in bone tissue while eliminating the negative impact of the supplement on the walls of the stomach and gastrointestinal tract.

[0034] However, a drawback of the prototype drug is its focus solely on bone fracture recovery and lack of systemic effects on musculoskeletal injuries. This means it has no positive effect on joint pathologies and injuries (arthrosis, arthritis, rheumatoid arthritis). This drawback is significant, as osteoporosis is increasingly associated with joint pathologies and complicates recovery from joint injuries. Another significant drawback of the prototype is its narrowly targeted action and lack of a personalized effect. Therefore, the supplement cannot prevent bone loss in complex cases, such as in postmenopausal women who do not have obvious osteoporosis. Common sites for such fractures in this group of women are the lumbar spine and femoral neck.

[0035] The technical problem addressed by the invention is the creation of a composition for the prevention and treatment of calcium deficiency and osteoporosis that overcomes the existing shortcomings of known technical solutions. The technical result achieved by the invention is to increase the effectiveness of the prevention and treatment of calcium deficiency and osteoporosis without side effects and a concomitant increase in calcium absorption in bone tissue, eliminating the risk of excess calcium accumulation in the body. The composition also provides a personalized medical effect, preventing bone loss in the lumbar spine and femoral neck in postmenopausal women without overt osteoporosis.

[0036] An additional technical result, which the invention is aimed at achieving, is to reduce the risk of developing inflammatory joint conditions, such as arthritis and arthrosis, as well as to protect against complications of rheumatoid arthritis, such as periodontitis (inflammation of the gums), when using the composition.

[0037] The essence of the invention is as follows.

[0038] A composition for the prevention and treatment of calcium deficiency and osteoporosis, containing tribasic calcium phosphate, magnesium hydroxide, cholecalciferol, pyridoxine hydrochloride, resveratrol, astragaloside IV, sodium selenate, zinc oxide and sodium tetraborate, wherein said components are in the following ratio, wt.%: tribasic calcium phosphate 70.0 - 90.0 magnesium hydroxide 5.0 - 20.0 cholecalciferol 0.006 - 0.04 pyridoxine hydrochloride 0.02 - 0.4 resveratrol 0.2 - 24.0 astragaloside IV 0.1 - 24.0 sodium selenate 0.0001 - 0.001 zinc oxide 0.135 - 1.5 sodium tetraborate 0.0003 - 0.002

[0039] Tribasic calcium phosphate is a key component of calcium metabolism in the body and serves as a building block for bone structure. The concentration of tribasic calcium phosphate in the composition ranges from 70.0 to 90.0% by weight. If the concentration of tribasic calcium phosphate exceeds the upper limit of the stated range, this may lead to calcium overaccumulation in the body and associated side effects. If the concentration of tribasic calcium phosphate is below the lower limit of the stated range, its amount will be insufficient to significantly improve bone mineral density. A preferred concentration of this component may be selected from the range of 76.0 to 85.0% by weight, while its more specific content may be limited to 81.6% by weight.

[0040] Magnesium hydroxide is present in the composition as a calcium absorption regulator, preventing calcium overdose and soft tissue calcification, and regulating vascular and muscle tone. The concentration of magnesium hydroxide in the composition ranges from 5 to 20% by weight. If the concentration of magnesium hydroxide exceeds the upper limit of the stated range, the risk of hypermagnesemia and associated side effects increases. If the concentration of magnesium hydroxide falls below the lower limit of the stated range, the risk of disrupting a key aspect of bone mineral metabolism—the Mg:Ca ratio—increases.When the Mg:Ca ratio decreases toward insufficient magnesium concentration, metabolic processes in the bone slow down, calcium absorption is reduced, and calcitonin is not properly stimulated, leading to inadequate bone structure maintenance and inadequate blood calcium regulation. Furthermore, an imbalance in the Mg:Ca ratio is associated with an increased risk of developing certain forms of arthritis, as toxic metals (primarily cadmium and lead) are deposited more quickly. Due to the accumulation of toxic elements in the joint due to an imbalance in the Mg:Ca ratio, joint function gradually deteriorates: range of motion decreases, joint deformation in the extremities and spine occurs—all of which significantly reduces the effectiveness of musculoskeletal rehabilitation in cases of joint injuries and pathologies. A concentration of this component selected from a range of 7.0 to 16.0 mass% may be preferable.%, and a more specific content of this component may be limited to 10.8 wt.%.

[0041] Cholecalciferol, also known as vitamin D3, improves calcium absorption by bones. Specifically, it participates in the formation of osteocalcin, a protein that facilitates the integration of calcium into bone structure. The concentration of cholecalciferol in the composition ranges from 0.006 to 0.04 wt.%. If the concentration of cholecalciferol is higher than the upper limit of the stated range, the risk of hypervitaminosis D and associated side effects increases. If the concentration of cholecalciferol is lower than the lower limit of the stated range, calcium absorption by bones will be significantly reduced. A concentration of this component selected from the range of 0.006 to 0.017 wt.% may be preferred, while a more specific content of this component may be limited to 0.0089 wt.%.

[0042] Pyridoxine hydrochloride, also known as vitamin B6, increases magnesium bioavailability in the body and, in combination with the other components of the composition, mediates regenerative processes in bone tissue. The concentration of pyridoxine hydrochloride in the composition ranges from 0.02 to 0.4% by weight. If the concentration of pyridoxine hydrochloride exceeds the upper limit of the stated range, the risk of hypervitaminosis B6 and associated side effects increases.If the pyridoxine hydrochloride concentration falls below the lower limit of the stated range, its effectiveness in increasing magnesium bioavailability is reduced, as well as its effectiveness in promoting bone regeneration. Pyridoxine hydrochloride regulates collagen cross-linking, both directly and through homocysteine-related pathways. This will lead to insufficient bone strength. A preferred concentration of this component may range from 0.09 to 0.366% by weight, while a more specific content of this component may be limited to 0.15%.

[0043] Resveratrol increases the effectiveness of the prevention and treatment of calcium deficiency and osteoporosis without side effects and increases calcium absorption in bone tissue, without the risk of excess calcium accumulation in the body. It also provides a personalized medical effect, preventing bone loss in the lumbar spine and femoral neck in postmenopausal women without overt osteoporosis. Furthermore, resveratrol reduces the risk of joint inflammation, such as arthritis and arthrosis, and protects against complications of rheumatoid arthritis, such as periodontitis (gum inflammation). The concentration of resveratrol in the composition ranges from 0.2 to 24.0% by weight.Resveratrol concentrations above the upper limit of the stated range increase the risk of gastrointestinal upset (nausea, diarrhea). Resveratrol concentrations below the lower limit of the stated range significantly reduce its effectiveness in counteracting molecular changes associated with osteoporosis, alleviating inflammation and joint damage associated with arthritis and arthrosis, and preventing complications such as periodontitis (gum disease). Therefore, resveratrol concentrations below the lower limit of the stated range significantly minimize its beneficial effects on bone and joint health. A preferred concentration of this component may range from 2.2 to 6.0% by weight, while a more specific content of this component may be limited to 4% by weight.

[0044] Astragaloside IV also enhances the prevention and treatment of calcium deficiency and osteoporosis without side effects and increases calcium absorption in bone tissue, without the risk of excess calcium accumulation in the body. It also provides a personalized medical effect by preventing bone loss in the lumbar spine and femoral neck in postmenopausal women without overt osteoporosis. The concentration of astragaloside IV in the composition ranges from 0.1 to 24% by weight. If the concentration of astragaloside IV exceeds the upper limit of the stated range, the risk of side effects such as fatigue (a feeling of greater weakness than usual) and headache increases.If the concentration of astragaloside IV is below the lower limit of the stated range, the positive therapeutic effect on osteoclast-related pathologies, including osteoporosis, periodontal disease, rheumatoid arthritis, and aseptic loosening of dentures, is significantly reduced. Therefore, if the concentration of astragaloside IV is below the lower limit of the stated range, the beneficial effect of astragaloside IV on bone tissue and joints is significantly minimized. A preferred concentration of this component may be selected from the range of 2.14 to 4.4% by weight, while a more specific content of this component may be limited to 3.3% by weight.

[0045] Sodium selenate, in combination with the other components of the composition, ensures the synthesis of amino acids that influence the activity of bone resorption processes. The concentration of sodium selenate in the composition ranges from 0.0001 to 0.001 wt.%. If the concentration of sodium selenate is higher than the upper limit of the stated range, the risk of selenium toxicosis and associated side effects increases. If the concentration of sodium selenate is lower than the lower limit of the stated range, the effectiveness of sodium selenate in preventing bone resorption is significantly reduced due to the inactivation of osteoclasts, which leads to reduced protection against the development of osteoporosis, osteoarthritis, and rheumatoid arthritis. A concentration of this component selected from the range of 0.0001 to 0.0009 wt.% may be preferred, while a more specific content of this component may be limited to 0.0007 wt.%.

[0046] Zinc oxide is present in the composition to participate in the metabolism of sex hormones, which has a positive effect on bone tissue regeneration. The concentration of zinc oxide in the composition is in the range of 0.135 - 1.5 wt.%. If the concentration of zinc oxide is higher than the upper limit of the stated range, the risk of excess zinc and associated side effects increases. If the concentration of zinc oxide is lower than the lower limit of the stated range, then a zinc oxide deficiency significantly reduces the process of normal bone tissue development and homeostasis, complicates the process of collagen matrix synthesis, mineralization and bone tissue turnover, reduces osteoblast differentiation and reduces the stimulation of osteoclast apoptosis, which affects bone resorption. A concentration of this component selected from the range of 0.135 to 0.839 wt.%, and a more specific content of this component may be limited to 0.139 wt.%.

[0047] Sodium tetraborate reduces the rate of renal excretion of macro- and micronutrients and suppresses excessive parathyroid hormone activity, which collectively improves calcium absorption. The sodium tetraborate concentration in the composition ranges from 0.0003 to 0.002% by weight. If the sodium tetraborate concentration exceeds the upper limit of the stated range, the risk of excess boron in the body and associated side effects increases. If the sodium tetraborate concentration is below the lower limit of the stated range, boron deficiency will lead to loss of macro- and micronutrients through the kidneys, leading to inadequate calcium absorption by bone tissue. Boron deficiency also increases the risk of spinal and joint disorders (arthrosis, arthritis), significantly reducing the effectiveness of musculoskeletal recovery following injuries and joint pathologies.The preferred concentration of this component may be selected from a range of 0.0009 to 0.0017 wt.%, and a more specific content of this component may be limited to 0.0014 wt.%. In their initial form, all of the above components of the composition are in a powder state, and therefore the developed composition can be obtained by mixing these components together in the presented proportions.

[0048] After the composition has been prepared, in order to improve its organoleptic properties, an additive of citric acid or another flavoring component may be added to its composition in an amount of 0.2 to 3.0 wt.% of the total mass of the resulting composition.

[0049] Also, after the preparation of the composition, in order to improve its flowability, an additive of silicon dioxide or another anti-caking agent can be added to its composition in an amount of 0.2 to 2.0 wt.% of the total weight of the resulting composition.

[0050] The invention can be made from known materials using known means, which indicates its compliance with the patentability criterion of “industrial applicability”.

[0051] The invention is characterized by a previously unknown set of essential features, distinguished by the fact that the composition for the prevention and treatment of calcium deficiency and osteoporosis includes components such as resveratrol and astragaloside IV in the specified concentrations. These components have the following effects on the human body:

[0052] — Resveratrol in combination with tribasic calcium phosphate at the specified concentration ensures the achievement of a personalized medical effect, consisting in the prevention of bone loss in the lumbar spine and femoral neck in postmenopausal women without obvious osteoporosis, due to the estrogen-like effect on the body and the increase in the expression of osteoprotegerin genes - a protective protein that blocks RANKL (receptor activator of the nuclear transcription factor NF-kB) to counteract the differentiation of osteoclasts at the precursor stage and mature forms.

[0053] By exerting an estrogen-like effect, resveratrol regulates vitamin D receptors in osteoblast-like cells and influences bone formation. The combination of vitamin D and resveratrol increases the latter's intracellular concentration, activation of estrogen receptors beta, and vitamin D receptor expression, leading to increased bioavailability of resveratrol and vitamin D, enhancing their ability to rapidly penetrate the cell membrane and reach target tissues. Resveratrol also counteracts molecular changes associated with osteoporosis, exerting anti-inflammatory, antioxidant, and gene-modifying effects by reducing serum GSH levels and the expression of FOXO1, SIRT1, and OPG genes. These effects of resveratrol effectively alleviate inflammation and joint damage in people with arthrosis and arthritis and prevent the development of rheumatoid arthritis complications such as periodontitis (gum disease).

[0054] Astragaloside IV, in combination with tribasic calcium phosphate and other components of the composition at the specified concentration, enhances osteoblast activity, producing a positive therapeutic effect on osteoclast-related pathologies, including osteoporosis, periodontal disease, rheumatoid arthritis, and aseptic loosening of dentures. Specifically, astragaloside IV exerts a potent inhibitory effect on the receptor activator of osteoclastogenesis induced by nuclear factor-κB and inhibits osteoclastogenesis by suppressing the extracellular signal regulating the kinase signaling pathway. Astragaloside IV may also reduce osteolysis.

[0055] The combination of essential features of the invention solves the problem of imbalance in activity between osteoclasts and osteoblasts by inhibiting RANKL and activating KLF2, which regulates the differentiation of monocytes into osteoclasts, exerting a positive effect on bone metabolism processes.

[0056] This ensures the achievement of a technical result consisting of increasing the effectiveness of the prevention and treatment of calcium deficiency and osteoporosis in the absence of side effects and a concomitant increase in the absorption of calcium in bone tissue, without the risk of excessive accumulation of calcium in the body, as well as obtaining, when using the composition, a personalized medical effect consisting in the prevention of bone loss in the lumbar spine and femoral neck in postmenopausal women without obvious osteoporosis.

[0057] The invention has a set of essential features previously unknown in the state of the art, which indicates its compliance with the patentability criterion of “novelty”.

[0058] A prior art composition for the prevention and treatment of calcium deficiency and osteoporosis is known, providing increased calcium absorption in bone tissue (a prior art composition). However, the prior art does not disclose a composition for the prevention and treatment of calcium deficiency and osteoporosis that specifically enhances calcium absorption in bone tissue—that is, calcium absorption throughout the entire bone volume, not just on its surface, but also on the surfaces of other organs, as occurs with adsorption. This ensures a more effective increase in bone mineral density and, therefore, more effective prevention and treatment of calcium deficiency and osteoporosis.

[0059] In view of this, the invention meets the patentability criteria.

[0060] "inventive level".

[0061] The invention is illustrated by the following figures.

[0062] Fig. 1 - Table with percentage ratios of components of each of the samples of the composition in accordance with the present invention.

[0063] Fig. 2 - Graph of changes in the concentration of calcium in the blood after 0.5, 1 and 10 hours after taking a suspension prepared using a sample of the composition in accordance with the present invention (the trend line is marked with position 1), and after taking the calcium-containing medicinal product “Calcium D3 Classic” (the trend line is marked with position 2).

[0064] Fig. 3 - Graph of changes in the concentration of calcium in the blood on the first, second and third days of taking a suspension prepared using a sample of the composition in accordance with the present invention (the trend line is marked with position 1) and taking the calcium-containing medicinal product “Calcium D3 Classic” (the trend line is marked with position 2).

[0065] To illustrate the possibility of implementation and a more complete understanding of the essence of the invention, an embodiment of it is presented below, which can be changed or supplemented in any way, while the present invention is in no way limited to the presented embodiment.

[0066] To prepare a composition for the prevention and treatment of calcium deficiency and osteoporosis, powdered cholecalciferol, pyridoxine hydrochloride, resveratrol, astragaloside IV, sodium selenate, zinc oxide, and sodium tetraborate were placed in a mixer and mixed. Thirty to 35% of the resulting mixture was then added to powdered magnesium hydroxide and mixed in the mixer. The remainder of the mixture was then added and mixed. Tribasic calcium phosphate powder was then added, 30 to 35% of its mass was mixed in the mixer, and the remainder of the tribasic calcium phosphate was added and mixed. The resulting mixture was passed through a 0.2 mm sieve with magnetic separation, yielding a composition for the prevention and treatment of calcium deficiency and osteoporosis.

[0067] A total of 8 samples of the composition, each with varying compositions, were prepared within the scope of the invention. The percentage ratios of the components in each of samples 1-8 of the composition according to the invention are presented in the table shown in Fig. 1.

[0068] The obtained samples 1-8 of the composition were tested for their effectiveness in the treatment and prevention of calcium deficiency and osteoporosis.

[0069] Two focus groups participated in the testing.

[0070] Focus Group 1 included 20 active athletes aged 40 to 55 years who had the following injuries:

[0071] — fresh fractures (arms, legs, shoulders, spinal vertebrae, craniofacial) with and without complications (10 people);

[0072] - old fractures in a chronic state (10 people).

[0073] Before the testing, all participants in Focus Group #1 underwent bone density testing using a DEXA osteodensitometer to assess bone mineral density. Before the testing, 19 of the 20 participants had osteopenia (-2.5 > T-score > -1), and 1 of the 20 had normal bone density (-1 > T-score > 1). Also before the testing, all participants in Focus Group #1 had their total blood calcium levels assessed. Half of the participants had normal blood calcium levels, and the other half had hypocalcemia.

[0074] Focus Group 1's composition testing lasted 6 months. During this period, participants in Focus Group 1 ingested a suspension prepared using samples 1-8 of the composition once daily. Specifically, 1.85 g of the composition sample was mixed with 50 ml of water to prepare the suspension. Throughout the entire testing period, each participant ingested a suspension prepared using one composition sample; that is, the efficacy of one composition sample was evaluated per participant.

[0075] Following the trial, a survey was conducted among focus group participants to assess their overall well-being and assess the presence of gastrointestinal complaints and discomfort. All participants reported improved overall well-being and the absence of any discomfort or gastrointestinal complaints associated with taking the suspension. Furthermore, blood tests at the end of the trial revealed that all participants in Focus Group #1 had normal blood calcium levels, indicating the absence of calcium overdose.

[0076] To assess the impact of the composition samples on changes in bone mineral density, participants in Focus Group #1 underwent repeat densitometry using a DEXA osteodensitometer. Based on these results, those participants in Focus Group #1 who had previously reported osteopenia had normal bone mineral density values ​​(-1 > T-score > 1), while the participant who previously had normal bone mineral density had an increased T-score within the normal range.

[0077] After the tests, all participants in focus group No. 1 were able to return to the training process due to the consolidation of previously existing fractures, which was established by the results of X-ray studies.

[0078] Focus group #2 included 36 women aged 50 to 70 years who, at the time of the study, were not receiving any hormone replacement therapy for the prevention or treatment of osteoporosis.

[0079] Before the testing, all participants in Focus Group 2 underwent bone mineral density testing using a DEXA osteodensitometer. Before the testing, 5 of the 36 participants had osteoporosis (T-score > 2.5), and 31 of the 36 participants had osteopenia (-2.5 > T-score > -1).

[0080] Focus Group 2 was a comparative study, divided into two subgroups, A and B. Participants in Subgroup A ingested a suspension prepared using samples 1–8 of the composition once daily for 14 months, using the same method as in Focus Group 1. Participants in Subgroup B ingested the calcium-containing medicinal product Calcium D3 Classic, as prescribed, also for 14 months. Throughout the study period, each participant in Subgroup A ingested a suspension prepared using one sample of the composition; therefore, the efficacy of one sample of the composition was evaluated on each participant in Subgroup A.

[0081] Subgroup A included 16 participants with osteopenia and 2 with osteoporosis, with 12 of the 18 participants having diagnoses such as gastritis and duodenal ulcer. Subgroup B included 15 participants with osteopenia and 3 with osteoporosis, with 11 of the 18 participants having diagnoses such as duodenal ulcer and colitis.

[0082] After participants in subgroups A and B took the first daily doses of the prescribed compositions and the drug, blood calcium levels were analyzed for all participants at 0.5, 1, and 10 hours after administration. The graph shown in Fig. 2 was obtained based on the analysis data. The analysis revealed that, when taking the calcium-containing drug Calcium D3 Classic, blood calcium levels were highest in the first 15-20 minutes after administration and significantly decreased after 1 and 10 hours, indicating that the drug tends to be rapidly absorbed and equally rapidly excreted from the body through the kidneys. As a result, the residence time of the drug in the blood is too short, and, consequently, the time for calcium incorporation into the bone structure is significantly limited.It was found that when taking the compositions according to the invention, a gradual increase in the calcium content in the blood was observed, and its maximum was observed by the 10th hour after taking the drug.

[0083] Over the next two days, participants in subgroups A and B had similar blood calcium levels analyzed, which were used to obtain the graph shown in Fig. 3. On the second and third days of taking the composition according to the invention, participants in subgroup A showed a consistently high blood calcium level, while participants in subgroup B showed a sudden increase in blood calcium levels and a decrease towards the end of the day.

[0084] At the end of the trial, participants in subgroups A and B were surveyed to assess their overall well-being and assess the presence of gastrointestinal complaints and discomfort. All participants in subgroup A reported improved overall well-being and the absence of discomfort or any gastrointestinal complaints associated with taking the suspension, while 13 of the 18 participants in subgroup B reported gastrointestinal discomfort while taking the drug.

[0085] To evaluate the effect of the composition samples on changes in bone mineral density, repeat densitometry was performed for the participants in subgroups A and B using a DEXA osteodensitometer. According to the results, the bone mineral density index of those participants in subgroup A for whom osteopenia was previously noted acquired normal values ​​(-1 > T-score > 1), and the participants who had an initial diagnosis of osteoporosis showed an increase in the T-score and a transition to a state of osteopenia (-2.5 > T-score > -1). According to the results of repeat densitometry of the participants in subgroup B for whom osteopenia was previously noted, 7 out of 15 showed an improvement in the T-score to normal values ​​(-1 > T-score > 1), 6 out of 15 showed no change in the T-score, and 2 out of 15 showed a deterioration in the T-score. Moreover, for three participants in subgroup B, who had an initial diagnosis of osteoporosis, neither the maintenance nor the improvement of the initial T-score value was noted.

[0086] Thus, the conducted studies confirm the effectiveness of the composition according to the invention in relation to the prevention and treatment of calcium deficiency and osteoporosis, and also confirm the absence of side effects from the gastrointestinal tract during the process of taking the composition orally.

[0087] The positive results achieved during the studies are due to the fact that the composition contains resveratrol and astragaloside IV, and they, as well as all other components of the composition, are present in its composition in optimal concentrations, as a result of which the problem of imbalance in the activities between osteoclasts and osteoblasts is solved, RANKL is inhibited and KLF2 is activated, regulating the differentiation of monocytes into osteoclasts, exerting a positive effect on bone metabolism processes, which causes active absorption of calcium by bone tissue.

[0088] The study also noted the composition's positive effects on joints and connective tissues, as well as accelerated recovery from joint injuries and diseases (arthrosis, arthritis, and rheumatoid arthritis). Specifically, Focus Group 2 included three participants with confirmed diagnoses of mild arthritis and arthrosis of the knee and shoulder joints, accompanied by common symptoms: pain at rest, significant pain with minor exertion, swelling, increased sensitivity, and a crepitant crunch in the affected joints. Focus Group 2 also included one participant with confirmed rheumatoid arthritis, accompanied by a complication of periodontitis (gum inflammation). These conditions were confirmed by blood and urine tests, X-rays, and MRI scans.During the study, all three patients diagnosed with arthritis and arthrosis simultaneously demonstrated a reduction in joint pain at rest and with minor exertion. Joint pain also ceased to bother the patients at night after 1.5 months of taking the composition. Analysis confirmed a reduction in inflammation, without any additional medication or other treatment for joint pathologies, including the use of nonsteroidal anti-inflammatory drugs. Prevention of joint degradation, a reduction in stiffness, and an increase in joint mobility were also noted. A participant with rheumatoid arthritis noted a reduction in synovial inflammation and an improvement in gum condition (a gradual deterioration had been observed prior to using the composition).Thus, the studies confirm the positive effects of the composition on joints and connective tissues. It possesses anti-inflammatory and chondroprotective properties and is associated with a positive effect in reducing the risk of complications in rheumatoid arthritis, allowing for a systemic effect on musculoskeletal injuries. All this significantly simplifies and accelerates the recovery process and improves the quality of life for patients with bone and joint injuries and pathologies.

[0089] Thus, the technical result is achieved, which consists in increasing the effectiveness of the prevention and treatment of calcium deficiency and osteoporosis in the absence of side effects and a concomitant increase in the absorption of calcium in bone tissue, without the risk of excessive accumulation of calcium in the body, as well as in obtaining, when using the composition, a personalized medical effect consisting in preventing bone loss in the lumbar spine and femoral neck in postmenopausal women without obvious osteoporosis.

Claims

Invention formula 1. A composition for the prevention and treatment of calcium deficiency and osteoporosis, containing tribasic calcium phosphate, magnesium hydroxide, cholecalciferol, pyridoxine hydrochloride, resveratrol, astragaloside IV, sodium selenate, zinc oxide and sodium tetraborate, wherein the said components are in the following ratio, by weight. %: tribasic calcium phosphate 70.0 - 90.0 magnesium hydroxide 5.0 - 20.0 cholecalciferol 0.006 - 0.04 pyridoxine hydrochloride 0.02 - 0.4 resveratrol 0.2 - 24.0 astragaloside IV 0.1 - 24.0 sodium selenate 0.0001 - 0.001 zinc oxide 0.135 - 1.5 sodium tetraborate 0.0003 - 0.002 2. The composition according to item 1, the components of which are in the following ratio, wt. %: tribasic calcium phosphate 76.0 - 85.0 magnesium hydroxide 7.0 - 16.0 cholecalciferol 0.006 - 0.017 pyridoxine hydrochloride 0.09 - 0.366 resveratrol 2.2 - 6.0 astragaloside IV 2.14 - 4.4 sodium selenate 0.0001 - 0.0009 zinc oxide 0.135 - 0.839 sodium tetraborate 0.0009 - 0.0017 3. The composition according to item 2, the components of which are in the following ratio, mass %: tribasic calcium phosphate 81.6, magnesium hydroxide 10.8, cholecalciferol 0.0089, pyridoxine hydrochloride 0.15, resveratrol 4.0, astragaloside IV 3.3, sodium selenate 0.0007, zinc oxide 0.139, sodium tetraborate 0.0014

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