RU2582973C1 - Anti-osteoporosis agent - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and represents a anti-osteoporotic agent containing trace elements in the form of borate and manganese salt and vitamin D3, characterised by additional introduction of natural conformers of amber or fumaric acid in the form of acid and ammonium salts of calcium, magnesium and zinc in aqua-chelate form, microelements in the form of fluoride and selenate as sodium or potassium salts, calcium caseinate enriched with glycine and mono-L-glutamate sodium; at that, components of the agent are taken in certain proportions, mg/dose.

EFFECT: invention provides for expansion of the range of medications for treatment of osteoporosis, improvement of therapeutic effect, as well as elimination of side effects and recurrences.

6 cl, 4 dwg, 3 tbl

Description

The invention relates to medicine, in particular to pharmacology, namely to medicines for the treatment and prevention of postmenopausal and involutional osteoporosis.

The search and development of new drugs intended for the treatment and prevention of diseases of postmenopausal and involutional osteoporosis is due to the widespread disease and the special severity of the course.

Known pharmacological and parapharmacological agents for the prevention and treatment of various types of age-related and endocrine-dependent osteoporosis.

Among the known drugs are many:

- monopreparations (calcium gluconate, glycerophosphate Ca, calcium chloride). However, these drugs do not have additional compounds, which means that they are not so well absorbed;

- vitamin and mineral preparations containing a group of various vitamins, micro and macro elements (Nutrimax + Vision ”,“ Complivit ”). These preparations contain insufficient amounts of calcium and are suitable only for prevention, but not for treatment;

- hormonally active compositions (Raloxifene, Calcitonin, parathyroid hormone);

- combined calcium preparations (Natecal, Calcium-D3 Nycomed, Vitrum Calcium + Vitamin D3). Compared to other drugs, they contain small amounts of calcium;

- as well as biological active food additives (BAA) (OsteoPlus, VITALINE).

Among the latter, sex hormones (primarily estrogens) and anabolic hormones, precursors and hormone-like analogues, their precursors, “synthetic” and herbal analogues of hormones, receptor agonists and inhibitors of resorption factors, for example, suppressing the action of parathyroid hormone (Lesnyak OM. Audit of the condition of the problem of osteoporosis in the Russian Federation // Preventive medicine. 2011. T. 2. S. 7-10).

All known means for the treatment of involutional osteoporosis and osteopenia in elderly men and women, in most cases, their actions are aimed at increasing the intake and absorption of calcium and related mineral components, at increasing the synthetic activity of osteoblasts and suppressing bone resorption by osteoclasts, enriching the intercellular matrix with minerals and collagen by saturating the body with excessively high amounts of plastic materials - natural components of bone tissue and participants biosynthesis, vitamin D, calcium-artificial compounds responsible for activating anabolic metabolism orientation hormone receptors.

Currently, all known means of local and systemic effects are used and, in fact, the synthetic potential of the body is being replaced due to the excess intake of activators and “building” material in combination with the “gold standard for the treatment of osteoporosis” - hormone replacement therapy (Povoroznyuk V.V., Grigoryeva N .V. Menopause and osteoporosis. Kiev: Health, 2004.356 s.). This approach pays off with relatively short courses of treatment (WHO. FRAX® WHO fracture risk assessment tool: calculation tool. Accessed February 14, 2011).

However, the known drugs do not have a sufficiently high efficiency of action, therefore, to prevent, inhibit or temporarily reverse the development of age-related involutional osteoporosis, not monthly or even annual courses of pharmacological and nutritional support and correction of osteogenesis are required, but lifelong antiosteoporosis therapy.

Of the known drugs, Calcemin (http://medprep.info/drug/medicament/895), designed to regulate calcium-phosphorus metabolism, was selected as a prototype. Calcemin contains calcium (as citrate or carbonate) 250 mg, vitamin D3 50 ME, copper (as copper oxide) 0.5 mg, zinc (as zinc oxide) 2 mg, manganese (as manganese sulfate) 0 , 5 mg, boron (as sodium borate) 50 mcg, inactive ingredients: maltodextrin, MCC, crosscarmellose sodium, acacia, stearic acid, soy polysaccharide, magnesium stearate.

The technical result of the present invention is to expand the arsenal of drugs and increase the therapeutic effect of the drug, through the use of components from natural conformers, as well as the elimination of side effects and relapses when using the claimed drug, intended for the treatment and prevention of postmenopausal and involutional osteoporosis.

The specified technical result is achieved due to the fact that the natural conformers of succinic or fumaric acid in the form of acidic and ammonium salts of calcium, magnesium and are additionally introduced into the anti-osteoporotic agent, which is a pharmacological composite containing microelements in the form of borate and manganese salt and vitamin D3. zinc in the aquahilate form, trace elements in the form of fluoride and selenate as sodium or potassium salts, calcium caseinate enriched in glycine and sodium mono-L-glutamate The best ratio of components in mg / dose:

natural conformers of amber or fumaric acid in the form of acidic and ammonium salts of calcium, magnesium and aqua chilate form 200-300 trace elements 5-10 enriched calcium caseinate glycine and sodium mono-L-glutaminate 75-150 vitamin d3 25-50 ME

In addition, the tool may contain auxiliary substances for the formation of its porosity.

In addition, microcellulose can be used as an aid.

In addition, stearic acid or magnesium stearate can be used as an auxiliary.

In addition, the tool can be made in a form suitable for oral administration.

In addition, the tool can be made in the form of capsules.

The claimed anti-osteoporotic agent differs from the prototype in the content in the composite of acidic and ammonium salts of calcium, magnesium and zinc in the aquahilate form of succinic or fumaric acid (200-300 mg), calcium caseinate enriched in glycine and sodium mono-L-glutaminate (75-150 mg) , as well as trace elements fluorine and selenium in the form of sodium or calcium salts (5-10 mg) and the absence of copper in its composition.

In connection with the use of derivatives of salts from the natural succinic acid conformer, its signal and substrate functions, which include activation of angiogenesis, activation of the expression of enzyme energy exchange systems, activation of the expression of glucose transporter, influence on proline hydroxylation reactions, and participation in oxidative transformations in mitochondria - the main accumulators of calcium in the intracellular matrix with its subsequent involvement in bone formation, are increased several times in comparison with salts of synt synthetic succinic acid having a 10-fold lower activity compared to the analogue of the natural succinic acid conformer used in the claimed tool.

The selected qualitative and quantitative composition of the presented composite was found experimentally and is optimal.

The invention is illustrated by the following figures:

in FIG. 1 shows the autocorrelation spectrum according to polarization-laser-radio-wave spectroscopy of ordinary synthetic succinic acid (manufactured by IzhBiofarm);

in FIG. 2 shows the autocorrelation spectrum according to the polarization-laser-radio-wave spectroscopy of succinic acid obtained from natural amber;

in FIG. 3 shows the autocorrelation spectrum according to the polarization-laser-radio wave spectroscopy of a synthetic analogue of natural succinic acid (manufactured by EcoMedService LLC, Tula) used in the claimed application for the invention.

in FIG. 4 - graphs comparing the effect of the course of drugs on the X-ray densitometric density of the femur after ovariectomy: A - the claimed anti-osteoporotic agent (X3); B - prototype Calcemin (S1).

The presented spectra of the autocorrelation function according to the data of polarization-laser-radio wave spectroscopy of different samples, the authors used the preparation of succinic acid (Fig. 3) is similar in its conformal composition to natural succinic acid obtained from natural amber (Fig. 2), which emphasizes its advantage in comparison with other forms of succinic acid (primarily synthetic).

The use of acidic aqua chelate hydrate forms - zinc fumarate, calcium succinate, magnesium succinate ensures the preservation of the natural conformer configuration and significantly increases the penetration and assimilation of elements such as calcium, zinc and magnesium necessary for the normal functioning of osteoblasts.

Calcium caseinate is added to the composite as a drug base to stabilize the components that make up the composite, as well as to increase the absorption of organic calcium due to its connection with the natural protein used in osteogenesis. In addition, caseinate is an easily but slowly assimilable protein and provides a sufficient amount of essential amino acids, including also proline, which cannot be synthesized by the body itself. Another useful property of casein is that it gives a feeling of satiety.

Glycine was added in a signal dose to easily activate glycine inhibitory receptors in order to prevent the possible activation of hormonal effects (from catecholamines and thyroid hormones, which can activate osteoclastic degradation of bone tissue by accelerating their metabolism).

Sodium monoglutaminate was added in a dose that in no way can be a source of glutamate excitotoxicity, but is a necessary component of influencing the sensitivity of the hypothalamus to activating and inhibitory signals (shown by Dilman V.M. et al. Back in 1976), a source of α-ketoglutarate , an absolutely necessary and limiting participant in the process of hydroxylation of proline to oxyproline. Glutamate is also a known activator of succinate dehydrogenase, which provides effective oxidation of endogenous and exogenous succinic acid. An additional and necessary factor in osteoblast formation is the use of vitamin D3 (cholecalciferol) in the formulation.

Biological research

Acute toxicity in mice, total genotoxicity in mice, and specific activity in rats were studied.

Acute toxicity

When testing the compositions developed by the authors, it turned out that the selected compositions have low toxicity, since the LD ₅₀ value for mice exceeded 2.5 g / kg of animal weight, which meets the requirements of hazard class 4 “low-hazard substances” (GOST 12.1.007-76 “Harmful” substances ”).

General genotoxicity

At the same time, genotoxicity tests were performed using the micronuclear mouse test. After the introduction of a 3-fold dose of drugs daily for 7 days, the number of micronuclei in the erythroid cells of the bone marrow of mice reached 4-5 per 1000 erythroid cells when each individual analyzed at least 2000 cells, which is at the level of intact norm. Positive control was performed when animals were irradiated at a dose of 1.6 Gray. This dose causes mild radiation sickness. After such irradiation, the number of micronuclei in different individuals from the same mouse population ranged from 25 to 60 cells per 1000 erythroid bone marrow cells, which indicates a high sensitivity to the genotoxic effects of the used animal population and at the same time confirms the lack of genotoxicity in the medicinal compositions created by the authors.

Specific activity

The activity of the anti-osteoporotic agent (composite) was tested on 72 female rats with preliminary bilateral ovariectomy and additional double subcutaneous injections (4 days interval) of dexamethosone (0.5 mg / kg), aggravating the course of osteoporosis after bilateral ovariectomy. In addition, the composite was tested on old Wistar female rats aged 13-14 months, in which the astral cycle ceased, the presence of phases of which was judged by a vaginal smear.

Bone density state was monitored non-invasively using X-ray densitometry on an X-ray tomograph in scanning mode.

X-ray densitometry was performed by the method of dual-energy X-ray absorptiometry at the end of feeding the animals with the drug. Elemental analysis of the bone tissue of the thigh was performed using atomic absorption spectrometry (Varian spectrometer) after a gravimetric study (laboratory electronic VLKT scales, measured with an accuracy of 0.5 mg), including estimates of the wet weight of the femur, dry weight after drying (in the thermostat at a temperature of 95-102 ° C, since the evaporation of bone fat begins at 104 ° C), the weight of ash (obtained by burning bones in a muffle liver). Research procedure: first, the wet weight of the bones was determined, then the weight of the dried bones, then ashing of the bones was carried out, burning them in a muffle furnace, to analyze the ash content and calculate the degree of mineralization. The resulting ash was prepared for atomic absorption spectroscopy and flame photometry to determine the elemental composition (K, Na, Ca, Mg, Zn) of bone tissue (femur) in order to assess the pharmacological properties of the developed preparation in comparison with the reference preparation.

The properties of the samples were evaluated by composition at the beginning and at the end of the experiment by NMR spectra (Brucker, 600 MHz, West Germany), organoleptically and visually when testing the degree of friability, adhesion, color change and humidity.

Using the method of H ⁺ NMR spectroscopy, the structural identity of the composition of each type of the obtained powder was identified and confirmed (high-resolution analytical NMR spectrometer 600 MG, Brukker, Germany). The discrepancy did not exceed 1.5% for each component of the given recipe, which is higher than the requirements laid down in the draft TU. No impurities were detected at the sensitivity level of the NMR spectrometer (1 ppm = 1 ppm). An anti-osteoporotic agent after daily oral administration (15 mg / rat, or 75 mg / kg) for 20 days contributed to a decrease in osteoporosis compared with control (ovariectomized females and old females of the post-reproductive period) by an average of 10-12% (table 1- 3, fig. 2). Particularly high efficacy was shown in females of the post-reproductive period, in which, along with an improvement in bone density, a resumption in some cases of the estrous phase of the cycle was found (according to the cytology of vaginal smears). Obviously, at this age, complete involution of the ovaries has not yet occurred, and the restoration of the hypothalamic-pituitary regulation provides some activation.

From the above data in the tables and a comparison of the influence of the course of the preparations on the X-ray densitometric density of the femur after ovariectomy (Fig. 4, A of the claimed anti-osteoporotic agent X3; B of the prototype Calcemin S1), it can be seen that the effectiveness of the proposed anti-osteoporotic agent (X3) is sufficient to restore the X-ray densitometrically determined bone density to almost normal levels against a background of ovariectomy.

Thus, the specific antiosteoporotic activity of the proposed antiosteoporotic agent is proved.

As shown by expert analysis and primary control of specific activity, the proposed antiosteoporotic agent can contribute to more effective treatment and prevention of age-related and postmenopausal osteoporosis. The bioavailability of the acid salts of succinic and fumaric acids used in the new preparation is increased due to the use of their natural conformers and hydrated salts of these conformers, which have increased permeability and assimilation in relation to low doses of macro- and microelements, which in turn contributes to a more effective inhibition of osteoporosis, affecting the ratio of activity of osteoclasts and osteoblasts. The use of small signal doses of the components and the absence of overload from calcium and vitamin D3 help to reduce the possible manifestations of side effects of drug therapy. Thus, the proposed composite as part of its long-term use technology will ultimately provide a reduction in complications (mortality) from fractures, social and economic losses from complications and consequences of osteoporosis, as well as a reduction in financial costs for the prevention and treatment of patients of the corresponding profile.

Thus, the new composite has shown good results and can be recommended for implementation in clinical practice, thereby expanding the arsenal of drugs for the treatment and prevention of involutional osteoporosis and osteopenia in older men and women.

Claims (6)

1. Anti-osteoporotic agent, which is a pharmacological composite containing trace elements in the form of borate and manganese salt and vitamin D3, characterized in that it additionally includes natural conformers of succinic or fumaric acid in the form of acidic and ammonium salts of calcium, magnesium and zinc in aquahilate form, trace elements in the form of fluoride and selenate as sodium or potassium salts, calcium caseinate enriched in glycine and sodium mono-L-glutaminate, in the following ratio of components in mg / dose:
natural conformers of amber or fumaric acid in the form of acidic and ammonium salts of calcium, magnesium and aqua chilate form 200-300 trace elements 5-10 enriched calcium caseinate glycine and sodium mono-L-glutaminate 75-150 vitamin d3 25-50 ME 2. Anti-osteoporotic agent according to claim 1, characterized in that it contains auxiliary substances for forming the porosity of the agent. 3. Anti-osteoporotic agent according to claim 2, characterized in that it contains microcellulose as an auxiliary substance. 4. Anti-osteoporotic agent according to claim 2, characterized in that it contains stearic acid or magnesium stearate as an auxiliary substance. 5. Anti-osteoporotic agent according to claim 1, characterized in that it is made in a form acceptable for oral use. 6. Anti-osteoporotic agent according to claim 5, characterized in that it is made in the form of capsules.

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