RU2613180C2 - Biologically active composition in form of lozenge - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: biologically active composition in the form suitable for oral resorption, contains L-theanine or diosgenin or a dry extract of Dioscorea villosa (wild yam) rhizomes containing these substances in effective amounts, and auxiliaries. The lozenges provide higher diosgenin bioavailability.

EFFECT: improved condition in case of physical fatigue of various origins.

2 cl, 4 ex

Description

The invention relates to the field of medicine and the food industry and relates to biologically active compounds that improve conditions in physical asthenia of various origins.

According to many authors, asthenia is based on overstrain and exhaustion of higher nervous activity. The immediate cause of asthenia can be an insufficient intake of nutrients, excessive energy expenditure or an upset metabolism. Any factors leading to depletion of the body can potentiate the development of asthenia: acute and chronic diseases, intoxication, poor nutrition, mental disorders, mental and physical overload, chronic stress, etc.

General recommendations for asthenia are reduced to the selection of the optimal mode of work and rest; refusal to contact with various harmful effects, including the use of alcohol; the introduction to the regime of the day of healing physical activity; adherence to a diet fortified with and corresponding to the underlying disease.

The medical treatment of asthenia in general medical practice is reduced to the appointment of adaptogens: ginseng, Rhodiola rosea, Chinese magnolia vine, eleutherococcus, pantocrine.

In particular, the application CN 102188628 (A) - 2011-09-21 describes tablets that are prepared by tabletting traditional Chinese medicinal raw materials such as wild ginseng, lemongrass, dogwood, morinda, eukemia, astragalus root, marine animal processed products, with using suitable auxiliary materials, and intended to increase physical strength, strengthen sexual function, against impotence, prospermia, lumbago, asthenia, premature decrepitude and the like.

A number of countries have adopted the practice of treating asthenia with large doses of B vitamins (see, for example, Sem Med Prof Med Soc. 1958 Dec 30; 34 (45): 1336-7 passim., Intensive vitamin B1-B12 therapy in pains & asthenia, ROYE PE, PMID: 13624788 [PubMed - indexed for MEDLINE] However, this method of therapy is limited in the use of a high percentage of adverse allergic reactions.

Some authors believe that complex compositions are optimal, including not only B vitamins, but also C, PP, as well as trace elements involved in their metabolism (zinc, magnesium, calcium). For example, such a complex is described in US patent 7998500 B2. The patent discloses a composition for women, nutritional supplements, and a method for administering a composition intended for use in nutritional supplements, where such a composition comprises vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, folic acid, vitamin D3, vitamin C, vitamin E, niacin, copper, magnesium, zinc and iron.

Often with asthenia, nootropics and neuroprotectors are used (ginkgo biloba, nootropil, aminalon, phezam, picamelon, pantogam), antidepressants - serotonin and dopamine reuptake inhibitors, antipsychotics (antipsychotics), procholinergic drugs (enerion). However, their effectiveness has not been conclusively proven due to the lack of major research in this area.

As the closest analogue, a composition can be selected to improve concentration, learning ability and memory, containing a complex of theanine and fermented rice bran extract containing GABA (WO 2005122798 (A1) - 2005-12-29).

The objective of the invention is to develop a biologically active composition with a wide range of applications and high bioavailability.

The problem is solved by a biologically active composition in the form of a tablet, suitable for oral absorption, containing a combination of L-theanine and diosgenin in effective amounts and auxiliary components.

The source of diosgenin may be dry extract of wild yam (rhizomes of dioscorea shaggy (Dioscorea villosa)).

Effective amounts of theanine and diosgenin (or its dry extract in terms of diosgenin) can be 25-200 mg and 5-100 mg, respectively.

Absorption tablets generally include pharmaceutically acceptable excipients selected from carriers such as sugars, sugar alcohols, cellulose derivatives, gums, pavs, stabilizers such as polyvinylpyrrolidone, preservatives, sweeteners, flavorings, food acids, glidants, lubricants, and the like.

The preferred form of the active composition is sublingual tablets containing E421 mannitol (carrier), polyvinylpolypyrrolidone (stabilizer), diosgenin in the form of an extract of wild yam (rhizomes of dioscorea furry (Dioscorea villosa)), L-theanine, sorbitol (sweetener), natural flavoring - a mixture of tropic fruit, maltitol (sweetener), polyethylene glycol (stabilizer), silicon dioxide (anti-caking agent), polyvinylpyrrolidone (stabilizer), citric acid (acidity regulator) in the following components in mass. %:

Polyvinylpolypyrrolidone 0.5-1.0 Diosgenin in the form of wild yam extract 5.0-10.0 L-Theanine 20.0-30.0 sorbitol 15.0-20.0 natural flavor 1.0-5.0 maltitol 15.0-20.0 polyethylene glycol 1.0-2.0 silica 0.5-1.0 polyvinylpyrrolidone 0.5-1.0 lemon acid 0.5-3.0 Mannitol rest

Directions for use: for adults, 1 tablet per day in the morning immediately after meals, it is advisable to keep the tablet under tongue until complete resorption. Duration of admission is 30 days, if necessary, the admission can be repeated.

L-theanine or ethyl-L-glutamine is an amino acid that is part of tea leaves and unblown kidneys. It was discovered and described by scientists in 1949, is present in black, green and white tea made from Camellia Sinensis.

In animal experiments, it was shown that theanine increases the content of serotonin, dopamine and GABA, has a high affinity for the structures of the glutaminergic system - AMPA, NMDA receptors, and also blocks glutamate metabotropic receptors of type 1 (1). A similar receptor profile has many drugs for the treatment of anxiety-depressive disorders.

This neurochemical effect of theanine makes it a direct neuroprotector, protecting neurons from the action of neurotoxic agents, including ischemia (2). It has not only a therapeutic, but also a preventive effect.

Theanine has anxiolytic properties and can increase mood (3), as well as reduce the effects of psychological and physiological stresses by reducing the severity of neuronal excitotoxicity (4).

In a study (5, 6), it was shown that theanine affects immunity by stimulating the function of lymphocytes, which reduces the likelihood of catarrhal diseases and also that this mechanism can serve as an element of cancer prevention.

A study by Foxe et al. (7) demonstrated that volunteers taking theanine made fewer mistakes when testing the attention span during monotonous activity, as they improved their ability to not respond to distractions. In another study by Park and colleagues (8), the positive effects of theanine on memory and attention were demonstrated in individuals with moderate cognitive decline, and these effects were recorded not only during tests, but also according to the results of an electrophysiological examination. Electrophysiological studies have shown that while taking theanine, an increase in the alpha rhythm of the brain is noted, which reflects a state of calm without signs of drowsiness.

Diosgenin, a plant-based steroid, is the main active ingredient in wild yam extract. It is obtained from the rhizomes / tubers of the hairy dioscrae plant (Dioscorea villosa), from Trigonella foenum (hay fenugreek, Greek fenugreek) and soybeans. Diosgenin is structurally similar to the DHEA (dehydroepiandrosterone) prohormone, which is produced in the human body by the adrenal glands, but an enzyme that is not found in the human body is needed to convert diosgenin to DHEA. However, it was found that diosgenin directly activates the membrane steroid receptors 1,25D3-MARRS in neurons, providing an increase in the clinical effect of the body's own DHEA (9). This important mechanism explains why diosgenin has a number of effects similar to DHEA. Diosgenin, as well as DHEA, has been shown to be effective for menopausal disorders (vaginal dryness, hot flashes, decreased libido), as well as for premenstrual syndrome and dysmenorrhea. DHEA, being a neurohormone, regulates many neuronal processes in the brain. Diosgenin, increasing the sensitivity of receptors to endogenous DHEA, is able to form DHEA-like effects without increasing the concentration of endogenous DHEA.

It was shown that both DHEA and diosgenin can positively affect the process of skeletal muscle recovery after prolonged physical exertion, contribute to the growth of vital energy, and enhance stress resistance.

In an experiment by Salimeh with colleagues (10), it was found that diosgenin is able to protect the heart muscle from damage during heavy physical exertion.

In an experiment on pituitary cells, it was shown that dioscin (a saponin form of diosgenin) increases the secretion of growth hormone. Increasing the synthesis of growth hormone in humans leads to an increase in muscle mass, stimulation of tissue regeneration, strengthening immunity, that is, it has a general anti-eigenic effect (anti-aging effect). This affects the quality of the skin and hair, daily activity, overcoming volitional disorders.

Diosgenin has revealed many additional beneficial properties:

- it was found that diosgenin, like DHEA, is able to enhance the utilization of glucose by muscles, which leads to a decrease in blood glucose levels;

- It was shown that diosgenin may be useful in food allergies;

- it was shown that diosgenin facilitates the manifestations of diabetic neuropathy;

- it was shown that diosgenin slows the rate of axonal degeneration in Alzheimer's disease, and also reduces the severity of cognitive impairment associated with aging;

- the regulatory effect of diosgenin on the bile duct tissue and the positive effect on bile synthesis are known;

- Diosgenin is used as a means of combating hyperpigmentation by inhibiting melanogenesis.

Many experiments have shown that:

- Diosgenin has a pronounced antioxidant effect, and is also widely known as a lipid-lowering agent, including due to the fact that it is a blocker of the key enzyme of lipogenesis of synthetase of fatty acids, and also reduces cholesterol;

- diosgenin increases bone density in female rats after ovorectomy.

Surprisingly, the inventors have found that the effects of L-theanine and diosgenin are clinically synergistic.

The proposed combination is mainly intended to improve the state of physical asthenia of various origins. The specified purpose is preferred, but the scope is not limited to them.

When using a combination of L-theanine and diosgenin, there is an increase in the level of vital energy and libido to a much greater extent than when taking each ingredient individually. This becomes noticeable after a few weeks of taking the drug.

It was shown that with irritability associated with physical exhaustion (dysphoria) and lethargy, optimal effects are achieved with the combined use of theanine and diosgenin. With the combined use of diosgenin and theanine, a more comfortable psychological state is manifested brighter and more harmonious.

Both agents are able to increase activity and stress resistance, improve cognitive functioning, emotional state, positively affect immunity

The combination of diosgenin and L-theanine more harmoniously affects the autonomic nervous system, in particular blood pressure, by regulating the synthesis of nitric oxide - one of the most important elements in controlling blood pressure in the human body.

It was found that at recommended dosages, the combination of L-theanine and diosgenin is effective and safe. Dosages of both components of the combination are optimal from the point of view of regulatory bodies (higher dosages are not recommended).

Diosgenin is able to increase the binding of estradiol to estrogen-dependent receptors in women, but does not cause estrogen-like effects in men, since it is not involved in the synthesis of estrogens and is not able to turn into estrogens in the human body.

Thus, the combination of diosgenin and L-theanine can be an important component in combination therapy for various conditions accompanied by asthenia, impaired normal metabolism, and immunity. It can be used as a biologically active food supplement in order to prevent such disorders and improve the general condition of patients.

At the same time, diosgenin is not sufficiently absorbed from the gastrointestinal tract, therefore, as a rule, oral forms of diosgenin are ineffective. According to the invention, the combination is made in the form of tablets absorbable in the oral cavity, which eliminates this drawback.

When the ingredients of the proposed combination in the oral cavity are in contact with the mucosa, the process of their diffusion into the sublingual capillaries and veins begins. In contrast to intragastric tablets, when taking tablets for resorption, it is possible to increase its bioavailability. A more direct entry of diosgenin into the bloodstream provides a faster and more complete effect, since only saliva enzymes act on it, and not all enzymes of the gastrointestinal tract, which occurs with intragastric administration.

In addition, the proposed resorption tablets have a number of significant advantages:

- they do not need to be washed down with water, therefore, can be taken in any situations of consumption;

- their intake is little dependent on food intake or the absorption of the digestive tract of a particular person;

- the content in the body of substances delivered in this way does not change in the presence of drugs and other biologically active additives.

The technology for manufacturing solid tablets is a direct compression method. The shape of the tablet is provided by the shape of the press tool of the IMA Kilian tablet press.

Example 1. Tablets for resorption.

L-Theanine thirty% Diosgenin twenty% beckons 19% sorbitol thirty% magnesium stearate one%

Example 2. Sublingual tablets.

Diosgenin in the form of wild yam extract 7% L-Theanine 28% sorbitol twenty% natural flavor - a mixture of tropical fruit 1.5% maltitol eighteen% polyethylene glycol 1.5% silica 0.5% polyvinylpyrrolidone 0.5% lemon acid 2.5% mannitol twenty% polyvinyl polypyrrolidone 0.5%

Example 3. The study of biological properties.

The effect of L-theanine on human activity was evaluated using tests. The effects of L-theanine on the psyche were tested on a small group of volunteers, divided into subgroups of "increased anxiety" and "low anxiety". Volunteers were patients aged 20 to 25 years. The level of their anxiety was evaluated on the Taylor scale. The subjects received either just water, or 200 mg of L-theanine in the form of a drink, or lozenges (150 mg of L-theanine plus 50 mg of diosgenin) once a day. 60 minutes after administration, an encephalogram was recorded. A dose of 200 mg L-theanine (dissolved in 100 ml of water) or a tablet resulted in a significantly higher level of alpha-wave generation than in subjects who received water. (An increase in the alpha-wave activity of the brain is a sign of increasing relaxation.) No adverse reactions have been identified.

An additional study also studied the effects of a single administration of theanine (150 and 200 mg) and diosgenin (50-100 mg) in conditionally healthy subjects with complaints of fatigue, memory impairment, stress, over a 2-month course. The control was a group taking theanine tablets without diosgenin also sublingually. In this study, the effect of drugs was evaluated by several subjective and objective indicators that assess mood, reaction rate, attention, psychomotor function and memory.

After taking the drug for two weeks, the mood improvement was significantly in the subjects in both groups, the anxiety of the subjects significantly decreased by 39.4% in the main group compared with the control. In a month from the start of the drug administration, the volunteers significantly improved short-term (by 72%) and long-term (by 81.7%) memory, volume (by 44.9%), and concentration of attention in comparison with the initial values.

Example 4. The study of bioavailability.

In the study, Wistar male rats were used (60 animals in total).

Animals received a balanced standard food of the Research Institute of Nutrition RAMS (general bivalent diet, OVR), a standard semi-synthetic diet (according to MU 1.2.2520-09). Animals were divided into 3 groups. The first group (control) was administered diosgenin in the form of a dry diluted extract through the esophagus. The second group - diosgenin sublingually, the third sublingual combination of diosgenin with theanine.

Blood plasma test results:

T max: 10 hours in the 3rd group, 8 hours in the 2nd, 6 hours in the control.

CLtot: 0.5 - in the control, 0.3 - in the second, 0.2 - in the third.

F (bioavailability indicator): 0.2% in the control group, 0.45% in the second and 0.6% in the third group.

T1 / 2: 8 hours for the third, 6 hours for the control, 7 hours for the second.

In addition, C max theanine increases on average 2.5-3 times.

Thus, the proposed tablets can improve the bioavailability of diosgenin and, accordingly, increase the effectiveness of prophylaxis when combined with theanine.

Bibliography

1. Nathan PJ, Lu K, Gray M, Oliver C. The neuropharmacology of L-theanine (N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent. J Herb Pharmacother. 2006; 6 (2): 21-30.

2. Cho HS1, Kim S, Lee SY, Park JA, Kim SJ, Chun HS. Protective effect of the green tea component, L-theanine on environmental toxins-induced neuronal cell death. Neurotoxicology. 2008 Jul; 29 (4): 656-62.

3. Ritsner MS, Miodownik C, Ratner Y, Shleifer T, Mar M, Pintov L, Lerner V. L-theanine relieves positive, activation, and anxiety symptoms in patients with schizophrenia and schizoaffective disorder: an 8-week, randomized, double -blind, placebo-controlled, 2-center study J Clin Psychiatry. 2011 Jan; 72 (1): 34-42.

4. Kimura K, Ozeki M, Juneja LR, Ohira H. L-Theanine reduces psychological and physiological stress responses. Biol Psychol. 2007 Jan; 74 (1): 39-45.

5. Bukowski JF, Percival SS. L-theanine intervention enhances human gammadelta T lymphocyte function. Nutr Rev. 2008 Feb; 66 (2): 96-102.

6. Percival SS, Bukowski JF, Milner J. Bioactive food components that enhance gammadelta T cell function may play a role in cancer prevention. J Nutr. 2008 Jan; 138 (1): 1-4.

7. Foxe JJ, Morie KP, Laud PJ, Rowson MJ, de Bruin EA, Kelly SP. Assessing the effects of caffeine and theanine on the maintenance of vigilance during a sustained attention task. Neuropharmacology. 2012 Jun; 62 (7): 2320-7.

8. Park SK, Jung IC, Lee WK, Lee YS, Park HK, Go HJ, Kim K, Lim NK, Hong JT, Ly SY, Rho SS. A combination of green tea extract and l-theanine improves memory and attention in subjects with mild cognitive impairment: a double-blind placebo-controlled study. J Med Food. 2011 Apr; 14 (4): 334-43.

9. Chihiro Tohda, Young-A Lee, Yukiori Goto & Ilka Nemere Diosgenin-induced cognitive enhancement in normal mice is mediated by 1.25D3-MARRS.

http://www.nature.com/srep/2013/131202/srep03395/full/srep03395.html

10. Salimeh A, Mohammadi M, Rashidi B. Preconditioning with diosgenin and treadmill exercise preserves the cardiac toxicity of isoproterenol in rats. J Physiol Biochem. 2013 Jun; 69 (2): 255-65. doi: 10.1007 / s13105-012-0208-5. Epub 2012 Sep 6.

Claims (3)

1. A biologically active composition in the form of a tablet suitable for oral absorption, characterized in that it contains L-theanine and diosgenin or a dry extract of rhizomes Dioscorea villosa (wild yam) containing it, Trigonella foenum (hay fenugreek, Greek fenugreek) and soybeans in effective amounts and excipients, where the indicated effective amounts of L-theanine and diosgenin (or its dry extract in terms of diosgenin) are 25-200 mg and 5-100 mg, respectively. 2. The biologically active composition according to claim 1, characterized in that the tablet is a sublingual tablet containing mannitol, polyvinyl polypyrrolidone, diosgenin in the form of wild yam extract, L-theanine, sorbitol, natural flavoring, maltitol, polyethylene glycol, silicon dioxide, polyvinylpyrrolide citric acid in the following components in mass. %: Polyvinylpolypyrrolidone 0.5-1.0 Diosgenin in the form of wild yam extract 5.0-10.0 L-Theanine 20.0-30.0 sorbitol 15.0-20.0 natural flavor 1.0-5.0 maltitol 15.0-20.0 polyethylene glycol 1.0-2.0 silica 0.5-1.0 polyvinylpyrrolidone 0.5-1.0 lemon acid 0.5-3.0 Mannitol rest