RU2706069C2 - Immunobiotic complex - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to an immunobiotic complex for normalizing intestinal microflora of an organism. Said complex includes dry microbial mass of living bacteria and biologically active substances (BAS). One dose of the complex contains two formulations, one of which contains lactobacteria LGG (lactic acid bacteria Lactobacillus rhamnosus) in amount of 3 × 10⁹ up to 4 × 10⁹ CFU per one dose, and the other contains BAS, specifically lysozyme in amount of 50 to 300 mg per single dose; fructooligosaccharides (WCF), namely: inulin or raftilose or raftilin in amount of 800–1000 mg per one dose; as well as choline and iodine or eicosapentoenoic acid and docosahexaenoic acid in amount of choline 50 to 100 mg, iodine 50 to 100 mcg, eicosapentoenoic acid 138 to 460 mg, docosahexaenoic acid 90 to 380 mg.

EFFECT: invention provides wider spectrum of its complex action, enhanced synergetic interaction between all active components.

1 cl, 5 ex

Description

The invention relates to the pharmaceutical and food industries, in particular drugs and biologically active additives for the prevention and treatment of dysbiosis and intestinal dysfunctions.

The prior art contains medicines for treating bacterial infections and dietary supplements to strengthen immunity, including a culture of living bacteria (bifidobacteria, lactobacilli) and biologically active substances, in particular lysozyme (Kuvaeva IB, Ladodo KS. Microecological and immune disorders in children: Dietary correction. - M: Medicine, 1991).

For example, from the patent of the Russian Federation No. 2071339, a means is known for the treatment and prevention of dysbiosis in pediatrics, gastroenterology, obstetrics and gynecology, as well as in veterinary medicine. The specified tool contains bifidobacteria in the amount of 10 ⁶ -10 ⁸ colony forming units (CFU) per dose of the drug and additional lysozyme in the amount of 5-20 mg. Its use allows you to: reduce the period of clinical and bacteriological recovery by 1.5-2 times, provide a pronounced and lasting therapeutic and prophylactic effect for dysbiosis, intestinal dysfunctions and infections; to provide correction of a number of indicators of homeostasis, for example, antiproteinase activity of blood serum, immunobiological reactivity; accelerate the normalization of the morphological structure and cellular factors of local immunity of the gastrointestinal mucosa; improve tolerability of drug and cytostatic therapy and other adverse effects on the body; reduce the consumption of antibiotics for a number of intestinal infections; reduce the frequency and severity of the course of infectious and inflammatory complications; reduce the incidence of dysbiosis, intestinal and respiratory diseases; provide the necessary microbiological purity of the birth canal, a quick and lasting recovery with colpitis of bacterial and hormonal origin.

There are also a number of bacterial probiotic preparations containing a culture of living bacteria and active substances, including lysozyme, and used to correct dysbacterioses and treat various gastrointestinal diseases (RF patent No. 2253672); for the prevention and treatment of urogenital infections (RF patent No. 2073520, No. 2146526); as food biologically active additives (RF patent No. 2144294, 2164765), etc.

From literary sources it is known that the combination of lysozyme and bifidobacteria as part of a single drug forms a system of natural protective factors that are mutually complementary, which provides faster replacement of lysozyme and bifidoflora deficiency, improvement and normalization of all representatives of normobiocenosis, increases antibacterial, antitoxic resistance to adverse effects (RF patent No. 2071339).

This property is used in a number of pharmaceuticals existing on the market, for example: kipatsid and bifilis (Encyclopedia of drugs and pharmaceutical products, http://www.rlsnet.ru/).

Kipatsid is a means to normalize the microflora of the oral cavity and gastrointestinal tract and is usually available in tablet form. 1 tablet of kipacid contains: acidophilic lactobacilli of antagonistically active strains NK1, K3Sh24, 100 al, activity of at least 108 CFU in 1 g and lysozyme at least 1 mg. The combination of two components, such as live acidophilic lactobacilli (acylact) and lysozyme in one tablet, provides a multiple enhancement of the biological properties of the living culture of lactobacilli and the enzyme. If lysozyme destroys mainly pathogens of purulent-inflammatory diseases, then acylact suppresses the activity of conditionally pathogenic microflora. Moreover, live lactobacilli immediately occupy a vacant niche in the intestinal microbiocenosis, which contributes to the treatment of dysbiosis.

Bifilis is an anti-inflammatory and antibacterial drug that normalizes the intestinal microflora. It can be produced in the form of bottles containing a dry lyophilized mass of live bifidobacteria (Bifidobacterium bifidum strain 1) of at least 10 million and lysozyme 10 mg in a single dose (5 doses in one bottle). The drug inhibits the growth and development of many conditionally pathogenic and pathogenic microorganisms, creating favorable conditions for normalizing the intestinal microflora and improving digestion. Due to the presence of lysozyme in the composition, it shows synergism with many antibiotics, has, in addition, anti-inflammatory activity, stimulates metabolic processes and erythropoiesis. Bifilis is intended for the treatment of dysbacterioses of various origins, intestinal dysfunction, acute intestinal infections, acute and chronic non-specific inflammatory diseases of the gastrointestinal tract, accompanied by inhibition of reparative processes of the mucous membrane, infectious and destructive complications in newborns and premature babies. This drug can be selected as the closest analogue of the claimed invention.

All the aforementioned drugs and dietary supplements containing live bacterial culture and biologically active substances in one preparation have a number of disadvantages, associated primarily with a relatively short shelf life and a decrease in the effectiveness of its use over time. In addition, these drugs have a fairly narrow scope.

The technical result of the use of the claimed invention is: to increase the shelf life of the drug and simplify storage conditions (without a required cold chain), expand the spectrum of its complex effects, strengthen synergies between all active components.

The claimed technical result is achieved by the fact that the immunobiotic complex contains a dry microbial mass of living bacteria and biologically active substances (BAS), which are used as lysozyme and at least one substance from the group: gluco-oligosaccharides (GOS), fructooligosaccharides (FOS). In this case, bacteria and biologically active substances are divided into different preparative forms.

Usually used as a formulation sachet bag. One dose of the complex includes two sachets: one with live bacteria, the other with biologically active substances. The contents of the bag can be mixed immediately before use or taken orally one after another. The quantitative content of live bacteria and biologically active substances in the immunobiotic complex usually differs for patients from different age groups.

For children from 0 to 3 years old, the complex contains:

LGG 3 * 10 ⁷ - 4 * 10 ⁹ CFU, (it is also possible to use any Bifidobacterium strains together with lactobacilli, while their total number corresponds to that indicated);

lysozyme - 50-100 mg,

gluco-oligosaccharides (GOS) or fructooligosaccharides (FOS) - 500-900 mg;

for children from 3 to 7 years:

LGG3 * 10 ⁷ -4 * 10 ⁹ CFU,

lysozyme - 100-150 mg,

gluco-oligosaccharides (GOS) or fructooligosaccharides (FOS) - 800-1000 mg;

for children from 7 to 14 years old:

LGG3 * 10 ⁹ - 4 * 10 ¹¹ CFU,

lysozyme - 150-250 mg,

gluco-oligosaccharides (GOS) or fructooligosaccharides (FOS) - 900-1200 mg;

for adults 18 years and older:

LGG 3 * 10 ⁹ -4 * 10 ¹¹ CFU,

lysozyme - 250-300 mg,

gluco-oligosaccharides (GOS) or fructooligosaccharides (FOS) - 1-1.5 gr.

It is preferable to use live lactobacilli LGG (strain of lactic acid bacteria Lactobacillus rhamnosus) in the claimed immunobiotic complex. Lactobacilli belong to probiotics, which favorably affect the human body, contributing to the formation of a full-fledged barrier of the intestinal mucosa, normalization of the protective mechanisms of the body and improve the balance of intestinal microflora. They positively affect the formation of a non-immunogenic protective barrier of the intestine, including competition with other bacteria, the synthesis of antimicrobial factors (primarily lactic acid), as well as the stimulation of mucin production and the regeneration of intestinal epithelium. In addition, for bacterial strains used in medicines and dietary supplements, a number of requirements are imposed: safety (especially for children due to the immaturity of their intestines); high antagonistic activity against pathogenic and conditionally pathogenic bacteria; human origin; high adhesive ability; stability during production and storage; and resistance to the aggressive effects of gastrointestinal acids. Most of all, LGG meets these requirements.

For the claimed invention, it is preferable to use the technology of packing bacteria strains in a sachet with an internal aluminum shell, which, unlike most known drugs and dietary supplements, allows the immunobiotic complex to be stored without additional cooling.

The main biologically active substances of the claimed immunobiotic complex include lysozyme and substances from the group of gluco-oligosaccharides (GOS) and fructooligosaccharides (FOS).

Lysozyme is a non-specific defense substance of the body that can destroy the cell wall of bacteria. In addition, it has antitoxic, immunomodulating properties, stimulates metabolic and reparative processes. Due to these properties, lysozyme as a whole increases the anti-infection resistance of the body.

GOS and FOS are prebiotics that selectively stimulate the growth of certain strains of the intestinal flora (lacto and bifidobacteria). The main properties of GOS / FOS are: stimulating the development of healthy intestinal microflora, maintaining immunity, and reducing the risk of allergies and infections. Oligosaccharides are not digested by gastrointestinal tract enzymes, are not absorbed in the small intestine and reach the colon, where they fulfill their purpose.

Our studies have shown the synergistic effect of the joint use of the three basic components of the complex: live lactobacilli LGG, lysozyme and oligosaccharides, which can significantly increase the effectiveness of their biological effects compared to separate use. Lactobacillus, which is a probitik, and GOS / FOS, which are a prebiotic, makes this complex synbiotic. Their combined use enhances the effect of using lactobacilli: it positively affects the attachment to the intestinal wall and the “survival” of lactobacilli in the digestive tract, enhances the competition of LGG with opportunistic microorganisms (UPB) for receptors on the surface of intestinal cells (enterocytes), and displays the so-called decontamination effect (removal of harmful bacteria from the body) and creates favorable conditions for the growth of its own (indigenous) flora, increases the transport of LGG bacteria to the nearest lymph node to provide the immune system th effects (GALT-system).

Lysozyme also has a strengthening, synergistic effect against congenital immunity factors in the intestine, at the local level. Lysozyme is a substituent component, filling the deficiency of the natural human protective protein on the gastrointestinal mucosa (MALT system), and LG lactobacilli exhibit a systemic effect by stimulating the formation of immunoglobulin A and increasing the concentration of secretory immunoglobulin A on the gastrointestinal mucosa (polymeric form of IgA).

In addition, this combination of components leads to an increase in innate immunity factors for the whole organism. The effect of lysozyme and acquired secretory immunoglobulin A on the mucous membranes of the upper and lower respiratory organs, gastrointestinal tract and genitourinary organs contributes to: reducing the frequency of repeated (recurrent) infections; removal / elimination (elimination) of etiologically significant microorganisms from chronic foci of infection (ENT organs, respiratory organs, gastrointestinal tract, organs of the urinary and reproductive systems); elimination of pathogens during their carriage; decontamination of UPB with dysbacteriosis of the mucous membranes; reduce the risk of severe and complicated course of infectious diseases.

The optimal synergistic effect of the immunobiotic complex is achieved with the indicated ratio of the basic components: LGG (or LGG together with bifidobacteria) - from 3 * 10 ⁷ to 4 * 10 ¹¹ CFU, lysozyme - from 50 to 300 mg, GOS / FOS - from 500 to 1500 mg .

To expand the scope of the complex, it may additionally contain the following biologically active substances: choline, B vitamins (B1, B2, B6, B9, etc.), iodine, doycozohexaenoic acid, omega-3 polyunsaturated fatty acids. The action of these substances is aimed at the formation, development and strengthening of the central nervous system.

Choline (vitamin B4) is a vitamin-like substance widely distributed in living organisms in which it synthesizes the most important neurotransmitter called acetylcholine. Choline prevents the destruction of the myelin layer of nerve fibers and enters the cell membrane. This is what allows choline to protect nerve cells from damage. Choline exhibits the following properties: membrane-protective (protects the cell membrane from damage and destruction); nootropic (improves metabolism in the nervous tissue); improves mental abilities and memory; soothing; antidepressant; prevents the formation of gallstones; normalizes fat metabolism (lowering cholesterol and the concentration of fatty acids in the blood); normalizes blood sugar (strengthens the walls of the pancreatic cells that produce insulin, which in turn affects the reduction of blood sugar); improves reproductive function in men (participating in the synthesis of prostaglandins in the prostate gland and increasing sperm motility).

Iodine is a mineral necessary for the normal functioning of the thyroid gland and the production of thyroid hormones, which in turn contribute to normal mental development. With iodine deficiency in adults, the following symptoms are noted: fatigue, headache, depressed mood, nervousness and irritability; weakening of memory and intelligence. Lack of iodine in children leads to poor intellectual development, inadequate behavioral reactions, manifestation of stunting, decreased immunity, and improper development of the reproductive system. During the prenatal period and in early childhood, iodine and thyroid hormones are necessary for the proper formation and maturation of the brain.

Polyunsaturated fatty acids (PUFAs) - called vitamin F. They can not be synthesized by the body, therefore, must necessarily come from outside. PUFA omega-3s are necessary for the full, normal development of the brain and vision. Their deficiency leads to the following symptoms: a deviation in the development of the nervous system, visual impairment and peripheral neuropathy. The most common and important omega-3 PUFAs are: eicosopentaenoic acid (EPA) and docosahexaenoic acid (DCG). DHA is an important structural component of the phospholipid membranes of cells of the whole body, and especially brain cells and the nervous system. DHA is found in large quantities in the gray matter of the brain, the retina of the eye, and sperm (up to 36.4% of all fatty acids). The effect of the use of DCG and EGC is: to improve cognitive abilities, attention and memory; reducing the risk of developing senile dementia and Alzheimer's disease; a decrease in blood levels of harmful low and medium density lipoproteins leading to atherosclerosis; the manifestation of hypocoagulation, anti-inflammatory and immunomodulating properties.

As studies have shown, the presence of these additional bioactive substances in the immunobiotic complex does not prevent the manifestation of a synergistic effect between the basic components, moreover, some of them, for example, choline, enhance the biological effectiveness of the remaining components. The choice of one or another of the additional biologically active substances is usually determined by the age group of patients.

An immunobiotic complex made in accordance with the claimed invention, in which iodine and choline are simultaneously present as additional biologically active substances, is preferably used for children aged 0 to 7 years, which will contribute to the normal development and formation of the nervous system (brain) in the child. Iodine for a child from 0 to 7 years old is necessary for the prevention of iodine deficiency conditions, for the normal synthesis of thyroid hormones, which take part in the regulation of brain activity and the development of the child's intelligence. Choline, increasing the metabolism in the nervous tissue, helps to cope with increased mental stress for children of preschool and school age, and also increases memory.

At the age of over 7 years, the body is already able to get a sufficient amount of iodine from products, and the formation of the brain is also completed, and such prevention is carried out, as a rule, with monodrugs of iodine and only in case of serious iodine deficiency. Also at this age, it is preferable to use PUFAs instead of choline, since they begin to predominate in the gray matter of the brain (about 37% of all acids). In addition, PUFAs are important for older people, since in addition to improving cognitive functions (attention and memory), they are able to prevent senile dementia and also have an antiatherosclerotic effect.

For children from 0 to 3 years, the claimed immunobiotic complex may additionally contain: choline - 30-60 mg, iodine - 30-50 μg for children on artificial feeding or 5-10 μg of iodine for children on breastfeeding, whose mothers take multivitamin complexes, containing at least 300 micrograms of iodine. For children from 3 to 7 years: choline - 80-120 mg, iodine - 80-100 mcg. For children from 7 to 14 years: omega-3 polyunsaturated fatty acids (PUFAs) - 250-300 mg, including eicosapentenoic (EPA) - 138 mg, docosagesaenoic acid (DHA) - 90 mg. For adults 18 years and older: omega-3 polyunsaturated fatty acids (PUFAs) - 900-1200 mg, including eicosapentenoic (EPA) - 460 mg, and docosagesaenoic acid (DHA) - 380 mg.

EXAMPLES OF IMPLEMENTATION

Example 1

The composition "Immunobiotic complex" for children 0-3 years old, designed to normalize the intestinal microflora, strengthen immunity and improve metabolic processes in the central nervous system. One dose of dietary supplement includes two separate parts, mixed before use and taken together. The preparative form in the form of sachets-bags (divided into two sachets-bags).

Bag No. 1: Live lactobacilli LGG in an amount of 3-4 * 10 ⁹ CFU 2

Bag No. 2: BAS

Lysozyme - 50 mg

Inulin or raftylose or raftilin - 800 mg;

Choline - 50 mg;

Iodine - 50 mcg.

Additionally, food coloring and sweetening agents may be used. The total net weight of each bag does not exceed 1.5 g.

All raw materials are produced using known technologies. Strains of lactobacilli LGG are obtained using freeze-drying technology (the so-called sublimation), as a result of which the outer shell of bacteria is hardened. Lysozyme in the preparation can be presented in the form of an enzyme (protein) obtained from egg white or by biosynthesis (produced by some bacteria and plants of the cruciferous family).

The resulting complex was tested for stability, biological effectiveness and shelf life. As a result of the storage stability test, the biological effectiveness of bag No. 1 in the form of live LGG lactobacilli decreased after 18 months to a number of 3 * 10 ⁸ CFU 2. The remaining biologically active substances of bag No. 2 showed the same biological efficiency as at the beginning of the tests.

Studies have shown that the shelf life of the complex compared with the drug kipatsid and bifilis increased from 12 to 18 months; storage conditions of the complex compared with the drug kipatsid and bifilis improved and can be stored at room temperature (the drug kipatsid is stored at a temperature of not more than 10 ° C). The complex can be used for children with lactase deficiency due to the technology of cultivation of raw materials on the hydrolyzate. Unlike bifilis, the complex contains prebiotics, due to which its biological effectiveness increased by 18%. The complex also contains choline and iodine (which are not included in the known bifilis complex), which has a beneficial effect on the formation and development of the central nervous system.

Before use, the contents of the bags were mixed and diluted in 20-50 ml of water at room temperature (not more than 25 ° C). It was consumed before, after, or during feeding. For prevention, the complex was used 2 times a day, with a course duration of 20 days. For treatment as part of complex therapy - 2-4 times a day, with a course duration of 40 days.

-1/8 курса лечения.The package of the “Immunobiotic complex” contains 20 pairs of sachets, designed to undergo 1 preventive course or

-1/8 course of treatment.

Example 2

Composition "Immunobiotic complex" for children from 3 to 7 years old, designed to strengthen immunity, normalize intestinal microflora and improve metabolic processes in the central nervous system. One dose of dietary supplement includes two separate parts, mixed before use and taken together.

The preparative form in the form of sachets-bags (divided into two sachets-bags).

Sachet No. 1: Live lactobacilli LGG in an amount of 3-4 * 10 ⁹ CFU 2.

Bag No. 2: BAS:

Lysozyme -120 mg;

Inulin or raftylose or raftilin - 1000 mg;

Choline -100 mg;

Iodine -100 mcg.

The total net weight of each bag does not exceed 1.5 g.

Before use, the contents of the bags are mixed and diluted in 20-50 ml of water at room temperature (not more than 25 ° C).

Use before, after or during meals, so the drug compares favorably with bifilis. For prevention 2 times a day, the duration of the course is 20 days. For treatment as part of complex therapy 2-4 times a day, the duration of the course is 40 days. Studies have shown its high efficiency. Resistance to external influences, shelf life and storage conditions are similar to those described above.

-1/8 курса лечения.The package of the “Immunobiotic complex” contains 20 pairs of sachets, designed to undergo 1 preventive course or

-1/8 course of treatment.

Example 3

Composition "Immunobiotic complex" for children from 7 to 14 years old, designed to strengthen immunity, normalize intestinal microflora and improve metabolic processes in the central nervous system. One dose of dietary supplement includes two separate parts, mixed before use and taken together.

The preparative form in the form of sachets-bags (divided into two sachets-bags).

Bag No. 1: Live lactobacilli LGG in an amount of 3-4 * 10 ⁹ CFU 2

Bag No. 2: BAS:

Lysozyme - 200 mg;

Inulin or raftylose or raftilin - 1000 mg;

omega-3 polyunsaturated fatty acids (PUFAs) acids - 270 mg, (including eicosapentenoic (EPA) 138 mg, docosagesaenoic acid (DHA) 90 mg).

The total net weight of each bag does not exceed 2 g.

Studies have shown its high efficiency. Resistance to external influences, shelf life and storage conditions are similar to those described above.

Before use, the contents of the bags are mixed and diluted in 20-50 ml of water at room temperature (not more than 25 ° C). Use before, after or with food. For prevention 2 times a day, the duration of the course is 20 days. For treatment as part of complex therapy 2-4 times a day, the duration of the course is 40 days.

-1/8 курса лечения.The package of the “Immunobiotic complex” contains 20 pairs of sachets, designed to undergo 1 preventive course or

-1/8 course of treatment.

Example 4

Composition "Immunobiotic complex" for children from 7 to 14 years in the form of tablets.

Tablets of different colors, made in an acid-resistant shell (enteric).

Tablet No. 1 contains LGG 3-4 * 10 ⁹ CFU 2

Tablet No. 2 contains:

Lysozyme - 200 mg,

Inulin - 1 g,

Omega-3 polyunsaturated fatty acids (PUFAs) acids - 270 mg, including: eicosapentenoic (EPA) - 138 mg, docosagesaenoic acid (DHA) - 90 mg.

Tablets are taken together during or after meals. The course of prevention or treatment is similar to that described for the complex in the form of sachets.

Example 5

Composition “Immunobiotic complex” (BAA) for children from 7 to 14 years old, designed to strengthen immunity, normalize intestinal microflora and improve metabolic processes in the central nervous system. One dose of dietary supplement includes two separate parts, mixed before use and taken together.

The preparative form in the form of sachets-bags (divided into two sachets-bags).

Sachet No. 1: Live lactobacilli LGG (number 3-4 × 10 * 9 CFU 2)

Bag No. 2:

Lysozyme - 300 mg;

Raftilin - 1000 mg;

omega-3 polyunsaturated fatty acids (PUFA) acids - 1 g, including: eicosapentenoic (EPA) - 460 mg, and docosagesaenoic acid (DHA) - 380 mg

The total weight of the bag is not more than 2 grams.

Claims (2)

1. An immunobiotic complex for normalizing the intestinal microflora of the body, including dry microbial mass of living bacteria and biologically active substances (BAS), characterized in that one dose of the complex contains two formulations, one of which includes lactobacillus LGG (a strain of lactic acid bacteria Lactobacillus rhamnosus) in an amount of 3 × 109 to 4 × 109 CFU per dose, and the other includes a biologically active substance, namely lysozyme in an amount of 50 to 300 mg per dose; fructooligosaccharides (FOS), namely: inulin or raftilose or raftilin in an amount of from 800 to 1000 mg per dose; as well as choline and iodine or eicosapentenoic acid and docosagesaenoic acid in the amount of: choline from 50 to 100 mg, iodine from 50 to 100 μg, eicosapentenoic acid from 138 to 460 mg, docosagesaenoic acid from 90 to 380 mg. 2. The immunobiotic complex according to claim 1, characterized in that the preparative form is a sachet bag with an internal aluminum shell