Phytocomplex of bergamot fruit, method for preparing and using as food additive and in pharmacology

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the pharmaceutical industry, namely to an agent with an antidyslipidemic and analgesic effect. The method for preparing the phytocomplex with the antidyslipidemic and analgesic effect, involving: a) grinding peeled bergamot fruit to prepare an undegraded mixture, b) introducing pectinolytic enzymes into the mixture; c) reducing pulp content; d) inactivating the above enzymes added at the stage b), to prepare a degraded mixture; e) performing ultrafiltration of the degraded mixture through membranes isolating the substances having a molecular weight of over 30,000 Da, to prepare a transparent solution; f) introducing the transparent solution on a polyphenol absorption column; g) washing the polyphenol absorption column with water and increasing pH to prepare an aqueous polyphenol fraction; h) transmitting the aqueous polyphenol fraction to cationic resin to recover the phytocomplex in an aqueous phase; i) drying the phytocomplex in the aqueous phase. The phytocomplex in the aqueous phase with the antidyslipidemic and analgesic effect. The phytocomplex with the antidyslipidemic and analgesic effect. A pharmaceutical composition with the antidyslipidemic effect containing the phytocomplex, and pharmaceutically acceptable additives. A pharmaceutical composition with the analgesic effect containing the phytocomplex, and pharmaceutically acceptable additives.

EFFECT: phytocomplex described above possesses the evident antidyslipidemic and analgesic effect.

11 cl

 

The invention relates to a phytocomplex (in particular, the dry extract)obtained from the albedo (white subcutaneous layer of the fruit of the bergamot, the method of its production and its application in the field of pharmacology and as a food additive. In case of application by oral administration phytocomplex has a distinctive property of rendering normalizing and regulating action in relation to levels of cholesterol, triglycerides and glucose in the blood, which has strong atherogenic effect. The effectiveness of this action is even more interesting because of its direct dependence on the presence in the body of the critical factors associated with hyperglycemia and overweight (metabolic syndrome). In addition, in tests on animals phytocomplex has antioxidant/anti-inflammatory action, developing together with the analgesic effect after oral administration, and in the case of local application after application to the skin with induced inflammation. Finally, according to research conducted on the lines of tumor cells in culture, ' has demonstrated a strong ability to suppress cell proliferation.

The LEVEL of TECHNOLOGY

Bergamot (Citrus Bergamia Risso&Poiteau) is a citrus fruit plant, protractus the e almost exclusively in limited areas of the Peninsula of Calabria, the three most well-known types which are named respectivelyFemminello, Fantastico and Castagnaro.

It is known that among the variety of citrus fruits Calabrian bergamot is a particularly precious and a niche product. In fact, these citrus fruits grow on a narrow strip of land in the province Reggio Calabria, stretching from the southern side of Tirreni to the South side Ionica, capturing area of the Strait of Messina. Thus, this is a band with a length of not more than 150 km, passing directly from the coastal area to the area of the foothills, located deep in Reggio Calabria. To date, the bergamot is used exclusively by the properties of its essential oil, which is especially popular in perfumery, as possessing a unique fragrance, and continues to be used the most famous manufacturers of perfumery as the basis for the production of numerous brands of perfume, and also for the production of "Acqua di Colonia". This oil is obtained by exfoliation of the uppermost layer (peel) peel of the bergamot.

It is also known that the bergamot is so pronounced antiseptic properties that for many years the product bergamot, Bergamon, produced and used as a disinfectant in the operating chambers. In addition, in traditional medicine known is try relaxing properties of extracts of bergamot and its important nutraceutical properties. Finally, water-alcohol solution essences of bergamot is used to produce a number of products (in particular, one of them is called Bergarytal), which is available as a spray, has anti-inflammatory effect on the skin and is especially effective for protection from mosquitoes. However, the discovery that some components essences of bergamot, such as bergapten, are potentially toxic effects have limited its application to search for ways to remove this component for the safe use of extracts and essential oils.

In the document Gardana Claudio et al. "Evaluation of flavonoids and furanocumarins from Citrus Bergamia (Bergamot) juice and identification of new compounds" MOLECULES (Basel, Switzerland) 2008, Vol.13, No. 9, September 18, 2008 (2008-09-18), pages 2220-2228 devoted exclusively to the study of the content of flavonoids and furanocoumarins in the sample of bergamot juice.

Patent WO2008/061536 (COSMEDICAL APS (Denmark)) describes, inter alia, compositions for the treatment of eye diseases through compositions that also contain bioflavonoids, and method for making such bioflavonoids from bergamot. This method does not imply the use of pectinolytic enzymes or selection using cationic resins and does not indicate the content of furocoumarin in the resulting product.

Article Mandalari Giuseppina et al. "Enzymatic hydrolysis of flavonoids and pectic oligosaccharides from bergamot (Citrus bergamia Risso) peel" Journa of Agricultural and Food Chemistry, American chemical society, Washington, USA t, No. 21, 1 October 2006, pages 8307-8313, describes the allocation of flavonoids and other compounds derived from the peel of the fruit of the bergamot, while the peel is regarded as a by-product of the manufacture of essential oil.

Article Giuseppe Gattuso et al. "The total flavonoid glycosides in bergamot juice (Citrus bergamia Risso)" Journal of Agricultural and Food Chemistry, t, No. 11, may 2006, describes a study conducted with the sole purpose of separating the two treated with dimethylformamide glycosylated flavonoids contained in the juice of bergamot industrial origin, or, in other words, describes the solvent, which may find its application in products of interest to medicine and/or cosmetology.

The authors of the present invention unexpectedly found that from the fruit of the bergamot, particularly from albedo, it is possible to obtain concentrated phyto complex, exhibiting a powerful therapeutic effect due to the positive effect on metabolism, but also due to the normalization of lipid and glycemic profiles in an individual suffering from relevant diseases. Fruits of citrus albedo is a layer lying between the epidermis, including the peel and pulp, it is formed by the cells of the tubular structure forming a real network with the conclusion of the greater part of the volume TKA and in the intercellular space. The phytocomplex, preferably obtained in the form of a dry extract, due to the specific method of isolation and purification, characterized in its components, a significant reduction (almost to the complete removal of) content present in fruits and is considered potentially toxic furocumarins bergapten and bergamottin), but at the same time, stores and even has enhanced described therapeutic effect.

Thus, an object of the present invention is a method, as claimed in paragraph 1 of the claims.

The method will be described in more detail later in this document.

Stage a (grind partially bezmashinnogo fruit):

The fruit, without the outer layer (peel) and partially obespylenny to remove the top skin, preferably crushed by a mill on little strips of a length less than 1 cm

Stage b (decrease in the content of pectin):

To the mixture obtained according to paragraph 1, make suitable for the degradation of pectin pectinolytic enzymes and after 20-40, preferably 30 minutes at a temperature depending on the type of enzyme used, get more liquid and, thus, better working product.

Stage c (highlighting the fibrous component of the liquid fraction):

The product according to paragraph 2 mainly through PEFC is therefore moved from the strainer into a clean centrifuge to the final content of the pulp is less than 0.5%.

Stage d (inactivation pectinolytic enzymes):

This can be achieved by pasteurization of liquid under paragraph c, and as a side effect of pasteurization will help to remove many of the remaining essential oils by evaporation.

Stage e (clarification of aqueous solution):

This is achieved by way of ultrafiltration installation, equipped with a semi-permeable membranes with selective permeability of molecular weight below 12000 Yes (particles with a weight of less than 12000 Yes pass through the membrane). Also possible is part according to the invention variant of the method, in which the brightening effect is carried out by processing bentonite clay.

Stage f (adsorption transparent solution on a column containing polystyrene adsorbent resin):

The selection of polyphenols from the remaining solution produced by seizing pores polystyrene adsorbent resin having pores with a diameter of 100-150 angstroms (e.g., SEPEABEAD SP 207 Mitsubishi). According to a variant of the method according to the invention polyphenols can also select through a mixture of ethyl or methyl alcohol and ethyl acetate in a ratio of 3:1 and then remove by subsequent concentration of the solvent (for example, by evaporation and on leaseho drying).

Stage g (removing a fraction of the polyphenols that are captured in the pores of the resin according to item f, and the decrease in the content of furocoumarin in dry product up to 400 mg/kg):

After washing the surface of the resin with hot water with a temperature of 40°C to remove the solvent after stage 5 of sugars and acids produce the extraction of the polyphenolic fraction of disclosure cycle of organic compounds characterized by an annular space structure, thereby giving them a linear configuration for the release of the cavities in which they are enclosed. This effect is achieved by increasing the pH to strong values (pH 12-14). This is done preferably through the use of hydroxides of alkali metals, which also destroy the bergapten, bergamottin. A similar effect can be achieved in the case of ethyl or methyl alcohol instead of the alkali solution. In this case there will be no destruction of bergapten and bergamottin.

Stage h (chemical stabilization of the phytocomplex in the aqueous phase): polyphenols in (open) the linear form is extremely unstable and usually are subject to redox reactions. You need as quickly as possible to bring them back in a circular state. This result is obtained by reducing the pH value is ia 14 to strongly acidic value (pH about 3). This effect is obtained by removing from the solution of the cations K+, Na+, etc. Is carried out by applying a strong cationic resins (for example, Relite CF H+ Mitsubishi). They replace the existing cations are positively charged hydrogens (H+). The total effect is the acidification of the solution to pH=3 and the removal of cations used are hydroxides of alkali metals. The result is a product that is more valuable from the point of view of nutritional properties.

Stage i (physical stabilization of the product; "drying"):

This is achieved by removing water, mainly due to evaporation in high vacuum and then at a temperature below 60°C until complete drying (due to achieve a residual moisture content below 14%). With the high value of humidity is suppressed growth of any organic pollutants (yeast, bacteria etc). Get the dry product.

It must be emphasized that the method of isolation and purification allows to significantly reduce the amount of furokumariny (bergapten, bergamottin), which creates certain problems due to their potential toxicity, however, detected only at the level of their content in the skin and in much higher doses than in the juice.

Phyto complex according to the invention in the form of a dry extract looks like a fine, water-soluble powder with a yellow-brown the Board, characteristic odor and a bitter taste. It can be enclosed in the capsule, put it in the shell, mixed with oils for the preparation of creams, etc. and, thus, be combined with pharmaceutically suitable excipients, which are common in food additives.

An additional object of the present invention is the phytocomplex, preferably in the form of a dry extract obtained from the albedo of the bergamot fruit according to the method according to the invention.

The authors of the present invention in addition established and it also is an object of the invention that the phytocomplex can be used in clinical practice and/or as a dietary Supplement, because it contains sufficient amounts of nutrients (folic acid, vitamins etc), and antioxidants (in particular, flavonoids), which allow you to apply it as antidyslipidemic and antiatherogenic funds. Also, the objects of the present invention are compositions of dry extract of bergamot, which, depending on the destination as antidyslipidemic, and/or anti-atherogenic, and/or anti-inflammatory/analgesic local and system tools, and/or anticancer drug, containing phytocomplex of the present invention, mainly in the form of a dry extract, together with to akami and/or fillers, widely used in the pharmaceutical industry.

The composition can be applied in liquid or other form freeze - dried, pellets, powder. It was shown that phyto complex exerts its therapeutic effect on inflammatory diseases of the skin in the case of local application, anti-inflammatory/analgesic effect after systemic injections of experimental animals and antiproliferative effect on tumor cells in culture. Preferably provides a dosage in the range from 20 to 40, mostly 30 mg/kg of body weight.

Additional objects of the present invention are therapeutic supplements antidyslipidemic, and/or anti-atherogenic type, and/or to protect vessels, depending on the auxiliary components of the phytocomplex according to the invention.

The phytocomplex of the present invention is a product of natural origin for food additives or pharmaceutical preparation, demonstrating the ability to normalize levels of cholesterol, fats and glucose in the blood through the combined effect of suppressing absorption of the precursors of cholesterol at the level of the gastrointestinal tract, occurring due to the presence of polyphenolic fractions, and also inhibit the activity of 3-hydroxy-3-methylglutaryl-COA (HMGCoA) reductase in mammals.

In addition, when studying the effects of the phytocomplex according to the invention in experiments on animals in order to prove the absence of toxic effects was installed complete preservation within the normal range of basic biochemical parameters of blood (total blood count, liver transaminases, and azotemia hypercreatininemia). These data were confirmed by microscopy autopsy material treated animals revealed the absence of fatty degeneration or necrotic effects in the liver and kidneys. In addition, histopathological examination of tissue of brain and peripheral nerves confirmed the absence of induced axonopathy or myelinopathy. The study of the toxicity of the phytocomplex showed the following results: "Toxicological analysis revealed no toxicity factors according to current regulations". In particular, together with the absence of the usual impurities citrus fruits also established the absence of pathological concentrations or, at least, values outside the normal values for heavy metals, pesticides, polychlorinated biphenyls, nitrites and nitrates, dyes, mold, along with the absence of ochratoxins, bacterial endotoxins, anaerobic pathogens and fungi. In the study of the organs of Guinea pigs liver, kidney) after oral administration of amount of substance equal to 80 mg/kg body weight/day, found no toxic effect.

It should be emphasized that the use of hydroxides of alkali metals, in particular KOH, significantly reduces the number contained furokumarinov, and get the phytocomplex seem much more complete in terms of functionality. The object ' of the present invention is characterized biological simplicity of polyphenolic profile, including major bioflavonoid in the following proportions:

Neorealty 29,6%+/-6,0
Naringin 32,4%+/-4,0
Neohesperidin 38,0%+/-6,0
Total 100,0%

According to the invention after a stage of the first method are phytocomplex in the form of a dry extract, which has a minimum content of neorickettsia, naringin, which is neohesperidine not lower than 250 g/kg, which is 25%. In addition, furokumariny under which imply bergapten, bergamottin, present in a concentration not exceeding 400 mg/kg

Unlike most e is strachov of flavonoids on the market ' according to the present invention is well soluble, in addition to alcohol, and also in water at room temperature (20°C). Additional studies of dry extract showed its equivalence with the substances contained in the juice of bergamot.

EXAMPLES

The effects of the phytocomplex tested on 100 patients with simple family hypercholesterinemia in combination with or without associated hypertriglyceridemia. Patients equally divided into randomized groups by sex (48 males and 52 females), average age at which ranged from 45 to 70 years. Patients were classified according to the levels of LDL cholesterol (LDLC) in the blood according to the risk categories defined by the National educational program on cholesterol (NCEP ATP III), National Institute of health (NHI). All individuals gave the pills at the rate of 500 mg/day for 30 days. To highlight the phytocomplex used biological genus citrusBergamia Rissoand Poiteauand used the fruit cropsCastagnaro,FemminelloandFantastico. The treatment lasted 1 month. Those patients (32 out of the total group), which at the time of the study were taking statins or other antidyslipidemic drugs, it was proposed to continue the treatment. After treatment, individuals were followed for 30 days after completion of reception of the phytocomplex. Received data is displayed on the have the following results:

1) all individuals have seen a decline in 20-32% of the levels of total cholesterol and LDL in the plasma on the background of the average increase HDL cholesterol by 30%.

2) Individuals with familial hypercholesterolemia, with source levels of cholesterol in the plasma 230-280 mg/DL and treated only with diet, showed a reduction in total cholesterol by 34±4%, LDL cholesterol by 32±5 and increasing the level of HDL cholesterol by 28±3%.

3) Individuals with familial hypercholesterolemia, with source levels of cholesterol in the plasma 200-230 mg/DL and treated only with diet, showed a reduction in total cholesterol in the plasma of 28±4%, LDL cholesterol by 22±2% and increase HDL cholesterol by 24±5%.

4) Individuals of the two previous groups that were taking statins showed a further reduction in total cholesterol in plasma at 20±3%, LDL cholesterol by 20±4% and increased HDL cholesterol by 15±3%.

5) Examined individuals with mixed dyslipidemia (hypercholesterolemia and hypertriglyceridemia) and which accounted for 40% of the total group (40 of 100), showed a decrease in the level of triglycerides in the plasma 38±6%.

6) Antidyslipidemic effect remained at a high level at 60---days after discontinuation of FITOCA the Plex when values of total cholesterol, averaging over 20±2% from baseline values before treatment.

7) At the end of the study using ultrasonic Doppler studied the reactivity of the vascular endothelium, which showed all of the treated patients, the improvement in average 34±5% compared with the control values.

8) In the examined individuals was not noted no significant differences in autochemistry for treatment depending on age and gender. In addition, the treatment did not cause any side effects or pathological differences in the parameters of the functioning of the major organs, detected clinically or by biochemical analysis of blood, along with a significant lowering of high blood pressure and high blood glucose in individuals with impaired glucose metabolism (21%) or hypertension (24% of the total group).

9) Additional effect was studied in tests on animals (Wistar rats), which through the introduction of carragenine in the paw induced a painful inflammatory response. In these animals, both local and systemic application of the phytocomplex bergamot caused the decrease caused by carrageenan local edematous inflammatory reaction together with the reduction of hyperalgesia.

10) Finally, incubation of the phytocomplex according to the invention with cells of human astrocytomas in culture decreased cell proliferation, timthe indicating its potential use as antitumor agents.

1. The method of obtaining the phytocomplex with antidyslipidemic and analgesic effect from the fruit of the bergamot, which includes the following stages:
a) grinding the fruit of the bergamot no upper skin and peel with getting decayed mixture,
b) introducing into this mixture of enzymes for the degradation of pectin;
c) reducing the amount of the pulp obtained in stage b) of this mixture to values below 0.5%;
(d) inactivation of these enzymes added at this stage b), to obtain the mixture of decayed;
e) ultrafiltration specified decayed mixture through the membrane, cut-off substances with molecular weight over 30,000 Yes, obtaining a clear solution;
f) depositing a transparent solution obtained at this stage (e) on a column containing polystyrene adsorbent resin for adsorption of polyphenols;
g) washing the specified column with the adsorbed polyphenols with water temperatures in the range of 30-50°C and raising the pH to values in the range of 12-14 using hydroxides of alkali metals, obtaining water polyphenolic fractions;
h) transferring the specified water polyphenolic fractions on a cationic resin with subsequent extraction by reducing the pH to values below 3.0 with getting ' in the aqueous phase;
i) drying of the phytocomplex in the aqueous phase with obtaining fitok is the complex from the fruit of the bergamot in the form of a dry extract.

2. The method according to claim 1, where these are used the fruits of bergamot belong to the species Femminello, Fantastico and/or Castagnaro.

3. The method according to any of the preceding paragraphs, where the specified stage b), these enzymes belong to pectinolytic type.

4. The method according to claim 1, where at this stage e) the process of lightening solution is performed by treatment with bentonite or by natural precipitation.

5. The method according to claim 1, where at this stage i) dry extract that value is a residual moisture content of <14%.

6. The method according to claim 1, where after this stage i) specified dry extract ground and/or further treated.

7. Phyto complex in the aqueous phase with antidyslipidemic and analgesic effect obtained in stage h) of the method according to claim 1.

8. The phytocomplex with antidyslipidemic and analgesic effect obtained by the method according to any one of claims 1 to 6.

9. The phytocomplex of claim 8 in the form of a dry extract, showing the minimum content of neorickettsia, naringin and neohesperidin not lower than 250 g/kg

10. Pharmaceutical composition with antidyslipidemic effect, containing phytocomplex according to any one of claims 7 or 8 and a pharmaceutically acceptable additive.

11. Pharmaceutical composition with analgesic effect for a person containing phytocomplex according to any one of claims 7 or 8, and pharmaceuticas is acceptable additives.



 

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5 cl, 2 tbl

FIELD: medicine.

SUBSTANCE: pharmaceutical composition in a dose of 4 g a day containing at least 90 wt % of ethyl eicosapentaenoate is administered into an individual having initial fasting triglycerides within the approximate range of 500 mg/dl to 2000 mg/dl for a period of time effective to reduce fasting triglycerides by at least 15% as compared to initial fasting triglycerides before the first administration of the pharmaceutical composition. The second version involves administering approximately 4 g a day of the pharmaceutical composition containing at least 96 wt % ethyl eicosapentaenoate into an individual with initial fasting triglycerides from approximately 500 mg/dl to approximately 2000 mg/dl receiving neither any pharmaceutical composition, nor a concomitant statin therapy, for a period of time effective to reduce fasting triglycerides by at least 25% as compared to another similar individual. The third version provides reducing triglycerides and apoliprotein B in an individual having initial fasting triglycerides from approximately 500 mg/dl to approximately 2000 mg/dl and receiving no concomitant therapy changing the lipid profile, and involves administering approximately 4 g a day of the pharmaceutical composition containing at least 96 wt % of ethyl eicosapentaenoate for a 12-week period. The individual shows the fasting triglycerides reduction by at least 25% and the fasting apoliprotein B reduction as compared to the reference having initial triglycerides within the range from 500 mg/dl to approximately 2000 mg/dl and receiving neither any pharmaceutical composition, nor a concomitant therapy changing the lipid profile.

EFFECT: method improvement.

4 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 4-trimethylammonio-butyrates of formula I

,

where A1, R1, m and n are as defined in the description and in the claim, as well as pharmaceutically acceptable salts thereof.

EFFECT: compounds inhibit carnitine palmitoyl transferase (CPT) activity, in particular CPT2 activity, and can be used as medicaments for therapeutic or preventive treatment of hyperglycemia, glucose tolerance disorders, diabetes and associated pathologies, non-insulin dependent diabetes mellitus, obesity, hypertension, insulin resistance syndrome, metabolic syndrome, hyperlipidemia, hypercholesterolemia, fatty liver disease, atherosclerosis, congestive heart failure and renal failure.

13 cl, 1 tbl, 39 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), or pharmacologically acceptable salts thereof, (I), where R1 is hydrogen, halogen, nitro, amino, cyano, C1-8 alkyl, C1-8 alkoxy, C1-8 alkyl, substituted with a halogen, C1-8 alkoxy, substituted with a halogen, C2-8 acyl or C6-10 aryl; R2 is hydrogen, C1-8 alkyl, C1-8 alkyl, substituted with a halogen, C1-8 alkyl, substituted C1-8 alkoxy, C6-10-aryl or aralkyl, consisting of C6-10 aryl and C1-8 alkylene; each of R3, R4, R5 and R6 is independently hydrogen or C1-8 alkyl; X is sulphur; Y is oxygen, NR8 or a bond, where R8 is hydrogen or C1-8 alkyl; p equals 0 or 1; A is oxygen, CH2 or N-OR9, where R9 is hydrogen, C1-8 alkyl or aralkyl, consisting of C1-8 aryl and C1-8 alkylene; which are used as a PPAR activator.

EFFECT: improved method.

17 cl, 26 tbl, 31 ex

FIELD: chemistry.

SUBSTANCE: invention relates to triazole compounds which are represented by specific chemical formulae and which can be used for preventing or treating diseases in which 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) participates, particularly dementia. It was found that the triazole derivative, in which one of 3rd and 5th positions of the triazole ring accommodates a (di)alkyl methyl or cycloalkyl, each substituted, -O-aryl or heterocyclic group, each of which can be substituted, or (lower alkylene)cycloalkyl, and the other position accommodates an aryl, heterocyclic or cycloalkyl group, each of which can be substituted, or a pharmaceutically acceptable salt thereof, has powerful inhibiting action on 11β-HSD1.

EFFECT: improved properties of the derivatives.

8 cl, 141 tbl, 89 ex

FIELD: biotechnology.

SUBSTANCE: agent is proposed which has diuretic and anti-inflammatory action. It is shown that the sodium salt of 4-carboxyphenyl-O-β-D-glucopyranoside increased the daily diuresis 2 times or more, at that the excretion of sodium and potassium ions is reduced compared to the control; its anti-inflammatory activity is slightly higher than that of nimesulide. Due to the combination of the diuretic effect with anti-inflammatory and antimicrobial activities the agent can be used for the treatment of nephritis, pyelonephritis, cystitis of stagnant phenomena in the systemic and pulmonary circulation due to heart failure.

EFFECT: increased water excretion thus contributing to reduction of swelling.

2 tbl

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