RU2794463C1 - Self-emulsing composition of the drug based on flavonoid polyphenol, a method for its production, pharmaceutical composition based on it and its application - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: group of inventions relates to a self-emulsifying composition of a drug based on a flavonoid polyphenol for obtaining drugs for the treatment of diseases, a method for producing the above composition, a pharmaceutical composition for obtaining drugs for the treatment of diseases, containing the above self-emulsifying composition, and the use of the above the self-emulsifying composition or the above pharmaceutical composition for the preparation of medicaments for the treatment of diseases. Self-emulsifying composition of a medicinal product based on a flavonoid polyphenol for the preparation of drugs for the treatment of diseases selected from the group: against bacteria, against viruses, anti-inflammatory agents, agents for suppressing allergies, agents for regulating immunity, antitumor agents, antioxidants, anti-aging agents, agents against anti-ultraviolet radiation, hormone deficiency agents, anti-hypertension agents, blood fat-lowering agents, atherosclerosis agents, senile dementia agents, enterovirus vesicular stomatitis agents, osteoporosis agents or liver protection agents, containing a drug complex a flavonoid polyphenol-based phospholipid, an oil phase, an emulsifier and a co-emulsifier, wherein the flavonoid polyphenol-based drug is baicalein; the mass ratio of baicalein and phospholipid is 1:1-1:8; the oil phase is one or more selected from the group consisting of ethyl oleate, isopropyl myristate and caprylic/capric acid glyceride; the emulsifier is one or more selected from the group consisting of caprylic/capric acid polyethylene glycol glyceride, Tween 80, octylphenyl polyoxyethylene ether; the co-emulsifier is propylene glycol monocaprylate and/or diethylene glycol monoethyl ether; and in terms of the total mass fraction of the oil phase, emulsifier and co-emulsifier, which is 100%, the oil phase is 10–30%, the emulsifier is 40–60% and the co-emulsifier is 30–40%. A method for producing the above self-emulsifying drug composition based on a flavonoid polyphenol, comprising the following production steps: (1) preparation of a flavonoid polyphenol-phospholipid drug complex: a flavonoid polyphenol-based drug and a phospholipid are dissolved in an organic solvent, coupled, and dried to remove the organic solvent to obtain a flavonoid polyphenol-phospholipid drug complex; (2) preparation of a self-emulsifying flavonoid polyphenol drug composition: the flavonoid polyphenol-phospholipid drug complex obtained in step (1) is fully mixed with the oil phase, emulsifier, and co-emulsifier in any order. Pharmaceutical composition for the preparation of medicines for the treatment of diseases selected from the following group: against bacteria, against viruses, anti-inflammatory agents, agents for suppressing allergies, agents for regulating immunity, antitumor agents, antioxidants, anti-aging agents, agents against ultraviolet radiation, agents for the treatment of deficiency hormones, anti-hypertension agents, blood fat-lowering agents, anti-atherosclerosis agents, anti-senile dementia agents, enteroviral vesicular stomatitis agents, osteoporosis agents or liver protection agents, containing the above self-emulsifying flavonoid polyphenol-based drug composition and a pharmaceutically acceptable excipient. Use of the above self-emulsifying flavonoid polyphenol-based drug composition or the above pharmaceutical composition for the preparation of medicines for the treatment of diseases selected from the group of anti-bacteria, anti-virus, anti-inflammatory agents, allergy suppressants, immune-regulatory agents, antitumor agents, antioxidants , anti-aging agents, anti-ultraviolet agents, agents for the treatment of hormone deficiency, agents for hypertension, agents for lowering blood fats, agents for atherosclerosis, agents for senile dementia, agents for the treatment of enteroviral vesicular stomatitis, agents for osteoporosis, or agents for protection liver.

EFFECT: above group of inventions makes it possible to increase the drug load of the composition, to increase the stability and bioavailability of the compositions.

17 cl, 2 dwg, 13 tbl, 16 ex

Description

FIELD OF TECHNOLOGY

The present invention relates to a self-emulsifying flavonoid polyphenol-based drug composition, a method for its preparation, a pharmaceutical composition based on it and its use, which are related to the field of drugs.

BACKGROUND OF THE INVENTION

At present, flavonoid polyphenol compounds are generally divided into three categories: (1) low molecular weight phenolic acids such as salicylic acid, cinnamic acid, p-hydroxycinnamic acid, caffeic acid, ferulic acid, and chlorogenic acid; (2) tannins, which are polyphenolic polymers and are divided into condensed tannins and hydrolytic tannins, where condensed tannins are polyphenols formed by linking flavanols through C4-C6 or C4-C8 bonds, and having different degrees of polymerization, and also called proanthocyanidin , and hydrolytic tannins are formed by ester formation of gallic acid or ellagic acid with hydroxyl groups on sugars such as glucose; (3) polyhydroxyflavonoids, where one type of polyhydroxyflavonoids is anthocyanins (anthocyanidin glycosides), which is one of plant pigments, and another type of polyhydroxyflavonoids are flavonoids in the narrow sense and their glycosides, where aglycones include flavones, flavonols, dihydroflavones, dihydroflavonols, isoflavones, dihydroisoflavones , chalcone, orange ketone, flavan, anthocyanidins, bisflavones, and flavonoids (Reference paper 1: Advances in intestinal biotransformation of polyphenol constituents [C]. Eighth Academic Annual Meeting of Chinese Medicine Chemistry Branch of Chinese Traditional Medicine Society, 2013).

Studies show that flavonoid polyphenol-based drugs have many pharmacological effects in various aspects, such as positive effects in anti-tumor, anti-coagulation, anti-bacteria, hormonal regulation, anti-oxidation, anti-aging, anti-atherosclerosis, anti-infection, anti- osteoporosis, against viruses, against microorganisms, regulation of blood fat and lowering blood sugar levels.

Limited by physical and chemical properties, oral formulations of flavonoid polyphenol drugs have low bioavailability, resulting in poor oral treatment effect. Therefore, it is clinically important to increase peak plasma concentrations (C _max ) and blood exposure (area under the curve, AUC) when administered orally via pharmaceutical methods.

A self-emulsifying drug delivery system (SEDDS) is a homogeneous mixture of oil phases, an emulsifier and a co-emulsifier, and can be used as both drug-containing and drug-delivering agent. Following oral administration, SEDDS can rapidly and spontaneously emulsify to form oil-in-water emulsion droplets in the gastrointestinal motility environment and gastrointestinal fluid environment.

Zhiqin WANG et al. reported that a self-emulsifying microemulsion encapsulating proanthocyanidins was prepared with caprylic/capric acid triglyceride as oil phase, castor oil, polyoxyethylene 40 as emulsifier, and 1,2-propanediol as co-emulsifier. Rapid emulsification is achieved when the three components have a 1:3:1 weight ratio with a drug load of 10%. Polyoxyethylene 40, castor oil, 1,2-propanediol, and caprylic/capric acid triglyceride were weighed at a weight ratio and mixed evenly in a water bath at 37°C, then some proanthocyanidins were mixed and dissolved in the formulation, and the mixture was equilibrated at 37°C for 1 hour to obtain a self-emulsifying microemulsion encapsulating proanthocyanidins, which has an average particle size of 63.6 ± 0.7 nm after 100-fold dilution with water (reference document 2: Chinese Patent Drug, 2013, 35 (12): 2749-2752).

Weiling ZHANG et al. reported that the excess quercetin ingredient was magnetically mixed with polyethylene glycol glyceryl oleate as oil phase, polyoxyethylene 35 castor oil as emulsifier, and diethylene glycol monoethyl ether as co-emulsifier, which have a ratio of 27.0:55.6:17.4 (wt: wt:wt) in a water bath at a constant temperature of 60°C to obtain a supersaturated solution of quercetin. The mixture was stirred for 24 hours at room temperature, equilibrated and centrifuged at 4000 rpm for 10 minutes, after which the supernatant was collected to obtain a self-emulsifying microemulsion encapsulating the quercetin ingredient. The self-emulsifying microemulsion has a maximum drug loading of 67.87 mg/g and an average particle size of 25.26 nm after 50-fold dilution with water (reference document 3: Journal of Shandong University, 2016, 54 (3): 41-49).

Zemin LI et al. reported that an excess of the curcumin ingredient was blended homogeneously with a medium chain fatty acid (medium chain triglyceride (MCT)) as the oil phase, polyoxyethylene hydrogenated castor oil (Cremophor RH40) as an emulsifier, and polyethylene glycol-400 (PEG-400). ) as a co-emulsifier, which have a ratio of 2:6:2 (w/w), were vortexed for 5 minutes and shaken for 48 hours at 37°C with the exclusion of light radiation. A sample was taken and centrifuged for 10 minutes at 12,000 rpm, and the supernatant was similarly taken to obtain a self-emulsifying microemulsion encapsulating the curcumin ingredient, which has greatly improved solubility. The self-emulsifying microemulsion has a maximum drug loading of 55.30 mg/g and an average particle size of 11.8 nm after 100-fold dilution with water (reference document 4: Journal of Chengdu Medical College, 2017, 12 (2): 155-59).

LuCAO et al. reported that glycerol triacetate was used as the oil phase, Cremophor EL and Cremophor RH40 were used as emulsifiers and isopropanol was used as co-emulsifier, where the ratio of glycerol triacetate:Cremophor EL:Cremophor RH40:isopropanol was 22:27:13.5:37, 8 (w/w). They were mixed until homogeneous with a magnetic stirrer in a water bath at 37°C to obtain a pure self-emulsifying microemulsion. An appropriate amount of resveratrol was added to the pure self-emulsifying microemulsion and dissolved using ultrasonic waves to obtain a self-emulsifying microemulsion of resveratrol. The self-emulsifying resveratrol microemulsion has a drug loading of 45 mg/g and an average particle size of 15 nm after 100-fold dilution with water (Reference Document 5: Lu CAO, Formulation and Studies of Resveratrol-SMEDDS [D]. Hebei: Hebei Medical University, 2014) .

Self-emulsifying microemulsions of proanthocyanidins, quercetin, curcumin, and resveratrol were prepared according to the methods in References 2-5, respectively. These self-emulsifying microemulsions were stored at 4°C and room temperature for 5 days, one month and two months separately. Changes in the appearance and physical stability of self-emulsifying microemulsions have been observed. The results show that self-emulsifying flavonoid polyphenol based drug microemulsions prepared according to the formulations in References 2-5 have obvious stability defects: semi-solids or precipitates are easily formed after being placed at 4°C, and drugs precipitate after rooms at room temperature for a certain period of time.

In addition, Xue KE et al. report that a pure self-emulsifying microemulsion drug delivery system (SMEDDS) was formulated according to formulation with Migly-col812/Maisine35-1 (1:1) as oil phases, Cremphor EL35/labrazol (2:1) as emulsifiers, and transcutol P as a co-emulsifier, excess baicalein was added, mixed and dissolved in a water bath at 37°C, removed after 24 h and centrifuged at a high speed of 12000 rpm ^-1 for 15 min, and the supernatant was collected to obtain a self-emulsifying microemulsion encapsulating the baicalein ingredient, which has a maximum drug loading of 18.1 ± 1.11 mg/g and forms a stable and homogeneous microemulsion within 3 minutes after 100-fold dilution with purified water. The resulting microemulsion has a particle size of 27.2 ± 0.56 nm. Compared with the ingredient baicalein (gastric tube), self-emulsifying microemulsion of baicalein, when administered orally to rats, increased C _max by 3.1 times and relative bioavailability (AUC) by 3.77 times (Reference Document 6: Chinese Journal of New Drugs, 2010, 19 (5): 371-395).

WenliLIU et al. reported that with caprylic/capric acid triglyceride (ODO, 25%) as oil phase, Cremophor RH40 (53.57%) as emulsifier and transcutol P (21.43%) as co-emulsifier, excess baicalein ingredient and oil phase, the emulsifier and co-emulsifier were stirred at 37° C. for 48 h, the mixture was centrifuged at 12,000 rpm for 20 min, and the supernatant was collected to obtain a self-emulsifying microemulsion encapsulating the baicalein ingredient, which has a maximum drug load of 32.02 mg/g and a size particles 27.54 nm after emulsification with water. Compared to a suspension of the ingredient baicalein (dispersed in a solution of 0.5% sodium carboxymethyl cellulose), self-emulsifying microemulsion of baicalein, when administered orally to rats, increased C _max by 1.6-fold and relative bioavailability (AUC) by 2.01-fold (Reference Document 7: Fitoterapia, 2012, 83: 1532-1539).

The self-emulsifying microemulsions prepared in References 6 and 7 significantly improve the oral bioavailability of baicalein. However, confirmatory experiments show that self-emulsifying microemulsions still have the following defects.

(1) The resulting self-emulsifying baicalein microemulsions readily form semi-solids or precipitate after being placed at 4°C, and drugs precipitate after being placed at room temperature for one month.

(2) Under the given conditions of oil phase, emulsifier, and co-emulsifier, drug loading of baicalein is difficult to further increase, which cannot meet the drug loading requirement for clinical treatment.

(3) Compared with the baicalein ingredient, self-emulsifying microemulsions increase _Cmax and AUC to a limited extent.

In addition, Changshun LIU et al. compared the pharmacokinetics of baicalin (BG), baicalin-phospholipid complex (BGPC), baicalin-containing SMEDDS (BG-SMEDDS), and SMEDDS with baicalin-phospholipid complex as an intermediate (BGPC-SMEDDS) in rats. The results show that compared to BG, BGPC, BG-SMEDDS and BGPC-SMEDDS have elevated plasma concentrations, and C _max 3.89, 11.01 and 6.70 times greater than in BG, and AUC _{0 →24 h} 2.46, 2.86 and 2.38 times higher than these values in BG. That is, for C _max baicalin self-emulsifying microemulsion > baicalin-phospholipid complex self-emulsifying microemulsion > baicalin-phospholipid complex; and for AUC _{0→24 h} baicalin self-emulsifying microemulsion > baicalin-phospholipid complex > self-emulsifying baicalin-phospholipid complex microemulsion.

SUMMARY OF THE INVENTION

An ideal self-emulsifying drug-containing composition should satisfy the following conditions: (1) when stored for a long time in a refrigerator or at room temperature, the self-emulsifying composition should be a clear and transparent liquid with a uniform appearance and not be layered; (2) when stored for a long time in the refrigerator or at room temperature, the self-emulsifying composition should be a clear and transparent liquid with a uniform appearance, and should not solidify or precipitate, in order to avoid the process of "heating and melting the drug mixture" before use and reduce degradation of the drug; (3) the self-emulsification efficiency should be high and nano-sized emulsion droplets should be formed as a result of rapid and spontaneous emulsification after dilution with a certain amount of water in a simulated gastrointestinal environment; (4) emulsion droplets resulting from spontaneous emulsification of the self-emulsifying mixture in the gastrointestinal tract after direct oral ingestion should be nano-sized (1-1000 nm) rather than micron-sized (>1 µm).

For drug-containing SEDDS, different drugs have different drug contents and stability due to different physical and chemical properties. In addition, changes in oil phase, emulsifier, co-emulsifier, and ratio will affect drug loading and self-emulsification efficiency, thereby affecting mucosal permeability and bioavailability of SEDDS, which generally do not follow laws.

Through intensive research into pharmaceutical preparations of a flavonoid polyphenol-based drug, the inventors of the present invention found that a self-emulsifying system obtained using a complex of a flavonoid polyphenol-based drug and phospholipids as an intermediate, which is composed of phospholipids and a polyphenol-based drug flavonoid series selected from baicalein, proanthocyanidin, quercetin, curcumin and resveratrol have positive effects in terms of good stability, high drug loading, high bioavailability, and the like.

In view of this, in one aspect, the present invention provides a self-emulsifying flavonoid polyphenol drug composition. Self-emulsifying drug composition based on flavonoid polyphenol series includes a drug complex based on flavonoid polyphenol and phospholipid, an oil phase, an emulsifier and a co-emulsifier, where the drug based on flavonoid polyphenol series includes one or more selected from the group consisting of baicalein, proanthocyanidin , quercetin, curcumin and resveratrol.

Optionally, the flavonoid polyphenol drug may further include other flavonoid polyphenol drugs in addition to baicalein, proanthocyanidin, quercetin, curcumin, and resveratrol, wherein the other flavonoid polyphenol drug is one or more selected from a group consisting of wogonin, ferulic acid, catechin, magnolol, honokiol, apigenin, hesperetin, rotenone, isobavachalcone, aureusidin, delphinidin and ginkgetin.

Preferably, the flavonoid polyphenol drug is baicalein, proanthocyanidin, quercetin, curcumin or resveratrol. Optionally, the self-emulsifying flavonoid polyphenol drug composition has a drug loading of 10-110 mg/g, preferably 10-100 mg/g. Optionally, the self-emulsifying flavonoid polyphenol drug composition has a particle size of 10-1000 nm.

Optionally, in the complex of the flavonoid polyphenol drug and the phospholipid, the weight ratio of the flavonoid polyphenol drug and the phospholipid is 1:1-1:15, optionally 1:1-1:8.

The flavonoid polyphenol-phospholipid drug complex consists of the flavonoid polyphenol-based drug and the phospholipid material. Optionally, the flavonoid polyphenol-phospholipid drug complex has a drug mixing ratio greater than or equal to 80%.

Optionally, the flavonoid polyphenol drug is an extract of the flavonoid polyphenol drug extracted from a traditional Chinese medicine drug and/or a chemically synthesized flavonoid polyphenol drug.

Optionally, baicalein may be artificially synthesized baicalein, an effective component extracted from a plant and characterized by a baicalein content of more than 50%, or a product obtained from a plant extract through transformation or recrystallization.

Optionally, the phospholipid is one or more selected from the group consisting of natural phospholipids and synthetic phospholipids.

Optionally, the natural phospholipids include one or more selected from the group consisting of soybean phospholipid and egg yolk phospholipid.

Optionally, the synthetic phospholipids include one or more selected from the group consisting of phosphoglyceride, sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylserineglycerol, glycerophosphatidic acid, distearylphosphatidylcholine, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine, and dimyristoylphosphatidylcholine. Preferably, the synthetic phospholipids are one or more selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol and glycerophosphatidic acid.

Optionally, the oil phase is one or more selected from the group consisting of vegetable oils and vegetable oil derivatives.

Optionally, vegetable oils include one or more selected from the group consisting of soybean oil, corn oil, olive oil, coconut oil, peanut oil, camellia oil and castor oil;

optional vegetable oil derivatives include one or more selected from the group consisting of sorbitan oleate, glyceryl oleate, glyceryl linoleate, polyethylene glycol glyceryl oleate (Labrafil® 1944cs), glyceryl monolinoleate (Maisine 35-1), ethyl oleate, ethyl linoleate, C8/C10 monoglyceride, coconut C8/C10 diglyceride Coconut Oil, C8/C10 Triglyceride, Caprylic Acid Triglyceride, Caprylic Acid Diglyceride, Caprylic Acid Monoglyceride, Capric Acid Monoglyceride, Capric Acid Diglyceride, Capric Acid Triglyceride, Caprylic/Capric Acid Monoglyceride, Caprylic/Capric Acid Glyceride, Caprylic/Capric Acid Triglyceride , isopropyl myristate, polyethylene glycol glyceryl linoleate (Labrafil®M2125CS), polyethylene glycol glyceryl laurate (Gelucire) and propylene glycol monocaprylate (Capryol 90).

Preferably, the oil phase is one or more phases selected from the group consisting of soybean oil, castor oil, ethyl oleate, isopropyl myristate and caprylic/capric acid glyceride.

Optionally, the emulsifier is one or more selected from the group consisting of caprylic/capric acid polyethylene glycol glyceride (labrazol or labraosol), polyethylene glycol (including PEG-200, PEG-400, PEG-600, PEG-800 (number after PEG means average molecular weight)), Tween (including Tween 20, Tween 21, Tween 40, Tween 60, Tween 61, Tween 80, Tween 81 and Tween 85, preferably Tween 80, Tween 60, Tween 20), Span 80, polyethylene glycol glyceryl oleate (Labrafil® 1944cs), polyethylene glycol glyceryl linoleate (Labrafil® M2125CS), phospholipids and octylphenyl polyoxyethylene ether (X-100). Preferably, the emulsifier is one or more of the following: caprylic/capric acid polyethylene glycol glyceride (labrazol or labraozol), Tween 80, Tween 85, Triton X-100 and Labrafil® 1944cs.

Optionally, the co-emulsifier is one or more co-emulsifiers selected from the group consisting of ethanol, propylene glycol, propylene carbonate, ethylene glycol monoethyl ether, glycerol furfural, dimethyl isosorbide, propylene glycol monocaprylate (Capryol 90), diethylene glycol monoethyl ether (transcutol HP or transcutol P), polyethylene glycol (including PEG-200, PEG-400, PEG-600 and PEG-800 (number after PEG indicates average molecular weight)), glycerin, caprylic/capric acid polyethylene glycol glyceride (labraosole) and benzyl alcohol. Preferably, the co-emulsifier is one or more of diethylene glycol monoethyl ether (transcutol HP or transcutol P), polyethylene glycol 400 (PEG-400), ethanol, and propylene glycol monocaprylate (Capryol 90).

Optionally, based on a total mass fraction of the oil phase, emulsifier and co-emulsifier of 100%, the oil phase is 10-50% (preferably 20-40%), the emulsifier is 30-60% (preferably 40-60%), and the co-emulsifier is 20-60% (preferably 30-50%).

In another aspect, the present invention provides a method for preparing the previous self-emulsifying drug composition based on a flavonoid polyphenol. The method includes the following stages of obtaining.

(1) A flavonoid polyphenol-phospholipid drug complex is prepared: A flavonoid polyphenol-based drug and phospholipids are dissolved in an organic solvent, coupled, and dried to remove the organic solvent to obtain a flavonoid polyphenol-phospholipid drug complex .

Optionally, the organic solvent is one or more selected from the group consisting of ethyl acetate, tetrahydrofuran, methanol, acetone, ethanol, absolute ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, diethyl ether, methyl ethyl ether , dioxane, butanone, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, DMSO and DMF, preferably one or more of ethyl acetate, tetrahydrofuran, methanol, ethanol, cyclohexane, DMSO and DMF.

(2) A self-emulsifying flavonoid polyphenol drug composition is obtained: the flavonoid polyphenol-phospholipid drug complex obtained in step (1) is completely mixed with the oil phase, emulsifier, and co-emulsifier in any order.

For example, the flavonoid polyphenol-phospholipid drug complex obtained in step (1) can be fully mixed directly with the oil phase, emulsifier and co-emulsifier.

Alternatively, the oil phase, emulsifier and co-emulsifier are mixed until homogeneous to obtain a pure self-emulsifying concentrate, and then the flavonoid polyphenol-phospholipid drug complex obtained in step (1) is added to the resulting pure self-emulsifying concentrate and fully mixed with it.

Alternatively, the flavonoid polyphenol-phospholipid drug complex obtained in step (1) is dissolved in either of the oil phase, emulsifier or co-emulsifier, and then the other two are added from the oil phase, emulsifier or co-emulsifier and mixed completely.

In another aspect, the present invention provides a pharmaceutical composition. The pharmaceutical composition includes the previous self-emulsifying flavonoid polyphenol based drug composition and an optional pharmaceutically acceptable excipient.

Optionally, the dosage form of the pharmaceutical composition includes an oral formulation, an injection formulation, a transdermal formulation, a transmucosal formulation, a pulmonary inhalation formulation, or an enteral formulation. Optionally, the dosage form of the pharmaceutical composition provides for drops, oral liquids, tablets, capsules (including soft capsules and hard capsules), granules, infusion granules, films, gel, powders, emulsions, micropills, suppositories, aerosols, sprays, powder aerosols, patches, adhesive plasters, solutions, ointments or creams.

The pharmaceutically acceptable excipient may be any conventional excipient in the pharmaceutical art. The specific excipient is selected depending on the route of administration for the treatment of a particular patient or the type and condition of the disease of a particular patient. For example, a pharmaceutically acceptable excipient includes conventional diluents, carriers, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, absorbent carriers, and lubricants in the pharmaceutical art. Flavorings, preservatives and sweeteners may also be added to the pharmaceutical composition, if necessary.

In another aspect, the present invention provides the use of the previous self-emulsifying flavonoid polyphenol-based drug composition or the previous pharmaceutical composition for the preparation of antibacterial, antiviral, anti-inflammatory, allergy suppressant, immune-regulatory, antitumor, antioxidant, anti-aging drugs. agents, anti-ultraviolet agents, agents for the treatment of hormone deficiency, agents for hypertension, agents for lowering blood fat, agents for atherosclerosis, agents for senile dementia, agents for the treatment of enteroviral vesicular stomatitis, agents for osteoporosis, or agents for protecting the liver.

Positive Effects

The self-emulsifying flavonoid polyphenol drug composition of the present invention has the positive effects of good stability, high drug loading and high bioavailability.

The self-emulsifying flavonoid polyphenol drug composition of the present invention is uniform liquid in appearance and has a drug load that can reach more than 100 mg/g (weight of flavonoid polyphenol drug/composition weight).

The self-emulsifying flavonoid polyphenol drug composition of the present invention is characterized by good self-emulsifying property. After dilution with water by 10-1000 times, the self-emulsifying drug composition based on the polyphenol of the flavonoid series can be quickly emulsified to form droplets with a particle size of 10-1000 nm.

BRIEF DESCRIPTION OF GRAPHICS

FIG. 1 is a graph showing the concentration-time curve of baicalin in the blood plasma of rats in test groups A, B and C in test example 2.

FIG. 2 is a graph showing the concentration-time curve of baicalin in the blood plasma of rats in test groups A, B and C in test example 2.

DETAILED DESCRIPTION

Specific embodiments of the present invention are described in detail below. It is to be understood that the embodiments described herein are intended to be illustrative and not intended to limit the present invention.

In the following examples 1 to 5, the rate of mixing of the flavonoid polyphenol drug and phospholipids in the flavonoid polyphenol drug and phospholipid complex is measured by high performance liquid chromatography (HPLC).

HPLC conditions

Chromatography column: Agilent ZORBAX SB C18 column (250 mm × 4.6 mm, 5 µm);

mobile phase: 0.05% phosphoric acid-methanol (35:65, v/v);

flow rate: 1.0 ml/min;

column temperature: 25°C (normal temperature);

injection volume: 10 μl;

detection wavelength: 275 nm.

Method of determination: 24 mg of a medicinal product based on a flavonoid polyphenol series is accurately weighed for comparison, placed in a 10 ml volumetric flask, absolute ethanol is added until dissolved and diluted to volume. Gently transfer 1 ml into a 100 ml volumetric flask and add absolute ethanol for dilution to the 24 µg/ml solution as a reference solution. Accurately weigh 135 mg of a drug complex based on a flavonoid polyphenol and phospholipid, place in a 50 ml volumetric flask, dissolve in absolute ethanol, dilute to the mark and shake evenly. Carefully transfer 1 ml into a 25 ml volumetric flask, add absolute ethanol until dissolved, dilute to the mark and shake evenly as test solution A. Accurately weigh 135 mg of a drug complex based on a polyphenol of the flavonoid series and a phospholipid, place in a 50 ml volumetric flask , add n-hexane to dissolve, dilute to volume, shake evenly and filter through a 0.45 µm organic membrane. Gently transfer 1 ml of the filtrate into a 25 ml volumetric flask, purge with nitrogen to remove the solvent, add absolute ethanol until dissolved, dilute to the mark and shake evenly as test solution B. Control solution, test solution A and test solution B accurately measure 10 µl each and determined in accordance with the previous HPLC method. The chromatogram is recorded and the content of the flavonoid polyphenol-phospholipid drug complex is calculated by the external standard method according to the peak area, which are recorded as Wsum and Wcom separately.

Mixing speed is calculated using the following formula:

mixing rate % = (Wcom/Wsum)*100%.

Example 1 Baicalein-Phospholipid Complexes Produced at Various Drug-Lipid Ratios (Mat Ratio of Baicalein Ingredient to Soybean Phospholipids)

The baicalein ingredient and soybean phospholipids were accurately weighed according to the drug-lipid ratio in Table 1, placed in a 1000 ml rotary evaporating flask, an appropriate amount of tetrahydrofuran was added, mixed with it, and shaken evenly. After the ingredient baicalein and phospholipids were completely dissolved and the solution of the compound became transparent, the rotary evaporator flask was placed still for 15-30 min and placed on the rotary evaporator so that the solvent evaporated at 40°C. After the substance in the rotary evaporating flask had foamed and taken the form of a honeycomb, continuous rotary evaporation was carried out for 1-2 hours. After obtaining the baicalein-phospholipid complex, the rotary evaporating flask was placed in an oven to dry for 3 days, and then the solids, the baicalein-phospholipid complexes, were carefully scraped off and placed in an oven for storage for later use.

Table 1. Compositions of baicalein-phospholipid complexes with various drug-lipid ratios and degrees of their mixing

Complex No. BAPC-1 BAPC-2 BAPC-3 BAPC-4 BAPC-5 Drug-lipid ratio (w:w) 1:3 1:4 1:5 1:6 1:7 Mixing rate (%) 99.5 100.5 99.3 100.2 99.1

Example 2 Baicalein Phospholipid Complexes Prepared Using Various Organic Solvents

The same method as in example 1 was used, except that the ingredient baicalein and soybean phospholipids were fed in a mass ratio of 1:3.5 (wt./wt.) and ethyl acetate, methanol, acetone, ethanol, absolute ethanol, n -propanol, isopropanol, n-butanol, isobutanol, tert-butanol, diethyl ether, methyl ethyl ether, dioxane, butanone, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, DMSO and DMF were used as solvents to prepare baicalein complexes -phospholipid. The mixing ratios were determined.

The results show that when the previous organic solvents were used, all resulting baicalein-phospholipid complexes had a mixing ratio greater than 80%.

Example 3 Baicalein Phospholipid Complexes Produced Using Various Phospholipids

The same method as in Example 1 was used, except that baicalein and phospholipids were supplied in a mass ratio of 1:3.5 (w/w) and natural phospholipids such as egg yolk phospholipid or soybean phospholipid, or Synthetic phospholipids such as phosphoglyceride, sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, glycerophosphatidic acid, distearylphosphatidylcholine, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine or dimyristoylphosphatidylcholine have been used as lipid materials for the preparation of phospholipid-phospholipid complexes. The mixing ratios were determined.

The results show that all baicalein-phospholipid complexes prepared using the previous phospholipids have a mixing ratio of greater than 80%.

Example 4 Baicalein Phospholipid Complexes Prepared Using Ingredient Baicalein from Various Sources

The same method as in Example 1 was used, except that the baicalein ingredient and soybean phospholipids were fed in a mass ratio of 1:3.5 (w/w), and the resulting chemically synthesized baicalein or baicalein extracts (containing baicalein greater than or equal to 50%) from a traditional Chinese medicine drug was used to prepare a series of baicalein-phospholipid complexes. The mixing ratios were determined.

The synthesized baicalein used in this example was purchased from Nanjing Zelang Biotechnology Co., Ltd.

The baicalein extract used in this example was obtained by the following method: Scutellaria baicalensis powder was sieved through a 20 mesh sieve, five times the volume of water was added to the Scutellaria baicalensis powder, enzymatically hydrolyzed at 38°C for 24 hours, dried to constant weight to obtain an enzymatically hydrolyzed powder Scutellaria baicalensis; then, ethanol with different concentrations (10%, 30%, 50%, 70%, 100%) was added separately to the powder in a 10-fold volume, extracted three times at an ultrasonic power of 70%, each time for 20 minutes, and filtered. The filtrate was distilled under reduced pressure and dried to constant weight so as to obtain extracts of baicalein with various contents.

As a result, all baicalein-phospholipid complexes had a degree of mixing greater than 80%.

Example 5. Obtaining various drug complexes based on a flavonoid polyphenol and a phospholipid

The same method as in Example 1 was used, except that proanthocyanidin, quercetin, curcumin or resveratrol, and soybean phospholipids were supplied in a mass ratio of 1:3.5 (w/w) to obtain a series of drug complexes based on flavonoid polyphenol and phospholipid. The results show that the degree of mixing of the drug was more than 90%, see table 2.

Table 2. Mixing ratios of various drug complexes based on a flavonoid polyphenol and a phospholipid

Complex No. BAPC-6 BAPC-7 BAPC-8 BAPC-9 Medicine Proanthocyanidin Quercetin Curcumin Resveratrol Mixing rate (%) 98.2 99.1 97.8 99.5

The following examples provide comparative examples and test cases:

1. The particle size of the self-emulsifying flavonoid polyphenol drug composition after emulsification was determined by the following method:

200 µl of a self-emulsifying flavonoid polyphenol drug composition was pipetted and slowly added to 20 ml of distilled water (37° C. water bath, slow stirring). The emulsification time of the self-emulsifying flavonoid polyphenol drug composition was recorded, and the emulsified solution was directly measured with a laser particle size analyzer to determine its particle size.

2. Drug loading in a self-emulsifying drug composition based on a flavonoid polyphenol was determined by the following method:

0.5 g of a self-emulsifying flavonoid polyphenol based drug composition was accurately weighed, placed in a 10 ml volumetric flask, dissolved in absolute ethanol, diluted to the mark, and shaken evenly. Carefully transfer 1 ml into a 50 ml volumetric flask, add 95% ethanol (containing 0.02% VC) to dissolve, dilute to the mark and shake evenly as a test solution. 30 mg of a flavonoid polyphenol drug ingredient was accurately weighed, placed in a 25 ml volumetric flask, absolute ethanol was added until dissolved, and diluted to volume. Gently transfer 1 ml into a 50 ml volumetric flask and add 95% ethanol (containing 0.02% VC) to dilute to a 24 μg/ml solution as a control solution. The test solution and control solution were accurately measured at 10 μl each and injected into the liquid chromatograph for separation and analysis. The chromatography column was an Agilent ZORBAX SB C18 column (250 mm × 4.6 mm, 5 μm), mobile phase 0.05% phosphoric acid-methanol (35:65 v/v), flow rate 1.0 ml/v min, the column temperature was 25°C and the detection wavelength was 275 nm. The chromatogram was recorded and the drug load in the self-emulsifying flavonoid polyphenol drug composition was calculated using the external standard method according to the peak area.

Example 6 Screening of oil phase, emulsifier, co-emulsifier used in a self-emulsifying flavonoid polyphenol-based drug composition and their ratio

(a) Preliminary preparation of a self-emulsifying baicalein composition

(1) Baicalein and soybean phospholipids were supplied in a mass ratio of 1:3.5 (w/w), coupled with tetrahydrofuran as a solvent, then the organic solvent was removed and dried to obtain a baicalein-phospholipid complex.

(2) With ethyl oleate as the oil phase, caprylic/capric acid polyethylene glycol glyceride (labraosole) as the emulsifier, and transcutol HP as the co-emulsifier, the oil phase, emulsifier and co-emulsifier were accurately weighed in a ratio of 2:5:3, placed in an appropriate container, and mixed to homogeneity to obtain a pure self-emulsifying concentrate.

(3) An appropriate amount (30% by weight of the pure self-emulsifying concentrate) of the baicalein-phospholipid complex in step (1) was weighed, placed in the pure self-emulsifiable concentrate in step (2), and placed in an oscillator in an air bath at a temperature of 25°C and a rotation speed 210 rpm After complete dissolution of the baicalein-phospholipid complex, a self-emulsifying baicalein composition was obtained.

The results demonstrated that the resulting self-emulsifying composition of baicalein, which is a homogeneous solution, can be fully emulsified within 2 minutes and has a particle size of 10-1000 nm.

(b) Self-emulsifying baicalein compositions prepared using various emulsifiers

A self-emulsifying baicalein composition was prepared in the same manner as in (a), except that labrasol was replaced by one of PEG-400, Tween 80, Tween 60, Tween 20, Tween 85, Span 80, polyethylene glycol glyceryl oleate (Labrafil® 1944cs), polyethylene glycol glyceryl linoleate (Labrafil®M2125CS), phospholipid ester and octylphenyl polyoxyethylene (Triton X-100), combinations of polyethylene glycol glyceride caprylic/capric acid and Tween 80, combinations of polyethylene glycol glyceride caprylic/capric acid and PEG-400, combinations of polyethylene glycol glyceride caprylic/capric acid and octylphenyl polyoxyethylene ether, combinations caprylic/capric acid polyethylene glycol glyceride and phospholipids, a combination of Tween 80 and PEG-400, a combination of Tween 80 and octylphenyl polyoxyethylene ether, or a combination of Tween 80 and phospholipids as an emulsifier to produce a self-emulsifying baicalein composition.

The results demonstrated that the resulting self-emulsifying composition of baicalein, which is a homogeneous solution, can be fully emulsified within 2 minutes and has a particle size of 10-1000 nm.

(c) Self-emulsifying baicalein compositions prepared using various co-emulsifiers

A self-emulsifying baicalein composition was prepared in the same manner as in (a), except that HP transcutol was replaced by one of ethanol, propylene glycol, polyethylene glycol, propylene carbonate, ethylene glycol monoethyl ether, furfural glycerin, dimethyl isosorbide, transcutol P, PEG 400, glycerol, labraosol and benzyl alcohol, HP transcutol and ethanol combinations, HP transcutol and propylene glycol combinations, HP transcutol and PEG 400 combinations, HP transcutol and glycerin combinations, HP transcutol and ethylene glycol monoethyl ether combinations, labraosol and ethanol combinations, labraosol and propylene glycol combinations, labraosol and PEG 400 or a combination of labraosole and glycerol as a co-emulsifier and Tween 80 was used as an emulsifier to prepare a self-emulsifying baicalein composition.

The results demonstrated that the resulting self-emulsifying composition of baicalein, which is a homogeneous solution, can be fully emulsified within 2 minutes and has a particle size of 10-1000 nm.

(d) Self-emulsifying baicalein compositions prepared using various oil phases

The self-emulsifying composition of baicalein was prepared in the same manner as in (a), except that the ethyl oleate was replaced by one of soybean oil, corn oil, olive oil, coconut oil, peanut oil, camellia oil, castor oil, sorbitan oleate, glyceryl oleate, glyceryl linoleate , polyethylene glycol glyceryl oleate (Labrafil®1944cs), Maisine 35-1, ethyl linoleate, C8/C10 monoglyceride, C8/C10 coconut oil diglyceride, C8/C10 coconut oil triglyceride, caprylic acid triglyceride, caprylic acid triglyceride, caprylic acid monoglyceride, capric acid monoglyceride, caprylic acid diglyceride, capric acid triglyceride, caprylic acid monoglyceride, caprylic/capric acid glyceride, caprylic/capric acid triglyceride, isopropyl myristate, polyethylene glycol glyceryl linoleate (Labrafil Capry®M2125CS), Gelucire and Capryol 90, combinations of ethyl oleate and caprylic/capric acid glyceride, combinations of ethyl oleate and isopropyl myristate, a combination of ethyl oleate and soybean oil, a combination of polyethylene glycol glyceryl linoleate and ethyl linoleate, a combination of polyethylene glycol glyceryl linoleate and olive oil, a combination of polyethylene glycol glyceryl linoleate and caprylic acid monoglyceride as the oil phase, and Tween 80 was used as an emulsifier to prepare a self-emulsifying baicalein composition.

The results demonstrated that the resulting self-emulsifying composition of baicalein, which is a homogeneous solution, can be fully emulsified within 2 minutes and has a particle size of 10-1000 nm.

(e) Self-emulsifying baicalein compositions prepared using different ratios of oil phase, emulsifier and co-emulsifier

(1) Baicalein and soybean phospholipids were supplied in a mass ratio of 1:3.5 (w/w), coupled with tetrahydrofuran as a solvent, then the organic solvent was removed and dried to obtain a baicalein-phospholipid complex.

(2) Oil phase, emulsifier and co-emulsifier with ethyl oleate as oil phase, Tween 80 as emulsifier and transcutol HP as co-emulsifier were accurately weighed in the ratio of 10%:60%:30%, 20%:50%:30% or 20 %:40%:40%, based on a total mass fraction of the three components, which is 100%, was placed in an appropriate container and mixed until smooth to obtain a pure self-emulsifying concentrate.

(3) An appropriate amount (30% by weight of the pure self-emulsifying concentrate) of the baicalein-phospholipid complex in step (1) was weighed, placed in the pure self-emulsifiable concentrate in step (2), and placed in an oscillator in an air bath at a temperature of 25°C and a rotation speed 210 rpm After complete dissolution of the baicalein-phospholipid complex, a self-emulsifying baicalein composition was obtained.

The results demonstrated that the resulting self-emulsifying composition of baicalein, which is a homogeneous solution, can be fully emulsified within 2 minutes and has a particle size of 10-1000 nm.

Example 7 Study of drug loading in a self-emulsifying drug composition based on a flavonoid polyphenol

(1) A flavonoid polyphenol drug (baicalein, proanthocyanidin, quercetin, curcumin, and resveratrol) and soybean phospholipids were supplied in a mass ratio of 1:3.5 (w/w), allowing a coupling reaction with tetrahydrofuran as a solvent, then the organic solvent was removed and dried to give a baicalein-phospholipid complex, a proanthocyanidin-phospholipid complex, a quercetin-phospholipid complex, a curcumin-phospholipid complex, and a resveratrol-phospholipid complex, respectively.

(2) With ethyl oleate as the oil phase, labraosole as the emulsifier, and transcutol HP as the co-emulsifier, the oil phase, emulsifier and co-emulsifier were precisely weighed at a ratio of 2:5:3, placed in an appropriate container, and mixed until uniform to obtain a pure self-emulsifying concentrate .

(3) The appropriate amount of baicalein-phospholipid complex, proanthocyanidin-phospholipid complex, quercetin-phospholipid complex, curcumin-phospholipid complex or resveratrol-phospholipid complex in step (1) was weighed, placed in 5 g of oil phase (ethyl oleate) or pure self-emulsifying concentrate on stage (2), heated to 37°C and stirred or shifted so that each phospholipid complex was completely mixed and dissolved. They were placed at room temperature for 24 hours to observe whether the drug precipitated. If no drug precipitated, then an appropriate amount of each phospholipid complex was added and the same procedure continued until no drug precipitated. The supernatant was collected and centrifuged at 12,000 rpm for 20 minutes. The supernatant was then collected and the saturation solubility of each flavonoid polyphenol-phospholipid drug complex in the oil phase and pure self-emulsifying concentrate was determined by the previous HPLC method.

The test results show that the baicalein-phospholipid complex can increase the saturated state solubility of baicalein in oil from 0.3 mg/g to more than 60 mg/g and increase the saturated state solubility of baicalein in a pure self-emulsifying concentrate (drug content in a self-emulsifying composition baicalein) from 20 mg/g to more than 100 mg/g.

The phospholipid complexes of proanthocyanidin, quercetin, curcumin and resveratrol can increase the saturation solubility of their respective active pharmaceutical ingredient in oil to over 60 mg/g and increase the saturation solubility in the pure self-emulsifying concentrate to over 100 mg/g.

The above tests show that the self-emulsifying flavonoid polyphenol drug composition of the present invention has a high drug loading.

Example 8 Self-Emulsifying Baicalein Compositions Prepared Using Various Oil Phases with Baicalein-Phospholipid Complex as an Intermediate

(1) Baicalein and soybean phospholipids were supplied in a mass ratio of 1:3.5 (w/w), coupled with tetrahydrofuran as a solvent, then the organic solvent was removed and dried to obtain a baicalein-phospholipid complex.

(2) With labrosol as emulsifier and transcutol HP as co-emulsifier, and using various oil phases shown in Table 3, the oil phase, emulsifier and co-emulsifier were accurately weighed in a ratio of 2:5:3, placed in a suitable container, and mixed until uniform to obtain a self-emulsifying concentrate.

(3) An appropriate amount of the baicalein-phospholipid complex in step (1) (delivered according to drug loading of 50 mg/g) was weighed, placed in the pure self-emulsifying concentrate in step (2), and placed in an oscillator in an air bath at 25° C and a rotation speed of 210 rpm. After complete dissolution of the baicalein-phospholipid complex, a self-emulsifying baicalein composition was obtained. The drug load and particle size after emulsification were determined. The results are shown in Table 3.

Table 3. Self-emulsifying compositions of baicalein obtained using various oil phases

Composition No. Oil phase Drug Load (mg/g) Emulsification time (min) Particle size (nm) SEDDS-1 Soybean oil 50.23 1 320 SEDDS-2 Castor oil 50.76 1 150 SEDDS-3 Ethyl oleate 50.15 1 280 SEDDS-4 Isopropyl myristate 50.34 1 403 SEDDS-5 Ethyl oleate:caprylic/capric acid glyceride (1:1) 50.54 1 230

Example 9 Self-Emulsifying Baicalein Compositions Prepared Using Various Emulsifiers with a Baicalein-Phospholipid Complex Intermediate

(1) Baicalein and soybean phospholipids were supplied in a mass ratio of 1:3.5 (w/w), coupled with tetrahydrofuran as a solvent, then the organic solvent was removed and dried to obtain a baicalein-phospholipid complex.

(2) With ethyl oleate as the oil phase and transcutol HP as the co-emulsifier, and using various emulsifiers shown in Table 4, the oil phase, emulsifier and co-emulsifier were accurately weighed in a ratio of 2:5:3, placed in a suitable container, and mixed until uniform to obtain a self-emulsifying concentrate.

(3) An appropriate amount of the baicalein-phospholipid complex in step (1) (delivered according to drug loading of 50 mg/g) was weighed, placed in the pure self-emulsifying concentrate in step (2), and placed in an oscillator in an air bath at 25° C and a rotation speed of 210 rpm. After complete dissolution of the baicalein-phospholipid complex, a self-emulsifying baicalein composition was obtained. The drug load and particle size after emulsification were determined. The results are shown in Table 4.

Table 4. Self-emulsifying compositions of baicalein obtained using various emulsifiers

Composition No. Emulsifier Drug Load (mg/g) Emulsification time (min) Particle size (nm) SEDDS-6 Labrazole 50.28 1 280 SEDDS-7 Tween 80 50.34 1 335 SEDDS-8 Triton X-100 50.68 1 280 SEDDS-9 Labrafil®1944cs 50.10 1 200 SEDDS-10 span 80 50.27 1 450

Example 10 Self-Emulsifying Baicalein Compositions Prepared Using Various Co-Emulsifiers with a Baicalein-Phospholipid Complex Intermediate

(1) Baicalein and soybean phospholipids were supplied in a mass ratio of 1:3.5 (w/w), coupled with tetrahydrofuran as a solvent, then the organic solvent was removed and dried to obtain a baicalein-phospholipid complex.

(2) With ethyl oleate as the oil phase and labrosol as the emulsifier, and using various co-emulsifiers shown in Table 5, the oil phase, emulsifier and co-emulsifier were accurately weighed in a ratio of 2:5:3, placed in a suitable container, and mixed until homogeneous with obtaining a self-emulsifying concentrate.

(3) An appropriate amount of the baicalein-phospholipid complex in step (1) (supplied according to the drug content of 50 mg/g) was weighed, placed in a pure self-emulsifying concentrate in step (2), and placed in an oscillator in an air bath at a temperature of 25° C and a rotation speed of 210 rpm. After complete dissolution of the baicalein-phospholipid complex, a self-emulsifying baicalein composition was obtained. The drug load and particle size after emulsification were determined. The results are shown in Table 5.

Table 5. Self-emulsifying compositions of baicalein obtained using various co-emulsifiers

Composition No. co-emulsifier Drug Load (mg/g) Emulsification time (min) Particle size (nm) SEDDS-11 Transcutol HP 50.54 1 280 SEDDS-12 Capryol 90 50.42 1 450 SEDDS-13 ethanol 50.41 1 170 SEDDS-14 propylene glycol 50.23 1 300 SEDDS-15 Glycerol 50.19 1 610

Example 11 Self-Emulsifying Baicalein Compositions Produced at Different Ratios of Oil Phase, Emulsifier and Co-Emulsifier with Baicalein-Phospholipid Complex as an Intermediate

(1) Baicalein and soybean phospholipids were supplied in a mass ratio of 1:3.5 (w/w), coupled with tetrahydrofuran as a solvent, then the organic solvent was removed and dried to obtain a baicalein-phospholipid complex.

(2) With ethyl oleate as the oil phase, labrosol as the emulsifier, and transcutol HP as the co-emulsifier, the oil phase, the emulsifier and the co-emulsifier were precisely weighed at various ratios of the oil phase, emulsifier and co-emulsifier in Table 6, placed in an appropriate container, and mixed until uniform with obtaining a pure self-emulsifying concentrate.

(3) An appropriate amount of the baicalein-phospholipid complex in step (1) (delivered according to drug loading of 50 mg/g) was weighed, placed in the pure self-emulsifying concentrate in step (2), and placed in an oscillator in an air bath at 25° C and a rotation speed of 210 rpm. After complete dissolution of the baicalein-phospholipid complex, a self-emulsifying baicalein composition was obtained. The drug load and particle size after emulsification were determined. The results are shown in Table 6.

Table 6. Self-emulsifying compositions of baicalein obtained at various ratios of the oil phase, emulsifier and co-emulsifier

Composition No. Oil phase: emulsifier: co-emulsifier (w/w) Drug Load (mg/g) Emulsification time (min) Particle size (nm) SEDDS-16 2:4:4 50.31 1 730 SEDDS-17 2:5:3 50.29 1 280 SEDDS-18 2:6:2 50.51 1 260 SEDDS-19 3:4:3 50.30 1 440 SEDDS-20 3:5:2 50.11 1 370

Example 12 Self-Emulsifying Compositions of Baicalein with Different Drug Contents Prepared with a Baicalein-Phospholipid Complex as an Intermediate

(1) Baicalein and soybean phospholipids were supplied in a mass ratio of 1:3.5 (w/w), coupled with tetrahydrofuran as a solvent, then the organic solvent was removed and dried to obtain a baicalein-phospholipid complex.

(2) With ethyl oleate as the oil phase, labrosol as the emulsifier, and transcutol HP as the co-emulsifier, the oil phase, emulsifier and co-emulsifier were accurately weighed in a ratio of 2:5:3, placed in an appropriate container, and mixed until uniform to obtain a pure self-emulsifying concentrate .

(3) Various amounts of the baicalein-phospholipid complex in step (1) were weighed, placed in the pure self-emulsifying concentrate in step (2), and placed in an oscillator in an air bath at 25° C. and 210 rpm. After complete dissolution of the baicalein-phospholipid complex, self-emulsifying baicalein compositions with various drug contents were obtained. The drug content and particle size after emulsification were determined. The results are shown in Table 7.

Table 7. Self-Emulsifying Baicalein Compositions with Different Drug Loads

Composition No. Drug Load (mg/g) Emulsification time (min) Particle size (nm) SEDDS-21 20.18 1 98 SEDDS-22 50.14 1 280 SEDDS-23 70.44 1 400 SEDDS-24 80.65 1 480 SEDDS-25 100.27 1 500

Example 13 Self-Emulsifying Baicalein Compositions Prepared with Baicalein-Phospholipid Complexes with Different Drug-Lipid Ratios as Intermediates

(1) With ethyl oleate as the oil phase, labrosol as the emulsifier, and transcutol HP as the co-emulsifier, the oil phase, emulsifier and co-emulsifier were accurately weighed at a ratio of 2:5:3, placed in an appropriate container, and mixed until uniform to obtain a pure self-emulsifying concentrate .

(2) A series of baicalein-phospholipid complexes in Example 1 (served according to a drug load of 100 mg/g) were weighed, placed in a pure self-emulsifying concentrate in step (1), and placed in an oscillator with an air bath at a temperature of 25°C and a speed rotation 210 rpm. After complete dissolution of the baicalein-phospholipid complex, a self-emulsifying baicalein composition was obtained. The drug load and particle size after emulsification were determined. The results are shown in Table 8.

Table 8 Self-Emulsifying Baicalein Compositions Prepared Using Baicalein-Phospholipid Complexes with Various Drug-Lipid Ratios

Composition No. Baicalein-phospholipid complex No. Drug content (mg/g) Emulsification time (min) Particle size (nm) SEDDS-26 BAPC-1 100.12 1 472 SEDDS-27 BAPC-2 100.23 1 513 SEDDS-28 BAPC-3 100.33 1 535 SEDDS-29 BAPC-4 100.41 1 564 SEDDS-30 BAPC-5 100.27 1 593

Example 14 Preparation of Various Self-Emulsifying Drug Compositions Based on a Flavonoid Polyphenol

(1) With ethyl oleate as the oil phase, labrosol as the emulsifier, and transcutol HP as the co-emulsifier, the oil phase, emulsifier and co-emulsifier were accurately weighed at a ratio of 2:5:3, placed in an appropriate container, and mixed until uniform to obtain a pure self-emulsifying concentrate .

(2) A series of drug complexes based on flavonoid polyphenol and phospholipid (supplied according to drug content of 20 mg/g to obtain compositions SEDDS-31, SEDDS-32, SEDDS-33 and SEDDS-34 and supplied according to load drug 100 mg/g to obtain compositions SEDDS-35, SEDDS-36, SEDDS-37 and SEDDS-38) were weighed, placed in a pure self-emulsifying concentrate in step (1) and placed in an oscillator with an air bath at a temperature of 25°C and rotation speed 210 rpm. After complete dissolution of the drug complex based on the flavonoid polyphenol series and the phospholipid, a self-emulsifying drug composition based on the flavonoid polyphenol series was obtained. The drug load and particle size after emulsification were determined. Self-emulsifying drug compositions based on flavonoid polyphenols with different drug loading and different particle sizes were obtained. The results are shown in Table 9.

Table 9. Self-Emulsifying Flavonoid Polyphenol Drug Compositions Prepared Using Various Flavonoid Polyphenol Drug Phospholipid Complexes

Composition No. Phospholipid Complex No. Drug Load (mg/g) Emulsification time (min) Particle size (nm) SEDDS-31 BAPC-6 20.05 1 85 SEDDS-32 BAPC-7 20.71 1 92 SEDDS-33 BAPC-8 20.32 1 76 SEDDS-34 BAPC-9 20.18 1 105 SEDDS-35 BAPC-6 100.22 1 476 SEDDS-36 BAPC-7 100.47 1 535 SEDDS-37 BAPC-8 100.32 1 512 SEDDS-38 BAPC-9 100.13 1 581

As can be seen from the results of Examples 6-14, all of the self-emulsifying flavonoid polyphenol drug compositions of the present invention can quickly emulsify to form nanosized droplets. Self-emulsifying drug compositions based on flavonoid polyphenols with different drug loadings were obtained in Examples 7-12. The self-emulsifying flavonoid polyphenol drug composition of the present invention is characterized by a drug loading of more than 100 mg/g, if required.

Test Example 1 Physical stability study of the self-emulsifying composition of baicalein of the present invention, the self-emulsifying flavonoid polyphenol microemulsions in Documents 2-7, and the self-emulsifying composition in Comparative Example 1

(1) Comparative Example 1 Preparation of a self-emulsifying baicalein composition encapsulating an ingredient of baicalein.

The oil phase, emulsifier and co-emulsifier were accurately weighed with ethyl oleate as the oil phase, Tween 80 as the emulsifier and transcutol HP as the co-emulsifier, the oil phase, emulsifier and co-emulsifier were accurately weighed in a ratio of 2:5:3, placed in an appropriate container and mixed until homogeneity to obtain a pure self-emulsifying concentrate. The baicalein ingredient was weighed, placed in a pure self-emulsifying concentrate and placed in an oscillator with an air bath at 25°C and a rotation speed of 210 rpm, left to oscillate for 24 hours and centrifuged at 12,000 rpm for 15 minutes. The supernatant was taken to give a self-emulsifying baicalein ingredient composition encapsulating baicalein.

(2) Comparative Example 2 Preparation of a self-emulsifying composition for a silymarin-phospholipid complex

According to the method in Studies on Self-Microemulsifying Drug Delivery Systems (SMEDDS) of Silymarin and Silymarin-Phospholipid Complex [D] (Linjie LIU, Shenyang, Shenyang Pharmaceutical University, 2007) with acetone as a solvent, silymarin and soybean phospholipids with a mass the ratio of 1:1 was heated under reflux at 55°C, concentrated under reduced pressure to a volume of liquid, quickly added to n-hexane to obtain a yellow precipitate. The upper liquid, which was a yellow-white emulsion, was filtered under reduced pressure and the precipitate was washed with n-hexane and dried in a vacuum oven at room temperature to give yellow-white solids, ie. silymarin-phospholipid complex. Weighed 70 g of the silymarin-phospholipid complex, added 250 g of a mixture of ethyl oleate and MCT (1:1), vortexed until dissolved, added 200 g of Cremophor EL and 50 g of transcutol and gently mixed in a water bath at 37°C to obtain a self-emulsifying composition .

(3) According to the formulations and production methods described in documents 2 to 7 (as described in the prior art of the present application), YZ-1 proanthocyanidin self-emulsifying microemulsion, YZ-2 quercetin self-emulsifying microemulsion, YZ-3 curcumin self-emulsifying microemulsion were obtained respectively , YZ-4 resveratrol self-emulsifying microemulsion, YZ-5 self-emulsifying baicalein microemulsion and YZ-6 self-emulsifying baicalein microemulsion.

(4) YZ-1, YZ-2, YZ-3, YZ-4, YZ-5, YZ-6, self-emulsifying composition in Comparative Example 1, and self-emulsifying composition of silymarin in Comparative Example 2, and self-emulsifying composition of baicalein, self-emulsifying composition proanthocyanidin, self-emulsifying quercetin composition, self-emulsifying curcumin composition and self-emulsifying resveratrol composition obtained in the above examples of the present invention were placed at 4°C and room temperature for 5 days, one month and two months separately. Changes in appearance were observed and physical stability was examined. The corresponding results are shown in Table 10.

Table 10

Name original 5 days 1 month 2 months 4°C Room temperature 4°C Room temperature 4°C Room temperature YZ-1 Light and transparent semi-solid Light and transparent semi-solid Light and transparent semi-solid Precipitate of the drug YZ-2 Light and transparent Sediment Light and transparent Sediment Precipitate of the drug Sediment Precipitate of the drug YZ-3 Light and transparent semi-solid Light and transparent semi-solid Precipitate of the drug semi-solid Precipitate of the drug YZ-4 Light and transparent semi-solid Light and transparent semi-solid Light and transparent semi-solid Precipitate of the drug YZ-5 Light and transparent Precipitate of the drug Light and transparent Precipitate of the drug Precipitate of the drug Precipitate of the drug Precipitate of the drug YZ-6 Light and transparent semi-solid Light and transparent semi-solid Precipitate of the drug semi-solid Precipitate of the drug Comparative Example 1 Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Precipitate of the drug Light and transparent Comparative Example 2 Light and transparent Precipitate of the drug Light and transparent Precipitate of the drug Light and transparent Precipitate of the drug Light and transparent SEDDS-4 Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent SEDDS-8 Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent SEDDS-12 Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent SEDDS-16 Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent SEDDS-25 Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent SEDDS-29 Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent SEDDS-31 Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent SEDDS-32 Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent SEDDS-33 Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent SEDDS-34 Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent SEDDS-35 Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent SEDDS-36 Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent SEDDS-37 Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent SEDDS-38 Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent Light and transparent

The results show that the series of self-emulsifying flavonoid polyphenol drug compositions prepared according to Documents 2-7 and Comparative Examples 1 and 2 readily form semi-solids or precipitates after placement at 4°C, and drug precipitates appear after placement. at room temperature for 1-2 months, showing poor stability.

The self-emulsifying flavonoid polyphenol drug compositions with flavonoid polyphenol drug-phospholipid complexes as carriers in the present invention still remain clear and transparent in appearance and have high stability after being placed at 4°C and room temperature in within 2 months.

Test Case 2 Plasma PK Study

(1) Preparation of a self-emulsifying composition of baicalein with a baicalein-phospholipid complex as an intermediate

(a) Baicalein and soybean phospholipids were fed in a mass ratio of 1:3.5 (w/w), coupled with tetrahydrofuran as a solvent, then the organic solvent was removed and dried to obtain a baicalein-phospholipid complex. (b) Oil phase, emulsifier and co-emulsifier accurately weighed with ethyl oleate as oil phase, Tween 80 as emulsifier and transcutol HP as co-emulsifier, oil phase, emulsifier and co-emulsifier accurately weighed in a ratio of 2:5:3, placed in an appropriate container and mixed until smooth to obtain a pure self-emulsifying concentrate. (c) An appropriate amount of the baicalein-phospholipid complex in step (a) was weighed, placed in the pure self-emulsifying concentrate in step (b), and placed in an oscillator in an air bath at 25° C. and 210 rpm. After complete dissolution of the baicalein-phospholipid complex, a self-emulsifying baicalein composition was obtained. The self-emulsifying composition was fully emulsified within 1 min after 100-fold dilution with water, and it was determined that the particle size was 10 nm and the drug loading was 20 mg/g.

(2) Test groups

Test Group A: The self-emulsifying baicalein composition obtained with the baicalein-phospholipid complex as an intermediate in the previous step (1) of the present invention (hereinafter referred to as BAPC-SMEDDS) was administered.

Test Group B: The self-emulsifying baicalein composition encapsulating the baicalein ingredient in Comparative Example 1 (hereinafter referred to as OBA-SMEDDS) was administered.

Test Group C: Ingredient baicalein (hereinafter referred to as BA) was administered.

(3) Test animals

Sprague-Dawley rats (male, 200 g) were fed for one week before the tests, they were forbidden to eat but not drink the night before the tests, and they were freely given water during the tests.

(4) Mode of administration and dosage

15 rats were randomly divided into three groups (test group A, test group B and test group C separately) with 5 rats in each group. Through a gastric tube (2-3 ml) a dose of 40 mg/kg was administered. 0.3 ml of blood was taken from the retroorbital venous plexus at 5, 15, 30, 45, 60, and 75 minutes and at 3, 6, 8, 10, 12, and 24 hours after injection, placed in a pre-heparinized conical centrifuge tube with a volume of 1, 5 ml and centrifuged at 4000 rpm for 15 min. The upper plasma was aspirated, stored in a refrigerator at -80°C and thawed at normal temperature before determination.

(5) Determination of plasma concentration

Processing of plasma samples: 100 µl of plasma was taken, placed in a 1.5 ml conical centrifuge tube, 10 µl of ascorbic acid (200 mg/ml), 20 µl of internal standard solution (500 ng/ml) and 300 µl of methanol were added, mixed for vortex for 60 s and centrifuged at 12,000 rpm for 10 min. Then the supernatant was aspirated, placed in a centrifuge tube, concentrated by centrifugation to remove the solvent (40°C), 200 μl of methanol:water (80:20) was added to dissolution, vortexed for 30 s and centrifuged at 12,000 rpm for 5 min. 20 μl of the supernatant was injected and the plasma concentration was determined under the following chromatography conditions (liquid chromatography-mass spectrometry).

HPLC conditions

Chromatography column: Agilent ZORBAX SB C18 column (250 mm × 4.6 mm, 5 µm);

flow rate: 1.0 ml/min;

injection volume: 20 µl;

column temperature: 25°C;

Mobile phase (elution gradient, see Table 11): acetonitrile-0.1% formic acid as eluent.

Table 11. Gradient elution of LC mobile phase

Time (min) Flow rate (ml/min) Eluent ratio (%) (v/v) acetonitrile 0.1% formic acid 0 1.0 20 80 5 1.0 thirty 70 20 1.0 50 50 25 1.0 20 80 thirty 1.0 20 80

Mass spectrometry conditions:

electrospray ion source (ESI), positive ion mode, multiple reaction monitoring (MRM).

Other parameters: sprayer pressure 40 psi inch, drying gas flow rate 9 l/min, drying gas temperature 350°C, capillary voltage 4000 V and dividing ratio 1:2.

MRM detection ion pair for quantitation: baicalin [M+H] + 447.0 → 271.1;

baicalein [M+H] + 271.1 → 122.8;

6-hydroxyflavone [M+H] + 239.0 → 137.0.

(6) Test results

6.1. After oral administration, baicalein is rapidly metabolized to baicalin in intestinal epithelial cells and liver tissues. The concentration-time curve of baicalin in blood plasma and the corresponding pharmacokinetic parameters are shown in FIG. 1 and in table 12.

The results show that the C _max and AUC _(0-t) of the self-emulsifying composition of baicalein with the baicalein-phospholipid complex as an intermediate of the present invention are 7.7 and 4.5 times higher than that of the baicalein ingredient, respectively, and 1.9 times and 1.3 times higher than the self-emulsifying composition of baicalein encapsulating baicalein, respectively. The relative bioavailability of BAPC-SMEDDS and the relative bioavailability of OBA-SMEDDS (relative to the ingredient baicalein), calculated from the plasma concentration of baicalin, were 448.7% and 342.5%, respectively.

Table 12. Pharmacokinetic parameters of baicalin in blood plasma

Name Unit rev. BAPC-SMEDDS OBA-SMEDDS BA AUC (0-t) mg/l*min 3802.1 ± 1194.3 2901.7 ± 210.9 847.3 ± 302.003 AUC (0-∞) mg/l*min 3823.3 ± 1198.7 2939.2 ± 220.8 848.9 ± 301.8 MRT (0-t) min 320.0±44.5 420.2 ± 69.2 354.9 ± 34.4 MRT (0-∞) min 327.6 ± 47.0 436.2 ± 88.8 357.7 ± 36.5 _Tmax min 42.0 ± 26.8 45.0±18.4 57.0 ± 16.4 _Cmax mg/l 15.3±2.2 8.2 ± 1.9 2.0±0.6 Relative bioavailability % 448.7 342.5 100.0

6.2. The plasma concentration-time curve of baicalein and the corresponding pharmacokinetic parameters are shown in FIG. 2 and in Table 13. C _max and AUC _(0-t) of the self-emulsifying composition of baicalein with the baicalein-phospholipid complex as an intermediate of the present invention are 4.6 and 3.7 times higher than that of the baicalein ingredient, respectively, and 1, 9 times and 1.2 times higher than self-emulsifying baicalein composition encapsulating baicalein, respectively. The relative bioavailability of BAPC-SMEDDS and the relative bioavailability of OBA-SMEDDS (relative to the ingredient baicalein) calculated from the plasma concentration of baicalein were 374.4% and 302.3%, respectively.

Table 13. Pharmacokinetic parameters of baicalein in blood plasma

Name Unit rev. BAPC-SMEDDS OBA-SMEDDS BA AUC (0-t) mcg/l*min 59404.7 ± 18640.9 47961.5 ± 10615.8 15864.8 ± 8964.4 AUC (0-∞) mcg/l*min 59612.0 ± 18614.0 51506.9 ± 10466.6 15880.4 ± 8996.5 MRT (0-t) min 254.2 ± 41.1 355.1 ± 71.4 239.8 ± 51.6 MRT (0-∞) min 259.6 ± 48.9 476.3 ± 234.6 240.5±52.8 _Tmax min 48.0 ± 16.4 39.0 ± 27.2 75.0±64.5 _Cmax µg/l 451.0 ± 365.6 238.0±72.5 99.1 ± 42.0 Relative bioavailability % 374.4 302.3 100.0

Claims (28)

1. Self-emulsifying composition of a medicinal product based on a flavonoid polyphenol for the preparation of drugs for the treatment of diseases selected from the group: against bacteria, against viruses, anti-inflammatory agents, agents for suppressing allergies, agents for regulating immunity, antitumor agents, antioxidants, anti-aging agents, anti-ultraviolet agents, hormone deficiency agents, anti-hypertension agents, blood fat-lowering agents, atherosclerosis agents, senile dementia agents, enteroviral vesicular stomatitis agents, osteoporosis agents or liver protection agents, containing a complex a flavonoid polyphenol drug and a phospholipid, an oil phase, an emulsifier and a co-emulsifier, wherein the flavonoid polyphenol drug is baicalein; the mass ratio of baicalein and phospholipid is 1:1-1:8; the oil phase is one or more selected from the group consisting of ethyl oleate, isopropyl myristate and caprylic/capric acid glyceride; the emulsifier is one or more selected from the group consisting of caprylic/capric acid polyethylene glycol glyceride, Tween 80, octylphenyl polyoxyethylene ether; the co-emulsifier is propylene glycol monocaprylate and/or diethylene glycol monoethyl ether; And in terms of the total mass fraction of the oil phase, emulsifier and co-emulsifier, which is 100%, the oil phase is 10-30%, the emulsifier is 40-60% and the co-emulsifier is 30-40%. 2. The self-emulsifying flavonoid polyphenol drug composition according to claim 1, wherein the self-emulsifying flavonoid polyphenol-based drug composition has a particle size after emulsification of 10-1000 nm. 3. Self-emulsifying drug composition based on polyphenol flavonoid series according to claim 1 or 2, where the phospholipids are one or more selected from the group consisting of natural phospholipids and synthetic phospholipids; where natural phospholipids include one or more selected from the group consisting of soybean phospholipid and egg yolk phospholipid; where the synthetic phospholipids include one or more selected from the group consisting of phosphoglyceride, sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylseringglycerin, glycerophosphatidic acid, distearylphosphatidylcholine, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine and dimyristoylphosphatidylcholine. 4. The self-emulsifying flavonoid polyphenol drug composition of claim 3, wherein the synthetic phospholipids are one or more selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, and glycerophosphatidic acid. 5. The self-emulsifying flavonoid polyphenol drug composition according to claim 1 or 2, wherein the caprylic/capric acid glyceride is a caprylic/capric acid triglyceride. 6. The flavonoid polyphenol self-emulsifying drug composition according to claim 1 or 2, wherein the flavonoid polyphenol self-emulsifying drug composition has a drug loading of 10-110 mg/g. 7. The self-emulsifying flavonoid polyphenol drug composition of claim 6, wherein the self-emulsifying flavonoid polyphenol drug composition has a drug load of 10-100 mg/g. 8. A method for producing a self-emulsifying drug composition based on a flavonoid polyphenol according to any one of paragraphs. 1-7, including the following stages of obtaining: (1) Preparation of a flavonoid polyphenol-phospholipid drug complex: A flavonoid polyphenol-based drug and a phospholipid are dissolved in an organic solvent, coupled, and dried to remove the organic solvent to obtain a flavonoid polyphenol-phospholipid drug complex ; (2) preparing a self-emulsifying flavonoid polyphenol drug composition: the flavonoid polyphenol-phospholipid drug complex obtained in step (1) is fully mixed with the oil phase, emulsifier, and co-emulsifier in any order. 9. The method according to claim 8, where in step (1) the organic solvent is one or more selected from the group consisting of ethyl acetate, tetrahydrofuran, methanol, acetone, ethanol, absolute ethanol, n-propanol, isopropanol, n-butanol , isobutanol, tert-butanol, diethyl ether, methyl ethyl ether, dioxane, butanone, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, DMSO and DMF. 10. The method of claim 9 wherein in step (1) the organic solvent is one or more selected from the group consisting of ethyl acetate, tetrahydrofuran, methanol, ethanol, cyclohexane, DMSO and DMF. 11. The method according to claim 8, wherein in step (2) the flavonoid polyphenol-phospholipid drug complex obtained in step (1) is completely mixed directly with the oil phase, emulsifier and co-emulsifier. 12. The method according to claim 8, where in step (2) the oil phase, emulsifier and co-emulsifier are mixed until homogeneous to obtain a pure self-emulsifying concentrate, and then the drug complex based on the polyphenol flavonoid series and the phospholipid obtained in step (1) is added to obtained pure self-emulsifying concentrate and completely mixed with it. 13. The method of claim 8, wherein in step (2), the flavonoid polyphenol-phospholipid drug complex obtained in step (1) is dissolved in any of the oil phase, emulsifier, or co-emulsifier, and then the other two are added from the oil phase. phase, emulsifier or co-emulsifier and completely mixed. 14. Pharmaceutical composition for the preparation of medicines for the treatment of diseases selected from the group: against bacteria, against viruses, anti-inflammatory drugs, allergy suppressants, immunity regulators, antitumor agents, antioxidants, anti-aging agents, anti-ultraviolet agents, agents for treatment of hormone deficiency, anti-hypertension, blood fat-lowering agents, anti-atherosclerosis agents, anti-senile dementia agents, enteroviral vesicular stomatitis agents, osteoporosis agents or liver protection agents, containing a self-emulsifying drug composition based on polyphenol flavonoid row according to any one of paragraphs. 1-7 and a pharmaceutically acceptable excipient. 15. The pharmaceutical composition of claim 14, wherein the dosage form of the pharmaceutical composition comprises an oral preparation, an injection preparation, a transdermal preparation, a transmucosal preparation, a pulmonary inhalation preparation, or an enteral preparation. 16. The pharmaceutical composition according to claim 14, where the dosage form of the pharmaceutical composition provides for drops, liquids for oral administration, tablets, capsules, granules, infusion granules, films, gel, powders, emulsions, micropills, suppositories, aerosols, sprays, powder aerosols, patches, adhesive plasters, solutions, ointments or creams. 17. The use of a self-emulsifying drug composition based on a flavonoid polyphenol according to any one of paragraphs. 1-7 or a pharmaceutical composition according to any one of paragraphs. 14-16 to obtain medicines for the treatment of diseases selected from the group: anti-bacteria, anti-virus, anti-inflammatory agents, allergy suppressants, immune-regulating agents, anti-tumor agents, antioxidants, anti-aging agents, anti-ultraviolet agents, treatment agents. lack of hormones, anti-hypertension agents, blood fat-lowering agents, anti-atherosclerosis agents, anti-senile dementia agents, enteroviral vesicular stomatitis agents, osteoporosis agents, or liver protection agents.

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