Self-emulsifying compositions of flavonoid polyphenol-based drugs, methods for their preparation, pharmaceutical compositions and uses

Abstract

A self-emulsifying composition of a flavonoid polyphenol-based drug based on a flavonoid polyphenol-phospholipid complex as an intermediate comprises a flavonoid polyphenol-phospholipid complex, an oil phase, an emulsifier, and an emulsifier aid, wherein the flavonoid polyphenol-based drug comprises one or more selected from the group consisting of baicalein, proanthocyanidin, quercetin, curcumin, and resveratrol. The self-emulsifying composition has beneficial effects such as good stability, high drug loading, and high bioavailability.

Description

[Technical Field]

[0001] The present invention relates to a self-emulsifying composition of flavonoid polyphenol drugs, its preparation method, pharmaceutical composition and use, which belong to the pharmaceutical field. [Background technology]

[0002] Flavonoid polyphenolic compounds are currently generally divided into three types: (1) small-molecule phenolic acids, such as salicylic acid, cinnamic acid, parahydroxycinnamic acid, caffeic acid, ferulic acid, and chlorogenic acid; and (2) tannins, which are polyphenol polymers and are divided into condensed tannins and hydrolyzed tannins. The former are polyphenols with different degrees of polymerization in which flavanols are linked by C4-C6 or C4-C8 bonds and are also called proanthocyanidins. The latter are formed by esterification of gallic acid or ellagic acid with the hydroxyl groups of sugars such as glucose. (3) Polyhydroxyflavones, one type being anthocyanin (a glycoside of anthocyan), a type of plant pigment, and the other types being flavones in the narrow sense and their glycosides, and aglycones include flavones, flavonols, flavanones, flavanonols, isoflavones, isoflavones, chalcones, aurones, flavans, anthocyans, biflavones, and flavonoids (see Non-Patent Document 1).

[0003] Research has shown that flavonoid polyphenol drugs have a wide range of pharmacological effects, such as antitumor, anticoagulant, antibacterial, hormone regulation, antioxidant, anti-aging, anti-atherosclerosis, anti-infection, anti-osteoporosis, antiviral, antimicrobial, blood lipid regulation and blood sugar reduction.

[0004] Due to the limitations of their physicochemical properties, oral formulations of flavonoid polyphenol drugs have poor bioavailability and poor therapeutic efficacy. Therefore, using pharmaceutical techniques to increase the blood concentration (Cmax) and blood exposure (AUC) of oral administration is of great clinical significance.

[0005] Self-emulsifying drug delivery systems (SEDDS) are homogeneous mixtures of an oil phase, an emulsifier, and an emulsifier co-agent. They can be used as drug carriers and delivery tools, and after oral administration, they can rapidly self-emulsify to form oil-in-water emulsion droplets in the aqueous medium environment of the gastrointestinal tract and gastrointestinal fluids.

[0006] Wang Zhiqin et al. reported that a self-assembled microemulsion loaded with proanthocyanidin raw materials was prepared using caprylic / capric triglyceride as the oil phase, polyoxyethylene 40 castor oil as the emulsifier, and 1,2-propylene glycol as the emulsifying aid. When the mass ratio of the three components was 1:3:1, emulsification was rapid and the drug loading was 10%. They weighed out polyoxyethylene 40 castor oil, 1,2-propylene glycol, and caprylic / capric triglyceride in the formulation ratio, stirred them in a water bath at 37°C to homogeneously mix them, added the prescribed amount of proanthocyanidins, mixed them, and dissolved them. The mixture was then left to stand at 37°C for 1 hour to obtain a self-assembled microemulsion of proanthocyanidins. After diluting the self-assembled microemulsion 100 times with water, the average particle size was (63.6±0.7) nm (see Non-Patent Document 2).

[0007] Zhang Weiling et al. reported that polyethylene glycol glyceryl oleate was used as the oil phase, polyoxyethylene 35 castor oil as the emulsifier, and diethylene glycol monoethyl ether as the emulsifier co-emulsifier in a ratio of 27.0:55.6:17.4 (w:w:w). Excess quercetin raw drug, the oil phase, the emulsifier, and the emulsifier co-emulsifier were placed in a 60°C constant temperature water bath with magnetic stirring to prepare a supersaturated solution of quercetin. The solution was shaken at room temperature for 24 hours to achieve equilibrium, and then centrifuged at 4000 r / min for 10 minutes to remove the supernatant, yielding a self-supporting microemulsion loaded with quercetin raw drug. The maximum drug content was 67.87 mg / g, and after dilution 50 times with water, the average particle size was 25.26 nm (see Non-Patent Document 3).

[0008] Li Zemin et al. reported that by uniformly mixing an excess of curcumin with the oil phase, emulsifier, and co-emulsifier (MCT:PEG-400:Cremophor RH40 = 2:2:6 (w / w)), the mixture was swirled for 5 minutes and then shaken at 37°C for 48 hours in the dark. The sample was then centrifuged at 12,000 r / min for 10 minutes and the supernatant was carefully separated. This resulted in the preparation of a self-supporting microemulsion containing curcumin. The solubility of the microemulsion was significantly improved, with a maximum drug loading of 55.30 mg / g. After dilution 100 times with water, the average particle size was 11.8 nm (see Non-Patent Document 4).

[0009] Cao Luo et al. reported that a blank self-assembled microemulsion was prepared by mixing triacetin as an oil phase, Cremophor EL and Cremophor RH40 as emulsifiers, and isopropanol as an emulsifying aid in a ratio of triacetin:Cremophor EL:Cremophor RH40:isopropanol = 22:27:13.5:37.8 (w / w) in a water bath at 37°C with magnetic stirring to homogeneity. An appropriate amount of resveratrol was then added to the blank self-assembled microemulsion and dissolved by ultrasound to obtain a resveratrol self-assembled microemulsion with a drug loading of 45 mg / g. After diluting 100 times with water, the average particle size was 15 nm (see Non-Patent Document 5).

[0010] Self-microemulsions of proanthocyanidins, quercetin, curcumin, and resveratrol were prepared using the methods described in References 2 to 5, and then left at 4°C and room temperature for 5 days, 1 month, and 2 months, respectively. Changes in appearance and properties were observed, and their physical stability was examined. As a result, it was found that the self-microemulsion mixtures of flavonoid polyphenol drugs prepared using the formulations in References 2 to 5 all had significant stability defects, and were prone to forming semisolids or precipitating after being left at 4°C, and drug precipitation occurred after being left at room temperature for a while.

[0011] In addition, Ke et al. prepared blank SMEDDS using Migly-col812 / Maisine35-1 (1:1) as the oil phase, CremphorEL35 / Labrasol (2:1) as the emulsifier, and Transcutol P as the emulsifying aid. Excess baicalein was added and dissolved by stirring in a water bath at 37°C. After 24 hours, the mixture was removed and heated at 12,000 r·min -1 The mixture was centrifuged at high speed for 15 minutes at 4°C and the supernatant was removed to prepare a self-suspended microemulsion loaded with baicalein raw material. The maximum drug loading was (18.1±1.11) mg / g. After diluting it 100 times with purified water, a stable and uniform microemulsion was formed within 3 minutes. The particle size of the microemulsion formed was 27.2±0.56 nm. When the baicalein self-suspended microemulsion was orally administered to rats, the Cmax increased by 3.1 times and the relative bioavailability (AUC) increased by 3.77 times compared to the baicalein raw material (administered orally) (see Non-Patent Document 6).

[0012] Wenli Liu et al. used Caprylic triglyceride (ODO, 25%) as the oil phase and Cremophor RH40 (53.57%) as the emulsifier. Using P (21.43%) as an emulsifier, excess baicalein raw drug, oil phase, emulsifier, and emulsifier were stirred at 37°C for 48 hours, and the mixture was then centrifuged at 12,000 rpm for 20 minutes, and the supernatant was collected to finally prepare a self-suspended microemulsion loaded with baicalein raw drug. The maximum drug loading was (32.02) mg / g, and the emulsion particle size after exposure to water was 27.54 nm. When the baicalein self-suspended microemulsion was orally administered to rats, the Cmax was increased by 1.6-fold, and the relative bioavailability (AUC) was increased by 2.01-fold compared to a suspension of baicalein raw drug (dispersed in 0.5% sodium carboxymethylcellulose solution) (see Non-Patent Document 7).

[0013] Although the self-microemulsions prepared in Non-Patent Document 6 and Non-Patent Document 7 both significantly improved the oral bioavailability of baicalein, verification experiments revealed that they still had the following defects:

[0014] (1) The prepared baicalein self-microemulsion mixture was prone to forming a semisolid or precipitation after being left at 4°C, and drug precipitation occurred after being left at room temperature for one month.

[0015] (2) Under the conditions of the given oil phase, emulsifier, and co-emulsifier, the drug loading of baicalein is difficult to further improve, and the drug loading requirements for clinical therapeutic doses cannot be met.

[0016] (3) Compared with the baicalein raw drug, the increase in Cmax and AUC is limited.

[0017] In addition, Liu Changjun et al. compared the pharmacokinetics in rats of baicalin (BG), baicalin phospholipid complex (BGPC), a self-emulsifying administration system directly loaded with baicalin (BG-SMEDDS), and a self-emulsifying administration system using a baicalin-phospholipid complex as an intermediate (BGPC-SMEDDS). They found that the plasma concentrations of BGPC, BG-SMEDDS, and BGPC-SMEDDS were all higher than those of BG, with Cmax values ​​3.89, 11.01, and 6.70 times those of BG, respectively, and AUC 0→24h were 2.46, 2.86, and 2.38 times that of BG, respectively. That is, Cmax was baicalin self-microemulsion > baicalin-phospholipid complex self-microemulsion > baicalin-phospholipid complex, and AUC 0→24h It was found that the order of the emulsions was baicalin self-microemulsion > baicalin-phospholipid complex > baicalin-phospholipid complex self-microemulsion. [Prior art documents] [Non-patent literature]

[0018] [Non-Patent Document 1] Research progress on the biotransformation of polyphenolic chemical components in the intestinal tract [C]. The 8th Annual Meeting of the Department of Traditional Chinese Medicine Chemistry, Chinese Academy of Traditional Chinese Medicine, 2013 [Non-patent document 2] Chinese Medicine, 2013, 35(12):2749~2752 [Non-patent document 3] Shandong University Bulletin, 2016, 54(3):41~49 [Non-patent document 4] Journal of Chengdu Medical Academy, 2017, 12(2):155~59 [Non-Patent Document 5] Cao ▲ Lu ▼. Research and Preparation of Resveratrol [D]. Hebei: Hebei Medical University, 2014 [Non-patent document 6] China New Drug Journal, 2010, 19(5):371~395 [Non-Patent Document 7] Fitoterapia, 2012, 83:1532~1539 Summary of the Invention [Problem to be solved by the invention]

[0019] An ideal drug-loaded self-emulsifying composition must meet the following requirements: (1) It must be a clear, transparent liquid with a uniform appearance and no segregation, even when stored for long periods under refrigerated or room temperature conditions. (2) It must be a clear, transparent liquid with a uniform appearance and no coagulation or precipitation, even when stored for long periods under refrigerated or room temperature conditions, thereby avoiding the need for heating and melting the drug mixture before use and reducing drug degradation. (3) It must have high self-emulsification efficiency and can rapidly self-emulsify to form nanoscale emulsion droplets when diluted with a certain amount of water to simulate the gastrointestinal environment. (4) After direct oral administration of the self-emulsifying mixture, the emulsion droplets formed by spontaneous emulsification in the gastrointestinal tract must be nanoscale (1-1000 nm) and not micronscale (>1 μm).

[0020] For drug-loaded SEDDS, different drugs have different physicochemical properties, resulting in different drug loading and stability. Furthermore, changes in the oil phase, emulsifier, and co-emulsifier, as well as their proportions, all affect the drug loading and self-emulsification efficiency, which in turn affects the mucosal penetration and bioavailability, but these effects are often not consistent.

[0021] As a result of extensive research into flavonoid polyphenol drug formulations, the present inventors have prepared a flavonoid polyphenol drug-phospholipid complex from a phospholipid and a flavonoid polyphenol drug selected from baicalein, proanthocyanidin, quercetin, curcumin, and resveratrol, and have discovered that a self-emulsifying system prepared using this as an intermediate has beneficial effects such as good stability, high drug loading, and high bioavailability. [Means for solving the problem]

[0022] In view of this, in aspect 1, the present invention provides: The present invention relates to a composition comprising a flavonoid polyphenol-phospholipid complex, an oil phase, an emulsifier, and an emulsifier aid, wherein the flavonoid polyphenol-based agent comprises one or more selected from baicalein, proanthocyanidin, quercetin, curcumin, and resveratrol; Preferably, the flavonoid polyphenol-based agent may include another flavonoid polyphenol-based agent other than baicalein, proanthocyanidin, quercetin, curcumin, and resveratrol, and the other flavonoid polyphenol-based agent is one or more selected from wogonin, ferulic acid, catechin, magnolol, honokiol, apigenin, hesperetin, rotenone, isobavachalcone, aureusidin, delphinidin, and ginkgetin; Preferably, the flavonoid polyphenolic agent is baicalein, proanthocyanidin, quercetin, curcumin, or resveratrol; Preferably, the drug loading of the self-emulsifying composition of flavonoid polyphenol drug is 10-110 mg / g, and preferably 10-100 mg / g; Preferably, the self-emulsifying composition of a flavonoid polyphenol drug has a particle size of 10 to 1000 nm.

[0023] Preferably, in the flavonoid polyphenol drug-phospholipid complex, the mass ratio (w / w) of the flavonoid polyphenol drug to the phospholipid is 1:1 to 1:15, and more preferably 1:1 to 1:8.

[0024] The flavonoid polyphenol drug-phospholipid complex is a complex of a flavonoid polyphenol drug and a phospholipid material, and preferably has a drug conjugation rate of 80% or more.

[0025] Preferably, the flavonoid polyphenol-based drug is a flavonoid polyphenol-based drug extract extracted from traditional Chinese medicine and / or a chemically synthesized flavonoid polyphenol-based drug.

[0026] Preferably, the baicalein may be artificially synthesized baicalein, an active ingredient extracted from a plant with a baicalein content of 50% or more, or a product extracted from a plant and prepared by conversion or recrystallization.

[0027] Preferably, the phospholipid is one or more selected from natural phospholipids and synthetic phospholipid materials, Preferably, the natural phospholipids include one or more selected from soybean phospholipids and egg yolk phospholipids, Preferably, the synthetic phospholipid comprises one or more selected from phosphoglyceride, sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, glycerophospholipid acid, distearoylphosphatidylcholine, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine, and dimyristoylphosphatidylcholine, and is preferably one or more selected from phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, and glycerophospholipid acid.

[0028] Preferably, the oil phase is one or more selected from vegetable oils and vegetable oil derivatives, Preferably, the vegetable oil comprises one or more selected from soybean oil, corn oil, olive oil, coconut oil, peanut oil, camellia oil, and castor oil; Preferably, the vegetable oil derivative is 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 oil C8 / C10 diglyceride, coconut oil C8 / C10 triglyceride, caprylic acid triglyceride, caprylic acid diglyceride, caprylic acid monoglyceride. glycerides, capric monoglyceride, capric diglyceride, capric triglyceride, caprylic / capric monoglyceride, caprylic / capric triglyceride, caprylic / capric triglyceride, isopropyl myristate, polyethylene glycol glyceryl linoleate (Labrafil® M2125CS), polyethylene glycol glyceryl laurate (Gelucire), propylene glycol monocaprylate (Capryol 90), Preferably, the oil phase is one or more selected from soybean oil, castor oil, ethyl oleate, isopropyl myristate, caprylic / capric triglyceride.

[0029] Preferably, the emulsifier is polyethylene glycol glyceryl caprylate caprate (labrasol or labraosol), polyethylene glycol (including PEG-200, PEG-400, PEG-600, PEG-800 (the number after PEG represents the average molecular weight)), Tween (including Tween 20, Tween 21, Tween 40, Tween 60, Tween 61, Tween 80, Tween 81, Tween 85, with Tween 80, Tween 60, and Tween 20 being preferred), Span 80 (span 80), polyethylene glycol glyceryl oleate (labrafil® 1944cs), polyethylene glycol glyceryl linoleate (Labrafil® M2125CS), phospholipids, polyoxyethylene octylphenyl ether (X-100), and preferably one or more of polyethylene glycol glyceryl caprylate caprate (labrasol or labraosol), Tween 80, Tween 85, Triton X-100, and labrafil® 1944cs.

[0030] Preferably, the emulsifier is one or more selected from 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 (the number after PEG indicates the average molecular weight)), glycerin, polyethylene glycol glyceryl caprylate and caprate (labraosol), and benzyl alcohol, and more preferably 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).

[0031] Preferably, when the total mass ratio of the oil phase, emulsifier, and emulsifier aid is taken as 100%, the oil phase is 10% to 50% (preferably 20% to 40%), the emulsifier is 30% to 60% (preferably 40% to 60%), and the emulsifier aid is 20% to 60% (preferably 30% to 50%).

[0032] In aspect 2, (1) Preparation of a flavonoid polyphenol drug-phospholipid complex: dissolving a flavonoid polyphenol drug and a phospholipid material in an organic solvent, and then performing a complex reaction. After that, the organic solvent is removed and the resulting mixture is dried to obtain a complex. Preferably, the organic solvent is at least one or more selected from ethyl acetate, tetrahydrofuran, methanol, acetone, ethanol, absolute ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, ethyl ether, methyl ethyl ether, dioxane, butanone, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, DMSO, and DMF, and preferably one or more of ethyl acetate, tetrahydrofuran, methanol, ethanol, cyclohexane, DMSO, and DMF; (2) Preparation of a self-emulsifying composition of a flavonoid polyphenol drug: thoroughly mixing the flavonoid polyphenol drug-phospholipid complex obtained in step (1) with an oil phase, an emulsifier, and an emulsifier co-agent in any order; For example, the flavonoid polyphenol drug-phospholipid complex obtained in step (1) may be directly and thoroughly mixed with an oil phase, an emulsifier, and an emulsifier aid. Alternatively, first, the oil phase, the emulsifier, and the emulsifier aid are uniformly mixed to prepare a blank self-emulsifying concentrate, and then the flavonoid polyphenol drug-phospholipid complex obtained in step (1) is added to the prepared blank self-emulsifying concentrate and mixed thoroughly; or Alternatively, the flavonoid polyphenol drug-phospholipid complex obtained in step (1) may be dissolved in either an oil phase, an emulsifier, or an emulsifier aid, and then the other two components are added and thoroughly mixed; and a method for preparing the self-emulsifying composition of the flavonoid polyphenol drug, comprising:

[0033] In a third aspect, a self-emulsifying composition of the flavonoid polyphenol-based agent and optionally a pharmaceutically acceptable auxiliary material is provided, Preferably, the dosage form of the pharmaceutical composition includes an oral formulation, an injection formulation, a transdermal formulation, a mucosal formulation, a pulmonary inhalation formulation, or an intestinal formulation; Preferably, the dosage form of the pharmaceutical composition is selected from the group consisting of drops, oral liquid, tablets, capsules (including soft capsules and hard capsules), granules, electuaries, films, gels, powders, emulsions, dripping pills, suppositories, aerosols, sprays, powder aerosols, patches, adhesive plasters, liquids, ointments, and creams.

[0034] Pharmaceutically acceptable auxiliary materials may be any conventional auxiliary materials in the field of pharmaceutical preparations.The selection of specific auxiliary materials depends on the administration method or the type and condition of disease for treating a specific patient.For example, pharmaceutically acceptable auxiliary materials may include conventional diluents, carriers, fillers, adhesives, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers and lubricants in the field of pharmacy.If necessary, flavorings, preservatives and sweeteners may be added to the pharmaceutical composition.

[0035] In a fourth aspect, the present invention provides use of the self-emulsifying composition of a flavonoid polyphenol drug or the pharmaceutical composition in the preparation of a medicament for antibacterial, antiviral, anti-inflammatory, allergic reaction suppression, immunomodulatory, antitumor, antioxidant, anti-aging, UV protection, treatment of hormone deficiency, antihypertensive, blood lipid reduction, antiatherosclerosis, anti-senile dementia, treatment of hand, foot and mouth disease, anti-osteoporosis, or liver protection. [Effects of the Invention]

[0036] The self-emulsifying composition of flavonoid polyphenol drugs of the present invention has the beneficial effects of good stability, high drug loading and high bioavailability.

[0037] The self-emulsifying composition of the flavonoid polyphenol drug of the present invention has a uniform liquid appearance and can reach a drug loading of 100 mg / g or more (W flavonoid polyphenol drug / W composition).

[0038] The self-emulsifying composition of the flavonoid polyphenol drug of the present invention has good self-emulsifying ability, and after diluting it with 10 to 1,000 times the amount of water, it can rapidly emulsify to form emulsion droplets with a particle size of 10 to 1,000 nm. [Brief explanation of the drawings]

[0039] [Figure 1] This is a graph of the baicalin concentration-time curve in the plasma of rats in test groups A, B, and C in Test Example 2. [Figure 2] This is a graph showing the baicalein concentration-time curve in the plasma of rats in test groups A, B, and C in Test Example 2. DETAILED DESCRIPTION OF THE INVENTION

[0040] Specific embodiments of the present invention will be described in detail below. It should be understood that the specific embodiments described here are merely for illustrative purposes and are not intended to limit the present invention.

[0041] In the following Examples 1 to 5, the conjugation ratio of the flavonoid polyphenol drug and the phospholipid in the flavonoid polyphenol drug-phospholipid complex is measured using high performance liquid chromatography (HPLC).

[0042] HPLC chromatography conditions: 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: 1.0mL / min, Column temperature: 25°C (room temperature), Injection volume: 10 μL Detection wavelength: 275nm.

[0043] Measurement method: 24 mg of flavonoid polyphenol drug reference material was accurately weighed and placed in a 10 ml volumetric flask. Anhydrous ethanol was added to dissolve and the volume was adjusted to the specified volume. 1 ml was accurately transferred and placed in a 100 ml volumetric flask. Anhydrous ethanol was added to dilute the solution to a concentration of 24 μg / ml, which was used as the reference material solution. 135 mg of flavonoid polyphenol drug-phospholipid complex was accurately weighed and placed in a 50 ml volumetric flask. The solution was dissolved with anhydrous ethanol, diluted to the specified volume, and shaken. 1 ml was accurately weighed and placed in a 25 ml volumetric flask. Anhydrous ethanol was added to dissolve and the solution was diluted to the specified volume, and shaken to use as test solution A. 135 mg of flavonoid polyphenol drug-phospholipid complex was accurately weighed and placed in a 50 ml volumetric flask. The solution was dissolved with n-hexane, adjusted to the specified volume, shaken, and filtered through a 0.45 μm organic membrane. 1 ml of the subsequent filtrate was precisely transferred into a 25 ml measuring flask, the solvent was removed by nitrogen purge, absolute ethanol was added to dissolve, and the solution was diluted to the graduated mark, followed by shaking to obtain test solution B. 10 μl of each of the reference solution, test solution A, and test solution B was precisely weighed and measured according to the above HPLC method, and the chromatograms were recorded. The content of the flavonoid polyphenol drug-phospholipid complex was calculated based on the peak area using the external standard method, and the W 総 and W 複合 It is written as follows.

[0044] The formula for calculating the composite rate is as follows:

number

[0045] Example 1: Baicalein-phospholipid complexes were prepared with different drug-lipid ratios (mass ratio of baicalein raw drug to soybean phospholipid).

[0046] Baicalein raw material and soybean phospholipids were precisely weighed according to the drug-lipid ratios shown in Table 1 and placed in a 1000ml rotary evaporator. An appropriate amount of tetrahydrofuran was added, and the mixture was shaken. After the baicalein raw material and phospholipids were completely dissolved and the composite solution became clear, the mixture was left to stand for 15-30 minutes, then placed in a rotary evaporator at 40°C to evaporate the solvent. After the contents of the rotary evaporator began to foam and form a honeycomb-like structure, the mixture was allowed to evaporate for 1-2 hours. After preparation was complete, the mixture was placed in a drying box and dried for 3 days. The baicalein-phospholipid complex solid was then lightly scraped off and stored in the drying box for further use.

[0047] [Table 1]

[0048] Example 2: Baicalein-phospholipid complexes were prepared in different organic solvents

[0049] The same method as in Example 1 was used, with the following differences: Baicalein raw material and soybean phospholipids were mixed at a mass ratio (w / w) of 1:3.5, and ethyl acetate, methanol, acetone, ethanol, absolute ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, ethyl ether, methyl ethyl ether, dioxane, butanone, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, DMSO, and DMF were used as reaction solvents to prepare baicalein-phospholipid complexes, and the conjugation rate was investigated.

[0050] As a result, it was found that when the above organic solvents were used as reaction solvents, the conjugation rates of all the obtained baicalein-phospholipid complexes were greater than 80%.

[0051] Example 3: Baicalein-phospholipid complexes were prepared with different phospholipids

[0052] The same method as in Example 1 was used, with the following differences: Baicalein raw material was mixed with phospholipids at a mass ratio (w / w) of 1:3.5, and natural phospholipids such as egg yolk phospholipids or soybean phospholipids, or synthetic phospholipids such as phosphoglycerides, sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, glycerophospholipid acid, distearoylphosphatidylcholine, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine, or dimyristoylphosphatidylcholine were used as lipid materials to prepare baicalein-phospholipid complexes, and the complexation rates were investigated.

[0053] As a result, it was found that the conjugation rate of all baicalein-phospholipid complexes prepared with the above phospholipids was 80% or higher.

[0054] Example 4: Baicalein-phospholipid complexes were prepared with different sources of baicalein raw materials

[0055] The same method as in Example 1 was used, with the following differences: Baicalein raw material and soybean phospholipids were mixed at a mass ratio (w / w) of 1:3.5, and a series of baicalein-phospholipid complexes were prepared using either chemically synthesized baicalein or baicalein extract extracted from traditional Chinese medicine (baicalein content ≥ 50%) as the baicalein raw material. The complexation ratio was then investigated.

[0056] The synthetic baicalein used in the examples was purchased from Nanjing Zhoulang Biotechnology Co., Ltd.

[0057] The baicalein extract used in this example was prepared as follows: Scutellaria root powder was sieved through a 20-mesh sieve, 5 times the volume of water was added, and enzymatically hydrolyzed at 38°C for 24 hours. The resulting powder was then dried to a constant weight to obtain enzymatically hydrolyzed Scutellaria root powder. Ten times the volume of ethanol of different concentrations (10%, 30%, 50%, 70%, 100%) was then added, and the resulting powder was subjected to three rounds of extraction using 70% ultrasonic power, each time for 20 minutes. The extraction was then filtered. The filtrate was then distilled under reduced pressure and dried to a constant weight to obtain baicalein extracts with different contents.

[0058] As a result, the baicalein / phospholipid conjugation ratio was 80% or higher in all cases.

[0059] Example 5: Different flavonoid polyphenol drug-phospholipid complexes were prepared

[0060] The same method as in Example 1 was used, with the following differences: A series of flavonoid polyphenol drug-phospholipid complexes were prepared by blending proanthocyanidin, quercetin, curcumin, and resveratrol with soybean phospholipids at a mass ratio (w / w) of 1:3.5. The drug conjugation rates were all found to be 90% or higher, as shown in Table 2.

[0061] [Table 2]

[0062] In the following examples, comparative examples and test examples, 1. The particle size of the emulsion of the obtained self-emulsifying composition of flavonoid polyphenol drug is measured by the following method. 200 μl of the self-emulsifying composition of flavonoid polyphenol-based drugs is transferred using a pipette and slowly added to 20 ml of distilled water (water bath at 37°C, slowly stirred), the emulsification time of the self-emulsifying composition of flavonoid polyphenol-based drugs is recorded, and the solution after emulsification is taken and its particle size is directly measured using a laser particle sizer. 2. The drug loading of the obtained self-emulsifying composition of flavonoid polyphenol drug is measured by the following method. 0.5g of flavonoid polyphenol drug self-emulsifying composition was precisely weighed and placed in a 10ml volumetric flask, dissolved with absolute ethanol, diluted to the mark, and shaken. 1ml was precisely weighed and placed in a 50ml volumetric flask, and 95% ethanol (containing 0.02% VC) was added to dissolve and diluted to the mark, and shaken to prepare the test sample solution. 30mg of flavonoid polyphenol drug raw material was precisely weighed and placed in a 25ml volumetric flask, dissolved with absolute ethanol to the volume, and 1ml was precisely transferred and placed in a 50ml volumetric flask, and diluted with 95% ethanol (containing 0.02% VC) to a concentration of 24μg / ml to prepare the reference substance solution. 10 μL of each test solution and reference substance solution were precisely weighed and injected into a liquid chromatograph for separation and analysis. The column was an Agilent ZORBAX SB C18 column (250 mm × 4.6 mm, 5 μm), the mobile phase was 0.05% phosphoric acid-methanol (35:65, v / v), the flow rate was 1.0 mL / min, the column temperature was 25°C, and the detection wavelength was 275 nm. Chromatograms were recorded, and the drug loading of the self-emulsifying composition of flavonoid polyphenol drugs was calculated based on the peak area using the external standard method.

[0063] Example 6: Selection of oil phase, emulsifier, emulsifier aid, and the ratio of the three components used in a self-emulsifying composition of a flavonoid polyphenol drug

[0064] a. Preliminary preparation of self-emulsifying composition of baicalein (1) Baicalein and soybean phospholipids were mixed in a mass ratio (w / w) of 1:3.5, and tetrahydrofuran was used as the reaction solvent. After the complexation reaction, the organic solvent was removed and the mixture was dried to obtain a baicalein-phospholipid complex. (2) Ethyl oleate was used as the oil phase, polyethylene glycol glyceryl caprylate caprate (labraosol) as the emulsifier, and transcutol HP as the co-emulsifier. The oil phase, emulsifier, and co-emulsifier were precisely weighed in a 2:5:3 ratio and placed in a suitable container. The mixture was then mixed uniformly to obtain a blank self-emulsifying concentrate. (3) Weigh out an appropriate amount (30% of the weight of the blank self-emulsifying concentrate) of the baicalein-phospholipid complex from step (1), add it to the blank self-emulsifying concentrate from step (2), and place it in an air bath vibrator at 25°C and 210 rpm. After the baicalein-phospholipid complex was completely dissolved, a self-emulsifying composition of baicalein was obtained.

[0065] As a result, it was found that the prepared self-emulsifying composition of baicalein was a homogeneous solution, could be completely emulsified within 2 minutes, and had a particle size in the range of 10 to 1000 nm.

[0066] b, Self-emulsifying compositions of baicalein were prepared with different emulsifiers A self-emulsifying composition of baicalein was prepared in the same manner as in (a) above, with the following differences: instead of labrasol, PEG-400, Tween 80, Tween 60, Tween 20, Tween 85, Span 80, polyethylene glycol glyceryl oleate (Labrafil® 1944cs), polyethylene glycol glyceryl linoleate (Labrafil® M2125CS), phospholipids, polyoxyethylene octylphenyl ether (Triton®), and PEG-400 were used. A self-emulsifying composition of baicalein was prepared using one of the following emulsifiers: polyethylene glycol glyceryl caprylate caprate and Tween 80; polyethylene glycol glyceryl caprylate caprate and PEG-400; polyethylene glycol glyceryl caprylate caprate and polyoxyethylene octylphenyl ether; polyethylene glycol glyceryl caprylate caprate and a phospholipid; Tween 80 and PEG-400; Tween 80 and polyoxyethylene octylphenyl ether; or Tween 80 and a phospholipid.

[0067] As a result, it was found that the prepared self-emulsifying composition of baicalein was a homogeneous solution, could be completely emulsified within 2 minutes, and had a particle size in the range of 10 to 1000 nm.

[0068] c, Self-emulsifying compositions of baicalein were prepared with different emulsifiers. A self-emulsifying composition of baicalein was prepared in the same manner as in (a) above, with the following difference: instead of transcutol HP, one of the following emulsifiers was used: ethanol, propylene glycol, polyethylene glycol, propylene carbonate, ethylene glycol monoethyl ether, glycerol furfural, dimethyl isosorbide, transcutol P, PEG400, glycerin, labraosol, or benzyl alcohol; or a combination of transcutol HP and ethanol; or a combination of transcutol HP and propylene glycol; or a combination of transcutol HP and PEG400; or a combination of transcutol HP and glycerin; or a combination of transcutol HP and ethylene glycol monoethyl ether; or a combination of labraosol and ethanol; or a combination of labraosol and propylene glycol; or a combination of labraosol and PEG400; or a combination of labraosol and glycerin; and Tween 80 was used as the emulsifier.

[0069] As a result, it was found that the prepared self-emulsifying composition of baicalein was a homogeneous solution, could be completely emulsified within 2 minutes, and had a particle size in the range of 10 to 1000 nm.

[0070] d, Self-emulsifying compositions of baicalein were prepared with different oil phases. Self-emulsifying compositions of baicalein were prepared in the same manner as above, with the following differences: instead of ethyl oleate, 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, coconut oil C8 / C10 diglyceride, coconut oil C8 / C10 triglyceride, caprylic acid, sorbitan ...sorbitan oleate, sorbitan oleate, polyethylene glycol glyceryl oleate (labrafil® 1944cs), Maisine 35-1, sorbitan oleate, C8 / C10 monoglyceride, coconut oil C8 / C10 diglyceride, coconut oil C8 / C10 triglyceride, caprylic acid, sorbitan oleate, sorbitan oleate, sorbitan oleate, sorbitan oleate, sorbitan oleate, sorbitan oleate, sorbitan oleate, sorbitan oleate, sorbitan oleate, sorbitan oleate, sorbitan oleate, sorbitan oleate, sorbitan oleate, sorbitan oleate, sorbitan oleate, sorbitan oleate, sorbitan oleate, sorbitan ole Liglyceride, Caprylic Diglyceride, Caprylic Monoglyceride, Capric Monoglyceride, Capric Diglyceride, Capric Triglyceride, Caprylic / Capric Monoglyceride, Caprylic / Capric Triglyceride, Isopropyl Myristate, Polyethylene Glycol Glyceryl Linoleate (Labrafil® M2125CS), Gelucire, Capryol A self-emulsifying composition of baicalein was prepared using one of the oil phases selected from the group consisting of glyceryl tri(caprylic / capric) esters, glyceryl tri(ethyl oleate), glyceryl tri(caprylic / capric) esters, glyceryl ethyl oleate, glyceryl isopropyl myristate, glyceryl ethyl oleate, glyceryl ethyl oleate, glyceryl polyethylene glycol linoleate, glyceryl polyethylene glycol linoleate, glyceryl polyethylene glycol linoleate, glyceryl polyethylene glycol linoleate, glyceryl polyethylene glycol monoglyceride caprylate as the oil phase, and Tween 80 as the emulsifier.

[0071] As a result, it was found that the prepared self-emulsifying composition of baicalein was a homogeneous solution, could be completely emulsified within 2 minutes, and had a particle size in the range of 10 to 1000 nm.

[0072] e. Self-emulsifying compositions of baicalein were prepared with different ratios of oil phase, emulsifier, and co-emulsifier. (1) Baicalein and soybean phospholipids were mixed in a mass ratio (w / w) of 1:3.5, and tetrahydrofuran was used as the reaction solvent. After the complexation reaction, the organic solvent was removed and the mixture was dried to obtain a baicalein-phospholipid complex.

[0073] (2) Ethyl oleate was used as the oil phase, Tween 80 as the emulsifier, and Transcutol HP as the emulsifier. The oil phase, emulsifier, and emulsifier were precisely weighed in a ratio of 10%:60%:30%, 20%:50%:30%, or 20%:40%:40%, assuming the sum of the mass ratios of the three components to be 100%. The oil phase, emulsifier, and emulsifier were then placed in a suitable container and mixed uniformly to obtain a blank self-emulsifying concentrate.

[0074] (3) An appropriate amount (30% of the weight of the blank self-emulsifying concentrate) of the baicalein-phospholipid complex from step (1) was weighed and added to the blank self-emulsifying concentrate from step (2), and placed in an air bath vibrator at 25°C and 210 rpm. After the baicalein-phospholipid complex was completely dissolved, a self-emulsifying baicalein composition was obtained.

[0075] As a result, it was found that the prepared self-emulsifying composition of baicalein was a homogeneous solution, could be completely emulsified within 2 minutes, and had a particle size in the range of 10 to 1000 nm.

[0076] Example 7: Drug Loading Considerations of Self-Emulsifying Compositions of Flavonoid Polyphenol Drugs

[0077] (1) Flavonoid polyphenolic agents (baicalein, proanthocyanidin, quercetin, curcumin, and resveratrol) were mixed with soybean phospholipids in a mass ratio (w / w) of 1:3.5, and tetrahydrofuran was used as the reaction solvent. After the complexation reaction, the organic solvent was removed and the mixture was dried to prepare a baicalein-phospholipid complex, a proanthocyanidin-phospholipid complex, a quercetin-phospholipid complex, a curcumin-phospholipid complex, and a resveratrol-phospholipid complex, respectively.

[0078] (2) Ethyl oleate was used as the oil phase, labraosol as the emulsifier, and transcutol HP as the co-emulsifier. The oil phase, emulsifier, and co-emulsifier were precisely weighed in a ratio of 2:5:3, placed in a suitable container, and mixed uniformly to obtain a blank self-emulsifying concentrate.

[0079] (3) Weigh appropriate amounts of the baicalein-phospholipid complex, proanthocyanidin-phospholipid complex, quercetin-phospholipid complex, curcumin-phospholipid complex, and resveratrol-phospholipid complex from step (1) and add them to 5 g of the oil phase (ethyl oleate) or the blank self-emulsifying concentrate from step (2). Heat to 37°C, stir, or shear until each phospholipid complex is thoroughly mixed and dissolved. Allow to stand at room temperature for 24 hours and observe whether the drug precipitates. If no drug precipitates, add an appropriate amount of each phospholipid complex and repeat the procedure until the drug precipitates. Centrifuge the supernatant at 12,000 rpm for 20 minutes. The supernatant was then collected and the saturated solubility of each flavonoid polyphenol drug-phospholipid complex in the oil phase and the blank self-emulsifying concentrate was measured using the HPLC method described above.

[0080] The test results showed that the baicalein-phospholipid complex could increase the saturated solubility of baicalein in oil from 0.3 mg / g to more than 60 mg / g, and increase the saturated solubility of baicalein in the blank self-emulsifying concentrate (i.e., the drug loading of the baicalein self-emulsifying composition) from 20 mg / g to more than 100 mg / g.

[0081] The phospholipid complexes of proanthocyanidins, quercetin, curcumin, and resveratrol were found to have saturated solubilities of 60 mg / g or more in the oil of their respective raw materials, and 100 mg / g or more in the blank self-emulsifying concentrate.

[0082] The above tests demonstrated that the self-emulsifying composition of the flavonoid polyphenol drug of the present invention has a high drug loading.

[0083] Example 8: Self-emulsifying compositions of baicalein were prepared with different oil phases using baicalein-phospholipid complex as an intermediate

[0084] (1) Baicalein and soybean phospholipids were mixed in a mass ratio (w / w) of 1:3.5, and tetrahydrofuran was used as the reaction solvent. After the complexation reaction, the organic solvent was removed and the mixture was dried to obtain a baicalein-phospholipid complex.

[0085] (2) Labrosol was used as an emulsifier, Transcutol HP as an emulsifier aid, and the different oil phases shown in Table 3 below were used. The oil phase, emulsifier, and emulsifier aid were precisely weighed in a ratio of 2:5:3 and placed in an appropriate container. The mixture was then mixed uniformly to obtain a blank self-emulsifying concentrate.

[0086] (3) An appropriate amount of the baicalein-phospholipid complex (formulated with a drug loading of 50 mg / g) from step (1) was weighed and added to the blank self-emulsifying concentrate from step (2), and placed in an air bath vibrator at a temperature of 25°C and a rotation speed of 210 rpm. After the baicalein-phospholipid complex was completely dissolved, a self-emulsifying baicalein composition was obtained, and its drug loading and emulsion particle size were measured. The results are shown in Table 3.

[0087] [Table 3]

[0088] Example 9: Baicalein-phospholipid complex was used as an intermediate to prepare self-emulsifying compositions of baicalein with different emulsifiers

[0089] (1) Baicalein and soybean phospholipids were mixed in a mass ratio (w / w) of 1:3.5, and tetrahydrofuran was used as the reaction solvent. After the complexation reaction, the organic solvent was removed and the mixture was dried to obtain a baicalein-phospholipid complex.

[0090] (2) Ethyl oleate was used as the oil phase, transcutol HP as the emulsifier, and different emulsifiers shown in Table 4 below were used. The oil phase, emulsifier, and emulsifier were precisely weighed in a ratio of 2:5:3 and placed in an appropriate container. The mixture was then mixed uniformly to obtain a blank self-emulsifying concentrate.

[0091] (3) An appropriate amount (formulated with a drug loading of 50 mg / g) of the baicalein-phospholipid complex from step (1) was weighed and added to the blank self-emulsifying concentrate from step (2), and placed in an air bath vibrator at 25°C and 210 rpm. After the baicalein-phospholipid complex was completely dissolved, a self-emulsifying baicalein composition was obtained, and its drug loading and emulsion particle size were measured. The results are shown in Table 4.

[0092] [Table 4]

[0093] Example 10: Baicalein-phospholipid complex was used as an intermediate to prepare self-emulsifying compositions of baicalein with different emulsifiers

[0094] (1) Baicalein and soybean phospholipids were mixed in a mass ratio (w / w) of 1:3.5, and tetrahydrofuran was used as the reaction solvent. After the complexation reaction, the organic solvent was removed and the mixture was dried to obtain a baicalein-phospholipid complex.

[0095] (2) Ethyl oleate was used as the oil phase, labrosol as the emulsifier, and different emulsifiers shown in Table 5 below were used. The oil phase, emulsifier, and emulsifier were precisely weighed in a ratio of 2:5:3 and placed in an appropriate container. The mixture was then mixed uniformly to obtain a blank self-emulsifying concentrate.

[0096] (3) An appropriate amount (formulated with a drug loading of 50 mg / g) of the baicalein-phospholipid complex from step (1) was weighed and added to the blank self-emulsifying concentrate from step (2), and placed in an air bath vibrator at a temperature of 25°C and a rotation speed of 210 rpm. After the baicalein-phospholipid complex was completely dissolved, a self-emulsifying baicalein composition was obtained, and its drug loading and emulsion particle size were measured. The results are shown in Table 5.

[0097] [Table 5]

[0098] Example 11: Baicalein self-emulsifying compositions were prepared with different ratios of oil phase: emulsifier: co-emulsifier using baicalein-phospholipid complex as an intermediate.

[0099] (1) Baicalein and soybean phospholipids were mixed in a mass ratio (w / w) of 1:3.5, and tetrahydrofuran was used as the reaction solvent. After the complexation reaction, the organic solvent was removed and the mixture was dried to obtain a baicalein-phospholipid complex.

[0100] (2) Ethyl oleate was used as the oil phase, labrosol as the emulsifier, and transcutol HP as the emulsifier. The oil phase, emulsifier, and emulsifier were precisely weighed and placed in a suitable container in different ratios of oil phase:emulsifier:emulsifier shown in Table 6 below, and then mixed uniformly to obtain blank self-emulsifying concentrates.

[0101] (3) An appropriate amount (formulated with a drug loading of 50 mg / g) of the baicalein-phospholipid complex from step (1) was weighed and added to the blank self-emulsifying concentrate from step (2), and placed in an air bath vibrator at a temperature of 25°C and a rotation speed of 210 rpm. After the baicalein-phospholipid complex was completely dissolved, a self-emulsifying baicalein composition was obtained, and its drug loading and emulsion particle size were measured. The results are shown in Table 6.

[0102] [Table 6]

[0103] Example 12: Self-emulsifying compositions of baicalein with different drug loadings were prepared using baicalein-phospholipid complex as an intermediate

[0104] (1) Baicalein and soybean phospholipids were mixed in a mass ratio (w / w) of 1:3.5, and tetrahydrofuran was used as the reaction solvent. After the complexation reaction, the organic solvent was removed and the mixture was dried to obtain a baicalein-phospholipid complex.

[0105] (2) Ethyl oleate was used as the oil phase, labrosol as the emulsifier, and transcutol HP as the emulsifier. The oil phase, emulsifier, and emulsifier were precisely weighed in a ratio of 2:5:3 and placed in a suitable container. The mixture was then mixed uniformly to obtain a blank self-emulsifying concentrate.

[0106] (3) Different masses of the baicalein-phospholipid complex from step (1) were weighed and added to the blank self-emulsifying concentrate from step (2), and placed in an air bath vibrator at 25°C and 210 rpm. After the baicalein-phospholipid complex was completely dissolved, self-emulsifying baicalein compositions with different drug loadings were obtained, and their drug loadings and emulsion particle sizes were measured. The results are shown in Table 7.

[0107] [Table 7]

[0108] Example 13: Self-emulsifying compositions of baicalein were prepared using baicalein-phospholipid complexes with different drug-lipid ratios as intermediates

[0109] (1) Ethyl oleate was used as the oil phase, labrosol as the emulsifier, and transcutol HP as the emulsifier aid. The oil phase, emulsifier, and emulsifier aid were precisely weighed in a ratio of 2:5:3 and placed in an appropriate container. The mixture was then mixed uniformly to obtain a blank self-emulsifying concentrate.

[0110] (2) A series of baicalein-phospholipid complexes (formulated with a drug loading of 100 mg / g) obtained in Example 1 were weighed and added to the blank self-emulsifying concentrate from step (1), and placed in an air bath vibrator at a temperature of 25°C and a rotation speed of 210 rpm. After the baicalein-phospholipid complexes were completely dissolved, the self-emulsifying baicalein compositions were obtained, and their drug loading and emulsion particle size were measured. The results are shown in Table 8.

[0111] [Table 8]

[0112] Example 14: Self-emulsifying compositions of different flavonoid polyphenolic agents were prepared

[0113] (1) Ethyl oleate was used as the oil phase, labrosol as the emulsifier, and transcutol HP as the emulsifier aid. The oil phase, emulsifier, and emulsifier aid were precisely weighed in a ratio of 2:5:3 and placed in an appropriate container. The mixture was then mixed uniformly to obtain a blank self-emulsifying concentrate.

[0114] (2) A series of flavonoid polyphenol drug-phospholipid complexes shown in Table 2 (compositions SEDDS-31, SEDDS-32, SEDDS-33, and SEDDS-34 were prepared, each containing a phospholipid complex with a drug loading of 20 mg / g; compositions SEDDS-35, SEDDS-36, SEDDS-37, and SEDDS-38 were prepared, each containing a phospholipid complex with a drug loading of 100 mg / g) were weighed and placed in the blank self-emulsifying concentrate from step (1) and placed in an air bath vibrator at 25°C and 210 rpm. After the flavonoid polyphenol drug-phospholipid complexes were completely dissolved, the self-emulsifying flavonoid polyphenol drug compositions were obtained, and the drug loading and emulsion particle size were measured. Self-emulsifying flavonoid polyphenol drug compositions with different drug loadings and particle sizes were obtained. The results are shown in Table 9.

[0115] [Table 9]

[0116] As can be seen from the results of Examples 6 to 14, all of the self-emulsifying compositions of flavonoid polyphenol drugs of the present invention can be rapidly emulsified to form nanoscale emulsion droplets. In Examples 7 to 12, self-emulsifying compositions of flavonoid polyphenol drugs with different drug loads were prepared, and the drug load of the self-emulsifying compositions of flavonoid polyphenol drugs of the present invention can reach 100 mg / g or more as needed.

[0117] Test Example 1: Consideration of the physical stability of the baicalein self-emulsifying composition of the present invention, the flavonoid polyphenol-based self-microemulsifying compositions of References 2 to 7, and the self-emulsifying composition of Comparative Example 1

[0118] (1) Comparative Example 1: Preparation of a self-emulsifying composition of baicalein loaded with baicalein raw material

[0119] Ethyl oleate was used as the oil phase, Tween 80 as the emulsifier, and Transcutol HP as the emulsifying agent. The oil phase, emulsifier, and emulsifying agent were precisely weighed in a 2:5:3 ratio and placed in a suitable container. The mixture was mixed uniformly to obtain a blank self-emulsifying concentrate. Baicalein raw material was then weighed and added to the blank self-emulsifying concentrate. The mixture was then placed in an air bath vibrator at 25°C and 210 rpm for 24 hours, after which it was centrifuged at 12,000 rpm for 15 minutes. The supernatant was removed to obtain a self-emulsifying baicalein composition loaded with the baicalein raw material.

[0120] (2) Comparative Example 2: Preparation of a self-emulsifying composition of silymarin phospholipid complex

[0121] According to the method described in the literature, "Liu Lin▲Shou▼. Study on Self-Microemulsifying Encapsulation of Silymarin and Its Phospholipid Complex. [D]. Shenyang, Shenyang Pharmaceutical University, 2007," acetone was used as the reaction solvent. Silymarin and soybean phospholipids were mixed in a 1:1 mass ratio. The mixture was heated to reflux at 55°C and concentrated under reduced pressure to a liquid volume. The mixture was then rapidly added to n-hexane to obtain a yellow precipitate. The upper layer was a pale yellow emulsion. The precipitate was filtered under reduced pressure, washed with n-hexane, and dried at room temperature in a vacuum drying box to obtain a pale yellow solid product: silymarin phospholipid complex. 70 g of silymarin phospholipid complex was weighed, added to 250 g of a 1:1 mixture of ethyl oleate and MCT, and dissolved by vortexing. 200 g of Cremophor EL and 50 g of Transcutol were added, and the mixture was gently stirred in a 37°C water bath to obtain the product.

[0122] (3) According to the formulations and preparation methods described in References 2 to 7 (as described in the Background Art of the present application), proanthocyanidin self-microemulsion YZ-1, quercetin self-microemulsion YZ-2, curcumin self-microemulsion YZ-3, resveratrol self-microemulsion YZ-4, baicalein self-microemulsion YZ-5, and baicalein self-microemulsion YZ-6 were prepared, respectively.

[0123] (4) YZ-1, YZ-2, YZ-3, YZ-4, YZ-5, YZ-6, the self-emulsifying composition of Comparative Example 1, the silymarin self-emulsifying composition of Comparative Example 2, the baicalein self-emulsifying composition, the proanthocyanidin self-emulsifying composition, the quercetin self-emulsifying composition, the curcumin self-emulsifying composition, and the resveratrol self-emulsifying composition prepared in the examples according to the present invention were left at 4°C and room temperature for 5 days, 1 month, and 2 months, respectively, and the changes in appearance and properties were observed, and the physical stability was considered. The relevant results are shown in Table 10.

[0124] [Table 10]

[0125] As a result, it was found that the self-emulsifying compositions of a series of flavonoid polyphenol-based drugs prepared in References 2 to 7, Comparative Example 1, and Comparative Example 2 were prone to forming semi-solids or precipitating after being left at 4°C, and drug precipitation occurred when left at room temperature for 1 to 2 months, resulting in poor stability.

[0126] The self-emulsifying composition of the flavonoid polyphenol drug of the present invention, which uses the flavonoid polyphenol drug-phospholipid complex as a carrier, remained clear and transparent in appearance and was highly stable after being left at 4°C and room temperature for 2 months.

[0127] Test Example 2: Plasma Pharmacokinetic Study

[0128] (1) A self-emulsifying composition of baicalein was prepared using a baicalein-phospholipid complex as an intermediate.

[0129] 1) Baicalein and soybean phospholipids were mixed in a mass ratio (w / w) of 1:3.5, and tetrahydrofuran was used as the reaction solvent. After the complexation reaction, the organic solvent was removed and the mixture was dried to obtain a baicalein-phospholipid complex. 2) Ethyl oleate was used as the oil phase, Tween 80 as the emulsifier, and Transcutol HP as the co-emulsifier. The oil phase, emulsifier, and co-emulsifier were precisely weighed in a 2:5:3 ratio and placed in a suitable container. The mixture was then uniformly mixed to obtain a blank self-emulsifying concentrate. 3) An appropriate amount of the baicalein-phospholipid complex from step 1 was weighed and added to the blank self-emulsifying concentrate from step 2. The mixture was then placed in an air bath vibrator at 25°C and 210 rpm. After the baicalein-phospholipid complex was completely dissolved, a baicalein self-emulsifying composition was obtained. After diluting the composition 100 times with water, it was completely emulsified within 1 minute, and its particle size was measured to be 10 nm and drug loading was measured to be 20 mg / g.

[0130] (2) Test grouping

[0131] Test group A: The self-emulsifying composition of baicalein (hereinafter referred to as BAPC-SMEDDS) prepared in (1) above using the baicalein-phospholipid complex of the present invention as an intermediate was administered.

[0132] Test group B: The self-emulsifying composition of baicalein loaded with the baicalein raw material drug in Comparative Example 1 (hereinafter referred to as OBA-SMEDDS) was administered.

[0133] Test group C: Baicalein raw drug (hereinafter referred to as BA) was administered.

[0134] (3) Test animals Sprague-Dawley rats, male, 200 g. The rats were kept for one week before the test, fasted the night before the test, and allowed free access to water during the experiment.

[0135] (4) Dosage form and dosage Fifteen rats were randomly divided into three groups (groups A, B, and C), with five rats per group. A 40 mg / kg dose of 40 mg / kg was administered orally (2-3 ml). At 5, 15, 30, 45, 60, and 75 minutes and 3, 6, 8, 10, 12, and 24 hours after administration, 0.3 ml of blood was collected from the retroorbital plexus. The blood was placed in a pre-heparinized 1.5 ml conical centrifuge tube and centrifuged at 4000 rpm for 15 minutes. The upper layer of plasma was aspirated and stored in a -80°C refrigerator. The blood was then thawed at room temperature before measurement.

[0136] (5) Measurement of blood concentration Plasma sample processing: 100 μL of plasma was taken and placed in a 1.5 mL conical centrifuge tube. 10 μL of ascorbic acid (200 mg / mL) and 20 μL of internal standard solution (500 ng / mL) were added. 300 μL of methanol was added, and the mixture was vortexed for 60 s. After centrifugation at 12,000 r / min for 10 min, the supernatant was aspirated and placed in a centrifuge tube. The mixture was centrifuged to concentrate the solvent, and the solvent was evaporated (40°C). 200 μL of methanol:water (80:20) was added to dissolve the plasma. The mixture was vortexed for 30 s and then centrifuged at 12,000 r / min for 5 min. 20 μL of the supernatant was taken and injected. The blood concentration (LC / MS) was measured under the following chromatographic conditions:

[0137] The HPLC chromatography conditions were as follows: Column: Agilent ZORBAX SB C18 column (250 mm x 4.6 mm, 5 μm) Flow rate: 1.0mL / min Injection volume: 20 μL Column temperature: 25℃ Mobile phase (gradient elution see Table 11): The eluent was acetonitrile-0.1% formic acid.

[0138] [Table 11]

[0139] The mass spectrometry conditions were as follows: Ion source: Electrospray ion source (ESI), detected in positive ion mode, multiple reaction monitoring mode (MRM). Other parameters were: nebulizer kit pressure was 40 psi, drying gas flow rate was 9 L / min, drying gas temperature was 350° C., capillary voltage was 4000 V, and split flow ratio was 1:2. MRM detection ion pair for quantification: Baicalin [M+H] + 447.0 → 271.1 Baicalein [M+H] +271.1 → 122.8 6-Hydroxy brass [M+H]+239.0→137.0

[0140] (6) Test results 6.1 After oral administration of baicalein, it was rapidly metabolized to baicalin in intestinal epithelial cells and liver tissue. The plasma baicalin concentration-time curve and related pharmacokinetic parameters were as shown in Figure 1 and Table 12.

[0141] The results showed that the Cmax of the self-emulsifying baicalein composition using the baicalein-phospholipid complex of the present invention as an intermediate was 7.7-fold and 1.9-fold higher than that of the baicalein raw drug and the self-emulsifying baicalein composition loaded with the baicalein raw drug, respectively, and the AUC(0-t) was 4.5-fold and 1.3-fold higher, respectively. The relative bioavailability of BAPC-SMEDDS and OBA-SMEDDS (relative to the baicalein raw drug) calculated based on the plasma baicalin concentration was 448.7% and 342.5%, respectively.

[0142] [Table 12]

[0143] 6.2 Plasma baicalein concentration-time curves and related pharmacokinetic parameters are shown in Figure 2 and Table 13. The Cmax of the self-emulsifying baicalein composition using the baicalein-phospholipid complex of the present invention as an intermediate was 4.6-fold and 1.9-fold higher, respectively, than that of the baicalein raw drug and the self-emulsifying baicalein composition loaded with the baicalein raw drug, and the AUC(0-t) was 3.7-fold and 1.2-fold higher, respectively. The relative bioavailabilities of BAPC-SMEDDS and OBA-SMEDDS (relative to the baicalein raw drug) calculated based on the plasma baicalein concentration were 374.4% and 302.3%, respectively.

[0144] [Table 13]

Claims

1. A self-emulsifying composition of a polyphenol-based drug, comprising a polyphenol-based drug-phospholipid complex, an oil phase, an emulsifier, and an emulsifier co-agent, The polyphenol drug is baicalein, In the polyphenol-based drug-phospholipid complex, the mass ratio of the polyphenol-based drug to the phospholipid is 1:1 to 1:8; The oil phase is one or more selected from ethyl oleate, isopropyl myristate, and glyceryl (caprylate / caprate); The emulsifier is one or more selected from polyethylene glycol glyceryl caprylate caprate, polysorbate 80, and polyoxyethylene octylphenyl ether; the emulsifier is selected from propylene glycol monocaprylate and / or diethylene glycol monoethyl ether; When the total mass ratio of the oil phase, emulsifier, and emulsifier aid is taken as 100%, the oil phase is 20% to 40%, the emulsifier is 40% to 60%, and the emulsifier aid is 30% to 50%; A self-emulsifying composition of a polyphenol-based drug, characterized in that the drug load of the polyphenol-based drug in the self-emulsifying composition (mg of polyphenol-based drug / g of self-emulsifying composition) is 10 to 110 mg / g.

2. The self-emulsifying composition of polyphenol-based drugs according to claim 1, characterized in that the oil phase is one or more selected from ethyl oleate, isopropyl myristate, and tri(caprylic / capric)glyceryl.

3. The self-emulsifying composition of polyphenol-based drugs according to claim 1, characterized in that the drug loading of the self-emulsifying composition of polyphenol-based drugs is 10-100 mg / g.

4. The self-emulsifying composition of a polyphenol-based drug according to claim 1 or 2, characterized in that emulsified droplets having a particle size of 10 to 1000 nm are formed after the self-emulsifying composition of a polyphenol-based drug is emulsified.

5. The phospholipid is one or more selected from natural phospholipids and synthetic phospholipid materials, The natural phospholipids include one or more selected from soybean phospholipids and egg yolk phospholipids, The self-emulsifying composition of polyphenol-based drugs according to claim 1 or 2, characterized in that the synthetic phospholipid comprises one or more selected from the group consisting of phosphoglycerides, sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, glycerophospholipid acid, distearoylphosphatidylcholine, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine, and dimyristoylphosphatidylcholine.

6. The self-emulsifying composition of polyphenol-based drugs according to claim 5, characterized in that the synthetic phospholipid is one or more selected from phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, and glycerophospholipid acid.

7. (1) Preparation of polyphenolic drug-phospholipid complex: dissolving polyphenolic drug and phospholipid in an organic solvent, undergoing a complexation reaction, removing the organic solvent, and drying to obtain the complex; (2) Preparation of a self-emulsifying composition of a polyphenol-based drug: thoroughly mixing the polyphenol-based drug-phospholipid complex obtained in step (1) with an oil phase, an emulsifier, and an emulsifier aid in any order; 7. A method for preparing a self-emulsifying composition of a polyphenol-based drug according to claim 1, comprising:

8. 8. The method according to claim 7, wherein 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, t-butanol, ethyl ether, methyl ethyl ether, dioxane, butanone, petroleum ether, hexane, cyclohexane, dichloromethane, chloroform, carbon tetrachloride, DMSO, and DMF.

9. 9. The method according to claim 8, wherein in step (1), the organic solvent is one or more of ethyl acetate, tetrahydrofuran, methanol, ethanol, cyclohexane, DMSO, and DMF.

10. The method according to claim 7, wherein in step (2), the polyphenol-phospholipid complex obtained in step (1) is directly and thoroughly mixed with an oil phase, an emulsifier, and an emulsifier co-agent.

11. The method according to claim 7, characterized in that the oil phase, emulsifier and emulsifier co-agent are first uniformly mixed to prepare a blank self-emulsifying concentrate, and then the polyphenol drug-phospholipid complex obtained in step (1) is added to the prepared blank self-emulsifying concentrate and mixed thoroughly.

12. The method according to claim 7, characterized in that the polyphenol-phospholipid complex obtained in step (1) is dissolved in either an oil phase, an emulsifier, or an emulsifier aid, and then the other two components are added and thoroughly mixed.

13. A pharmaceutical composition comprising the self-emulsifying composition of a polyphenol-based drug according to any one of claims 1 to 6, and optionally pharmaceutically acceptable auxiliary materials.

14. The pharmaceutical composition according to claim 13, wherein the dosage form of the pharmaceutical composition comprises an oral formulation or an enteral formulation.

15. 15. The pharmaceutical composition of claim 14, wherein the dosage form of the pharmaceutical composition comprises drops, oral liquid, capsules, emulsion, or liquid.

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