WO2020207417A1 - 黄酮多酚类药物自乳化组合物、其制备方法、药物组合物及用途 - Google Patents

黄酮多酚类药物自乳化组合物、其制备方法、药物组合物及用途 Download PDF

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WO2020207417A1
WO2020207417A1 PCT/CN2020/083837 CN2020083837W WO2020207417A1 WO 2020207417 A1 WO2020207417 A1 WO 2020207417A1 CN 2020083837 W CN2020083837 W CN 2020083837W WO 2020207417 A1 WO2020207417 A1 WO 2020207417A1
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WIPO (PCT)
Prior art keywords
self
emulsifier
baicalein
drug
flavonoid polyphenol
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PCT/CN2020/083837
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English (en)
French (fr)
Inventor
刘玉玲
廖恒锋
高越
董武军
刘志华
王邦源
张运
冯遇
周君卓
刘璐
叶军
杨艳芳
夏学军
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北京五和博澳药业有限公司
中国医学科学院药物研究所
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Application filed by 北京五和博澳药业有限公司, 中国医学科学院药物研究所 filed Critical 北京五和博澳药业有限公司
Priority to AU2020256609A priority Critical patent/AU2020256609B2/en
Priority to EP20787816.6A priority patent/EP3954380A4/en
Priority to MX2021012268A priority patent/MX2021012268A/es
Priority to US17/602,423 priority patent/US11771660B2/en
Priority to KR1020217036618A priority patent/KR102497718B1/ko
Priority to BR112021020359A priority patent/BR112021020359A2/pt
Priority to SG11202111116VA priority patent/SG11202111116VA/en
Priority to CA3132454A priority patent/CA3132454C/en
Priority to JP2021560466A priority patent/JP2022530752A/ja
Publication of WO2020207417A1 publication Critical patent/WO2020207417A1/zh
Priority to ZA2021/08771A priority patent/ZA202108771B/en

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    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
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    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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Definitions

  • the invention relates to a flavonoid polyphenol drug self-emulsifying composition, its preparation method, pharmaceutical composition and application, belonging to the field of medicine.
  • Flavonoid polyphenol compounds are generally divided into three categories: (1) Small molecules of phenolic acids, such as salicylic acid, cinnamic acid, caffeic acid, ferulic acid, chlorogenic acid, etc.; (2) ) Tannin, a polymer of polyphenols, is divided into condensed tannins and hydrolyzed tannins. The former are polyphenols with different degrees of polymerization connected by flavanols through C4-C6 or C4-C8 bonds.
  • proanthocyanidins the latter is formed by esterification of gallic acid or ellagic acid with hydroxyl groups on sugars such as glucose; (3) Polyhydroxyflavonoids, a type of anthocyanin, which is one of plant pigments Glycosides), the other is the narrow sense of flavonoids and their glycosides.
  • Aglycones include flavonoids, flavonols, dihydroflavonoids, dihydroflavonols, isoflavones, dihydroisoflavones, chalcones, orange ketones, flavans , Anthocyanins, diflavonoids, and flavonoids (Document 1: Research progress on intestinal biotransformation of polyphenol chemical components [C]. The 8th Annual Conference of Chinese Medicine Chemistry Branch of Chinese Society of Chinese Medicine, 2013).
  • flavonoid polyphenols have many pharmacological effects, such as anti-tumor, anti-coagulation, antibacterial, regulating hormone, anti-oxidation, anti-aging, anti-atherosclerosis, anti-infection, anti-osteoporosis, anti- Virus, antimicrobial, blood lipid regulation and blood sugar lowering have good effects.
  • Self-emulsifying delivery system is a homogeneous mixture formed by oil phase, emulsifier and co-emulsifier. It can be used as a drug carrier and delivery tool. After oral administration, it can be used in gastrointestinal peristalsis and an aqueous medium of gastrointestinal fluid. Under the environment, it can quickly spontaneously emulsify to form oil-in-water emulsion droplets.
  • MCT medium chain fatty acid
  • Cremophor RH40 polyoxyethylene hydrogenated castor oil
  • PEG-400 polyethylene glycol-400
  • Cremophor RH40 2:2:6(w/w)
  • the sample was taken out at 12000r/min, centrifuged for 10 minutes, and the supernatant was accurately taken to prepare a self-microemulsion containing curcumin bulk drug, which significantly improved its solubility.
  • the maximum drug loading is 55.30mg/g, and the average particle size is 11.8nm after being diluted 100 times with water (Reference 4: Journal of Chengdu Medical College, 2017, 12(2): 155-59).
  • Ke Xue et al. reported using Migly-col812/Maisine35-1 (1:1) as the oil phase, CremphorEL35/Labrasol (2:1) as the emulsifier, and Transcutol P as the co-emulsifier.
  • the blank SMEDDS was prepared according to the prescription and added Excess baicalein was stirred and dissolved in a 37°C water bath, and then taken out after 24h, centrifuged at a high speed of 12,000 r ⁇ min -1 for 15 minutes, and the supernatant was absorbed to prepare a self-microemulsion containing baicalein raw materials.
  • the drug amount is (18.1 ⁇ 1.11) mg/g.
  • the maximum drug load was (32.02) mg/g, the emulsified particle size is 27.54nm after contact with water.
  • the Cmax of baicalein from microemulsion rats orally administered to 1.6 times the relative bioavailability (AUC) increased to 2.01 times (Document 7: Fitorick, 2012, 83:1532-1539).
  • the prepared baicalein self-microemulsion mixture is easy to form semi-solid or precipitate after being placed at 4°C, and the drug will precipitate after being placed at room temperature for one month;
  • Cmax Baicalin self-microemulsion> Baicalin-phospholipid complex self-microemulsion> Baicalin-phospholipid complex
  • AUC 0 ⁇ 24h Baicalin self-microemulsion> Baicalin-phospholipid complex> Baicalin-phospholipid complex Self-microemulsion of things.
  • the ideal drug-loaded self-emulsifying composition should meet the following conditions: (1) Stored for a long time under cold storage or room temperature, it should be a clear and transparent liquid with uniform appearance, and no delamination should occur; (2) Under cold storage or room temperature conditions For long-term storage, it should be a clear and transparent liquid with a uniform appearance, and should not be solidified or precipitated.
  • the present invention provides a flavonoid polyphenol drug self-emulsifying composition, characterized in that the flavonoid polyphenol drug self-emulsifying composition comprises a flavonoid polyphenol drug-phospholipid complex, an oil phase, Emulsifiers and co-emulsifiers, the flavonoid polyphenol drugs include one or more selected from baicalein, proanthocyanidins, quercetin, curcumin and resveratrol.
  • the flavonoid polyphenol drugs may also include baicalein, proanthocyanidins, quercetin, curcumin, and other flavonoid polyphenol drugs other than resveratrol, and the other flavonoid polyphenol drugs are selected from One of wogonin, ferulic acid, catechin, magnolol, honokiol, apigenin, tangerin, rotenone, psoralen, antirrhinum, delphinium, and ginkgo Or multiple.
  • the flavonoid polyphenol drug is baicalein, proanthocyanidin, quercetin, curcumin or resveratrol; optionally, the drug loading amount of the flavonoid polyphenol drug self-emulsifying composition is 10- 110 mg/g, preferably 10-100 mg/g.
  • the particle size of the flavonoid polyphenol drug self-emulsifying composition is 10-1000 nm.
  • the mass ratio (w/w) of the flavonoid polyphenol drug to the phospholipid is 1:1-1:15, and may be 1:1-1: 8.
  • the flavonoid polyphenol drug-phospholipid complex is formed by compounding a flavonoid polyphenol drug and a phospholipid material.
  • the drug compounding rate of the flavonoid polyphenol drug-phospholipid complex is ⁇ 80%.
  • the flavonoid polyphenol drug is a flavonoid polyphenol drug extract extracted from traditional Chinese medicine and/or a chemically synthesized flavonoid polyphenol drug;
  • the baicalein may be artificially synthesized baicalein, an effective component of plant-extracted baicalein with a content of more than 50%, or a plant-extracted product prepared by transformation or recrystallization.
  • 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 synthetic phospholipid comprises selected from the group consisting of glycerophospholipid, sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, glycerophosphatidic acid, distearoylphosphatidyl One or more of choline, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylethanolamine, and dimyristoylphosphatidylcholine; preferably selected from phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol One or more of glycerol phosphatidic acid.
  • the oil phase is one or more selected from vegetable oils and vegetable oil derivatives
  • the vegetable oil includes one or more selected from soybean oil, corn oil, olive oil, coconut oil, peanut oil, camellia oil, and castor oil;
  • the vegetable oil derivative includes selected from the group consisting of sorbitol oleate, glyceryl oleate, glyceryl linoleate, and polyethylene glycol oleate (labrafil 1944cs), monolinoleic acid glyceride (Maisine35-1), 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, Capric acid monoglyceride, Capric acid diglyceride, Capric acid triglyceride, Caprylic acid monoglyceride, Caprylic acid glyceride, Caprylic acid Triglycerides, isopropyl myristate, linoleic acid polyethylene glycol glyceride,
  • the oil phase is one or more selected from soybean oil, castor oil, ethyl oleate, isopropyl myristate, and glyceryl caprylate.
  • the emulsifier is selected from caprylic acid capric acid polyethylene glycol glyceride (labrasol or labraosol), polyethylene glycol (including: PEG-200, PEG-400, PEG-600, PEG-800 (PEG) The following numbers indicate average molecular weight)), Tween (including: Tween 20, Tween 21, Tween 40, Tween 60, Tween 61, Tween 80, Tween 81, Tween 85, preferably Tween 80, Tween 60, Tween 20), Span 80 (span 80), oleic acid polyethylene glycol glyceride (labrafil 1944cs), linoleic acid polyethylene glycol glyceride (Labrafil M2125CS), one or more of phospholipids, and octylphenyl polyoxyethylene ether (X-100); preferably caprylic acid capric acid polyethylene glycol glyceride (labrasol or labraosol), Tween
  • the co-emulsifier is selected from ethanol, propylene glycol, propylene carbonate, ethylene glycol monoethyl ether, glycerol furfural, dimethyl isosorbide, propylene glycol monocaprylate (Capryol 90), two Ethylene glycol monoethyl ether (transcutol HP or transcutol P), polyethylene glycol (including: PEG-200, PEG-400, PEG-600, PEG-800 (the number after PEG indicates the average molecular weight)), glycerin, caprylic acid One or more of labraosol and benzyl alcohol; preferably diethylene glycol monoethyl ether (transcutol HP or transcutol P), polyethylene glycol 400 (PEG-400) , Ethanol, propylene glycol monocaprylate (Capryol 90) one or more.
  • the oil phase is 10-50% (preferably 20-40%), and the emulsifier is 30-60% (preferably 40-60%), co-emulsifier 20-60% (preferably 30-50%)
  • the organic solvent is selected from ethyl acetate, tetrahydrofuran, methanol, acetone, ethanol, absolute ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, ethyl ether, methyl alcohol
  • ethyl ether dioxane, butanone, petroleum ether, hexane, cyclohexane, methylene chloride, chloroform, carbon tetrachloride, DMSO, DMF, preferably ethyl acetate
  • ester tetrahydrofuran, methanol, ethanol, cyclohexane, DMSO, and DMF.
  • the flavonoid polyphenol drug-phospholipid complex obtained in step (1) can be directly and fully mixed with the oil phase, emulsifier and co-emulsifier.
  • step (1) first mix the oil phase, emulsifier and co-emulsifier uniformly to prepare a blank self-emulsifying concentrate, and then add the flavonoid polyphenol drug-phospholipid complex obtained in step (1) to the prepared blank self-emulsifying concentrate In the liquid, mix well.
  • the flavonoid polyphenol drug-phospholipid complex obtained in step (1) is first dissolved in any one of the oil phase, emulsifier or co-emulsifier, and then the other two components are added and mixed thoroughly.
  • the present invention provides a pharmaceutical composition, which is characterized by comprising the above-mentioned flavonoid polyphenol drug self-emulsifying composition and optionally pharmaceutically acceptable excipients.
  • the dosage form of the pharmaceutical composition includes: oral preparation, injection preparation, transdermal administration preparation, mucosal administration preparation, pulmonary inhalation administration preparation, or enteral administration preparation; optionally, the drug
  • the dosage forms of the composition include: drops, oral liquids, tablets, capsules (including: soft capsules and hard capsules), granules, granules, films, gels, powders, emulsions, dripping pills, suppositories, aerosols Agent, spray, powder mist, patch, patch, solution, ointment or cream.
  • the pharmaceutically acceptable excipients can be any conventional excipients in the field of pharmaceutical preparations.
  • the choice of specific excipients will depend on the mode of administration or disease type and state used to treat a particular patient.
  • pharmaceutically acceptable excipients include diluents, carriers, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, and lubricants commonly used in the pharmaceutical field. If necessary, flavors, preservatives and sweeteners can also be added to the pharmaceutical composition.
  • the present invention provides the above-mentioned flavonoid polyphenol drug self-emulsifying composition, or the above-mentioned pharmaceutical composition is used in the preparation of antibacterial, antiviral, anti-inflammatory, allergic inhibition, immune regulation, anti-tumor, anti-oxidation, anti-aging, anti-aging Use of ultraviolet radiation, treatment of hormone deficiency, anti-hypertension, lowering blood lipid, anti-atherosclerosis, anti-senile dementia, treatment of hand, foot and mouth disease, anti-osteoporosis or liver protection medicine.
  • the flavonoid polyphenol drug self-emulsifying composition of the invention has the beneficial effects of good stability, high drug loading and high bioavailability.
  • the appearance of the flavonoid polyphenol self-emulsifying composition of the present invention is a uniform liquid, and the drug loading can reach more than 100 mg/g (W flavonoid polyphenol medicine/W composition).
  • the flavonoid polyphenol drug self-emulsifying composition of the present invention has good self-emulsifying ability. After being diluted with 10-1000 times of water, it can be quickly emulsified to form emulsion droplets with a particle size of 10-1000 nm.
  • Figure 1 is a graph showing the concentration-time curve of baicalin in the 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 baicalein in the plasma of rats in test groups A, B, and C in Test Example 2.
  • Chromatographic column Agilent ZORBAX SB C18 column (250mm ⁇ 4.6mm, 5 ⁇ m);
  • Determination method accurately weigh 24mg of flavonoid polyphenol drug reference substance, put it in a 10ml volumetric flask, add absolute ethanol to dissolve and make the volume, precisely pipette 1ml into a 100ml volumetric flask, add absolute ethanol to dilute to a concentration of 24 ⁇ g/ml The solution, as the reference solution. Accurately weigh 135mg of flavonoid polyphenols-phospholipid complex, put it in a 50ml volumetric flask, dissolve and dilute to the mark with absolute ethanol, and shake it well. Accurately measure 1ml, place it in a 25ml volumetric flask, add absolute ethanol to dissolve and dilute to the mark, shake well, and use it as test solution A.
  • Table 1 The prescription of baicalein-phospholipid complex with different drug-to-lipid ratio and its compound rate
  • N-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, diethyl ether, methyl ethyl ether, dioxane, butanone, petroleum ether, hexane, cyclohexane, dichloromethane , Chloroform, carbon tetrachloride, DMSO, DMF are used as reaction solvents to prepare baicalein-phospholipid complex, and to investigate the complex rate.
  • the difference is: according to the mass ratio (w/w) of baicalein crude drug and phospholipid of 1:3.5, use natural phospholipids: egg yolk phospholipids or soybean phospholipids, or synthetic phospholipids: Glyceryl phosphate, sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidylglycerol, glycerophosphatidic acid, distearoylphosphatidylcholine, dipalmitoylphosphatidylcholine, Dipalmitoylphosphatidylethanolamine or dimyristoylphosphatidylcholine was used as lipid material to prepare baicalein-phospholipid complex, and the compounding rate was investigated respectively.
  • natural phospholipids egg yolk phospholipids or soybean phospholipids
  • synthetic phospholipids Glyceryl phosphate, sphingomyelin
  • the difference is: according to the mass ratio (w/w) of baicalein crude drug and soybean phospholipid of 1:3.5, the baicalein crude drug is chemically synthesized baicalein or traditional Chinese medicine.
  • the extracted baicalein extract (the content of baicalein ⁇ 50%) is used to prepare a series of baicalein-phospholipid complexes. And examine the recombination rate.
  • the synthetic baicalein used in this example was purchased from Nanjing Zelang Biotechnology Co., Ltd.
  • the baicalein extract used in this example was prepared by the following method: Scutellaria baicalensis powder was sieved through a 20-mesh sieve, added with 5 times the amount of water, enzymatically hydrolyzed at 38°C for 24 hours, dried to constant weight to obtain the baicalensis enzyme hydrolyzed powder, and then added separately 10 times the amount of ethanol with different concentrations (10%, 30%, 50%, 70%, 100%) was extracted 3 times under the ultrasonic power of 70%, each 20 minutes, and filtered. The filtrate was distilled under reduced pressure and dried to constant weight to obtain baicalein extracts with different contents.
  • Example 2 Using the same method as in Example 1, the difference is: using proanthocyanidins, quercetin, curcumin, resveratrol and soybean phospholipids at a mass ratio (w/w) of 1:3.5 to prepare a series of flavonoid polyphenols Drug-phospholipid complex. The results show that the drug compounding rate is above 90%, see Table 2.
  • the emulsified particle size of the obtained flavonoid polyphenol drug self-emulsifying composition is determined as follows:
  • the drug loading of the obtained flavonoid polyphenol drug self-emulsifying composition is determined as follows:
  • the chromatographic column is an Agilent ZORBAX SB C18 column (250mm ⁇ 4.6mm, 5 ⁇ m), and the mobile phase is 0.05% phosphoric acid-methanol (35: 65, v/v), the flow rate is 1.0 mL/min, the column temperature is 25°C, and the detection wavelength is 275 nm. Record the chromatogram, and calculate the drug loading of the flavonoid polyphenol self-emulsifying composition according to the external standard method according to the peak area.
  • Example 6 The oil phase, emulsifier and co-emulsifier used in the self-emulsifying composition of flavonoids and polyphenols and the ratio of the three Screening
  • baicalein and soybean phospholipid feed with tetrahydrofuran as the reaction solvent. After the compound reaction, remove the organic solvent and dry to obtain the baicalein-phospholipid complex;
  • step (3) Weigh an appropriate amount (30% of the weight of the blank self-emulsifying concentrate) of the baicalein-phospholipid complex of step (1), and place it in the blank self-emulsifying concentrate of step (2), and place it in an air bath In the oscillator, the temperature is 25°C and the rotation speed is 210 rpm. After the baicalein-phospholipid complex is completely dissolved, the baicalein self-emulsifying composition is obtained.
  • the prepared baicalein self-emulsifying composition is a homogeneous solution, which can be emulsified completely within 2 minutes, and the particle size is in the range of 10-1000 nm.
  • the baicalein self-emulsifying composition was prepared by the same method as in a. above, except that: PEG-400, Tween 80, Tween 60, Tween 20, Tween 85, Span 80, oleic acid polyethylene Labrafil glycerides 1944cs), linoleic acid polyethylene glycol glyceride (Labrafil M2125CS), one of phospholipids, octylphenyl polyoxyethylene ether (Triton X-100), or a combination of caprylic acid capric acid polyethylene glycol glyceride and Tween 80, or caprylic acid capric acid polyethylene glycol glycerin
  • the prepared baicalein self-emulsifying composition is a homogeneous solution, which can be emulsified completely within 2 minutes, and the particle size is in the range of 10-1000 nm.
  • the baicalein self-emulsifying composition was prepared by the same method as in above a., except that ethanol, propylene glycol, polyethylene glycol, propylene carbonate, ethylene glycol monoethyl ether, glycerol furfural, dimethyl
  • the prepared baicalein self-emulsifying composition is a homogeneous solution, which can be emulsified completely within 2 minutes, and the particle size is in the range of 10-1000 nm.
  • the baicalein self-emulsifying composition was prepared by the same method as described above, except that soybean oil, corn oil, olive oil, coconut oil, peanut oil, camellia oil, castor oil, sorbitol oleate, and glyceryl oleate were used to prepare the self-emulsifying composition of baicalein.
  • the prepared baicalein self-emulsifying composition is a homogeneous solution, which can be emulsified completely within 2 minutes, and the particle size is in the range of 10-1000 nm.
  • baicalein self-emulsifying composition with different oil phase, emulsifier, and co-emulsifier ratio
  • baicalein and soybean phospholipid feed with tetrahydrofuran as the reaction solvent. After the compound reaction, remove the organic solvent and dry to obtain the baicalein-phospholipid complex;
  • the prepared baicalein self-emulsifying composition is a homogeneous solution, which can be emulsified completely within 2 minutes, and the particle size is in the range of 10-1000 nm.
  • Ethyl oleate is used as the oil phase
  • labarosol is the emulsifier
  • transcutol HP is the co-emulsifier.
  • step (3) Weigh an appropriate amount of the baicalein-phospholipid complex, procyanidin-phospholipid complex, quercetin-phospholipid complex, curcumin-phospholipid complex, and resveratrol-phospholipid complex from step (1), and add them separately 5g oil phase (ethyl oleate) or the blank self-emulsifying concentrate obtained in step (2), heat to 37°C, stir or shear to fully mix and dissolve the phospholipid complexes, and place at room temperature for 24 hours to observe whether the drug Separate, if no drug is precipitated, add appropriate amount of each phospholipid complex, and operate in the same way until the drug is precipitated. Take the supernatant and centrifuge at 12000r/min for 20min. Then the supernatant is taken, and the saturated solubility of the above-mentioned flavonoid polyphenols-phospholipid complexes in the oil phase and the blank self-emulsifying concentrate is determined by the HPLC method.
  • baicalein-phospholipid complex can increase the saturated solubility of baicalein in oil from 0.3mg/g to more than 60mg/g, and can make the saturated solubility of baicalein in the blank self-emulsifying concentrate (ie baicalein)
  • the drug loading of the self-emulsifying composition increased from 20mg/g to more than 100mg/g.
  • the phospholipid complex of proanthocyanidin, quercetin, curcumin and resveratrol has been measured so that the saturated solubility of their respective raw materials in oil can reach more than 60mg/g, and the saturated solubility in the blank self-emulsifying concentrate can reach Above 100mg/g.
  • Example 8 Preparation of baicalein self-emulsifying composition using different oil phases using baicalein-phospholipid complex as intermediate
  • baicalein and soybean phospholipid feed with tetrahydrofuran as the reaction solvent. After the compound reaction, remove the organic solvent and dry to obtain the baicalein-phospholipid complex;
  • step (3) Weigh an appropriate amount of the baicalein-phospholipid complex from step (1) (dosing at a drug loading of 50 mg/g) and place it in the blank self-emulsifying concentrate of step (2), and place it in an air bath to shake In the vessel, the temperature is 25°C and the rotation speed is 210 rpm. After the baicalein-phospholipid complex was completely dissolved, the baicalein self-emulsifying composition was obtained, and its drug loading and emulsified particle size were measured at the same time. The results are shown in Table 3.
  • Example 9 Preparation of baicalein self-emulsifying combination with baicalein-phospholipid complex as intermediate and different emulsifiers Thing
  • baicalein and soybean phospholipid feed with tetrahydrofuran as the reaction solvent. After the compound reaction, remove the organic solvent and dry to obtain the baicalein-phospholipid complex;
  • baicalein and soybean phospholipid feed with tetrahydrofuran as the reaction solvent. After the compound reaction, remove the organic solvent and dry to obtain the baicalein-phospholipid complex;
  • Example 11 Using baicalein-phospholipid complex as intermediate, using different oil phase: emulsifier: co-emulsifier ratio Example Preparation of Baicalein Self-emulsifying Composition
  • baicalein and soybean phospholipid feed with tetrahydrofuran as the reaction solvent. After the compound reaction, remove the organic solvent and dry to obtain the baicalein-phospholipid complex;
  • emulsifier co-emulsifier ratio, accurately weigh the oil phase and emulsify Mixing agent and co-emulsifier in a suitable container, and get a blank self-emulsifying concentrate;
  • Example 12 Preparation of baicalein self-emulsifying compositions with different drug loadings using baicalein-phospholipid complex as an intermediate
  • baicalein and soybean phospholipid feed with tetrahydrofuran as the reaction solvent. After the compound reaction, remove the organic solvent and dry to obtain the baicalein-phospholipid complex;
  • step (3) Weigh the baicalein-phospholipid complex of step (1) of different quality into the blank self-emulsifying concentrate of step (2), and place it in an air bath shaker at a temperature of 25° C. and a rotation speed of 210 rpm. After the baicalein-phospholipid complex was completely dissolved, the baicalein self-emulsifying composition with different drug loading amounts was obtained, and the drug loading amount and emulsified particle size were measured at the same time. The results are shown in Table 7.
  • composition number Drug loading (mg/g) Emulsification time (min) Particle size (nm)
  • Example 13 Preparation of baicalein self-emulsifying composition using baicalein-phospholipid complexes with different drug-to-lipid ratios as intermediates
  • Example 2 Weigh the series of baicalein-phospholipid complexes obtained in Example 1 (dosed according to the drug loading amount of 100mg/g) and place them in the blank self-emulsifying concentrate of step (1), and place it in an air bath shaker The temperature is 25°C and the speed is 210rpm. After the baicalein-phospholipid complex was completely dissolved, the baicalein self-emulsifying composition was obtained, and the drug loading and emulsifying particle size were measured at the same time. The results are shown in Table 8.
  • Example 14 Preparation of different self-emulsifying compositions of flavonoids and polyphenols
  • the flavonoid polyphenol drug self-emulsifying composition is obtained, and its drug loading and emulsifying particle size are measured at the same time to obtain flavonoid polyphenols with different drug loading amounts and different particle sizes Drug self-emulsifying composition, the results are shown in Table 9.
  • Example 7 to Example 12 prepared flavonoid polyphenol drug self-emulsifying compositions with different drug loading amounts. According to needs, the flavonoid polyphenol drug self-emulsifying composition of the present invention has a drug loading amount of more than 100 mg/g.
  • Test Example 1 The baicalein self-emulsifying composition of the present invention, the flavonoid polyphenol self-microemulsions of documents 2-7, and comparative examples 1 Investigation of the physical stability of the self-emulsifying composition
  • ethyl oleate as the oil phase
  • Tween 80 as the emulsifier
  • transcutol HP as the co-emulsifier.
  • procyanidin self-microemulsion YZ-1 procyanidin self-microemulsion YZ-1
  • quercetin self-microemulsion YZ-2 quercetin self-microemulsion YZ-2
  • curcumin self-microemulsion Milk YZ-3 resveratrol self-microemulsion YZ-4
  • baicalein self-microemulsion YZ-5 baicalein self-microemulsion YZ-6.
  • the self-emulsifying composition of the flavonoid polyphenol medicine with the flavonoid polyphenol medicine-phospholipid complex as a carrier is placed at 4°C and room temperature for 2 months, the appearance properties are still clear and transparent, and the stability is high.
  • baicalein and soybean phospholipid (w/w) 1:3.5, use tetrahydrofuran as the reaction solvent. After the compound reaction, remove the organic solvent and dry to obtain the baicalein-phospholipid complex;
  • 2Use ethyl oleate Ester is the oil phase
  • Tween 80 is the emulsifier
  • transcutol HP is the co-emulsifier, according to the ratio of 2:5:3, accurately weigh the oil phase, emulsifier and co-emulsifier in a suitable container, mix well to obtain a blank Self-emulsifying concentrate;
  • the baicalein self-emulsifying composition is obtained.
  • the composition is fully emulsified within 1 min after being diluted with 100 times of water, and the particle size is determined to be 10 nm, and the drug loading is 20 mg/g.
  • Test group A The baicalein self-emulsifying composition of the present invention using the baicalein-phospholipid complex as an intermediate (hereinafter labeled as BAPC-SMEDDS) prepared in (1) above
  • Test group B The baicalein self-emulsifying composition (labeled OBA-SMEDDS hereinafter) containing the raw material of baicalein in Comparative Example 1
  • Test group C give baicalein raw material (labeled as BA below)
  • Sprague-Dawley rat male, 200g.
  • the rats were fed for one week before the experiment, fasted the night before the experiment, and could not help but drink freely during the experiment.
  • 15 rats were randomly divided into 3 groups (respectively test group A, test group B, test group C), 5 rats in each group. Gavage at a dose of 40mg/kg (2 ⁇ 3ml), and take blood from the retroorbital venous plexus at 5, 15, 30, 45, 60, 75 min and 3, 6, 8, 10, 12, 24 h after administration. 0.3 mL, placed in a pre-heparinized 1.5 mL conical centrifuge tube, centrifuged at 4000 r/min for 15 minutes, aspirated the upper plasma, stored in the refrigerator at -80 °C, and thawed at room temperature before measurement.
  • Plasma sample processing Take 100 ⁇ L of plasma, place in a 1.5mL conical centrifuge tube, add 10 ⁇ L of ascorbic acid (200mg/mL), 20 ⁇ L of internal standard solution (500ng/ml), then add 300 ⁇ L of methanol, vortex and mix for 60s, at 12,000r/ Centrifuge for 10 minutes at 1 minute, then aspirate the supernatant, place it in a centrifuge tube, concentrate to remove the solvent (40°C), add 200 ⁇ L of methanol: water (80:20) to dissolve, vortex for 30s, centrifuge at 12000r/min for 5min, Take 20 ⁇ L of the supernatant for injection, and determine the plasma concentration (liquid chromatography-mass spectrometry) according to the proposed following chromatographic conditions.
  • the chromatographic column is an Agilent ZORBAX SB C18 column (250mm ⁇ 4.6mm, 5 ⁇ m);
  • the flow rate is 1.0mL/min
  • the injection volume is 20 ⁇ L;
  • the column temperature is 25°C;
  • the ion source is electrospray ion source (ESI), positive ion mode detection, multi-ion reaction monitoring mode (MRM);
  • baicalin After being taken orally into the body, baicalin will be rapidly metabolized into baicalin in intestinal epithelial cells and liver tissues.
  • concentration-time curve of baicalin in plasma and related pharmacokinetic parameters are shown in Figure 1 and Table 12.
  • the concentration-time curve of baicalein in plasma and related pharmacokinetic parameters are shown in Figure 2 and Table 13.
  • the Cmax of the baicalein self-emulsifying composition with the baicalein-phospholipid complex of the present invention as an intermediate is compared with that of the baicalein raw material
  • the drug and the baicalein self-emulsifying composition containing the raw material of baicalein are increased by 4.6 times and 1.9 times, respectively, and the AUC (0-t) is increased by 3.7 times and 1.2 times, respectively.
  • the relative bioavailability of BAPC-SMEDDS and OBA-SMEDDS (relative to the baicalein crude drug) calculated based on the concentration of baicalein in plasma were 374.4% and 302.3%, respectively.

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Abstract

一种基于黄酮多酚类药物-磷脂复合物为中间体的黄酮多酚类药物自乳化组合物，包含黄酮多酚类药物-磷脂复合物、油相、乳化剂和助乳化剂，所述黄酮多酚类药物包括选自黄芩素、原花青素、槲皮素、姜黄素和白藜芦醇中的一种或多种。所述自乳化组合物具有稳定性好、载药量高、生物利用度高等有益效果。

Description

黄酮多酚类药物自乳化组合物、其制备方法、药物组合物及用途 技术领域
本发明涉及一种黄酮多酚类药物自乳化组合物、其制备方法、药物组合物及用途，属于医药领域。
背景技术
黄酮多酚类化合物目前一般被分为3大类：(1)小分子的酚酸类物质，如水杨酸、桂皮酸、对羟基桂皮酸咖啡酸、阿魏酸、绿原酸等；(2)单宁，为多酚的聚合物，分为缩合单宁和水解单宁，前者是由黄烷醇类物质通过C4-C6或C4-C8键连接而成的不同聚合度的多酚，也称为原花色素，后者由没食子酸或鞣花酸与葡萄糖等糖类上的羟基成酯而形成；(3)多羟基黄酮类，一类为植物色素之一的花色苷(为花色素的糖苷)，另一类则为狭义的黄酮及其糖苷，苷元有黄酮、黄酮醇、二氢黄酮、二氢黄酮醇、异黄酮、二氢异黄酮、查尔酮、橙酮、黄烷、花色素、双黄酮、类黄酮(文献1：多酚类化学成分肠道生物转化研究进展[C].中华中医药学会中药化学分会第八届学术年会，2013)。
研究表明，黄酮多酚类药物具有多方面的药理作用，如抗肿瘤、抗凝血、抑菌、调节激素、抗氧化、抗衰老、抗动脉粥样硬化、抗感染、抗骨质疏松、抗病毒、抗微生物、调血脂和降血糖等多方面有着良好的效果。
受理化性质的限制，黄酮多酚类药物口服制剂生物利用度差，使得口服治疗的效果不佳。因此，通过制剂学技术提高口服给药的血药浓度(Cmax)和血液暴露量(AUC)，具有重要临床意义。
自乳化递送系统(SEDDS)是由油相、乳化剂和助乳化剂形成的均一混合物，可用作药物的包载与递送工具，口服给药后，在胃肠道蠕动及胃肠液水性介质环境下，即可快速自发乳化形成水包油型乳滴。
王至秦等报道了以三辛葵酸甘油酯为油相，聚氧乙烯40蓖麻油为乳化剂,1，2-丙二醇为助乳化剂，制备了一种包载原花青素原料药的自微乳。三者质量比为1：3：1时乳化迅速，载药量10％。按配比称取聚氧乙烯40蓖麻油、1，2-丙二醇和三辛葵酸甘油酯，于37℃水浴搅拌混匀，再加入处方量的原花青素混合使溶解，37℃平衡1h得到原花青素自微乳液，用水稀释100倍后平均粒径为(63.6±0.7)nm(文献2：中成药，2013，35(12)：2749-2752)。
张伟玲等报道了以油酸聚乙二醇甘油酯为油相，聚氧乙烯35蓖麻油为乳化剂，二乙二醇单乙基醚为助乳化剂，三者比例为27.0：55.6：17.4(w：w：w)，并将过量槲皮素原料药与油相、乳化剂和助乳化剂置于60℃恒温水浴中磁力搅拌，制备槲皮素的过饱和溶液。室温下振荡24h平衡后，4 000r/min离心10min，取上清液，即制备得到了一种包载槲皮素原料药的自微乳。最大药量为67.87mg/g，用水稀释50倍后平均粒径为25.26nm(文献3：山东大学学报，2016，54(3)：41-49)。
李泽民等报道了以中链脂肪酸(MCT)为油相，聚氧乙烯氢化蓖麻油(Cremophor RH40)为乳化剂,聚乙二醇－400(PEG-400)为助乳化剂，三者比例为MCT：PEG-400：Cremophor RH40＝2：2：6(w/w)，并将过量姜黄素原料药与油相、乳化剂和助乳化剂混匀，涡旋5min后，37℃避光震摇48h。取出样品12000r/min，离心10min，精密取上清液，即制备了一种包载姜黄素原料药的自微乳，显著提高了其溶解度。最大载药量为55.30mg/g，用水稀释100倍后平均粒径为11.8nm(文献4:成都医学院学报，2017，12(2)：155-59)。
曹璐等报道了以三乙酸甘油酯为油相，Cremophor EL和Cremophor RH40为乳化剂,异丙醇为助乳化剂，比例为三乙酸甘油酯：Cremophor EL∶Cremophor RH40：异丙醇＝22：27：13.5：37.8(w/w)。在37℃水浴条件下，磁力搅拌混合均匀，得到空白自微乳。将适量白藜芦醇加入空白自微乳中，超声溶解，即可得白藜芦醇自微乳。载药量为45mg/g，用水稀释100倍后平均粒径为15nm(文献5：曹璐.白藜芦醇的研制[D].河北：河北医科大学，2014)。
按文献2到5所述方法分别制备原花青素、槲皮素、姜黄素和白藜芦醇自微乳，将其在4℃和室温分别放置5天、1月及2月，观察外观性状的变化，考察其物理稳定性，结果表明，按文献2-5处方制备的黄酮多酚类药物自微乳混合物均存在明显稳定性缺陷：在4℃放置后易形成半固体或析出，室温放置一段时间后即发生药物析出。
另外，柯学等报道了以Migly-col812/Maisine35-1(1：1)为油相，CremphorEL35/Labrasol(2：1)为乳化剂，Transcutol P为助乳化剂，按处方制备空白SMEDDS,加入过量黄芩素，在37℃水浴中搅拌溶解，24h后取出，于12 000r·min -1高速离心15min，吸取上清液，即制备得到一种包载黄芩素原料药的自微乳，最大载药量为(18.1±1.11)mg/g，将其在纯化水中稀释100倍后3min内即形成稳定均一的微乳，形成的微乳粒径为27.2±0.56nm。与黄芩素原料药(口服灌胃)相比，黄芩素自微乳大鼠口服给药的Cmax提高至3.1倍，相对生物利用度(AUC)增加至3.77倍(文献6：中国 新药杂志，2010，19(5)：371-395)。
Wenli Liu等报道了以Caprylic capric triglyceride(ODO,25％)为油相，Cremophor RH40(53.57％)为乳化剂，Transcutol P(21.43％)为助乳化剂，并将过量黄芩素原料药与油相、乳化剂和助乳化剂在37℃条件下搅拌48h，再将混合物于12000rpm离心20min，取上清液，最终制备得到包载黄芩素原料药的自微乳，最大载药量为(32.02)mg/g，遇水后乳化粒径为27.54nm。与黄芩素原料药混悬液(分散于0.5％羧甲基纤维素钠溶液)相比，黄芩素自微乳大鼠口服给药的Cmax提高至1.6倍，相对生物利用度(AUC)增加至2.01倍(文献7：Fitoterapia,2012,83:1532-1539)。
文献6和文献7中制备的自微乳均使黄芩素的口服生物利用度明显提高，但验证性实验表明，其仍存在如下缺陷：
(1)制备的黄芩素自微乳混合物，4℃放置后易形成半固体或析出，室温放置一个月即发生药物析出；
(2)在给定的油相、乳化剂、助乳化剂条件下，黄芩素载药量难以进一步提高，无法满足临床治疗剂量对载药量的要求；
(3)与黄芩素原料药相比，Cmax以及AUC增加的幅度有限。
此外，刘昌顺等比较了黄芩苷(BG)、黄芩苷磷脂复合物(BGPC)、直接包载黄芩苷的自微乳给药系统(BG-SMEDDS)、以黄芩苷-磷脂复合物为中间体的自微乳给药系统(BGPC-SMEDDS)在大鼠体内的药动学，结果表明，与BG相比，BGPC、BG-SMEDDS、BGPC-SMEDDS的血浆浓度均有所增加，Cmax分别为BG的3.89、11.01和6.70倍，AUC 0→24h分别为BG的2.46倍、2.86倍和2.38倍。即Cmax：黄芩苷自微乳>黄芩苷-磷脂复合物的自微乳>黄芩苷-磷脂复合物，AUC 0→24h：黄芩苷自微乳>黄芩苷-磷脂复合物>黄芩苷-磷脂复合物的自微乳。
发明内容
理想的载药自乳化组合物，应满足以下条件：(1)在冷藏或室温条件下长期贮存，应为外观均一的澄清透明液体，不应发生分层；(2)在冷藏或室温条件下长期贮存，应为外观均一的澄清透明液体，不应发生凝固或沉淀，避免使用前“将药物混合物加热融化”的处理环节，减少药物降解；(3)自乳化效率高，模拟胃肠环境，加一定量的水稀释后，可快速自发乳化，形成纳米级的乳滴；(4)自乳化混合物直接口服后，在胃肠中自发乳化形成的乳滴，应为纳米级(1-1000nm)，而不应为微米级(>1μm)。
对于载药SEDDS，不同药物由于理化性质不同，载药量及稳定性也不相同。并且，油相、乳化剂和助乳化剂以及比例的改变，都会对载药量及自乳化效率产生影响，进而影响其粘膜渗透性以及生物利用度，但这种影响往往无固定规律可循。
本发明人对黄酮多酚类的药物制剂进行深入研究发现，将磷脂与选自黄芩素、原花青素、槲皮素、姜黄素和白藜芦醇中黄酮多酚类药物制成黄酮多酚类药物-磷脂复合物，以此为中间体制备的自乳化系统具有稳定性好、载药量高、生物利用度高等有益效果。
鉴于此，一方面，本发明提供一种黄酮多酚类药物自乳化组合物，其特征在于，所述黄酮多酚类药物自乳化组合物包含黄酮多酚类药物-磷脂复合物、油相、乳化剂和助乳化剂，所述黄酮多酚类药物包括选自黄芩素、原花青素、槲皮素、姜黄素和白藜芦醇中的一种或多种。
可选地，所述黄酮多酚类药物还可以包括黄芩素、原花青素、槲皮素、姜黄素和白藜芦醇以外的其他黄酮多酚类药物，所述其他黄酮多酚类药物为选自汉黄芩素、阿魏酸、儿茶素、厚朴酚、和厚朴酚、芹菜素、陈皮素、鱼藤酮、补骨脂乙素、金鱼草素、飞燕草素、银杏素中的一种或多种。
优选地，所述黄酮多酚类药物为黄芩素、原花青素、槲皮素、姜黄素或白藜芦醇；可选地，所述黄酮多酚类药物自乳化组合物的载药量为10-110mg/g，优选10-100mg/g。可选地，所述黄酮多酚类药物自乳化组合物的粒径为10-1000nm。
可选地，所述黄酮多酚类药物-磷脂复合物中，黄酮多酚类药物与磷脂的质量比(w/w)为1:1-1:15，可选为1:1-1:8。
所述的黄酮多酚类药物-磷脂复合物由黄酮多酚类药物与磷脂材料复合而成，可选地，所述黄酮多酚类药物-磷脂复合物的药物复合率≥80％。
可选地，所述黄酮多酚类药物为中药提取的黄酮多酚类药物提取物和/或化学合成的黄酮多酚类药物；
可选地，所述黄芩素可以是人工合成的黄芩素，还可以是植物提取的黄芩素含量在50％以上的有效组分，还可以是植物提取经转化或重结晶制备的产物。
可选地，所述磷脂为选自天然磷脂、合成磷脂材料中的一种或多种；
可选地，所述天然磷脂包括选自大豆磷脂、蛋黄磷脂中的一种或多种；
可选地，所述合成磷脂包括选自磷酸甘油脂、鞘磷脂、磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰肌醇、磷脂酰甘油、甘油磷脂酸、二硬脂酰磷脂酰胆碱、二棕榈酰磷脂酰胆碱、二棕榈酰磷脂酰乙醇胺、二肉蔻酰磷脂酰胆碱中的一种或多种；优选为 选自磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰甘油、甘油磷脂酸中的一种或多种。
可选地，所述的油相为选自植物油、植物油衍生物中的一种或多种；
可选地，所述植物油包括选自大豆油、玉米油、橄榄油、椰子油、花生油、山茶油、蓖麻油中的一种或多种；
可选地，所述植物油衍生物包括选自油酸山梨醇酯、油酸甘油酯、亚油酸甘油酯、油酸聚乙二醇甘油酯(labrafil
Figure PCTCN2020083837-appb-000001
1944cs)、单亚油酸甘油酯(Maisine35-1)、油酸乙酯、亚油酸乙酯、C8/C10甘油单酯、椰子油C8/C10甘油双酯、椰子油C8/C10甘油三酯、辛酸甘油三酯、辛酸甘油二酯、辛酸甘油单酯、癸酸甘油单酯、癸酸甘油二酯、癸酸甘油三酯、辛癸酸甘油单酯、辛癸酸甘油酯、辛癸酸甘油三酯、肉豆蔻酸异丙酯、亚油酸聚乙二醇甘油酯(Labrafil
Figure PCTCN2020083837-appb-000002
M2125CS)、月桂酸聚乙二醇甘油酯(Gelucire)、丙二醇单辛酸酯(Capryol 90)中的一种或多种；
优选地，所述油相为选自大豆油、蓖麻油、油酸乙酯、肉豆蔻酸异丙酯、辛癸酸甘油酯中的一种或多种。
可选地，所述乳化剂为选自辛酸癸酸聚乙二醇甘油酯(labrasol或labraosol)、聚乙二醇(包括：PEG-200、PEG-400、PEG-600、PEG-800(PEG后面数字表示平均分子量))、吐温(包括：吐温20、吐温21、吐温40、吐温60、吐温61、吐温80、吐温81、吐温85，优选吐温80、吐温60、吐温20)、司盘80(span 80)、油酸聚乙二醇甘油酯(labrafil
Figure PCTCN2020083837-appb-000003
1944cs)、亚油酸聚乙二醇甘油酯(Labrafil
Figure PCTCN2020083837-appb-000004
M2125CS)、磷脂、辛基苯基聚氧乙烯醚(X-100)中的一种或多种；优选为辛酸癸酸聚乙二醇甘油酯(labrasol或labraosol)、吐温80、吐温85、Triton X-100、labrafil
Figure PCTCN2020083837-appb-000005
1944cs中的一种或多种。
可选地，所述助乳化剂为选自乙醇、丙二醇、碳酸丙二酯、乙二醇单乙基醚、甘油糠醛、二甲基异山梨酯、丙二醇单辛酸酯(Capryol 90)、二乙二醇单乙基醚(transcutol HP或transcutol P)、聚乙二醇(包括：PEG-200、PEG-400、PEG-600、PEG-800(PEG后面数字表示平均分子量))、甘油、辛酸癸酸聚乙二醇甘油酯(labraosol)、苯甲醇中的一种或多种；优选为二乙二醇单乙基醚(transcutol HP或transcutol P)、聚乙二醇400(PEG-400)、乙醇、丙二醇单辛酸酯(Capryol 90)中的一种或多种。
可选地，以油相、乳化剂与助乳化剂三者的组成质量比为100％计，油相为10-50％(优选为20-40％)，乳化剂为30-60％(优选为40-60％)，助乳化剂为20-60％(优选为30-50％)
另一方面，提供一种上述黄酮多酚类药物自乳化组合物的制备方法，其特征在于， 包括如下制备步骤：
(1)黄酮多酚类药物-磷脂复合物的制备：取黄酮多酚类药物与磷脂材料，溶解于有机溶剂中，经复合反应后，去除有机溶剂，干燥，即得；
可选地，所述有机溶剂为选自乙酸乙酯、四氢呋喃、甲醇、丙酮、乙醇、无水乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、乙醚、甲基乙基醚、二氧六环、丁酮、石油醚、己烷、环己烷、二氯甲烷、氯仿、四氯化碳、DMSO、DMF中的至少一种或多种，优选为乙酸乙酯、四氢呋喃、甲醇、乙醇、环己烷、DMSO、DMF中的一种或多种。
(2)黄酮多酚类药物自乳化组合物的制备：将步骤(1)所得的黄酮多酚类药物-磷脂复合物与油相、乳化剂和助乳化剂以任意的顺序充分混合；
例如，可以将步骤(1)所得的黄酮多酚类药物-磷脂复合物与油相、乳化剂和助乳化剂直接充分混合。
或者，先将油相、乳化剂和助乳化剂混合均匀，制备空白自乳化浓缩液，然后将步骤(1)所得的黄酮多酚类药物-磷脂复合物加入至所制得的空白自乳化浓缩液中，充分混合。
或者，将步骤(1)所得的黄酮多酚类药物-磷脂复合物先溶于油相、乳化剂或助乳化剂中的任一者中，再加入另外两种成分，充分混合。
另一方面，本发明提供一种药物组合物，其特征在于，包含上述的黄酮多酚类药物自乳化组合物以及任选存在的药学上可接受的辅料。
可选地，所述药物组合物的剂型包括：口服制剂、注射制剂、经皮给药制剂、粘膜给药制剂、肺部吸入给药制剂或肠道给药制剂；可选地，所述药物组合物的剂型包括：滴剂、口服液、片剂、胶囊剂(包括：软胶囊、硬胶囊)、颗粒剂、冲剂、膜剂、凝胶剂、散剂、乳剂、滴丸剂、栓剂、气雾剂、喷雾剂、粉雾剂、贴剂、贴膏剂、溶液剂、软膏剂或乳膏剂。
药学可接受的辅料可以是药物制剂领域中任何常规的辅料。特定辅料的选择将取决于用于治疗特定患者的给药方式或疾病类型和状态。例如，可以作为药学可接受的辅料包括药学领域常规的稀释剂、载体、填充剂、粘合剂、湿润剂、崩解剂、吸收促进剂、表面活性剂、吸附载体和润滑剂。必要时，还可以在药物组合物中加入香味剂、防腐剂和甜味剂。
另一方面，本发明提供上述黄酮多酚类药物自乳化组合物，或者上述药物组合物在制备抗菌、抗病毒、抗炎、抑制变态反应、调节免疫、抗肿瘤、抗氧化、抗衰老、抗紫 外辐射、治疗激素缺乏、抗高血压、降血脂、抗动脉粥样硬化、抗老年痴呆、治疗手足口病、抗骨质疏松或保护肝脏的药物中的用途。
有益效果：
本发明的黄酮多酚类药物自乳化组合物具有稳定性好、载药量高、生物利用度高的有益效果。
本发明的黄酮多酚类药物自乳化组合物的外观性状为均一液体，载药量可以达到100mg/g以上(W黄酮多酚类药物/W组合物)。
本发明的黄酮多酚类药物自乳化组合物具有良好的自乳化能力，加10-1000倍的水进行稀释后，可快速乳化形成粒径在10-1000nm的乳滴。
附图说明
图1是试验例2中受试组A、B、C大鼠血浆中黄芩苷浓度-时间曲线图。
图2是试验例2中受试组A、B、C大鼠血浆中黄芩素浓度-时间曲线图。
具体实施方式
以下对本发明的具体实施方式进行详细说明。应当理解的是，此处所描述的具体实施方式仅用于示例性地对本发明进行说明，并不用于限制本发明。
以下实施例1-5中，采用高效液相色谱法(HPLC法)测定所得黄酮多酚类药物-磷脂复合物中黄酮多酚类药物与磷脂的复合率。
HPLC色谱条件：
色谱柱：Agilent ZORBAX SB C18柱(250mm×4.6mm，5μm)；
流动相：0.05％磷酸-甲醇(35:65,v/v)；
流速：1.0mL/min；
柱温：25℃(常温)；
进样量：10μL检测波长：275nm。
测定方法：精密称取黄酮多酚类药物对照品24mg，置10ml容量瓶中，加无水乙醇溶解并定容，精密移取1ml置100ml容量瓶，加无水乙醇稀释成浓度为24μg/ml的溶液，作为对照品溶液。精密称取135mg黄酮多酚类药物-磷脂复合物，置50ml容量瓶中，用无水乙醇溶解并稀释至刻度，摇匀。精密量取1ml，置25ml容量瓶中，加入无水乙醇溶解并稀释至刻度，摇匀，作为供试液A。精密称取135mg黄酮多酚类药物-磷脂复合物， 置50ml容量瓶中，加正己烷溶解并定容，摇匀，经0.45um有机膜过滤。精密移取续滤液1ml于25ml容量瓶中，氮吹除去溶剂，加入无水乙醇溶解并稀释至刻度，摇匀，作为供试液B。分别精密量取对照液、供试液A和B各10μl，照上述HPLC方法依法测定，记录色谱图，根据峰面积按外标法计算黄酮多酚类药物-磷脂复合物的含量，分别记为W 总和W 复合。
复合率计算公式：
复合率％＝(W 复合/W 总)*100％
实施例1采用不同药脂比(黄芩素原料药与大豆磷脂质量比)制备黄芩素-磷脂复合 物。
按表1的药脂比精密称取黄芩素原料药和大豆磷脂，置于1000ml旋蒸瓶中，加入适量四氢呋喃混合摇匀，待黄芩素原料药与磷脂溶解完全且复合溶液澄清后，放置15～30min，置于旋蒸仪上，40℃挥干溶剂。待旋蒸瓶中物体起泡呈蜂窝状后，继续旋蒸1～2h，制备完成，将其放入干燥箱中干燥3d后，轻轻刮下黄芩素-磷脂复合物固体，置于干燥箱内保存备用。
表1不同药脂比的黄芩素-磷脂复合物处方及其复合率
Figure PCTCN2020083837-appb-000006
实施例2采用不同有机溶剂制备黄芩素-磷脂复合物
采用实施例1相同的方法，所不同的是：按黄芩素原料药与大豆磷脂的质量比(w/w)为1：3.5投料，分别采用乙酸乙酯、甲醇、丙酮、乙醇、无水乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、乙醚、甲基乙基醚、二氧六环、丁酮、石油醚、己烷、环己烷、二氯甲烷、氯仿、四氯化碳、DMSO、DMF作为反应溶剂，制备黄芩素-磷脂复合物，并考察复合率。
结果表明，采用上述有机溶剂作为反应溶剂时，所得所有的黄芩素-磷脂复合物的复合率均大于80％。
实施例3采用不同磷脂制备黄芩素-磷脂复合物
采用实施例1相同的方法，所不同的是：按黄芩素原料药与磷脂的质量比(w/w)为1：3.5投料，分别采用天然磷脂：蛋黄磷脂或大豆磷脂等，或合成磷脂：磷酸甘油脂、鞘磷 脂、磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰肌醇、磷脂酰甘油、甘油磷脂酸、二硬脂酰磷脂酰胆碱、二棕榈酰磷脂酰胆碱、二棕榈酰磷脂酰乙醇胺或二肉蔻酰磷脂酰胆碱为脂质材料，制备黄芩素-磷脂复合物，并分别考察复合率。
结果表明，采用上述磷脂制备的所有黄芩素-磷脂复合物的复合率均在80％以上。
实施例4采用不同来源的黄芩素原料药制备黄芩素-磷脂复合物
采用实施例1相同的方法，所不同的是：按黄芩素原料药与大豆磷脂的质量比(w/w)为1：3.5投料，所述黄芩素原料药分别采用化学合成的黄芩素或中药提取的黄芩素提取物(黄芩素含量≥50％)制备系列黄芩素-磷脂复合物。并考察复合率。
该实施例所使用的合成黄芩素：购自南京泽郎生物科技有限公司。
该实施例所使用的黄芩素提取物采用以下方法制备：将黄芩药粉过20目筛，加5倍量水，在38℃下酶解24h，干燥至恒重得黄芩酶解药粉，再分别加10倍量不同浓度乙醇(10％、30％、50％、70％、100％)，在超声功率为70％下提取3次，每次20min，过滤。将滤液减压蒸馏并干燥至恒重，得到不同含量的黄芩素提取物。
结果，所有的黄芩素/磷脂的复合率均在80％以上。
实施例5制备不同的黄酮多酚类药物-磷脂复合物
采用实施例1相同的方法，所不同的是：分别采用原花青素、槲皮素、姜黄素、白藜芦醇与大豆磷脂按质量比(w/w)1：3.5投料，制备系列黄酮多酚类药物-磷脂复合物。结果表明药物复合率均在90％以上，见表2。
表2不同黄酮多酚类药物-磷脂复合物的药物复合率
Figure PCTCN2020083837-appb-000007
以下实施例、对比例和试验例中，
1、所得黄酮多酚类药物自乳化组合物的乳化粒径按如下方法测定：
用移液枪移取200μl黄酮多酚类药物自乳化组合物缓慢加入20ml蒸馏水中(37℃水浴，缓慢搅拌)，记录黄酮多酚类药物自乳化组合物乳化时间，并取乳化后的溶液用激光粒度仪直接测定其粒径。
2、所得黄酮多酚类药物自乳化组合物的载药量按如下方法测定：
精密称取0.5g黄酮多酚类药物自乳化组合物置10ml容量瓶中，用无水乙醇溶解并 稀释至刻度，摇匀。精密量取1ml，置50ml容量瓶中，加入95％乙醇(含0.02％VC)溶解并稀释至刻度，摇匀，作为供试品溶液。另精密称取黄酮多酚类药物原料药30mg，置25ml容量瓶中，加无水乙醇溶解并定容，精密移取1ml置50ml容量瓶，加入95％乙醇(含0.02％VC)稀释成浓度为24μg/ml的溶液，作为对照品溶液。精密量取供试品溶液和对照品溶液各10μl注入液相色谱仪进行分离分析，色谱柱为Agilent ZORBAX SB C18柱(250mm×4.6mm，5μm)，流动相为0.05％磷酸-甲醇(35:65,v/v)，流速为1.0mL/min，柱温为25℃，检测波长为275nm。记录色谱图，根据峰面积按照外标法计算黄酮多酚类药物自乳化组合物的载药量。
实施例6黄酮多酚类药物自乳化组合物所用油相、乳化剂和助乳化剂以及三者比例 的筛选
a、黄芩素自乳化组合物的初步制备
(1)按黄芩素与大豆磷脂的质量比(w/w)1:3.5投料，以四氢呋喃为反应溶剂，经复合反应后，去除有机溶剂，干燥，得黄芩素-磷脂复合物；
(2)以油酸乙酯为油相，辛酸癸酸聚乙二醇甘油酯(labraosol)-为乳化剂，transcutol HP为助乳化剂。按2：5：3的比例，精密称取油相、乳化剂和助乳化剂于适当容器内，混合均匀，得空白自乳化浓缩液；
(3)称取适量(空白自乳化浓缩液重量的30％)步骤(1)的黄芩素-磷脂复合物，置于步骤(2)的空白自乳化浓缩液中，并将其置于空气浴振荡器中，温度25℃，转速210rpm。待黄芩素-磷脂复合物溶解完全后，得黄芩素自乳化组合物。
结果表明，所制备的黄芩素自乳化组合物为均一溶液，可在2min中内乳化完全，且粒径在10-1000nm范围内。
b、采用不同乳化剂制备黄芩素自乳化组合物
采用上述a、中相同的方法制备黄芩素自乳化组合物，所不同的是：以PEG-400、吐温80、吐温60、吐温20、吐温85、Span 80、油酸聚乙二醇甘油酯(labrafil
Figure PCTCN2020083837-appb-000008
1944cs)、亚油酸聚乙二醇甘油酯(Labrafil
Figure PCTCN2020083837-appb-000009
M2125CS)、磷脂、辛基苯基聚氧乙烯醚(Triton X-100)中的一种、或辛酸癸酸聚乙二醇甘油酯与吐温80的组合、或辛酸癸酸聚乙二醇甘油酯与PEG-400的组合、或辛酸癸酸聚乙二醇甘油酯与辛基苯基聚氧乙烯醚的组合、或辛酸癸酸聚乙二醇甘油酯与磷脂的组合、或吐温80与PEG-400的组合、或吐温80与辛基苯基聚氧乙烯醚的组合、或吐温80与磷脂的组合代替labrasol为乳化剂，制备黄芩素自乳化组合物。
结果表明，所制备的黄芩素自乳化组合物为均一溶液，可在2min中内乳化完全，且粒径在10-1000nm范围内。
c、采用不同助乳化剂制备黄芩素自乳化组合物
采用上述a、中相同的方法制备黄芩素自乳化组合物，所不同的是：以乙醇、丙二醇、聚乙二醇、碳酸丙二酯、乙二醇单乙基醚、甘油糠醛、二甲基异山梨酯、transcutol P、PEG400、甘油、labraosol、苯甲醇中的一种、或transcutol HP与乙醇的组合、或transcutol HP与丙二醇的组合、或transcutol HP与PEG400的组合、或transcutol HP与甘油的组合、或transcutol HP与乙二醇单乙基醚的组合、或labraosol与乙醇的组合、或labraosol与丙二醇的组合、或labraosol与PEG400的组合、或labraosol与甘油额组合，代替transcutol HP为助乳化剂，以吐温80为乳化剂，制备黄芩素自乳化组合物。
结果表明，所制备的黄芩素自乳化组合物为均一溶液，可在2min中内乳化完全，且粒径在10-1000nm范围内。
d、采用不同油相制备黄芩素自乳化组合物
采用上述相同的方法制备黄芩素自乳化组合物，所不同的是：以大豆油、玉米油、橄榄油、椰子油、花生油、山茶油、蓖麻油、油酸山梨醇酯、油酸甘油酯，亚油酸甘油酯、油酸聚乙二醇甘油酯(labrafil
Figure PCTCN2020083837-appb-000010
1944cs)、Maisine35-1、亚油酸乙酯、C8/C10甘油单酯、椰子油C8/C10甘油双酯、椰子油C8/C10甘油三酯、辛酸甘油三酯、辛酸甘油二酯、辛酸甘油单酯、癸酸甘油单酯、癸酸甘油二酯、癸酸甘油三酯、辛癸酸甘油单酯、辛癸酸甘油酯、辛癸酸甘油三酯、肉豆蔻酸异丙酯、亚油酸聚乙二醇甘油酯(Labrafil
Figure PCTCN2020083837-appb-000011
M2125CS)、Gelucire、Capryol 90中的一种，或油酸乙酯与辛癸酸甘油酯的组合，或油酸乙酯与肉豆蔻酸异丙酯的组合，或油酸乙酯与大豆油的组合，或亚油酸聚乙二醇甘油酯与亚油酸乙酯的组合，或亚油酸聚乙二醇甘油酯与橄榄油的组合，或亚油酸聚乙二醇甘油酯与辛酸甘油单酯的组合代替油酸乙酯为油相，以吐温80为乳化剂，制备黄芩素自乳化组合物。
结果表明，所制备的黄芩素自乳化组合物为均一溶液，可在2min中内乳化完全，且粒径在10-1000nm范围内。
e、采用不同的油相、乳化剂、助乳化剂比例制备黄芩素自乳化组合物
(1)按黄芩素与大豆磷脂的质量比(w/w)1:3.5投料，以四氢呋喃为反应溶剂，经复合反应后，去除有机溶剂，干燥，得黄芩素-磷脂复合物；
(2)以油酸乙酯为油相，吐温80为乳化剂，transcutol HP为助乳化剂。按三者的组 成质量比总和为100％计，以油相：乳化剂：助乳化剂＝10％：60％：30％、或20％：50％：30％、或20％：40％：40％的比例，精密称取油相、乳化剂和助乳化剂于适当容器内，混合均匀，得空白自乳化浓缩液；
(3)称取适量(空白自乳化浓缩液重量的30％)步骤(1)的黄芩素-磷脂复合物置于步骤(2)的空白自乳化浓缩液中，并将其置于空气浴振荡器中，温度25℃，转速210rpm。待黄芩素-磷脂复合物溶解完全后，得黄芩素自乳化组合物。
结果表明，所制备的黄芩素自乳化组合物为均一溶液，可在2min中内乳化完全，且粒径在10-1000nm范围内。
实施例7黄酮多酚类药物自乳化组合物的载药量考察
(1)按黄酮多酚类药物(黄芩素、原花青素、槲皮素、姜黄素、白藜芦醇)与大豆磷脂的质量比(w/w)1:3.5投料，以四氢呋喃为反应溶剂，经复合反应后，去除有机溶剂，干燥，分别制得黄芩素-磷脂复合物、原花青素-磷脂复合物、槲皮素-磷脂复合物、姜黄素-磷脂复合物、白藜芦醇-磷脂复合物；
(2)以油酸乙酯为油相，labraosol为乳化剂，transcutol HP为助乳化剂。按2：5：3的比例精密称取油相、乳化剂和助乳化剂于适当容器内，混合均匀，得空白自乳化浓缩液；
(3)称取适量步骤(1)的黄芩素-磷脂复合物、原花青素-磷脂复合物、槲皮素-磷脂复合物、姜黄素-磷脂复合物、白藜芦醇-磷脂复合物，分别加入5g油相(油酸乙酯)或步骤(2)所得的空白自乳化浓缩液中，加热至37℃，搅拌或剪切分别使各磷脂复合物充分混合、溶解，室温放置24h，观察药物是否析出，如无药物析出，再分别加适量各磷脂复合物，同法操作，直至药物析出，取上清液于12000r/min离心20min。然后取上清液，采用所述HPLC法测定上述各黄酮多酚类药物-磷脂复合物在油相和空白自乳化浓缩液中的饱和溶解度。
测试结果表明，黄芩素-磷脂复合物可使黄芩素在油中的饱和溶解度从0.3mg/g增加至60mg/g以上，可使黄芩素在空白自乳化浓缩液中的饱和溶解度(即黄芩素自乳化组合物的载药量)从20mg/g增加至100mg/g以上。
测得原花青素、槲皮素、姜黄素、白藜芦醇的磷脂复合物使其各自的原料药在油中的饱和溶解度可达60mg/g以上，在空白自乳化浓缩液中的饱和溶解度可达100mg/g以上。
以上试验表明，本发明的黄酮多酚类药物自乳化组合物的载药量高。
实施例8：以黄芩素-磷脂复合物为中间体采用不同的油相制备黄芩素自乳化组合物
(1)按黄芩素与大豆磷脂的质量比(w/w)1:3.5投料，以四氢呋喃为反应溶剂，经复合反应后，去除有机溶剂，干燥，得黄芩素-磷脂复合物；
(2)以labrosol为乳化剂，transcutol HP为助乳化剂，采用下表3所示不同的油相，按2：5：3的比例精密称取油相、乳化剂和助乳化剂于适当容器内，混合均匀，得空白自乳化浓缩液；
(3)称取适量步骤(1)的黄芩素-磷脂复合物(按照载药量为50mg/g投料)置于步骤(2)的空白自乳化浓缩液中，并将其置于空气浴振荡器中，温度25℃，转速210rpm。待黄芩素-磷脂复合物溶解完全后，得黄芩素自乳化组合物，同时测定其载药量和乳化粒径，结果见表3。
表3不同油相制备的黄芩素自乳化组合物
Figure PCTCN2020083837-appb-000012
实施例9：以黄芩素-磷脂复合物为中间体采用不同的乳化剂制备黄芩素自乳化组合 物
(1)按黄芩素与大豆磷脂的质量比(w/w)1:3.5投料，以四氢呋喃为反应溶剂，经复合反应后，去除有机溶剂，干燥，得黄芩素-磷脂复合物；
(2)以油酸乙酯为油相，transcutol HP为助乳化剂，采用下表4所示不同的乳化剂，按2：5：3的比例精密称取油相、乳化剂和助乳化剂于适当容器内，混合均匀，得空白自乳化浓缩液；
(3)称取适量(按照载药量为50mg/g投料)步骤(1)的黄芩素-磷脂复合物置于步骤(2)的空白自乳化浓缩液中，并将其置于空气浴振荡器中，温度25℃，转速210rpm。待黄芩素-磷脂复合物溶解完全后，得黄芩素自乳化组合物，同时测定其载药量和乳化粒 径，结果见表4。
表4不同乳化剂制备的黄芩素自乳化组合物
Figure PCTCN2020083837-appb-000013
实施例10：以黄芩素-磷脂复合物为中间体采用不同的助乳化剂制备黄芩素自乳化组 合物
(1)按黄芩素与大豆磷脂的质量比(w/w)1:3.5投料，以四氢呋喃为反应溶剂，经复合反应后，去除有机溶剂，干燥，得黄芩素-磷脂复合物；
(2)以油酸乙酯为油相，labrosol为乳化剂，采用下表5所示不同的助乳化剂，按2：5：3的比例精密称取油相、乳化剂和助乳化剂于适当容器内，混合均匀，得空白自乳化浓缩液；
(3)称取适量(按照载药量为50mg/g投料)步骤(1)的黄芩素-磷脂复合物置于步骤(2)的空白自乳化浓缩液中，并将其置于空气浴振荡器中，温度25℃，转速210rpm。待黄芩素-磷脂复合物溶解完全后，得黄芩素自乳化组合物，同时测定其载药量和乳化粒径，结果见表5。
表5不同助乳化剂制备的黄芩素自乳化组合物
Figure PCTCN2020083837-appb-000014
实施例11：以黄芩素-磷脂复合物为中间体，采用不同的油相：乳化剂：助乳化剂比 例制备黄芩素自乳化组合物
(1)按黄芩素与大豆磷脂的质量比(w/w)1:3.5投料，以四氢呋喃为反应溶剂，经复合反应后，去除有机溶剂，干燥，得黄芩素-磷脂复合物；
(2)以油酸乙酯为油相，labrosol为乳化剂，transcutol HP为助乳化剂，采用下表6所示不同的油相：乳化剂：助乳化剂比例，精密称取油相、乳化剂和助乳化剂于适当容器内，混合均匀，得空白自乳化浓缩液；
(3)称取适量(按照载药量为50mg/g投料)步骤(1)的黄芩素-磷脂复合物置于步骤(2)的空白自乳化浓缩液中，并将其置于空气浴振荡器中，温度25℃，转速210rpm。待黄芩素-磷脂复合物溶解完全后，得黄芩素自乳化组合物，同时测定其载药量和乳化粒径，结果见表6。
表6不同油相：乳化剂：助乳化剂比例制备的黄芩素自乳化组合物
Figure PCTCN2020083837-appb-000015
实施例12：以黄芩素-磷脂复合物为中间体制备不同载药量的黄芩素自乳化组合物
(1)按黄芩素与大豆磷脂的质量比(w/w)1:3.5投料，以四氢呋喃为反应溶剂，经复合反应后，去除有机溶剂，干燥，得黄芩素-磷脂复合物；
(2)以油酸乙酯为油相，labrosol为乳化剂，transcutol HP为助乳化剂，按2：5：3的比例精密称取油相、乳化剂和助乳化剂于适当容器内，混合均匀，得空白自乳化浓缩液；
(3)称取不同质量的步骤(1)的黄芩素-磷脂复合物置于步骤(2)的空白自乳化浓缩液中，并将其置于空气浴振荡器中，温度25℃，转速210rpm。待黄芩素-磷脂复合物溶解完全后，得不同载药量的黄芩素自乳化组合物，同时测定其载药量和乳化粒径，结果见表7。
表7不同载药量的黄芩素自乳化组合物
组合物编号 载药量(mg/g) 乳化时间(min) 粒径(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
实施例13：以不同的药脂比的黄芩素-磷脂复合物为中间体制备黄芩素自乳化组合物
(1)以油酸乙酯为油相，labrosol为乳化剂，transcutol HP为助乳化剂，按2：5：3的比例，精密称取油相、乳化剂和助乳化剂于适当容器内，混合均匀，得空白自乳化浓缩液；
(2)称取实施例1所得的系列黄芩素-磷脂复合物(按照载药量100mg/g投料)置于步骤(1)的空白自乳化浓缩液中，并将其置于空气浴振荡器中，温度25℃，转速210rpm。待黄芩素-磷脂复合物溶解完全后，得黄芩素自乳化组合物，同时测定其载药量和乳化粒径，结果见表8。
表8不同药脂比的黄芩素-磷脂复合物制备的黄芩素自乳化组合物
Figure PCTCN2020083837-appb-000016
实施例14：制备不同的黄酮多酚类药物自乳化组合物
(1)以油酸乙酯为油相，labrosol为乳化剂，transcutol HP为助乳化剂，按2：5：3的比例，精密称取油相、乳化剂和助乳化剂于适当容器内，混合均匀，得空白自乳化浓缩液；
(2)称取表2中系列黄酮多酚类药物-磷脂复合物(制备组合物SEDDS-31、SEDDS-32、SEDDS-33、SEDDS-34，磷脂复合物按照载药量为20mg/g投料；制备组合物SEDDS-35、SEDDS-36、SEDDS-37、SEDDS-38，磷脂复合物按照载药量为100mg/g投料)置于步骤(1)的空白自乳化浓缩液中，并将其置于空气浴振荡器中，温度25℃，转速210rpm。待黄酮多酚类药物-磷脂复合物溶解完全后，得黄酮多酚类药物自乳化组合 物，同时测定其载药量和乳化粒径，得到不同载药量和不同粒径的黄酮多酚类药物自乳化组合物，结果见表9。
表9不同黄酮多酚类药物-磷脂复合物制备的黄酮多酚类药物自乳化组合物
Figure PCTCN2020083837-appb-000017
从实施例6到实施例14的结果可以看出，本发明的黄酮多酚类药物自乳化组合物均能快速乳化形成纳米级乳滴。实施例7至实施例12制备了不同载药量的黄酮多酚类药物自乳化组合物，根据需要，本发明的黄酮多酚类药物自乳化组合物的载药量高达100mg/g以上。
试验例1：本发明黄芩素自乳化组合物、文献2-7的黄酮多酚类自微乳、以及对比例 1的自乳化组合物的物理稳定性考察
(1)对比例1包载黄芩素原料药的黄芩素自乳化组合物制备
以油酸乙酯为油相，吐温80为乳化剂，transcutol HP为助乳化剂。按2：5：3的比例精密称取油相、乳化剂和助乳化剂于适当容器内，混合均匀，得空白自乳化浓缩液，再称取黄芩素原料药置空白自乳化浓缩液中，并将其置于空气浴振荡器中，温度25℃，转速210rpm，振荡24h，12000rpm离心15min，取上清液即制得所述包载黄芩素原料药的黄芩素自乳化组合物。(2)对比例2水飞蓟素磷脂复合物自乳化组合物的制备
按文献【刘琳婕.水飞蓟素及其磷脂复合物自微乳化胶囊的研究.[D].沈阳，沈阳药科大学，2007】方法，以丙酮为反应溶剂，水飞蓟素、大豆磷脂质量比为1：1，55℃加热回流，减压浓缩至液体体积为后，迅速加入到正己烷中，得黄色沉淀物，上层液体为黄 白色乳浊液，减压过滤，用正己烷洗涤沉淀，置于真空干燥箱中室温干燥，得黄白色固体产物，即水飞蓟素磷脂复合物。称取70g水飞蓟素磷脂复合物，加250g油酸乙酯与MCT的混合物(1：1)，涡旋混合使之溶解，加入200g Cremophor EL，以及50g Transcutol，37℃水浴中温和搅拌即得。
(3)按文献2-7所述处方和制备方法(如本申请背景技术中所述)，分别制得原花青素自微乳YZ-1、槲皮素自微乳YZ-2、姜黄素自微乳YZ-3、白藜芦醇自微乳YZ-4、黄芩素自微乳YZ-5和黄芩素自微乳YZ-6。
(4)将YZ-1，YZ-2，YZ-3，YZ-4，YZ-5，YZ-6，对比例1的自乳化组合物，对比例2的水飞蓟素自乳化组合物，本发明中上述实施例制备的黄芩素自乳化组合物，原花青素自乳化组合物，槲皮素自乳化组合物，姜黄素自乳化组合物和白藜芦醇自乳化组合物，在4℃和室温分别放置5天、1月及2月，观察外观性状的变化，进行物理稳定性考察，相关结果见表10。
表10
Figure PCTCN2020083837-appb-000018
Figure PCTCN2020083837-appb-000019
Figure PCTCN2020083837-appb-000020
结果表明：按文献2-7，以及对比例1和对比例2制备的系列黄酮多酚类药物自乳化组合物，4℃放置后易形成半固体或析出，室温放置1-2个月即发生药物析出，稳定性较差。
本发明的以黄酮多酚类药物-磷脂复合物为载体的黄酮多酚类药物自乳化组合物在4℃以及室温放置2个月后，外观性状依然澄清透明，稳定性高。
试验例2：血浆药代动力学研究
(1)制备以黄芩素-磷脂复合物为中间体的黄芩素自乳化组合物
①按黄芩素与大豆磷脂的质量比(w/w)1:3.5投料，以四氢呋喃为反应溶剂，经复合反应后，去除有机溶剂，干燥，得黄芩素-磷脂复合物；②以油酸乙酯为油相，吐温80为乳化剂，transcutol HP为助乳化剂，按2：5：3的比例，精密称取油相、乳化剂和助乳化剂于适当容器内，混合均匀，得空白自乳化浓缩液；③称取适量步骤①的黄芩素-磷脂复合物置于步骤②的空白自乳化浓缩液中，并将其置于空气浴振荡器中，温度25℃，转速210rpm。待黄芩素-磷脂复合物溶解完全后，得黄芩素自乳化组合物。该组合物用100倍水稀释后1min内乳化完全，测定其粒径为10nm，载药量为20mg/g。
(2)试验分组
受试组A：给予上述(1)中制得的本发明的以黄芩素-磷脂复合物为中间体的黄芩素自乳化组合物(以下标记为BAPC-SMEDDS)
受试组B：给予对比例1中包载黄芩素原料药的黄芩素自乳化组合物(以下标记为OBA-SMEDDS)
受试组C：给予黄芩素原料药(以下标记为BA)
(3)试验动物
Sprague-Dawley大鼠，雄性，200g。大鼠试验前喂养一周，试验前一夜禁食，不禁水，实验期间自由饮水。
(4)给药方式及剂量
大鼠15只，随机分成3组(分别为受试组A、受试组B、受试组C)，每组各5只。按40mg/kg剂量灌胃给药(2～3ml)，给药后分别于5，15，30，45，60，75min和3、6、8、10、12、24h眼眶后静脉丛取血0.3mL，置预先肝素化的1.5mL尖底离心管中，4000r/min离心15min，吸取上层血浆，置-80℃冰箱保存，测定前常温放置解冻。
(5)血药浓度测定
血浆样品处理：取血浆100μL，置1.5mL尖底离心管，加入抗坏血酸10μL(200mg/mL)、内标溶液20μL(500ng/ml)，再加入300μL甲醇，涡旋混合60s，于12，000r/min离心10min，然后吸取上清液，置离心管中，离心浓缩挥去溶剂(40℃)，再加200μL甲醇：水(80：20)溶解，涡旋30s后，于12000r/min离心5min，取上清液20μL进样，按拟定的下述色谱条件测定血药浓度(液相色谱-质谱联用)。
HPLC色谱条件：
色谱柱为Agilent ZORBAX SB C18柱(250mm×4.6mm，5μm)；
流速为1.0mL/min；
进样体积为20μL；
柱温为25℃；
流动相(梯度洗脱见表11)：洗脱剂为乙腈-0.1％甲酸。
表11 LC流动相梯度洗脱
Figure PCTCN2020083837-appb-000021
质谱条件：
离子源为电喷雾离子源(ESI)，正离子方式检测，多离子反应监测模式(MRM)；
其他参数：雾化器压力40psi，干燥气流速9L/min，干燥气温度350℃，毛细管电压4000V，分流比1：2。
用于定量的MRM检测离子对：黄芩苷[M+H]+447.0→271.1；
黄芩素[M+H]+271.1→122.8；
6-羟基黄铜[M+H]+239.0→137.0。
(6)试验结果
6.1黄芩素口服进入体内后会在肠道上皮细胞和肝脏组织被快速代谢为黄芩苷，血浆中黄芩苷浓度-时间曲线和相关药代参数如图1及表12所示。
结果表明：本发明黄芩素-磷脂复合物为中间体的黄芩素自乳化组合物的C max相比于黄芩素原料药和包载黄芩素原料药的黄芩素自乳化组合物分别提高了7.7倍和1.9倍，AUC (0-t)分别提高了4.5倍和1.3倍。以血浆中黄芩苷浓度计算的BAPC-SMEDDS和OBA-SMEDDS(相对于黄芩素原料药)的相对生物利用度分别为448.7％和342.5％。
表12黄芩苷血浆药代参数
Figure PCTCN2020083837-appb-000022
6.2血浆中黄芩素浓度-时间曲线和相关药代参数如图2及表13所示，本发明黄芩素-磷脂复合物为中间体的黄芩素自乳化组合物的C max相比于黄芩素原料药和包载黄芩素原料药的黄芩素自乳化组合物分别提高了4.6倍和1.9倍，AUC (0-t)分别提高了3.7倍和1.2倍。以血浆中黄芩素浓度计算的BAPC-SMEDDS和OBA-SMEDDS(相对于黄芩素原料药)的相对生物利用度分别为374.4％和302.3％。
表13黄芩素血浆药代参数
Figure PCTCN2020083837-appb-000023

Claims (8)

  1. 一种黄酮多酚类药物自乳化组合物，其特征在于，包含黄酮多酚类药物-磷脂复合物、油相、乳化剂和助乳化剂，所述黄酮多酚类药物包括选自黄芩素、原花青素、槲皮素、姜黄素和白藜芦醇中的一种或多种；
    可选地，所述黄酮多酚类药物还可以包括黄芩素、原花青素、槲皮素、姜黄素和白藜芦醇以外的其他黄酮多酚类药物，所述其他黄酮多酚类药物为选自汉黄芩素、阿魏酸、儿茶素、厚朴酚、和厚朴酚、芹菜素、陈皮素、鱼藤酮、补骨脂乙素、金鱼草素、飞燕草素、银杏素中的一种或多种；
    可选地，所述黄酮多酚类药物为黄芩素、原花青素、槲皮素、姜黄素或白藜芦醇；
    可选地，所述黄酮多酚类药物自乳化组合物的载药量为10-110mg/g，优选10-100mg/g；
    可选地，所述黄酮多酚类药物自乳化组合物的粒径为10-1000nm。
  2. 根据权利要求1所述的黄酮多酚类药物自乳化组合物，其特征在于，所述黄酮多酚类药物-磷脂复合物中，黄酮多酚类药物与磷脂的质量比为1:1-1:15，可选为1:1-1:8。
  3. 根据权利要求1或2所述的黄酮多酚类药物自乳化组合物，其特征在于，所述磷脂为选自天然磷脂、合成磷脂材料中的一种或多种；
    可选地，所述天然磷脂包括选自大豆磷脂和蛋黄磷脂中的一种或多种；
    可选地，所述合成磷脂包括选自磷酸甘油脂、鞘磷脂、磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰肌醇、磷脂酰甘油、甘油磷脂酸、二硬脂酰磷脂酰胆碱、二棕榈酰磷脂酰胆碱、二棕榈酰磷脂酰乙醇胺、二肉蔻酰磷脂酰胆碱中的一种或多种；优选为选自磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰甘油、甘油磷脂酸中的一种或多种。
  4. 根据权利要求1-3任一项所述的黄酮多酚类药物自乳化组合物，其特征在于，所述的油相为选自植物油、植物油衍生物中的一种或多种；
    可选地，所述植物油包括选自大豆油、玉米油、橄榄油、椰子油、花生油、山茶油、蓖麻油中的一种或多种；
    可选地，所述植物油衍生物包括选自油酸山梨醇酯、油酸甘油酯、亚油酸甘油酯、油酸聚乙二醇甘油酯、单亚油酸甘油酯、油酸乙酯、亚油酸乙酯、C8/C10甘油单酯、椰子油C8/C10甘油双酯、椰子油C8/C10甘油三酯、辛酸甘油三酯、辛酸甘油二酯、辛酸甘油单酯、癸酸甘油单酯、癸酸甘油二酯、癸酸甘油三酯、辛癸酸甘油单酯、辛癸酸甘油酯、辛癸酸甘油三酯、肉豆蔻酸异丙酯、亚油酸聚乙二醇甘油酯、月桂酸聚乙二醇甘油酯、丙二醇单辛酸酯中的一种或多种；
    优选地，所述油相为选自大豆油、蓖麻油、油酸乙酯、肉豆蔻酸异丙酯、辛癸酸甘油酯中的一种或多种。
  5. 根据权利要求1-4任一项所述的黄酮多酚类药物自乳化组合物，其特征在于，所述乳化剂为选自辛酸癸酸聚乙二醇甘油酯、聚乙二醇、吐温、司盘80、油酸聚乙二醇甘油酯、亚油酸聚乙二醇甘油酯、磷脂、辛基苯基聚氧乙烯醚中的一种或多种；
    优选为辛酸癸酸聚乙二醇甘油酯、吐温80、吐温85、辛基苯基聚氧乙烯醚、油酸聚乙二醇甘油酯中的一种或多种。
  6. 根据权利要求1-5任一项所述的黄酮多酚类药物自乳化组合物，其特征在于，所述的助乳化剂为选自乙醇、丙二醇、碳酸丙二酯、乙二醇单乙基醚、甘油糠醛、二甲基异山梨酯、丙二醇单辛酸酯、二乙二醇单乙基醚、聚乙二醇、甘油、辛酸癸酸聚乙二醇甘油酯、苯甲醇中的一种或多种；
    优选为二乙二醇单乙基醚、聚乙二醇400、乙醇、丙二醇单辛酸酯中的一种或多种。
  7. 根据权利要求1-6任一项所述的黄酮多酚类药物自乳化组合物，其特征在于，以油相、乳化剂与助乳化剂三者的总质量比为100％计，油相为10-50％(优选为20-40％)，乳化剂为30-60％(优选为40-60％)，助乳化剂20-60％(优选为30-50％)。
  8. 权利要求1-7任一项所述的黄酮多酚类药物自乳化组合物的制备方法，其特征在于，包括如下制备步骤：
    (1)黄酮多酚类药物-磷脂复合物的制备：取黄酮多酚类药物与磷脂，溶解于有机溶剂中，经复合反应后，去除有机溶剂，干燥，即得；
    可选地，所述有机溶剂为选自乙酸乙酯、四氢呋喃、甲醇、丙酮、乙醇、无水乙醇、正丙醇、异丙醇、正丁醇、异丁醇、叔丁醇、乙醚、甲基乙基醚、二氧六环、丁酮、石油醚、己烷、环己烷、二氯甲烷、氯仿、四氯化碳、DMSO、DMF中的一种或多种，优选为乙酸乙酯、四氢呋喃、甲醇、乙醇、环己烷、DMSO、DMF中的一种或多种。
    (2)黄酮多酚类药物自乳化组合物的制备：将步骤(1)所得的黄酮多酚类药物-磷脂复合物与油相、乳化剂和助乳化剂以任意的顺序充分混合；
    可选地，将步骤(1)所得的黄酮多酚类药物-磷脂复合物与油相、乳化剂和助乳化剂直接充分混合；
    或者，先将油相、乳化剂和助乳化剂混合均匀，制备空白自乳化浓缩液，然后将步骤(1)所得的黄酮多酚类药物-磷脂复合物加入至所制得的空白自乳化浓缩液中，充分混合；
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113925862A (zh) * 2021-12-17 2022-01-14 北京五和博澳药业股份有限公司 一种预防和/或治疗炎症风暴的药物组合物及其制剂与应用

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112773787A (zh) * 2021-01-17 2021-05-11 卢奕 一种黄酮多酚类药物自乳化组合物
CN113350515B (zh) * 2021-05-31 2023-03-17 浙江中医药大学 一种漆黄素磷脂复合物及其制备方法和应用
CN114712311B (zh) * 2022-04-15 2023-05-23 青岛科技大学 一种丝素蛋白肽自组装载药纳米粒的制备及其肾保护作用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101088524A (zh) * 2006-06-12 2007-12-19 大百汇生物科技（深圳）有限公司 黄芩天然活性成分的磷脂复合物及其制备方法和制剂

Family Cites Families (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6696484B2 (en) 1997-10-31 2004-02-24 University Of Chicago Office Of Technology And Intellectual Property Method and compositions for regulation of 5-alpha reductase activity
NZ535988A (en) 2002-04-30 2005-09-30 Unigen Pharmaceuticals Inc Formulation of a mixture of free-B-ring flavonoids and flavans as a therapeutic agent
CA2641451C (en) 2006-02-09 2012-10-02 Merck & Co., Inc. Polymer formulations of cetp inhibitors
EP1837030A1 (en) * 2006-03-09 2007-09-26 INDENA S.p.A. Phospholipid complexes of curcumin having improved bioavailability
JP5358574B2 (ja) 2007-08-17 2013-12-04 アルション セラピューティクス， インコーポレイテッド 高濃度の局所麻酔薬調合物
GB0807605D0 (en) 2008-04-28 2008-06-04 Diurnal Ltd Lipid composition
SI2229940T1 (sl) * 2009-03-20 2016-01-29 Bioxtract S.A. Farmacevtski sestavek s protivnetnimi in antihistaminskimi lastnostmi
CN101579291B (zh) * 2009-05-20 2011-06-15 清华大学 一种白藜芦醇磷脂复合物纳米乳液及其制备方法与应用
CN101704838A (zh) * 2009-11-30 2010-05-12 浙江大学 一种黄芩素磷脂复合物及其制备方法
US8835509B2 (en) * 2010-05-31 2014-09-16 Arbro Pharmaceuticals Ltd. Self emulsifying drug delivery system for a curcuminoid based composition
US20140271867A1 (en) 2013-03-15 2014-09-18 Monosol Rx, Llc Film delivery system for active ingredients
KR20130089414A (ko) * 2012-02-02 2013-08-12 순천향대학교 산학협력단 바이칼린의 자가미세유화시스템 제제화 방법
CN103083683B (zh) * 2013-02-05 2015-02-11 广东华南药业集团有限公司 一种灯盏花素磷脂复合物及其制备方法和应用
CN103169657A (zh) * 2013-03-06 2013-06-26 华中科技大学 一种含灯盏花素磷脂复合物的自乳化剂及其制备方法和用途
CN103877149A (zh) * 2014-03-18 2014-06-25 新疆维吾尔自治区药物研究所 香青兰总黄酮磷脂复合物、香青兰总黄酮磷脂复合物自乳化剂及其制备方法
CN104382888B (zh) * 2014-11-06 2017-02-15 江苏隆力奇生物科技股份有限公司 一种白藜芦醇磷脂复合物自微乳颗粒的制备方法
US20170281573A1 (en) * 2016-03-31 2017-10-05 Pharcon Inc. Medicinal composition for enhanced delivery of triterpenes
CN113768901B (zh) 2016-04-26 2023-09-22 北京五和博澳药业股份有限公司 一种磷脂壳聚糖药物递送系统及其制备方法和用途
CN107308133A (zh) * 2016-04-27 2017-11-03 周意 姜黄素药物制剂
CN107007569B (zh) * 2017-03-23 2019-08-30 徐州医科大学 一种载槲皮素和白藜芦醇的磁性脂质纳米粒及其制备方法

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101088524A (zh) * 2006-06-12 2007-12-19 大百汇生物科技（深圳）有限公司 黄芩天然活性成分的磷脂复合物及其制备方法和制剂

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
CHINESE JOURNAL OF NEW DRUGS, vol. 19, no. 5, 2010, pages 371 - 395
CHINESE PATENT DRUG, vol. 35, no. 12, 2013, pages 2749 - 2752
FITOTERAPIA, vol. 83, 2012, pages 1532 - 1539
JOURNAL OF CHENGDU MEDICAL COLLEGE, vol. 12, no. 2, 2017, pages 155 - 59
JOURNAL OF SHANDONG UNIVERSITY, vol. 54, no. 3, 2016, pages 41 - 49
KE, XUE ET AL.: "Preparation of Baicalein Self-microemulsifying Drug Delivery Systems and Oral Bioavailability in Rat", CHINESE JOURNAL OF NEW DRUGS, vol. 19, no. 5, 15 March 2010 (2010-03-15), pages 1 - 7, XP055742303 *
LU CAO: "Formulation and Studies of Resveratrol-SMEDDS [D", 2014, HEBEI MEDICAL UNIVERSITY

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113925862A (zh) * 2021-12-17 2022-01-14 北京五和博澳药业股份有限公司 一种预防和/或治疗炎症风暴的药物组合物及其制剂与应用

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