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WO2016127925A1 - Combinaison de médicaments à base de composé flavonoïde et son utilisation - Google Patents

Combinaison de médicaments à base de composé flavonoïde et son utilisation Download PDF

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Publication number
WO2016127925A1
WO2016127925A1 PCT/CN2016/073632 CN2016073632W WO2016127925A1 WO 2016127925 A1 WO2016127925 A1 WO 2016127925A1 CN 2016073632 W CN2016073632 W CN 2016073632W WO 2016127925 A1 WO2016127925 A1 WO 2016127925A1
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Prior art keywords
pharmaceutical composition
emulsifier
composition according
oil
compound
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PCT/CN2016/073632
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English (en)
Chinese (zh)
Inventor
孟坤
张波
张颉
申清波
金明吉
徐更
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Beijing Shenogen Pharma Group Ltd
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Beijing Shenogen Pharma Group Ltd
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Priority to CN201680006886.8A priority Critical patent/CN107205982A/zh
Publication of WO2016127925A1 publication Critical patent/WO2016127925A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—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
    • 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 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • the present invention relates to a pharmaceutical composition of a flavonoid compound, the use of which is in the field of medicine.
  • Flavonoids are a class of compounds that exist in nature and have a 2-phenylchromone structure. Studies have shown that flavonoids have cardiovascular system activity, antibacterial, antiviral activity and antitumor activity.
  • Acoladine also known as icariin, icariin
  • icariin is a flavonoid compound.
  • Acrolatine is a new effective monomer obtained by enzymatic conversion of the main active ingredient icariin extracted from Chinese herbal medicine Epimedium. Its structure is as follows:
  • R is selected from hydrogen, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy group, containing one or more halogen atoms (C 1 -C 4) alkyl, halo, cyano, Or a (C 1 -C 4 )alkoxy group substituted with one or more halogen atoms.
  • Applicants have found that such compounds generally have the disadvantage of poor solubility in water and very low bioavailability for oral administration. This deficiency limits the full utilization of the above flavonoid compounds. Accordingly, there is a need for a pharmaceutical composition suitable for the flavonoid compound represented by the above formula (I), which is capable of improving the bioavailability of the above drug, and which is low in production cost and suitable for industrial production.
  • Another object of the present invention is to provide a use of the pharmaceutical composition of the flavonoid compound of the present invention for the preparation of a medicament for use in a disease associated with abnormal cell proliferation.
  • a further object of the present invention is to provide a medicament for anti-cell abnormal proliferation-related diseases, which comprises the pharmaceutical composition of the present invention.
  • the present invention provides a pharmaceutical composition of a flavonoid compound, which is a self-emulsification dosage form, which is self-emulsified in the body to form an O/W type nanoemulsion after oral administration, and the nanoparticle size of the nanoemulsion is 10 in vivo.
  • the flavonoid compound is a compound having the following structural formula:
  • R is selected from hydrogen, (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy group, containing one or more halogen atoms (C 1 -C 4) alkyl, halogen, cyano or (C 1 -C 4 ) alkoxy group substituted with one or more halogen atoms.
  • the flavonoid compound is a compound having the following structural formula:
  • Said R is selected from the group consisting of trifluoromethyl, methyl, ethyl or methoxy.
  • the flavonoid compound in the pharmaceutical composition is administered in an amount of from 2 to 30%.
  • the pharmaceutical composition comprises a flavonoid compound, an oil phase solvent, an emulsifier, a co-emulsifier, and an antioxidant.
  • the mass ratio of the oil phase solvent, the emulsifier and the co-emulsifier in the pharmaceutical composition is from 1.0:0.7 to 5.0:1.0 to 5.0.
  • the mass ratio of the oil phase solvent, emulsifier and co-emulsifier in the pharmaceutical composition is from 1.0:2.0 to 3.0:1.5 to 3.0.
  • the pharmaceutical composition further comprises a pH adjusting agent.
  • the pH adjusting agent is one or more of citric acid, malic acid and tartaric acid.
  • the emulsifier is an emulsifier having an HLB value of 12-17.
  • the emulsifier is an emulsifier having an HLB value of 14-15.
  • the emulsifier is capable of dissolving the flavonoid compound.
  • the emulsifier is 20-60% by mass of the pharmaceutical composition, by mass ratio.
  • the emulsifier is 40-45% by mass of the pharmaceutical composition, by mass ratio.
  • the emulsifier is a nonionic surfactant.
  • the emulsifier comprises one or more selected from the group consisting of polyoxyethylene hydrogenated castor oil, polyethylene glycol dodecyl stearate, cetyl alcohol and stearyl alcohol.
  • the oil phase solvent is capable of dissolving the flavonoid compound.
  • the oil phase solvent comprises a selected from the group consisting of soybean oil, peanut oil, corn oil, castor oil, olive oil, peppermint oil, oleic acid, rapeseed oil, sesame oil, hydrogenated castor oil, ethyl oleate, oleic acid glycerin.
  • the co-emulsifier is capable of dissolving the flavonoid compound.
  • the co-emulsifier is an alcohol solvent.
  • the co-emulsifier comprises one or both selected from the group consisting of isopropanol, ethanol, and polyhydric alcohol.
  • the polyhydric alcohol comprises one or more selected from the group consisting of polyethylene glycol, diethylene glycol monoethyl ether, glycerin and propylene glycol.
  • the polyethylene glycol comprises a polyethylene glycol 200, a polyethylene glycol 300, a polyethylene glycol 400, a polyethylene glycol 600, a polyethylene glycol 900, a polyethylene glycol 1000, and a polyethylene glycol 1500.
  • polyethylene glycol 2000 One or several.
  • Another aspect of the invention also provides the use of a pharmaceutical composition of the invention in the manufacture of a medicament for use in a disease associated with abnormal cell proliferation.
  • Still another aspect of the present invention provides a medicament for anti-cell abnormal proliferation-related diseases, which comprises the pharmaceutical composition of the present invention.
  • the drug is an oral preparation or an injection.
  • the oral preparation includes several kinds of soft capsules, hard capsules, oral liquids, and suspensions.
  • the invention has the beneficial effects that the invention overcomes the characteristics that the existing flavonoid compound is difficult to dissolve in water and oil, and the flavonoid compound is made into a self-emulsification dosage form, thereby fully improving the biological utilization of the flavonoid compound in the animal body. degree.
  • the pharmaceutical composition of the present invention has the advantage of a long shelf life and exhibits good stability in acid, alkaline, light and oxidation experiments.
  • Figure 1 shows the pharmaceutical composition of Formula 1 fed to Beagle dogs at a dose of 40 mg/kg, resulting in individual and mean plasma concentrations.
  • Figure 2 shows the pharmaceutical composition of Formulation 4 fed to Beagle dogs at a dose of 40 mg/kg, resulting in individual and mean plasma concentrations.
  • Figure 3 is a graph showing the individual and mean blood concentration of a prescription 9 acrolatine pharmaceutical composition fed to a beagle dog at a dose of 40 mg/kg.
  • Figure 4 is a graph showing the dissolution profile of the Formula 1 soft capsule of Example 3 at 40 ° C, 0 days, 2 weeks, and 1 month.
  • nano-emulsion also known as “microemulsion” is a thermodynamically stable, asymmetrical, nano-scale particle size formed by an aqueous phase, an oil phase, a surfactant, and a co-surfactant. Homogeneous, transparent or translucent homogeneous dispersion system.
  • the usual nanoemulsions are classified into three types, namely, oil-in-water type nano-emulsion, water-in-oil type nano-milk, and bicontinuous type nano-milk.
  • self-emulsifying means that the pharmaceutical composition of the present invention is automatically emulsified by body fluids after oral administration.
  • O/W type nanoemulsion refers to a pharmaceutical composition of the present invention which, after oral administration, can be self-emulsified to form O/W type nanoemulsion while improving bioavailability. .
  • drug loading mass of the pharmaceutically active ingredient in the pharmaceutical composition / total mass of the pharmaceutical composition.
  • HLB value refers to a hydrophilic-lipophilic balance value which is used to indicate the difference in emulsifying ability of an emulsifier. If the larger the HLB, the greater the hydrophilic effect, the stable the oil-in-water emulsion; conversely, the smaller the HLB, the greater the lipophilic effect, and the water-in-oil emulsion system can be stabilized.
  • emulsifier refers to a class of surfactants. When it is dispersed on the surface of the dispersoid, a film or an electric double layer is formed, so that the dispersed phase is charged, thereby preventing the small droplets of the dispersed phase from coagulating with each other, thereby forming a stable emulsion.
  • nonionic surfactant as used herein means that dissociation does not occur when dissolved in water, and the lipophilic group in the molecule is substantially the same as the lipophilic group of the ionic surfactant.
  • the water group is mainly composed of a certain number of oxygen-containing groups such as hydroxyl groups.
  • medium chain triglycerides are extracted from coconut oil or from palm oil. They are a mixture of saturated triglycerides, and the acids which are linked to glycerol are mainly octanoic acid (C 8 H 16 O 2 ) and sunflower acid (C 10 H 20 O 2 ), and their contents are not less than 95%.
  • polyoxyethylene (40) hydrogenated castor oil (Cremophor RH40) CAS number is 61788-85-0, produced by BASF Corporation, purchased from Wuhan Xindadi Environmental Protection Materials Co., Ltd.
  • vitamin E acetate herein is produced by BASF Corporation and purchased from Guangzhou Feirui Chemical Co., Ltd.
  • polyethylene glycol dodecyl stearate produced in this article is purchased from Wuhan Xindadi Environmental Protection Materials Co., Ltd.
  • immediate chain triglyceride herein is commercially available from Shanghai Huihui International Trading Co., Ltd., the brand of Ireland, Kerry, under the trade number 102148027.
  • diethylene glycol monoethyl ether herein is purchased from Sinopharm Chemical Reagent Co., Ltd., product number 30059328.
  • a method for preparing icariin is disclosed in the patent publication No. CN 101302548.
  • the method uses icariin as a raw material, and is hydrolyzed by ⁇ -glucosidase, and the precipitate obtained by centrifugation of the hydrolyzate is dissolved in acetone, and the supernatant is obtained by centrifugal filtration.
  • the supernatant obtained by centrifugation was recrystallized with water to obtain pure extract of icariin, and the pure icariin was yellow powdery crystal.
  • the icariin in the present invention is purchased from Shaanxi Jiahe Plant Chemical Co., Ltd., with a purity of 90%.
  • protecting group of compound v affords compound vi.
  • the method of removal also varies accordingly, primarily in the "Protective Groups in Organic Synthesis" (Greene T. W. et al., John Wiley & Sons, New York, 1991).
  • Preferred protecting groups are benzyl, benzoyl, benzyloxycarbonyl, TBDMS (tert-butyldimethylsilyl), THP (tetrahydropyranyl), methyl, MOM (methoxymethyl), PMB (p-methoxybenzyl) and the like.
  • Compound vi can be prepared by reacting compound vi with isopentenyl bromide under basic conditions.
  • Solvents suitable for the reaction include: methanol, DMF (N,N-dimethylformamide), THF (tetrahydrofuran), water, toluene, DME (1,2-dimethoxyethane), and a mixed solvent such as methanol. - water, DMF-water, tetrahydrofuran-water, and the like.
  • the solvent used in the reaction is preferably water.
  • Suitable bases for the reaction include: potassium hydroxide, potassium carbonate, cesium carbonate, sodium methoxide, sodium hydride, potassium t-butoxide, DBU (1,8-diazabicyclo-bicyclo(5,4,0) -7-undecene), n-butyllithium, LDA (lithium diisopropylamide), LHMDS (lithium hexamethyldisilazide), etc.
  • the reaction temperature is usually between about 0-100 ° C
  • the reaction The time is 1-20 hours.
  • the compound of formula (i), phloroglucinol, was purchased from Acros Corporation under the trade designation 131040250.
  • the structural formula of the active ingredient is as follows:
  • the compound of formula (II) is prepared according to Scheme 1, wherein P is a methyl group, a compound Acquired from Acros, product number 125660050; compound Purchased from Acros, the product number is 303401010.
  • the compound of formula (II) can also be prepared according to the method disclosed in Example 1 of WO2013104263.
  • the Cremophor RH40 was heated to 40 ° C, allowed to melt into a liquid state, and then a predetermined amount of a liquid sample of oleic acid and PEG 400 was sequentially added to the ethanol solution, and dispersed uniformly into a uniform liquid solution.
  • HPMC hydroxypropylmethylcellulose
  • the molecular structure of the active ingredient is as follows:
  • a compound of formula (III) is prepared according to Scheme 1, wherein P is methoxymethyl, a compound Purchased from Enamine, product number EN300-134167; compound Purchased from Acros, the product number is 147980010.
  • the preparation method of this example is similar to the preparation method of Example 3 except that the oleic acid in Example 3 was replaced with vitamin E acetate in this example.
  • the structural formula of the active ingredient is as follows:
  • the compound of formula (IV) is prepared according to Scheme 1, wherein P is methoxymethyl, the compound of formula (ii) is the same as the compound of formula (ii) of Example 4; Purchased from Acros, the product number is 305730050.
  • the preparation method of this example is similar to the preparation method of Example 3, except that in this example, vitamin E acetate is used instead of the oleic acid in Example 3, and polyethylene glycol dodecyl stearate is substituted.
  • the structural formula of the active ingredient is as follows:
  • the compound of formula (V) is prepared according to Scheme 1, wherein P is methoxymethyl, and the compound of formula (ii) is the same as the compound of formula (ii) of Example 4; Purchased from Acros, the product number is 153410050.
  • the preparation method of this example was similar to the preparation method of Example 3, except that the medium chain triglyceride was used in place of the oleic acid in Example 3 in this example.
  • the structural formula of the active ingredient is as follows:
  • the compound of the formula (VI) is prepared according to the scheme of Scheme 1, wherein P is a methoxymethyl group, and the compound of the formula (ii) of the present embodiment is the same as the compound of the formula (ii) of the embodiment 4, the compound Purchased from Acros, the product number is 105750010.
  • the preparation method of this example is similar to the preparation method of Example 3, except that the oleic acid in Example 3 was replaced with monoglyceride in this example.
  • the structural formula of the active ingredient is as follows:
  • the compound of the formula (VII) is prepared according to the scheme of Scheme 1, wherein P is a methoxymethyl group, and the compound of the formula (ii) of the present embodiment is the same as the compound of the formula (ii) of the embodiment 4, the compound Purchased from Acros, the product number is 306,350,010.
  • the preparation method of this embodiment is similar to the preparation method of Example 3, except that propylene carbonate is used in place of oleic acid in Example 3, and diethylene glycol monoethyl ether is used instead of the polymerization in Example 3.
  • the structural formula of the active ingredient is as follows:
  • the compound of the formula (VIII) is prepared according to the scheme of Scheme 1, wherein P is a methoxymethyl group, and the compound of the formula (ii) of the present embodiment is the same as the compound of the formula (ii) of the embodiment 4, the compound Purchased from Acros, the product number is 154550050.
  • the preparation method of this example is similar to the preparation method of Example 3, except that polyethylene glycol (PEG400) in Example 3 was replaced with diethylene glycol monoethyl ether in this example.
  • the structural formula of the active ingredient is as follows:
  • the compound of the formula (IX) is prepared according to the scheme of Scheme 1, wherein P is a methoxymethyl group, and the compound of the formula (ii) of the present embodiment is the same as the compound of the formula (ii) of the embodiment 4, the compound Purchased from Acros, the product number is 212970050.
  • a liquid sample of a prescribed amount of the active ingredient and polyoxyethylene (40) hydrogenated castor oil PEG400 is sequentially added, and the solution is added to the above solution system under stirring to completely dissolve it to obtain a yellow transparent
  • the solution may be accelerated by ultrasonication, high-speed shear dispersion or heating to 40 ° C if necessary to accelerate the dissolution of the compound of formula (IX). Disperse and homogenize into a uniform liquid solution.
  • HPMC hydroxypropylmethylcellulose
  • HPMC hydroxypropylmethylcellulose
  • Two healthy beagle dogs were selected, weighing 10.0 ⁇ 1.0kg, male. Fasting 16 hours before the test, 4 hours after the administration, free feeding and drinking, and administering the capsule of Example 3 at a dose of 40 mg/kg, 0.167, 0.5, 1, 2, 4, 6, 8 after administration. Blood samples were taken from the forelimb vein for 24 hours, placed in a plastic tube with heparin, centrifuged, and the plasma was separated and stored at -20 ° C for testing.
  • the elimination half-life t 1/2 of the drug in the plasma of the Beagle dog after oral administration of the capsule of Example 3 was 4.8 hours; the peak time T max was 1.0 hour; the peak concentration C max was 1.5 ⁇ g ⁇ mL -1 , respectively; The area under the time curve AUC0-24 hours was 4.6 ⁇ g ⁇ h ⁇ mL -1 . See Table 1, Table 2, and Figure 1 for details.
  • Two healthy beagle dogs weighing 10.0 ⁇ 1.0 kg, male, fasted 16 hours before the test, freely fed and drinking 4 hours after the administration, and the capsule of the administration example 6 was administered at a dose of 40 mg/kg.
  • 1 mL of blood was taken from the forelimb veins at 0.167, 0.5, 1, 2, 4, 6, 8, and 24 hours, placed in a plastic tube with heparin, centrifuged, and plasma was separated and stored at -20 ° C for testing.
  • the elimination half-life t 1/2 of the drug in the plasma of the Beagle dog after oral administration of the capsule of Example 6 was 5.5 hours; the peak time T max was 0.8 hours; the peak concentration C max was 0.5 ⁇ g ⁇ mL -1 , respectively; The area under the time curve AUC0-24h was 2.0 ⁇ g ⁇ h ⁇ mL -1 . See Table 3, Table 4 and Figure 2 for details.
  • Two healthy beagle dogs were selected, weighing 10.0 ⁇ 1.0kg, male. Fasting 16 hours before the test, 4 hours after the administration, and 2 days after the administration, the drug was administered at a dose of 40 mg/kg, and the drug was administered at 1167, 0.5, 1, 2, 4, after administration. At 6 and 8 hours, 1 mL of blood was taken from the forelimb vein, placed in a plastic tube with heparin, centrifuged, and the plasma was separated and stored at -20 ° C for testing.
  • the elimination half-life t 1/2 of the drug in the plasma after oral administration of the capsule of the beagle dog was 4.8 hours; the peak time T max was 1.0 hour; the peak concentration C max was 1.5 ⁇ g ⁇ mL -1 ; The area under the time curve AUC0-24 hours was 4.6 ⁇ g ⁇ h ⁇ mL -1 . See Table 5, Table 6, and Figure 3 for details.
  • the soft capsules prepared from the formulation 1 of Example 3 were selected for stability studies to examine trends in drug content, impurities, dissolution and disintegration time limits.
  • the stability lofting condition is 40 ° C, 75% relative humidity.
  • the self-emulsified prescription 1 soft capsules are sealed in a single aluminum foil and sampled at 0 days, 2 weeks, and 1 month respectively.
  • the dissolution test conditions are as follows:

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
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  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une combinaison de médicaments contenant de l'icaritine. La combinaison de médicaments est une formulation auto-émulsifiante, et après administration par voie orale, ladite combinaison s'auto-émulsionne à l'intérieur du corps pour former une nano-émulsion de type huile dans l'eau, la classe granulométrique de la nano-émulsion étant comprise entre 10 et 200 nm.
PCT/CN2016/073632 2015-02-13 2016-02-05 Combinaison de médicaments à base de composé flavonoïde et son utilisation Ceased WO2016127925A1 (fr)

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CN201680006886.8A CN107205982A (zh) 2015-02-13 2016-02-05 一种黄酮化合物的药物组合物及其用途

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CN201510079190 2015-02-13
CN201510079190.5 2015-02-13

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107982249A (zh) * 2016-10-27 2018-05-04 四川曼赛思医药科技有限公司 一种含淫羊藿素及其衍生物以及他们的盐与增溶剂的药物组合物
CN115175676A (zh) * 2020-03-10 2022-10-11 鲁南制药集团股份有限公司 淫羊藿苷元的医药用途

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CN114129518B (zh) * 2020-09-04 2025-09-05 北京盛诺基医药科技股份有限公司 一种氟可拉定的纳米胶束制剂及其制备方法和用途

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CN101513388A (zh) * 2009-03-27 2009-08-26 贾晓斌 淫羊藿苷元微乳剂及其制备方法
CN101528038A (zh) * 2006-10-25 2009-09-09 盛诺基医药科技有限公司 用于治疗与雌激素受体相关的疾病的化合物和方法

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CN101528038A (zh) * 2006-10-25 2009-09-09 盛诺基医药科技有限公司 用于治疗与雌激素受体相关的疾病的化合物和方法
CN101513388A (zh) * 2009-03-27 2009-08-26 贾晓斌 淫羊藿苷元微乳剂及其制备方法

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WANG, JINYAN ET AL.: "Preliminary study on absorption characteristics in intestine of icaritin self-microemulsion via Caco-2 cell model.", CHINESE TRADITIONAL AND HERBAL DRUGS., vol. 43, no. 3, 31 March 2012 (2012-03-31), pages 476 - 481 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107982249A (zh) * 2016-10-27 2018-05-04 四川曼赛思医药科技有限公司 一种含淫羊藿素及其衍生物以及他们的盐与增溶剂的药物组合物
CN115175676A (zh) * 2020-03-10 2022-10-11 鲁南制药集团股份有限公司 淫羊藿苷元的医药用途

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