WO2016127925A1

WO2016127925A1 - Drug combination of flavonoid compound and use of same

Info

Publication number: WO2016127925A1
Application number: PCT/CN2016/073632
Authority: WO
Inventors: 孟坤; 张波; 张颉; 申清波; 金明吉; 徐更
Original assignee: 北京盛诺基医药科技有限公司
Priority date: 2015-02-13
Filing date: 2016-02-05
Publication date: 2016-08-18
Also published as: CN107205982A

Abstract

An Icaritin-containing drug combination. The drug combination is a self-emulsifying formulation, and after oral administration, the combination self-emulsifies inside the body to form an O/W-type nano-emulsion, where the particle-size range of the nano-emulsion is 10 nm to 200 nm.

Description

Pharmaceutical composition of flavonoid compound and use thereof

Technical field

The present invention relates to a pharmaceutical composition of a flavonoid compound, the use of which is in the field of medicine.

Background technique

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, 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:

In the Chinese patent application No. 200780039276.9, a class of flavonoid compounds typified by acrolatine has been proposed for the preparation of abnormal cell proliferation, particularly cancer drugs. The use of such flavonoid compounds in the preparation of selective estrogen receptor modulators is proposed in Chinese Patent Application No. 03129242.9.

However, when the applicant develops a class of flavonoid compounds typified by acrolatine, the structure of the compound is as shown in formula (I):

Wherein 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.

Summary of the invention

It is an object of the present invention to provide a flavonoid pharmaceutical composition which overcomes the drawbacks of the existing flavonoid pharmaceutical compositions which have low bioavailability, high production cost, low scale production and poor stability.

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.

In one aspect, 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. -200 nm, 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.

Preferably, 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.

Preferably, the flavonoid compound in the pharmaceutical composition is administered in an amount of from 2 to 30%.

Preferably, the pharmaceutical composition comprises a flavonoid compound, an oil phase solvent, an emulsifier, a co-emulsifier, and an antioxidant.

Preferably, 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.

Most preferably, 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.

Preferably, the pharmaceutical composition further comprises a pH adjusting agent.

More preferably, the pH adjusting agent is one or more of citric acid, malic acid and tartaric acid.

Preferably, the emulsifier is an emulsifier having an HLB value of 12-17.

Most preferably, the emulsifier is an emulsifier having an HLB value of 14-15.

Preferably, the emulsifier is capable of dissolving the flavonoid compound.

Preferably, the emulsifier is 20-60% by mass of the pharmaceutical composition, by mass ratio.

Most preferably, the emulsifier is 40-45% by mass of the pharmaceutical composition, by mass ratio.

Preferably, the emulsifier is a nonionic surfactant.

More preferably, 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.

Preferably, the oil phase solvent is capable of dissolving the flavonoid compound.

Preferably, 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. Ester, glycerol linoleate, glyceryl caprylate, isopropyl myristate, isopropyl palmitate, vitamin E acetate, propylene glycol monocaprylate, propylene carbonate and medium chain triglyceride One or several.

Preferably, the co-emulsifier is capable of dissolving the flavonoid compound.

Preferably, the co-emulsifier is an alcohol solvent.

Preferably, the co-emulsifier comprises one or both selected from the group consisting of isopropanol, ethanol, and polyhydric alcohol.

Preferably, 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. And 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.

Preferably, 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. At the same time, 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.

DRAWINGS

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.

detailed description

The following examples are intended to exemplify the invention, and are not intended to limit the invention, and modifications, changes, variations and the like are possible within the scope of the invention.

Unless otherwise stated, the term "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.

Unless otherwise stated, the term "self-emulsifying" as used herein means that the pharmaceutical composition of the present invention is automatically emulsified by body fluids after oral administration.

Unless otherwise stated, the term "O/W type nanoemulsion" as used herein 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. .

Unless otherwise stated, the "drug loading" herein is calculated by the following formula: drug loading = mass of the pharmaceutically active ingredient in the pharmaceutical composition / total mass of the pharmaceutical composition.

Unless otherwise stated, "HLB value" herein 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.

Unless otherwise stated, "emulsifier" as used herein 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.

Unless otherwise stated, "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.

Unless otherwise stated, "medium chain triglycerides" herein 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%.

Unless otherwise stated, the "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.

Unless otherwise stated, "vitamin E acetate" herein is produced by BASF Corporation and purchased from Guangzhou Feirui Chemical Co., Ltd.

Unless otherwise stated, the "polyethylene glycol dodecyl stearate" produced in this article is purchased from Wuhan Xindadi Environmental Protection Materials Co., Ltd.

Unless otherwise stated, "medium chain triglyceride" herein is commercially available from Shanghai Huihui International Trading Co., Ltd., the brand of Ireland, Kerry, under the trade number 102148027.

Unless otherwise stated, "monoglyceride" herein is available from Arbitec, Inc., CAS No. 26402-26-6.

Unless otherwise stated, "propylene carbonate" in this article was purchased from Tai'an Yuxin Chemical Co., Ltd. CAS number: 108-32-7.

Unless otherwise stated, "diethylene glycol monoethyl ether" herein is purchased from Sinopharm Chemical Reagent Co., Ltd., product number 30059328.

Example 1

Preparation of acrolatine

Aclatin, also known as Epimedium, is extracted from the Chinese herbal medicine Epimedium.

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 β-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%.

Example 2

Preparation of compounds of formula (I)

The preparation route of the compound of formula (I) is as shown in Scheme 1:

In this method, P is a protecting group, and the reaction of the first step is a technique well known in the art, in the application The detailed description of the specification of the publication of the publication No. 200610165354.7 is hereby incorporated by reference.

Removal of the protecting group of compound v affords compound vi. Depending on the protecting group, 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.

Example 3

Prescription 1

The structural formula of the active ingredient is as follows:

Preparation of the compound of formula (II)

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.

Prescription 1 method

1. Weigh a prescribed amount of citric acid, BHA and BHT in a suitable container, then add ethanol to dissolve all the solids.

2. 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.

3. Weigh a prescribed amount of the compound of formula (II), add it to the above solution system under stirring, and completely dissolve it to obtain a yellow transparent solution. If necessary, use ultrasonic, high-speed shear dispersion or heat to 40 ° C, etc. Ways to accelerate the dissolution of the compound of formula (II).

4. The above solution is enclosed in a soft capsule or filled into a hard capsule of hydroxypropylmethylcellulose (HPMC) and sealed.

Example 4

Prescription 2

The molecular structure of the active ingredient is as follows:

Preparation of compound of formula (III)

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.

Prescription 2 method

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.

Example 5

Prescription 3

The structural formula of the active ingredient is as follows:

Preparation of compounds of formula (IV)

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.

Prescription 3 method

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 polyoxyethylene (40) hydrogenated castor oil of Example 3.

Example 6

Prescription 4

The structural formula of the active ingredient is as follows:

Preparation of compound of formula (V)

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.

Prescription 4 method

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.

Example 7

Prescription 5

The structural formula of the active ingredient is as follows:

Preparation of compound of formula (VI)

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.

System of law

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.

Example 8

Prescription 6

The structural formula of the active ingredient is as follows:

Preparation of a compound of formula (VII)

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.

Prescription 6 method

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. Ethylene glycol (PEG400).

Example 9

Prescription 7

The structural formula of the active ingredient is as follows:

Preparation of a compound of formula (VIII)

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.

Prescription 7 method

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.

Example 10

Prescription 8

The structural formula of the active ingredient is as follows:

Preparation of compounds of formula (IX)

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.

Prescription 8 method

1. In a solution of oleic acid and propylene glycol, 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.

2. The above solution is enclosed in a soft capsule or filled into a hard capsule of hydroxypropylmethylcellulose (HPMC) and sealed.

Example 11

Prescription 9

System of law

1. Mixing the medium chain triglyceride with the polyethylene glycol solution, and sequentially adding a liquid sample of the prescribed amount of acrolatine and polyoxyethylene (40) hydrogenated castor oil PEG400, and adding the above solution system under stirring. To completely dissolve it, to obtain a yellow transparent solution, if necessary, can use ultrasonic, high-speed shear dispersion or heating to 40 ° C to accelerate the dissolution of acorridine. Disperse and homogenize into a uniform liquid solution.

Example 12

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 μg·mL ^-1 , respectively; The area under the time curve AUC0-24 hours was 4.6 μg·h·mL ^-1 . See Table 1, Table 2, and Figure 1 for details.

Table 1

Table 2

Example 13

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 μg·mL ^-1 , respectively; The area under the time curve AUC0-24h was 2.0 μg·h·mL ^-1 . See Table 3, Table 4 and Figure 2 for details.

table 3

Table 4

Example 14

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 μg·mL ^-1 ; The area under the time curve AUC0-24 hours was 4.6 μg·h·mL ^-1 . See Table 5, Table 6, and Figure 3 for details.

table 5

Table 6

Example 15

Stability investigation

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:

Dissolution method USP II method (paddle method)

Dissolution medium 0.1N hydrochloric acid

Medium volume 500ml

Speed 100 rpm

Temperature 37.5 ° C

Test dose 1 capsule / cup

The stability test results are shown in Table 7.

Table 7 prescription 1 soft capsule stability test results

Table 8 Test results of related substances in prescription 1 gelatin capsules

Table 9 prescription 1 soft capsule stability dissolution test results

It can be seen that the content of prescription 1 soft capsules is almost unchanged; the total amount of impurities increases slightly, mainly due to the relative retention time of 0.17 and the relative retention time of 0.49 impurities; 40 ° C, 2 weeks and 40 ° C, 1 month capsule dissolution and 0 There was no significant change in the day.

Claims

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 formed in the body has a particle size ranging from 10 to 200 nm. A 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 pharmaceutical composition according to claim 1, wherein the flavonoid compound is a compound having the following structural formula:

R is selected from the group consisting of trifluoromethyl, methyl, ethyl or methoxy.
The pharmaceutical composition according to claim 1 or 2, wherein the flavonoid compound in the pharmaceutical composition is administered in an amount of 2 to 30%.
The pharmaceutical composition according to claim 1 or 2, wherein the pharmaceutical composition comprises a flavonoid compound, an oil phase solvent, an emulsifier, a co-emulsifier, and an antioxidant; preferably, the oil in the pharmaceutical composition The mass ratio of phase solvent, emulsifier and co-emulsifier is 1.0:0.7-5.0: 1.0 to 5.0; most preferably, the mass ratio of the oil phase solvent, the emulsifier and the co-emulsifier in the pharmaceutical composition is from 1.0:2.0 to 3.0:1.5 to 3.0.
The pharmaceutical composition according to claim 4, wherein said pharmaceutical composition further comprises a pH adjusting agent; preferably, said pH adjusting agent is one of citric acid, malic acid and tartaric acid Or several.
The pharmaceutical composition according to claim 4, wherein the emulsifier is an emulsifier having an HLB value of 12 to 17; preferably, the emulsifier is an emulsifier having an HLB value of 14 to 15.
The pharmaceutical composition according to claim 6, wherein said emulsifier is capable of dissolving said flavonoid compound.
The pharmaceutical composition according to claim 5 or 6, wherein the emulsifier is 20-60% by mass of the pharmaceutical composition by mass ratio; preferably, the emulsifier is a pharmaceutical composition 40-45% of the mass.
The pharmaceutical composition according to claim 5 or 6, wherein the emulsifier is a nonionic surfactant.
The pharmaceutical composition according to claim 5 or 6, wherein the emulsifier comprises a polyoxyethylene hydrogenated castor oil, polyethylene glycol dodecahydroxystearate, cetyl alcohol and stearyl alcohol. One or several of them.
The pharmaceutical composition according to claim 4 or 5, wherein the oil phase solvent is capable of dissolving the flavonoid compound.
The pharmaceutical composition according to claim 11, wherein the oil phase solvent comprises a solvent selected from the group consisting of soybean oil, peanut oil, corn oil, castor oil, olive oil, peppermint oil, oleic acid, rapeseed oil, and sesame oil. Hydrogenated castor oil, ethyl oleate, glyceryl oleate, glyceryl linoleate, glyceryl caprylate, isopropyl myristate, isopropyl palmitate, vitamin E acetate, propylene glycol monocaprylate, One or more of propylene carbonate and medium chain triglycerides.
The pharmaceutical composition according to claim 4, wherein said co-emulsifier is capable of dissolving said flavonoid compound.
The pharmaceutical composition according to claim 13, wherein the co-emulsifier is an alcohol solvent.
The pharmaceutical composition according to claim 14, wherein said co-emulsifier comprises one or two selected from the group consisting of isopropanol, ethanol and polyhydric alcohol; preferably, said polyhydric alcohol One or more selected from the group consisting of polyethylene glycol, diethylene glycol monoethyl ether, glycerin, and propylene glycol are included.
The pharmaceutical composition according to claim 15, wherein the polyethylene glycol comprises a polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 600, poly One or more of ethylene glycol 900, polyethylene glycol 1000, polyethylene glycol 1500, and polyethylene glycol 2000.
Use of the pharmaceutical composition according to any one of claims 1 to 16 for the preparation of a medicament for use in a disease associated with abnormal cell proliferation.
A medicament for anti-cell abnormal proliferation-related diseases, which comprises the pharmaceutical composition according to any one of claims 1 to 16.
The medicine according to claim 18, wherein the medicine is an oral preparation or an injection; and the oral preparation comprises one or more of a soft capsule, a hard capsule, an oral liquid, and a suspension.