CN106727309A - Polymer micelle solution containing Quercetin and its preparation method and application - Google Patents
Polymer micelle solution containing Quercetin and its preparation method and application Download PDFInfo
- Publication number
- CN106727309A CN106727309A CN201611185252.1A CN201611185252A CN106727309A CN 106727309 A CN106727309 A CN 106727309A CN 201611185252 A CN201611185252 A CN 201611185252A CN 106727309 A CN106727309 A CN 106727309A
- Authority
- CN
- China
- Prior art keywords
- quercetin
- polymer micelle
- solution containing
- polymer
- micelle solution
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- 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
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
Abstract
The present invention relates to a kind of polymer micelle solution containing Quercetin and its preparation method and application.The polymer micelle solution includes Quercetin, amphipathic nature polyalcohol micellar material, stabilizer and water, and each component weight/mass percentage composition is respectively Quercetin 0.3%~1.5%, micellar material 10%, stabilizer 0.5%~3%, water 85.5%~89.2%.The polymer micelle solution that this contains Quercetin overcomes the defect that Quercetin is insoluble in water, while the cross-film barrier across Quercetin during oral absorption, can significantly extend the release in vitro time of Quercetin and improve complete releasing degree.Polymer micelle good biocompatibility of the invention, can increase bioavilability, and improve the stability of Quercetin.
Description
Technical field
The present invention relates to biological pharmacy technical field, more particularly, to a kind of amphipathic nature polyalcohol ferment containing Quercetin
Solution and its preparation method and application.
Background technology
Quercetin, also known as quercetin, Quercetin, as medicine, with preferable eliminating the phlegm, antitussive action, and can have certain
Antiasthmatic effect.In addition with the capillary resistance that reduces blood pressure, strengthens, reduce capillary fragility, reducing blood lipid, expansion hat
Shape artery, increases the effect such as CF.Quercetin is widely used in treatment chronic bronchitis, and to coronary heart disease and hypertension
Patient also has auxiliary therapeutic action.Modern medicine study shows that Quercetin also has good antitumor action, existing abroad
It is applied to clinical treatment tumour.But the stability of Quercetin is poor, and circulating half-life is short in vivo, it is difficult to effective to reach disease
Stove position, and Quercetin is insoluble in water, and oral administration biaavailability is poor.
The content of the invention
Based on this, it is necessary to provide a kind of polymer latex containing Quercetin of the bioavilability that can improve Quercetin
Beam solution and its preparation method and application.
A kind of polymer micelle solution containing Quercetin, including each component with following weight/mass percentage composition：
Wherein, the amphipathic nature polyalcohol micellar material coats the Quercetin and forms core shell structure.
Wherein in one embodiment, the polymer micelle solution includes each group with following weight/mass percentage composition
Point：
Quercetin 0.5%~1.0%；
Amphipathic nature polyalcohol micellar material 10%；And
Stabilizer 1.5%~2.5%；
Balance of water.
Wherein in one embodiment, the amphipathic nature polyalcohol micellar material is selected from polyethylene glycol-vinyl acyl in oneself
Amine-vinyl acetate co-polymer, NaTDC, polyoxyethylene, Pegylation shitosan, PVP, imitative cell membrane phosphoric acid
At least one in choline, polyaminoacid and Poly(D,L-lactide-co-glycolide.
Wherein in one embodiment, the stabilizer is selected from water-soluble vitamin E, POLOXAMER 407 and tween
80 is at least one.
Wherein in one embodiment, the weight/mass percentage composition of the Quercetin is 0.7%；The amphipathic nature polyalcohol glue
Beam material is polyethylene glycol-caprolactam-vinyl acetate co-polymer；The stabilizer is POLOXAMER 407, described
The weight/mass percentage composition of stabilizer is 2%.
A kind of preparation method of the polymer micelle solution containing Quercetin described in any of the above-described embodiment, including it is as follows
Step：
Step one：The Quercetin is matched somebody with somebody with the amphipathic nature polyalcohol micellar material according to corresponding weight/mass percentage composition
Than being dissolved in organic solvent, it is equal to mixing that stirring is completely dissolved the Quercetin and the amphipathic nature polyalcohol micellar material
It is even, obtain the organic solution containing Quercetin and amphipathic nature polyalcohol micellar material；
Step 2：Volatilization removes the organic solvent in the solution completely, obtain comprising the Quercetin with it is described
The polymer thin-film material of amphipathic nature polyalcohol micellar material；
Step 3：The polymer thin-film material is added according to corresponding weight/mass percentage composition proportioning contains the stabilization
In the aqueous solution of agent, it is vortexed and stirs, obtains the polymer micelle solution containing Quercetin.
Wherein in one embodiment, the organic solvent is at least in acetone, methyl alcohol, ethyl acetate and glacial acetic acid
Kind.
Wherein in one embodiment, the volume mass ratio of the organic solvent and the amphipathic nature polyalcohol micellar material
It is (0.1-0.3) mL:100mg.
Wherein in one embodiment, the stirring in the step one is the magnetic agitation in water-bath, and the temperature of water-bath is
40~60 DEG C；
Stirring in the step 3 is magnetic agitation, and mixing speed is 500~700rpm, and mixing time is 0.5~2h.
The answering in antineoplastic is prepared of the polymer micelle solution containing Quercetin described in any of the above-described embodiment
With.
Amphipathic nature polyalcohol micellar material in the above-mentioned polymer micelle solution containing Quercetin can spontaneous shape in water
Into the polymer micelle of stabilization, it has the structure of hydrophobic inner core-hydrophilic outer shell, and hydrophobic inner core can be as hydrophobic drug Mongolian oak
The bank of Pi Su, by insoluble drug Quercetin solubilising in kernel, can increase the stability of Quercetin, improve its biological utilisation
Degree, promotes it to absorb；Hydrophilic outer shell not only strengthens the stability of polymer micelle, and affect polymer micelle with it is outside
The effect of environment, so as to influence polymer micelle behavior in vivo.Polymer micelle has thermodynamics very high steady
Qualitative, multi-point has hydrophobic interaction in structure, polymer micelle is had dynamic stability higher, because
This its good thermodynamic stability and dynamic stability, are prevented from medicine and separate out in vivo, it is ensured that packaging medicine it is steady
It is qualitative.
The preparation method process is simple of the above-mentioned polymer micelle solution containing Quercetin, envelop rate is high, production cost compared with
It is low, be conducive to industrialized production, have a good application prospect, while being conducive to advancing the industrialization development of liquid crystal nanometer.
Brief description of the drawings
Fig. 1 is the particle diameter and current potential of the polymer micelle containing Quercetin containing different stabilizers in embodiment 2；
Fig. 2 is the particle diameter of the polymer micelle containing Quercetin with different stabilizers concentration in embodiment 3；
Fig. 3 is particle diameter, polydispersity coefficient, the bag of the polymer micelle containing Quercetin of different dosages in embodiment 4
Envelope rate, drugloading rate and current potential；
Fig. 4 is the particle diameter and envelop rate of the polymer micelle containing Quercetin under the different magnetic agitation times of embodiment 5；
Fig. 5 is the electron scanning electromicroscopic photograph of the polymer micelle containing Quercetin in embodiment 6；
Fig. 6 is the means of differential scanning calorimetry figure (A in embodiment 7：Quercetin；B：Polymer micelle containing Quercetin；C：It is empty
White polymer micelle)；
Fig. 7 is the powder x-ray diffraction figure (A in embodiment 7：Quercetin；B：Quercetin and blank polymer micella
Physical mixture；C：Polymer micelle containing Quercetin；D：Blank polymer micella)；
Fig. 8 is the infrared absorpting light spectra (A in embodiment 8：Quercetin；B：The thing of Quercetin and blank polymer micella
Reason mixture；C：Blank polymer micella；D：Polymer micelle containing Quercetin)；
Fig. 9 is the polymer micelle release in vitro schematic diagram containing Quercetin in embodiment 9；
Figure 10 is influence schematic diagram of manual simulation's gastro-intestinal Fluid to Qu-PMs particle diameters in embodiment 10；
Figure 11 is influence schematic diagram (A of manual simulation's gastro-intestinal Fluid to Qu-PMs particle diameters in embodiment 10：PH 1.2,2h；B：
PH 7.4,4h；C：PH 7.4,6h；D：PH 7.4,8h)；
Figure 12 be embodiment 11 in Qu-PMs colloidal solution deposit particle diameter and envelop rate stability schematic diagram at room temperature；
Figure 13 is the average of beasle dog gavage Quercetin bulk drug and the polymer micelle containing Quercetin in embodiment 12
Blood concentration-time change curve (n=3).
Specific embodiment
For the ease of understanding the present invention, the present invention is described more fully below with reference to relevant drawings.In accompanying drawing
Give presently preferred embodiments of the present invention.But, the present invention can be realized in many different forms, however it is not limited to this paper institutes
The embodiment of description.On the contrary, the purpose for providing these embodiments is to make the understanding to the disclosure more thorough
Comprehensively.
Unless otherwise defined, all of technologies and scientific terms used here by the article with belong to technical field of the invention
The implication that technical staff is generally understood that is identical.The term for being used in the description of the invention herein is intended merely to description tool
The purpose of the embodiment of body, it is not intended that in the limitation present invention.Term as used herein "and/or" includes one or more phases
The arbitrary and all of combination of the Listed Items of pass.
The polymer micelle solution containing Quercetin of one implementation method, it is included with each of following weight/mass percentage composition
Component：
Wherein, amphipathic nature polyalcohol micellar material cladding Quercetin forms core shell structure.
Preferably, the polymer micelle solution includes each component with following weight/mass percentage composition：
Quercetin 0.5%~1.0%；
Amphipathic nature polyalcohol micellar material 10%；And
Stabilizer 1.5%~2.5%；
Balance of water.
Amphipathic nature polyalcohol micellar material is selected from polyethylene glycol-caprolactam-vinyl acetate co-polymer
(soluplus), NaTDC, polyoxyethylene (PEO), Pegylation shitosan (PEG-CS), PVP (PVP), imitative thin
At least one in after birth phosphocholine, polyaminoacid and Poly(D,L-lactide-co-glycolide (PLGA).
Phenolic hydroxyl group is carried in Quercetin structure, phenolic hydroxyl group is easy to form intermolecular hydrogen bonding and carbonyl between.Preferably, amphiphilic
Property polymer latex beam material be polyethylene glycol-caprolactam-vinyl acetate co-polymer.Polyethylene glycol-vinyl oneself
Lactams-vinyl acetate co-polymer has the amphipathic of hydrophilic section and Vinylcaprolactam homopolymer-vinylacetate hydrophobic section
Structure, CMC value (6.44 × 10-8mol·L-1) very low, the polymer micelle of stabilization can be spontaneously formed in water.Hydrophobic section
Vinylcaprolactam homopolymer-vinylacetate forms hydrophobic inner core, embeds insoluble drug, can while raising solubility property
Strengthen its stability.The polymer micelle hydrophobic inner core that polyethylene glycol-caprolactam-vinyl acetate co-polymer is formed
Carbonyl structure with amide groups and acetyl group, can form hydrogen bond with the phenolic hydroxyl group of Quercetin, it is thus possible to form stabilization bag
The core shell structure for covering.
Stabilizer is selected from water-soluble vitamin E (TPGS), POLOXAMER 407 (F127) and Tween 80 (Tween80)
It is at least one.
Preferably, in the polymer micelle solution containing Quercetin of present embodiment, the weight/mass percentage composition of Quercetin
It is 0.7%；Amphipathic nature polyalcohol micellar material is polyethylene glycol-caprolactam-vinyl acetate co-polymer；Stabilizer
It is POLOXAMER 407, the weight/mass percentage composition of stabilizer is 2%.
Present embodiment additionally provides a kind of preparation method of the above-mentioned polymer micelle solution containing Quercetin, and it includes
Following steps：
Step one：Quercetin is dissolved in amphipathic nature polyalcohol micellar material according to corresponding weight/mass percentage composition proportioning to be had
In machine solvent, stirring makes Quercetin and amphipathic nature polyalcohol micellar material be completely dissolved to well mixed, obtains containing Quercetin
And the organic solution of amphipathic nature polyalcohol micellar material；
Step 2：Volatilization removes the organic solvent in solution completely, obtains comprising Quercetin and amphipathic nature polyalcohol micella
The polymer thin-film material of material；
Step 3：Polymer thin-film material is added according to corresponding weight/mass percentage composition proportioning contains the water-soluble of stabilizer
In liquid, it is vortexed and stirs, obtains the polymer micelle solution containing Quercetin.
Organic solvent is preferably but not limited to be acetone, methyl alcohol, ethyl acetate and glacial acetic acid, and organic solvent and amphipathic
The volume mass ratio of compound micellar material is (0.1-0.3) mL:100mg.
Stirring in step one is the magnetic agitation in water-bath, and the temperature of water-bath is 40~60 DEG C.
Stirring in step 3 is magnetic agitation, and mixing speed is 500~700rpm, and mixing time is 0.5~2h.It is preferred that
, mixing speed is 650rpm, and mixing time is 2h.
The above-mentioned polymer micelle solution containing Quercetin can be widely applied to prepare in antineoplastic.What is obtained is anti-swollen
Tumor medicine has good stability, and bioavilability is greatly improved than single Quercetin, and absorption efficiency is also greatly improved.
It is below specific embodiment part.
Embodiment 1：The preparation of the polymer micelle solution containing Quercetin.
Weigh a certain amount of Quercetin (Qu) and 100mg carriers soluplus (polyethylene glycol-caprolactam-vinegar
Vinyl acetate copolymer) it is dissolved in 0.2mL acetone, magnetic agitation is completely dissolved it, is well mixed, then in 50 DEG C of water-bath magnetic
Power is stirred, and volatilization removes acetone, obtains the polymer thin-film material comprising Quercetin Yu amphipathic nature polyalcohol micellar material；Weigh
Stabilizer is soluble in water, is configured to the certain density aqueous solution；The aqueous solution containing stabilizer is added into prepared polymer
Make system gross weight for 1g in thin-film material, be vortexed, 650rmp magnetic agitations obtain final product the polymer micelle solution containing Quercetin
(Qu-NPs)。
Embodiment 2：Shadow of the stabilizer type to the polymer micelle (hereinafter referred to as " polymer micelle ") containing Quercetin
Ring.
Influence of the variety classes stabilizer to polymer micelle is investigated, preparation method is with embodiment 1, polymer micelle solution
1%TPGS, 1%F127,1%Tween80 and deionized water is respectively adopted.Wherein Quercetin consumption 0.7% (7mg), magnetic force is stirred
Mix 2h.Using polymer micelle particle diameter, Zeta potential and envelop rate as inspection target.
Particle diameter and potential measurement method, with ultra-pure water diluted polymer micellar solution after, take 0.5mL polymer micelle solution
It is added in sample cell, 25 DEG C of balance 2min determine polymer micelle using Zetasizer Nano ZS90 particle size determinations instrument
Particle size, polydispersity coefficient (PDI) and Zeta potential.
The envelop rate of Quercetin is determined using membrane filter method, membrane filter method refers to non-encapsulated medicine (exhausted with free crystallite
It is most of) and two kinds of forms presence of medium (small part) are dissolved in, therefore filtering with microporous membrane can be used to retain free crystallite,
Drug concentration for having dissolved can approx be considered the solubility of medicine.
Precision measures the Qu-PMs colloidal solution 0.5mL of dilution, and non-encapsulated medicine is filtered off with 0.45 μm of miillpore filter, will
Filtrate is demulsified with methyl alcohol, constant volume 10mL volumetric flasks, and HPLC methods determine content；Another precision measures the Qu-PMs colloidal solution of dilution
0.5mL is in 10mL volumetric flasks, plus methyl alcohol demulsification, constant volume, and the content of medicine, computational envelope rate are determined using HPLC
(entrapment efficiency, EE).
HPLC conditions are as follows：Chromatographic column：Odyssil C18 (250 × 4.6mm, 5 μm)；Mobile phase：Methyl alcohol：0.2% phosphoric acid
(60：40)；Column temperature：35℃；Detection wavelength：375nm；Flow velocity：1.0mL·min-1；Sample size：20μL.
As shown in Figure 1A and 1B, as a result show, under conditions of addition different stabilizers TPGS, F127, Tween80,
The polymer micelle of 100nm is yielded less than, and envelop rate is preferable, is all higher than 80%.Using 1%TPGS as stabilizer, system
Standby polymer micelle particle diameter (62.11 ± 0.53nm) and PDI (0.081 ± 0.02) are smaller, but envelop rate is relatively minimum
(83.02 ± 3.46%), Zeta potential is -5.19 ± 1.83mV, and easily aggregation is found in placement process.Made using 1%F127
It is stabilizer, prepares polymer micelle particle diameter (61.64 ± 0.35nm) and PDI (0.017 ± 0.02) is smaller, and envelop rate is most
(95.85 ± 2.86) high, Zeta (- 13.63 ± 1.45) is minimum.Polymer micelle is prepared using 1%Tween80 as stabilizer
The characteristics of to use 1%F127 similar as stabilizer, but easily aggregation is found in placement process, be not added with stabilizer prepare it is poly-
Compound micella particle diameter and PDI are relatively large.
Embodiment 3：Influence of the stabilizer concentration to polymer micelle.
Influence of the different stabilizers concentration to polymer micelle is investigated, preparation method is with embodiment 1, polymer micelle solution
Weight/mass percentage composition is respectively adopted for 0.5%F127,1%F127,2%F127 and 3%F127.Wherein Quercetin consumption 0.7%
(7mg), magnetic agitation 2h.Using polymer micelle particle diameter and envelop rate as inspection target, method is with embodiment 2.
As shown in Fig. 2 as a result showing, particle diameter and envelop rate influence of the 0.5-2%F127 concentration on polymer micelle is smaller,
Envelop rate is both greater than 85%.Polymer micelle particle diameter prepared by 3%F127 is larger (107nm), and 0.5%, 1% and 2%F127 systems
Standby polymer micelle particle diameter is smaller.
Embodiment 4：Influence of the dosage to polymer micelle.
Influence of the different dosages to polymer micelle is investigated, preparation method is distinguished with embodiment 1, the dosage of Quercetin
It is 0.3% (3mg), 0.5% (5mg), 0.7% (7mg), 1.0% (10mg), 1.5% of polymer micelle solution gross weight
(15mg).Wherein stabilizer is 2%F127, magnetic agitation 2h.Using polymer micelle particle diameter, PDI, drugloading rate and envelop rate as
Inspection target, method is with embodiment 2.
Result is shown in Fig. 3.Fig. 3 A particle size results show, with the increase of dosage, polymer micelle particle diameter gradually increases, when
When dosage is 10mg, the polymer micelle particle diameter containing Quercetin significantly increases.When dosage is 15mg, particle diameter is drastically
It is 559.23 ± 19.41nm to increase, and PDI is 0.427 ± 0.104, and this shows that the medicine of unentrapped forms crystallite in the solution.
Fig. 3 B envelop rate results show that, as dosage increases, the envelop rate of medicine is in rising trend, when dosage is
When 0.7%, the envelop rate of medicine is maximum, and when dosage is 1.0%, envelop rate is less than 60%, has half medicine not encapsulated,
Utilization ratio of drug is relatively low.When dosage is 1.5%, envelop rate only has 2.29%.
Fig. 3 B drugloading rate results show that, as dosage increases, the drugloading rate of medicine is in rising trend, when dosage is
When 0.7%, the drugloading rate of medicine is maximum, and when dosage is 1.0%, drugloading rate begins to decline, and drugloading rate has 5.01%, works as throwing
When dose is 1.5%, drugloading rate only has 0.34%.
Fig. 3 C current potential results show that, as dosage increases, the Zeta potential of medicine is in rising trend, when dosage reaches
When 7%, the Zeta potential of polymer micelle is minimum, and then as the increase of dosage, Zeta potential has change trend.
Comprehensive analysis result above, with the increase of Quercetin dosage, particle diameter, drugloading rate, envelop rate and Zeta potential
Absolute value all increased.The increase of polymer micelle medicine carrying amount, i.e., the medication amount that polymer micelle kernel is contained increases, more
Medicine wrap into kernel, cause interior nuclear diameter to become big, so polymer micelle particle diameter just increases.Simultaneously as hydrophobic inner core
Space is limited, increases the input amount of Quercetin, during beyond kernel Drug loading capacity, necessarily has part Quercetin to wrap into core,
The utilization rate of raw material can so be made to be reduced.When dosage is 1.0%, the particle diameter of the polymer micelle containing Quercetin exceedes
100nm, it may be possible to due to increasing when dosage, the reason of hydrophobic inner core diameter increase.When dosage is 1.5%, at this moment surpass
The ability of polymer micelle medicine carrying is crossed, medicine forms crystallite in aqueous.Therefore from particle diameter, envelop rate, the load of particle
Dose and Zeta potential consider that suitable dosage should be controlled in 0.7% (7mg).
Embodiment 5：Influence of the magnetic agitation time to polymer micelle.
Investigate influence of the different magnetic agitation times to micella, preparation method with embodiment 1, mixing time is respectively 0.5,
1st, 1.5 and 2h.Wherein stabilizer is 2%F127, and dosage is 0.7% (7mg).Using polymer micelle particle diameter and envelop rate as
Inspection target, method is with embodiment 2.
As shown in figure 4, result shows, as magnetic agitation time lengthening polymer micelle particle diameter diminishes, there is no conspicuousness
Change, PDI diminishes with magnetic agitation time lengthening.Influence of the magnetic agitation time to envelop rate is little.The magnetic agitation time
For 2h obtains that polymer micelle grain particle diameter is small, and distribution is narrower, and envelop rate is also preferable.Consider selection magnetic agitation
2h。
The result of comprehensive prescription above and technique each embodiment, the optimal preparation technology of optimization and prescription：Dosage is
7mg, with 2%F127 as stabilizer, 650rpm magnetic agitations 2h.
Embodiment 6：The Morphological Characterization of polymer micelle.
In order to investigate the form of polymer micelle and the size of particle, observed using electron scanning Electronic Speculum (SEM) method.
Polymer micelle freeze-dried powder sample preparation containing Quercetin.Take polymer micelle colloidal solution, add 5% it is sweet
Dew alcohol freeze drying protectant, is put into -80 DEG C of refrigerator pre-freeze 12h, is subsequently placed in lyophilized 24h in freeze drier, you can obtain pie
Polymer micelle freeze-dried powder containing Quercetin.
Polymer micelle freeze-dried powder sample containing Quercetin prepared by embodiment 1 is placed in the copper disk for being stained with insulating cement
On, metal spraying 2.5min, vacuum drying, with electronics ESEM scanning imagery, is observed and taken pictures.Its result is as shown in figure 5, result
Polymer micelle containing Quercetin prepared by display ESEM display is spherical in shape or spherical, average grain diameter about 100nm.
Embodiment 7：Crystal formation research of the Quercetin in polymer micelle system.
In order to investigate existence of the Quercetin in polymer micelle, divided using DSC and X-ray diffraction (XRD)
Analysis is determined.
DSC：The prepared medicine that carries of appropriate 5mg Quercetins (Qu), blank polymer micelle freeze-drying powder and embodiment 1 is taken respectively to gather
Compound micelle freeze-drying powder (Qu-PMs) freeze-dried powder carries out dsc analysis.DSC conditions are：10 DEG C/min of programming rate, measurement range
30-400 DEG C, empty aluminium dish is blank, and furnace gas is nitrogen.
DSC results are shown in Fig. 6.Result shows that Quercetin bulk drug is present in the form of crystal formation, is shown in DSC figures
Occur 2 peaks at 134 DEG C and 325 DEG C, 134 DEG C of peak is one dehydration peak of medicine, and 325 DEG C of peak is significantly molten medicine one
Melt endothermic peak；Blank polymer micella four endothermic peaks of appearance, and the polymer micelle containing Quercetin and blank polymer glue
The endothermic peak of beam is consistent, this glass transition temperature with carrier and contacts relevant each other, at 134 DEG C and 325 DEG C
There is not the endothermic peak of bulk drug.DSC results show that dispersion of the Quercetin in polymer micelle and bulk drug crystal formation are not
With.From DSC figures it can also be seen that peak and blank polymer micella of the polymer micelle containing Quercetin at about 350 DEG C
Movement is there occurs compared to peak shape position, this illustrates to be there may be between Quercetin and amphipathic nature polyalcohol micellar material certain
Active force.
X-ray diffraction (XRD)：Take appropriate Quercetin (Qu), blank polymer micelle freeze-drying powder (PMs), blank polymer
Drug-carrying polymer micelle freeze-dried powder (Qu-PMs) sample prepared by the physical mixture and embodiment of micelle freeze-drying powder and bulk drug,
Carry out XRD analysis.XRD conditions are：Scanning angle be 3 °≤2 θ≤50 °, step-length 0.9min-1,2 seconds residence times, voltage is
40KV, electric current is 25mA.
The result of X-ray diffraction analysis is shown in Fig. 7.Result shows that Quercetin bulk drug is presented spreading out for obvious crystalline structure
Penetrate peak；Quercetin is still presented the crystal formation of medicine in the physical mixture of Quercetin bulk drug and blank polymer micelle freeze-drying powder
The diffraction maximum of structure, illustrates that Quercetin still exists with the structure of crystal formation in physical mixture；And the polymerization containing Quercetin
Also have many peaks in the XRD of thing micella, but unlike that in bulk drug or physical mixed medicine crystal formation diffraction maximum, this demonstrate
There is the crystalline structure different from Quercetin bulk drug in polymer micelle in Quercetin.From physical mixed, blank polymer glue
The movement of diffraction maximum illustrates to be existed between Quercetin and polymer certain in beam and the polymer micelle containing Quercetin
Interact.XRD results also indicate that Quercetin may exist in polymer micelle with molecular state or amorphous state.
Embodiment 8：The interaction (FTIR) of Quercetin and amphipathic nature polyalcohol micellar material.
In order to investigate the interaction of Quercetin and amphipathic nature polyalcohol micellar material, using infrared spectrum analysis,
To the physical mixed of Quercetin (Qu), blank polymer micelle freeze-drying powder (PMs), blank polymer micelle freeze-drying powder and bulk drug
Thing and drug-carrying polymer micelle freeze-dried powder (Qu-PMs) carries out sample structure signature analysis prepared by embodiment 1.
Freeze drying example is pressed into powder first, a certain amount of KBr (KBr) is added, is well mixed, under infrared lamp
Dry and remove unnecessary moisture, be pressed into thin slice, infrared spectrometric analyzer is placed in, in 400~4000cm-1Scope determination sample it is red
External spectrum.
The results of FT-IR is shown in Fig. 8 A, Fig. 8 B, Fig. 8 C and Fig. 8 D.Molecule can be observed by infrared spectrum displacement and intensity
Between with the presence or absence of interact.Result shows that many features absworption peak occurs in the infrared spectrum of Quercetin bulk drug：OH is flexible to shake
Dynamic peak (3700-3300cm-1)；C=O absworption peaks (1670cm-1)；C-C stretching vibration peaks (1612cm-1)；C-H flexural vibrations peaks
(1456,1383, and 866cm-1)；C-O stretching vibration peaks (1272cm on ring structure-1) and C-O stretching vibration peaks (1070-
1050cm-1), this is consistent with the report of document.Also there is many features absworption peak in blank micella：OH stretching vibration peaks
(3500-3250cm-1)；Sp3CH stretching vibration peaks (2932cm-1, methylene)；C=O absorbs (1742cm-1, ester group), C=O inhales
Receive (1641cm-1, amide groups).Can be with the INFRARED ABSORPTION figure of the physical mixture of blank polymer micella and Quercetin bulk drug
Find out, both manifested the characteristic absorption of blank micella, also manifested the characteristic absorption peak of Quercetin；Polymer containing Quercetin
There is characteristic absorption peak in micella：C=O absorbs (1737cm-1, 1636cm-1), with C=O absworption peaks (1742cm in blank micella-1,
1641cm-1) compare, displacement is changed, and C=O absorbs (1636cm-1) peak broadens, this explanation Quercetin in Quercetin micella
Hydrogen bond is formd between phenolic hydroxyl group and the carbonyl of polymer.
Embodiment 9：The release behavior and releasing theory of the polymer micelle containing Quercetin.
The insoluble drug release behavior of the polymer micelle containing Quercetin is studied using Bag filter method.Because Quercetin is insoluble in
Water, and the solubility very little in gastro-intestinal Fluid, are extremely difficult to sink conditions, therefore, from 35% ethanol as dissolution medium
To meet sink conditions, the release conditions of bulk drug Quercetin and the polymer micelle containing Quercetin are compared, be experiment in vivo
Research provides reference.
Dosage is prepared for 5%, 7% and 9% prepares Qu-PMs solution according to optimal prescription respectively, while preparing Quercetin
Propylene glycol solution, respectively take certain sample and be placed in bag filter (molecular cut off 14000), bag filter two ends are tightened, by pastille
Bag filter is placed in the ethanol dissolution mediums of 100mL 35%, is discharged under the conditions of 37 ± 0.5 DEG C, rotating speed are for 100rpm, fixed
When sample 4mL, and the synthermal dissolution medium of supplement respective amount in time, through 0.45 μm of filtering with microporous membrane, obtains subsequent filtrate, uses
HPLC determines the content of medicine.The cumulative release percentage of medicine when calculating different time points, draws cumulative release curve.
High-efficient liquid phase chromatogram condition：Chromatographic column：Odyssil C18 (250 × 4.6mm, 5 μm)；Mobile phase：Methyl alcohol：0.2%
Phosphoric acid (60：40)；Column temperature：35℃；Detection wavelength：375nm；Flow velocity：1.0mL·min-1；Sample size：20μL.
Its releasing result is shown in Fig. 9.Result shows that the basic release in 24h of Quercetin bulk drug is complete, reaches 96.13%；
And the polymer micelle containing Quercetin only discharges 26.22% in 24h, 57.78% is released in 240h, with bulk drug
Compare, the polymer micelle containing Quercetin has obvious slow releasing function.Test result indicate that, soluplus polymer micelles
Can be as the carrier of sustained release preparation.
Also known from result, the Qu-PMs releases about 70% of dosage 7mg and 9mg in 240h, and dosage 5mg
Qu-PMs is discharged less than 60%, and dosage is bigger, discharges faster, and early stage release is very fast, and later stage release becomes slow.
The release in vitro feature of sustained release preparation can be evaluated according to following equations and according to its coefficient correlation substantially：
Zero-order drug releasing theory：Y=k1t+a1
Primary drug releasing theory：Ln (100-y)=k2t+a2
Higuchi equations (diffusion equation)：Y=k3t0.5+a3
Wherein, y is cumulative release percentage, and t is sample time, a1~a3It is constant, k1~k3It is release constant.By Mongolian oak
The dropout value of Pi Su is fitted investigation medicine from the releasing mechanism in polymer micelle by above-mentioned equation, with correlation coefficient r
Determine the best fit model of preparation.Regression equation is shown in Table 1 obtained by fitting.
The different releasing theory fit equations of the Qu-PMs of table 1
Note:Y, total release percentage；T, sample time；R, coefficient correlation.
Result shows, by Higuchi equation models, coefficient correlation (R2＞ 0.98) it is big, fitting effect preferably, shows Qu-
PMs releases are the drug release modes based on diffusion, and drug molecule is diffused into release and is situated between at leisure from the hydrophobic inner core position of micella
Matter.Due to that may there is hydrogen bond action between hydroxyl and the carbonyl of hydrophobic inner core on drug molecular structure, cause insoluble drug release more
Plus it is slow.The release of the different polymer micelle containing Quercetin of dosage is in similar trend, with the increase Mongolian oak of dosage
The trend that the release of Pi Su is slightly accelerated.Relative to Quercetin bulk drug, the polymer micelle containing Quercetin totally presents bright
Aobvious slow release effect.
Embodiment 10：Stability of the polymer micelle containing Quercetin in gastro-intestinal Fluid is simulated.
In order to ensure nano-carrier can conduct drugs to absorption site, it is necessary to investigate nano-carrier in different pH value
Stability in manual simulation's gastro-intestinal Fluid, method is as follows.
Precision takes 9mL artificial simulation gastric juices (without enzyme), and the Qu-PMs solution for adding 1mL embodiments 1 to prepare, vibration is mixed
Close, place 2h, Qu-PMs particle diameters are determined using Zetasizer Nano ZS90 particle instruments.
Precision takes 9mL artificial simulation intestinal juices (without enzyme), adds embodiment 1 to prepare 1mL Qu-PMs solution, and vibration mixes,
4h, 6h, 8h are placed, Qu-PMs particle diameters are determined using Zetasizer Nano ZS90 particle instruments.
As a result result shows as shown in table 2, Figure 10 and Figure 11 A-11D, in different pH value drug-carrying polymer micelle
Change in manual simulation's gastro-intestinal Fluid is different.Hatch 2h in the artificial simulation gastric juices of pH1.2, particle diameter from 61.54 ±
0.494nm is changed into 70.72 ± 2.77nm；Hatch 4h, 6h, 8h in the artificial simulation intestinal juice of pH7.4, particle diameter is respectively 60.38
± 0.64nm, 61.07 ± 0.47nm and 61.03 ± 0.94nm.In a word, though particle diameter is changed in manual simulation's gastro-intestinal Fluid,
It is respectively less than 100nm, this shows that the polymer micelle containing Quercetin is relatively stable in manual simulation's gastro-intestinal Fluid.This be containing
The absorption in vivo of the polymer micelle of Quercetin is laid a good foundation.
Influence of the manual simulation's gastro-intestinal Fluid of table 2 to Qu-PMs particle diameters
Embodiment 11：Stability of the polymer micelle containing Quercetin under analog room temperature.
Investigate stability of the Qu-PMs under analog room temperature.By the polymer latex containing Quercetin prepared by embodiment 1
Beam colloidal solution is placed 3 months at room temperature, is sampled at 30 days, 60 days and 90 days respectively, determines the polymer containing Quercetin
The particle diameter and envelop rate (method is with embodiment 5) of micella.As a result result show as shown in Figure 12 and Biao 3, the particle diameter of Qu-PMs,
, at 90 days without there is obvious change, the Qu-PMs colloidal solution of preparation has good stability for envelop rate and outward appearance.
The Qu-PMs colloidal solution of table 3 shelf stability at room temperature
Embodiment 12：The pharmacokinetic of the polymer micelle containing Quercetin.
The pharmacokinetic property of the Qu-PMs colloidal solution for preparing is investigated, method is as follows.
The male beagle dogs 6 of health are taken, fasting 12h, free water before administration.6 beasle dogs are randomly divided into 2 groups：The
One group with 16mgkg-1The Quercetin micella of dosage gives beasle dog gavage；Second group with 16mgkg-1The Quercetin of dosage is mixed
Outstanding solution (0.3%CMCNa) gives beasle dog gavage as a control group.0.5 after administration, 1,2,3,4,6,8,10,12,24,48h from
Hind leg vein blood vessel takes blood about 3mL, and whole blood is placed in the pipe of heparin, 5000rpm centrifugation l0min separated plasmas, -20 DEG C of preservations；
The accurate blank plasma 0.1mL that draws adds methyl alcohol 0.3mL, 25% hydrochloric acid 0.1mL, vortex mixing in 1.5mL centrifuge tubes
2min, in 50 DEG C of heating water bath 10min, 12000rpm centrifugation 10min, takes the μ L sample introductions of supernatant 100, is determined with HPLC methods and contained
Amount.
High-efficient liquid phase chromatogram condition is as follows：Chromatographic column：Odyssil C18 (250 × 4.6mm, 5 μm), pre-column (4.6 ×
12.5mm, 5 μm)；Mobile phase：Methyl alcohol：0.2% phosphoric acid (60：40)；Column temperature：35℃；Detection wavelength：375nm, flow velocity：
1.0mL·min-1；Sample size：100μL.
Single dose plasma drug concentration data is processed using 3P87 programs, according to blood concentration, calculates Quercetin mouthful
C after clothesmax、Tmax、T1/2、AUC0-∞Deng pharmacokinetic parameter.The relative bioavailability of Qu-PMs colloidal solution is as the following formula
Calculate：F=AUCQu-PMs/AUCQu × 100%.Two kinds of preparations are with one compartment model and weight as 1/C2When fitting after with reality
Border curve is most consistent.
Average Drug-time curve after two kinds of preparation gastric infusions is shown in Figure 13.The pharmacokinetic parameter and Relative biological of model
Availability the results are shown in Table 4, wherein, Cmax and Tmax uses measured value, and other specification is calculated by 3p87 softwares and obtained.Beasle dog body
Interior blood concentration result shows that Quercetin bulk drug (Qu) organizes the short (T of peak timemaxIt is 5.31 ± 1.08h), up to Cmax
(Cmax) it is 5.24 ± 1.32 μ gmL-1, subsequent concn declines rapidly, fluctuates larger, and medicine has been can't detect during to 24h.Medicine
Biological half-life (T1/2) it is 4.94 ± 2.03h, area (AUC under drug-time curve0~∞) it is 37.68 ± 16.8 μ gh-1·
mL-1.Mean residence time (MRT) is 7.18 ± 2.25h, and 24h is completely eliminated from vivo substantially, shows that it is metabolized in vivo fast
Speed.And after the polymer micelle experimental group (Qu-PMs) containing Quercetin is administered orally, TmaxIt is 7.02 ± 2.02h, CmaxFor
7.56±3.28μg·mL-1, T1/2It is 10.81 ± 3.7h, MRT is 7.18 ± 2.25h, AUC0~∞It is 107.84 ± 54.4 μ g
h-1·mL-1.The T of Qu-PMs1/2It is respectively 2.19 times and 3.77 times of Qu with MRT, shows that polymer micelle makes medicine in vivo
Slack-off, increased retention is eliminated, so that also maintaining higher concentration in 48h, illustrates that Qu-PMs has good delaying in vivo
Characteristic is released, and bioavilability significantly improves (AUC0~∞It is 2.86 times of Quercetin).Test result indicate that oral Qu-PMs is molten
Liquid energy is obviously improved Quercetin in beasle dog body absorption process, promotes the absorption of medicine, effectively improves medicine biological utilisation
Degree, for the research of Quercetin oral formulations provides theoretical foundation.
Pharmacokinetic parameter (n=3) after the Quercetin of table 4 is oral
Note：AUC, area under the drug-time curve；T1/2, eliminate half-life period；Cmax, peak serum concentration；Tmax, PC reach peak
Time.
The material and its concentration that above example is used are intended only as example, it is appreciated that in other embodiments, accordingly
Material and its concentration be not limited to described in embodiment, such as amphipathic nature polyalcohol micellar material be also selected from NaTDC,
Polyoxyethylene, Pegylation shitosan, PVP, imitative cell membrane phosphocholine, polyaminoacid or poly lactic-co-glycolic acid are common
One kind in polymers, or selected from two or more mixture in soluplus and these polymeric materials etc..
Each technical characteristic of embodiment described above can be combined arbitrarily, to make description succinct, not to above-mentioned reality
Apply all possible combination of each technical characteristic in example to be all described, as long as however, the combination of these technical characteristics is not deposited
In contradiction, the scope of this specification record is all considered to be.
Embodiment described above only expresses several embodiments of the invention, and its description is more specific and detailed, but simultaneously
Can not therefore be construed as limiting the scope of the patent.It should be pointed out that coming for one of ordinary skill in the art
Say, without departing from the inventive concept of the premise, various modifications and improvements can be made, these belong to protection of the invention
Scope.Therefore, the protection domain of patent of the present invention should be determined by the appended claims.
Claims (10)
1. a kind of polymer micelle solution containing Quercetin, it is characterised in that including with each of following weight/mass percentage composition
Component：
Wherein, the amphipathic nature polyalcohol micellar material coats the Quercetin and forms core shell structure.
2. the polymer micelle solution containing Quercetin as claimed in claim 1, it is characterised in that the polymer micelle is molten
Liquid includes each component with following weight/mass percentage composition：
Quercetin 0.5%~1.0%；
Amphipathic nature polyalcohol micellar material 10%；And
Stabilizer 1.5%~2.5%；
Balance of water.
3. the polymer micelle solution containing Quercetin as claimed in claim 1 or 2, it is characterised in that the amphipathic
Compound micellar material be selected from polyethylene glycol-caprolactam-vinyl acetate co-polymer, NaTDC, polyoxyethylene,
In Pegylation shitosan, PVP, imitative cell membrane phosphocholine, polyaminoacid and Poly(D,L-lactide-co-glycolide
It is at least one.
4. the polymer micelle solution containing Quercetin as claimed in claim 1 or 2, it is characterised in that the stabilizer choosing
It is at least one from water-soluble vitamin E, POLOXAMER 407 and Tween 80.
5. the polymer micelle solution containing Quercetin as claimed in claim 1 or 2, it is characterised in that the Quercetin
Weight/mass percentage composition is 0.7%；The amphipathic nature polyalcohol micellar material is polyethylene glycol-caprolactam-acetic acid second
Enoate copolymer；The stabilizer is POLOXAMER 407, and the weight/mass percentage composition of the stabilizer is 2%.
6. the preparation method of a kind of polymer micelle solution containing Quercetin as any one of Claims 1 to 5, its
It is characterised by, comprises the following steps：
Step one：The Quercetin and the amphipathic nature polyalcohol micellar material are matched according to corresponding weight/mass percentage composition molten
In organic solvent, stirring makes the Quercetin and the amphipathic nature polyalcohol micellar material be completely dissolved to well mixed, obtains
To the organic solution containing Quercetin and amphipathic nature polyalcohol micellar material；
Step 2：Volatilization removes the organic solvent in the solution completely, obtains comprising the Quercetin and the amphiphilic
The polymer thin-film material of property polymer latex beam material；
Step 3：The polymer thin-film material is added containing the stabilizer according to corresponding weight/mass percentage composition proportioning
In the aqueous solution, it is vortexed and stirs, obtains the polymer micelle solution containing Quercetin.
7. the preparation method of the polymer micelle solution containing Quercetin as claimed in claim 6, it is characterised in that described to have
Machine solvent is at least one in acetone, methyl alcohol, ethyl acetate and glacial acetic acid.
8. the preparation method of the polymer micelle solution containing Quercetin as claimed in claim 7, it is characterised in that described to have
Machine solvent is (0.1-0.3) mL with the volume mass ratio of the amphipathic nature polyalcohol micellar material:100mg.
9. the preparation method of the polymer micelle solution containing Quercetin as any one of claim 6~8, its feature
It is that the stirring in the step one is the magnetic agitation in water-bath, and the temperature of water-bath is 40~60 DEG C；
Stirring in the step 3 is magnetic agitation, and mixing speed is 500~700rpm, and mixing time is 0.5~2h.
10. the polymer micelle solution containing Quercetin as any one of Claims 1 to 5 is preparing antineoplastic
In application.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611185252.1A CN106727309A (en) | 2016-12-20 | 2016-12-20 | Polymer micelle solution containing Quercetin and its preparation method and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611185252.1A CN106727309A (en) | 2016-12-20 | 2016-12-20 | Polymer micelle solution containing Quercetin and its preparation method and application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106727309A true CN106727309A (en) | 2017-05-31 |
Family
ID=58894145
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611185252.1A Pending CN106727309A (en) | 2016-12-20 | 2016-12-20 | Polymer micelle solution containing Quercetin and its preparation method and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106727309A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108047271A (en) * | 2017-12-06 | 2018-05-18 | 石家庄学院 | A kind of quercetin dimer derivative and its preparation method and application |
| CN108851084A (en) * | 2018-06-06 | 2018-11-23 | 福建省农业科学院农业工程技术研究所 | A kind of site specific DDS for colon micella of load Quercetin and preparation method thereof |
| CN109999002A (en) * | 2019-05-22 | 2019-07-12 | 福州大学 | A kind of preparation method of quercetin nano particle and its preparing the application on anti-breast cancer medicines |
| CN110302391A (en) * | 2019-07-01 | 2019-10-08 | 大连民族大学 | A kind of glucan-Quercetin polymer medicament carrying micelle preparation and preparation method thereof |
| CN113197852A (en) * | 2021-04-20 | 2021-08-03 | 上海应用技术大学 | Cannabidiol nano micelle preparation and preparation method thereof |
| CN115192578A (en) * | 2022-06-20 | 2022-10-18 | 山东大学齐鲁医院 | Preparation of mixed micelle carrying quercetin and nintedanib |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101982168A (en) * | 2010-11-02 | 2011-03-02 | 山东大学 | Quercetin nano-micelle preparation and preparation method thereof |
-
2016
- 2016-12-20 CN CN201611185252.1A patent/CN106727309A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101982168A (en) * | 2010-11-02 | 2011-03-02 | 山东大学 | Quercetin nano-micelle preparation and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| LINGHUI DIAN EL AL.: "Enhancing oral bioavailability of quercetin using novel soluplus polymeric micelles", 《NANOSCALE RESEARCH LETTERS》 * |
| 吴金花等: "载有槲皮素的PEG-PE胶束对乳腺癌细胞耐药性的逆转效应", 《基础医学与临床》 * |
| 杨小云等: "槲皮素嵌段共聚物胶束大鼠体内药动学研究", 《广东化工》 * |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108047271A (en) * | 2017-12-06 | 2018-05-18 | 石家庄学院 | A kind of quercetin dimer derivative and its preparation method and application |
| CN108047271B (en) * | 2017-12-06 | 2020-05-26 | 石家庄学院 | Quercetin dimer derivative and preparation method and application thereof |
| CN108851084A (en) * | 2018-06-06 | 2018-11-23 | 福建省农业科学院农业工程技术研究所 | A kind of site specific DDS for colon micella of load Quercetin and preparation method thereof |
| CN108851084B (en) * | 2018-06-06 | 2021-06-15 | 福建省农业科学院农业工程技术研究所 | Colon positioning micelle loaded with quercetin and preparation method thereof |
| CN109999002A (en) * | 2019-05-22 | 2019-07-12 | 福州大学 | A kind of preparation method of quercetin nano particle and its preparing the application on anti-breast cancer medicines |
| CN110302391A (en) * | 2019-07-01 | 2019-10-08 | 大连民族大学 | A kind of glucan-Quercetin polymer medicament carrying micelle preparation and preparation method thereof |
| CN110302391B (en) * | 2019-07-01 | 2022-11-08 | 大连民族大学 | Glucan-quercetin polymer drug-loaded micelle preparation and preparation method thereof |
| CN113197852A (en) * | 2021-04-20 | 2021-08-03 | 上海应用技术大学 | Cannabidiol nano micelle preparation and preparation method thereof |
| CN113197852B (en) * | 2021-04-20 | 2022-12-09 | 上海应用技术大学 | Cannabidiol nano micelle preparation and preparation method thereof |
| CN115192578A (en) * | 2022-06-20 | 2022-10-18 | 山东大学齐鲁医院 | Preparation of mixed micelle carrying quercetin and nintedanib |
| CN115192578B (en) * | 2022-06-20 | 2023-05-30 | 山东大学齐鲁医院 | Preparation of quercetin and nilamide mixed micelle |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106727309A (en) | Polymer micelle solution containing Quercetin and its preparation method and application | |
| Dou et al. | Preparation and evaluation in vitro and in vivo of docetaxel loaded mixed micelles for oral administration | |
| Huang et al. | The efficacy of nimodipine drug delivery using mPEG-PLA micelles and mPEG-PLA/TPGS mixed micelles | |
| Zhou et al. | pH-responsive polymeric micelles self-assembled from amphiphilic copolymer modified with lipid used as doxorubicin delivery carriers | |
| CN106727336B (en) | Oridonin cubic liquid crystal nanoparticles and preparation method thereof | |
| CN105232459B (en) | A kind of poorly water soluble drugs polymer micelle composition and preparation method thereof redissolving self assembly | |
| CN103435718B (en) | The hyaluronic acid cholesteryl ester that PEG modifies | |
| Moogooee et al. | Synthesis and in vitro studies of cross-linked hydrogel nanoparticles containing amoxicillin | |
| CN108186605A (en) | A kind of drug-loading nanoparticles based on tannic acid and its preparation method and application | |
| Wang et al. | Preparation and properties of hydroxycamptothecin-loaded nanoparticles made of amphiphilic copolymer and normal polymer | |
| Han et al. | A novel cabazitaxel-loaded polymeric micelle system with superior in vitro stability and long blood circulation time | |
| Zhu et al. | Effect of taste masking technology on fast dissolving oral film: dissolution rate and bioavailability | |
| Li et al. | Novel β-1, 3-d-glucan porous microcapsule enveloped folate-functionalized liposomes as a Trojan horse for facilitated oral tumor-targeted co-delivery of chemotherapeutic drugs and quantum dots | |
| CN104163915A (en) | Cholesterol-poloxamer-cholesterol triblock copolymer, preparation method and application thereof | |
| CN103720675B (en) | A kind of have the curcumin prodrug micelle of isotope of redox-sensitive, micelle monomer and preparation method thereof | |
| CN102357075A (en) | Docetaxel nano preparation and preparation method thereof | |
| Shan et al. | Preparation of Icaritin-loaded mPEG-PLA micelles and evaluation on ischemic brain injury | |
| Yan et al. | In vitro and in vivo evaluation of poly (acrylic acid) modified mesoporous silica nanoparticles as pH response carrier for β-elemene self-micro emulsifying | |
| Kzar et al. | Everolimus loaded NPs with FOL targeting: preparation, characterization and study of its cytotoxicity action on MCF-7 breast cancer cell lines | |
| CN106361724A (en) | 20(R)-ginsenoside Rg3 slow release nanometer microsphere composition, and preparation method thereof | |
| Lin et al. | A novel drug delivery system of mixed micelles based on poly (ethylene glycol)‐poly (lactide) and poly (ethylene glycol)‐poly (ɛ‐caprolactone) for gambogenic acid | |
| CN104784117A (en) | Curcumin mixed micelle oral preparation and preparation method thereof | |
| Zhang et al. | Deoxycholic acid-grafted PEGylated chitosan micelles for the delivery of mitomycin C | |
| CN105288631B (en) | A kind of new anticancer drug nanometer formulation and preparation method thereof | |
| CN106581647A (en) | PH response insulin slow release nanoparticle, and preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170531 |
|
| RJ01 | Rejection of invention patent application after publication |