CN108379227A - A kind of polymer micelle and preparation method thereof containing rutin - Google Patents
A kind of polymer micelle and preparation method thereof containing rutin Download PDFInfo
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- CN108379227A CN108379227A CN201810525567.9A CN201810525567A CN108379227A CN 108379227 A CN108379227 A CN 108379227A CN 201810525567 A CN201810525567 A CN 201810525567A CN 108379227 A CN108379227 A CN 108379227A
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- rutin
- polymer micelle
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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
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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Abstract
A kind of polymer micelle containing rutin by rutin and contains the carrier of rutin according to 1：3~100 mass ratio composition；Rutin and carrier are dissolved in organic solvent by the method for preparing the polymer micelle solution for containing rutin, including (1), and then under high velocity agitation, the organic solvent dissolved with carrier and rutin is added dropwise in distilled water；(2) organic solvent in (1) product is vapored away, then through membrane filtration, collects filtrate to get product.The present invention can improve a kind of solubility of Chinese medicine hardly soluble active ingredient rutin and improve bioavilability.
Description
Technical field
The present invention relates to a kind of polymer micelles and preparation method thereof containing rutin, belong to field of medicaments.
Background technology
Rutin (rutin) also known as rutin sophorin, rutin are a flavone compounds derived from a wealth of sources, nature
Many plant such as sophora bud, duck wheat, dandelion etc. are all rich in rutin, with anti-oxidant, antibacterial, anti-inflammatory, anticonvulsion, neural guarantor
The multiple biological activities such as shield and cardiovascular and cerebrovascular protective effect.Due to its extensive bioactivity, higher safety and enrich
Source, rutin is commonly used in health care.Country rutin only has tablet listing at present, due to rutin poorly water-soluble, stomach and intestine
Road dissolution rate is low, oral administration biaavailability is extremely low, limits the performance and clinical application of rutin drug effect.To improve it in water
Dissolubility and raising bioavilability, research and development novel rutin preparation will be the effective ways for improving rutin therapeutic effect, have weight
The clinical meaning wanted.
In order to expand the clinical application of rutin, improve its drug effect, pharmacy worker has attempted a variety of methods to improve reed
The indissoluble sex chromosome mosaicism of fourth, is such as made solid dispersions, liposome is made, and is made from micro emulsion drug delivery system etc., to a certain extent
Solves the indissoluble sex chromosome mosaicism of rutin.However, these methods are respectively present some problems, such as available cosolvent or cosolvent
Fewer, toxic side effect (such as solubilizer and inclusion compound) and aging phenomenon (such as solid dispersion)；And it is big in the prescription of micro emulsion
The surfactant of application is measured there are genotoxic potential, although liposome increases drug absorption and then lacks application because cost is too high
Foreground.For this reason, it may be necessary to find other solubilization methods, wherein polymer micelle is with its property stabilization, good biocompatibility, increasing
The advantages that molten ability is strong, receives more and more attention, the carrier material that can form polymer micelle is usually amphipathic copolymerization
Object, the hydrophilic chain of these polymer and the length of hydrophobic chain are appropriate, voluntarily assemble in water, and hydrophobic section forms the hydrophobic core of micella
Core, and hydrophilic section is got married boom column shell in micella shape, and micella is made to have spherical nucleocapsid structure.Investigation discovery, there is presently no
Increase the relevant report of the solubility of rutin using amphipathic copolymer as carrier.
Invention content
The object of the present invention is to provide a kind of polymer micelles and preparation method thereof containing rutin, can improve in one kind
The solubility and raising bioavilability of medicine hardly soluble active ingredient rutin.
In order to achieve the above-mentioned object of the invention, the technical solution adopted by the present invention is：
A kind of polymer micelle containing rutin by rutin and contains the carrier of rutin according to 1：The mass ratio of (3~100)
Composition.
Further, the carrier is amphipathic nature polyalcohol maleic rosin-macrogol ester, and hydrophobic grouping is Malaysia pine
Perfume base, hydrophilic radical are polyethylene glycol of the molecular weight 200~6000.
A kind of preparation method for the polymer micelle solution containing rutin, includes the following steps：
The carrier material and rutin are dissolved in organic solvent, then under high velocity agitation, will be dissolved with carrier by step 1
Material and the organic solvent of rutin are added dropwise in distilled water；
Step 2 vapors away the organic solvent in step 1 product, then through membrane filtration, collects filtrate, as contain
The polymer micelle solution of rutin.
Further, the organic solvent in step 1 is methanol, ethyl alcohol, acetone, one in ethyl acetate and dimethyl sulfoxide
Kind or several mixed solvents.
Further, the volume mass ratio of organic solvent and the polymer latex beam material is (2~20mL):100mg.
Further, the volume ratio of organic solvent and distilled water is 1：(2~10).
Further, the distilled water in step 1 can also be replaced with physiological saline.
Further, the stirring in step 1 is magnetic agitation in water-bath, and the temperature of water-bath is 25~50 DEG C.
Further, the operation of volatile organic solvent is carried out in 50 DEG C of water-baths in step 2；Filtering uses 0.22 μ
The miillpore filter of m carries out.
Beneficial effects of the present invention：
The present invention uses solvent evaporation method, will using maleic rosin-polyethylene glycol as amphiphilic material support
Rutin contains in the hydrophobic inner core of maleic rosin-polyethylene glycol, and the polymer micelle for containing rutin is made；Wherein, hydrophobic group
Group is maleic rosin base, is core, and hydrophilic radical is polyethylene glycol, containing multiple hydroxyls, when concentration is more than critical micelle concentration
When, hydrophilic outer shell can be formed, more drug molecules are accommodated, contains more rutins, improves the solubility of rutin in water, about
It is 10 times of bulk pharmaceutical chemicals, overcomes rutin and be insoluble in the defect of water, and improve release.
By the form of polymer micelle, also there is apparent slow releasing function, improve the dissolution rate of rutin, improve oral
Bioavilability；Meanwhile amphiphilic material used also has preferable biodegradability.
Description of the drawings
Fig. 1 is the release in vitro schematic diagram of rutin and rutin polymer micelle.
Fig. 2 is that the Drug-time curve figure in rat blood is administered orally in rutin and rutin polymer micelle.
Specific implementation mode
Below by embodiment, the invention will be further described.
Embodiment 1
It weighs 100mg rutins and 500mg maleic rosins polyethylene glycol (2000) ester is dissolved in the hot absolute ethyl alcohols of 10mL, add dropwise
Enter into the 30mL distilled water quickly stirred.In 50 DEG C of stirring in water bath, ethyl alcohol is flung to, by acquired solution through 0.22 μm of filter membrane mistake
Filter collects filtrate to get the polymer micelle solution of rutin is contained.
Embodiment 2
It weighs 90mg rutins and 510mg maleic rosins polyethylene glycol (1000) ester is dissolved in the hot absolute ethyl alcohols of 10mL, add dropwise
Enter into the 30mL distilled water quickly stirred.In 50 DEG C of stirring in water bath, ethyl alcohol is flung to, by acquired solution through 0.22 μm of filter membrane mistake
Filter collects filtrate to get the polymer micelle solution of rutin is contained.
Embodiment 3
It weighs 80mg rutins and 520mg maleic rosins polyethylene glycol (200) ester is dissolved in the hot absolute ethyl alcohols of 10mL, be added dropwise
Into the 30mL distilled water quickly stirred.In 50 DEG C of stirring in water bath, ethyl alcohol is flung to, by acquired solution through 0.22 μm of membrane filtration,
Filtrate is collected to get the polymer micelle solution of rutin is contained.
It is measured by the polymer micelle for containing rutin made from above-mentioned different prescriptions using high performance liquid chromatography (HPLC) method
The entrapment efficiency and drugloading rate of solution, laser granulometry measure particle size, and the results are shown in Table 1.Solution is investigated
Stability, stabilization time is all higher than for 24 hours three kinds of solution at room temperature.
The quality evaluation (n=3) of the different prescription rutin polymer micelle solution of table 1
| Container name | Encapsulation rate (%) | Drugloading rate (%) | Average grain diameter (nm) |
| Maleic rosin polyethylene glycol 2000 ester | 84.5% | 14.1% | 143 |
| Maleic rosin cetomacrogol 1000 ester | 82.6% | 12.4% | 128 |
| Maleic rosin polyethylene glycol 200 ester | 80.3% | 10.7% | 106 |
Embodiment 4
By the micellar solution freeze-drying obtained by Examples 1 to 3, respectively obtains three kinds of polymer micelles for containing rutin and freeze
Dry powder, then the solubility of rutin and the rutin polymer micelle freeze-dried powder in water is measured using HPLC.
Excessive rutin and rutin polymer micelle freeze-dried powder are respectively put into the test tube for filling 10mL purified waters, ultrasound
To not being redissolved, it is then placed in oscillator (100r/min), 25 DEG C of oscillations for 24 hours, after balance to be dissolved, take out saturated solution,
It is placed in a centrifuge, 10000r/min centrifuges 6min.Accurate Aspirate supernatant and with methanol dilution, is measured using HPLC, is recorded
Peak area.The solubility of rutin in rutin and rutin polymer micelle freeze-dried powder can be obtained by regression equation.
The experiment exam solubility of different prescription rutins and rutin polymer micelle, the results are shown in Table 2.As shown in Table 2, reed
The solubility of fourth in water is 82.7 μ g/mL, by the rutin dissolving in water of the drug-carrying polymer micelle prepared by embodiment 1
Degree is 832 μ g/mL, and compared with bulk pharmaceutical chemicals, solubility improves 10 times.
The solubility (n=3) of 2 rutin of table and its polymer micelle in water
| Sample name | Rutin | Embodiment 1 | Embodiment 2 | Embodiment 3 |
| Solubility (μ g/mL) | 82.7±2.36 | 832±23.5 | 815±20.1 | 803±20.5 |
Embodiment 5
The vitro release of rutin polymer micelle
It takes rutin polymer micelle is freeze-dried to be approximately equivalent to rutin 20mg in right amount, direct plunges into stripping rotor, with reference to China
Paddle method in 2015 editions four general rules of pharmacopeia measures dissolution rate and release, is that dissolution is situated between with the simulated gastric fluid containing 1% Tween 80
Matter, rotating speed 100r/min, dissolution fluid temperature are 37 ± 0.5 DEG C, operate, in preset point in time sampling 5mL, and add in accordance with the law
The synthermal dissolution medium of same volume.The sample of taking-up is crossed into 0.22 μm of membrane filtration, takes subsequent filtrate as test solution.With
Rutin in high performance liquid chromatograph determination sample, and calculate cumulative defaultlogic.Using cumulative defaultlogic as ordinate,
Time is abscissa, draws stripping curve, as a result such as Fig. 1.
It will be seen from figure 1 that bulk pharmaceutical chemicals release is rapid, 15min cumulative in vitro dissolves out external when percentage is 47.1%, 3h
Cumulative defaultlogic reaches 78.2%, and then, release tends to be slow, and cumulative in vitro dissolution percentage is 85.2% when 12h.It presses
Rutin polymer micelle obtained by embodiment 1 releases the drug slower in drug release initial stage (0~2h), and cumulative in vitro dissolves out percentage when 2h
Not up to 20%；2~6h drug releases are very fast, and cumulative in vitro dissolution percentage has reached 86.3% when 6h；Hereafter, drug release is steady, 12h
When cumulative in vitro dissolution percentage be 92.3%.Compared with bulk pharmaceutical chemicals, rutin polymer micelle provided by the invention has apparent
Sustained releasing character.
Embodiment 6
Pharmacokinetic of the rutin polymer micelle in rat body
Trial drug：It is freeze-dried by rutin polymer micelle made from embodiment 1, before use with physiological saline solution, system
At the solution of the 2mg/mL containing rutin；Rutin bulk pharmaceutical chemicals are made into the 0.5% carboxymethyl cellulose suspension of the 2mg/mL containing rutin, as
Reference preparation.
It is administered and takes blood scheme：SD rats 12, weight are 180 ± 20g, are randomly divided into 2 groups.Fasted for one day prior is tested,
Free water gavages rutin raw material and rutin polymer micelle solution (being equivalent to bulk pharmaceutical chemicals 40mg/kg) respectively.When scheduled
Between point, blood is taken to rat eye socket, is placed in the plastic centrifuge tube containing 1% heparin sodium, centrifugal separation plasma, is measured with HPLC each
The plasma drug level at a time point.As a result using administration time as abscissa, medicine-is drawn by ordinate of the blood concentration of rutin
When curve, as shown in Figure 2.
As a result：As shown in Figure 2, after oral medication, the blood medicine peak time of rutin bulk pharmaceutical chemicals is about in 2h, peak blood drug level
(Cmax) it is 8.92 μ g/mL, the peak time of rutin polymer micelle made from embodiment 1 is about 36.5 μ g/ in 6h, Cmax
ML, about the 4.1 of bulk pharmaceutical chemicals times, eliminate slack-off in vivo, the mean residence time of drug in vivo are extended, under Drug-time curve
Area significantly increases, and illustrates the oral absorption for improving rutin and bioavilability.
Polymer micelle solution is a kind of intermediate dosage form, can be made into freeze-dried powder preservation, note can further be made as needed
The suitable dosage forms such as agent or oral preparation, such as oral solution, tablet, capsule, granule are penetrated, auxiliary material safety used can be protected fully
Safety and the compliance for demonstrate,proving Clinical practice, can be widely used for the prevention of relevant disease.Health food is may also be fabricated which, for improving
Adjust body function.
Claims (9)
1. a kind of polymer micelle containing rutin, which is characterized in that by rutin and contain the carrier of rutin according to 1：3~100
Mass ratio composition.
2. a kind of polymer micelle containing rutin as described in claim 1, which is characterized in that the carrier is amphipathic
Object maleic rosin-macrogol ester is closed, hydrophobic grouping is maleic rosin base, and hydrophilic radical is molecular weight 200~6000
Polyethylene glycol.
3. a kind of preparation method for the polymer micelle solution containing rutin, which is characterized in that include the following steps：
Mass ratio is 1 by step 1：3~100 rutin is dissolved in organic solvent with the carrier for containing rutin, then in high-speed stirring
It mixes down, the organic solvent dissolved with carrier and rutin is added dropwise in distilled water；
Step 2 vapors away the organic solvent in step 1 product, then through membrane filtration, collects filtrate, as contain rutin
Polymer micelle solution.
4. a kind of preparation method for the polymer micelle solution containing rutin as claimed in claim 3, which is characterized in that step
Organic solvent in one is methanol, ethyl alcohol, acetone, one or more of ethyl acetate and dimethyl sulfoxide mixed solvent.
5. a kind of preparation method for the polymer micelle solution containing rutin as claimed in claim 3, which is characterized in that organic
The volume mass ratio of solvent and the polymer latex beam material is 2~20mL:100mg.
6. a kind of preparation method for the polymer micelle solution containing rutin as claimed in claim 3, which is characterized in that organic
The volume ratio of solvent and distilled water is 1：2~10.
7. a kind of preparation method for the polymer micelle solution containing rutin as claimed in claim 3, which is characterized in that step
Distilled water in one can also be replaced with physiological saline.
8. a kind of preparation method for the polymer micelle solution containing rutin as claimed in claim 3, which is characterized in that step
Stirring in one is magnetic agitation in water-bath, and the temperature of water-bath is 25~50 DEG C.
9. a kind of preparation method for the polymer micelle solution containing rutin as claimed in claim 3, which is characterized in that step
The operation of volatile organic solvent is carried out in 50 DEG C of water-baths in two；Filtering is carried out using 0.22 μm of miillpore filter.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810525567.9A CN108379227B (en) | 2018-05-28 | 2018-05-28 | Rutin-entrapped polymer micelle and preparation method thereof |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810525567.9A CN108379227B (en) | 2018-05-28 | 2018-05-28 | Rutin-entrapped polymer micelle and preparation method thereof |
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| Publication Number | Publication Date |
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| CN108379227A true CN108379227A (en) | 2018-08-10 |
| CN108379227B CN108379227B (en) | 2021-01-12 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114788871A (en) * | 2021-01-25 | 2022-07-26 | 山东大学 | Application of oligomeric rutin in preparation of tumor-targeted product and oligomeric rutin-bortezomib tumor-targeted drug delivery system |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101831066A (en) * | 2010-03-31 | 2010-09-15 | 中国林业科学研究院林产化学工业研究所 | Method for preparing rosin-based surfactant |
| US20110144298A1 (en) * | 2009-12-10 | 2011-06-16 | Usa As Represented By The Secretary Of The Army | Copolymerization of Hydroxytyrosol with Flavonoids Mediated by Horseradish Peroxidases |
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- 2018-05-28 CN CN201810525567.9A patent/CN108379227B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20110144298A1 (en) * | 2009-12-10 | 2011-06-16 | Usa As Represented By The Secretary Of The Army | Copolymerization of Hydroxytyrosol with Flavonoids Mediated by Horseradish Peroxidases |
| CN101831066A (en) * | 2010-03-31 | 2010-09-15 | 中国林业科学研究院林产化学工业研究所 | Method for preparing rosin-based surfactant |
Non-Patent Citations (4)
| Title |
|---|
| CHEN CHEN ET AL: "Chitosan-poly(ε-caprolactone)-poly(ethylene glycol) graft copolymers: Synthesis, self-assembly, and drug release behavior", 《JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A》 * |
| GYU NAM LIM ET AL: "Physical Characteristic and In vitro Transdermal Delivery of PCL-b-PEG Micelles Containing Quercetin and Rutin", 《POLYMER-KOREA》 * |
| RIBEIRO ET AL: "Solubilisation of griseofulvin, quercetin and rutin in micellar formulations of triblock copolymers E62P39E62 and E137S18E137", 《INTERNATIONAL JOURNAL OF PHARMACEUTICS》 * |
| 卢建芳，等: "聚马来松香PEG酯的合成及性能研究", 《化学试剂》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114788871A (en) * | 2021-01-25 | 2022-07-26 | 山东大学 | Application of oligomeric rutin in preparation of tumor-targeted product and oligomeric rutin-bortezomib tumor-targeted drug delivery system |
| CN114788871B (en) * | 2021-01-25 | 2024-02-06 | 山东大学 | Application of oligorutin in preparation of tumor targeting products and oligorutin-bortezomib tumor targeting drug delivery system |
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