CN106109418A - Ursolic acid solid dispersion and preparation method thereof - Google Patents
Ursolic acid solid dispersion and preparation method thereof Download PDFInfo
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- CN106109418A CN106109418A CN201610508093.8A CN201610508093A CN106109418A CN 106109418 A CN106109418 A CN 106109418A CN 201610508093 A CN201610508093 A CN 201610508093A CN 106109418 A CN106109418 A CN 106109418A
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- ursolic acid
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
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Abstract
The invention discloses a kind of ursolic acid solid dispersion and preparation method thereof, its component includes: ursolic acid, surfactant and pH adjusting agent.It is characterized in that being codissolved in dehydrated alcohol ursolic acid and surfactant, 40 DEG C of heating in water bath stirrings are completely dissolved to feeding intake, then, add pH adjusting agent, Rotary Evaporators is utilized to be volatilized by ethanol, at 60 90 DEG C, vacuum drying oven is dried, pulverize with pulverizer, obtain the solid dispersion of ursolic acid.The ursolic acid solid dispersion of the present invention can improve the dissolution of ursolic acid, and because adding acid regulator, medicine is absorbed in intestinal, promote it preferably to play the hydrotropy effect of surfactant, thus improve dissolution rate and the bioavailability of ursolic acid further.
Description
Technical field
The present invention relates to the field of Chinese medicines, be specifically related to a kind of ursolic acid solid dispersion and preparation method thereof.
Background technology
Ursolic acid, has another name called maloic acid, ursolic acid, and in plant kingdom, distribution is the widest.Current study show that ursolic acid has anti-liver
The pharmacodynamics effect widely such as inflammation, antitumor, antiinflammatory antiviral, blood fat reducing, atherosclerosis and enhancing immunity, and toxicity
Low, untoward reaction is few.But being dissolved in water owing to ursolic acid is extremely difficult, bioavailability is extremely low simultaneously so that it is be difficult to what performance was had
Extensively pharmacological effect.
Insoluble medicine solid dispersant refers to that medicine is dispersed in a certain solid with states such as molecule, amorphous, crystallites
Dispersion formed in body carrier.In medical solid dispersant, due to the high dispersion state of medicine, and because of frequently with parent
Aqueous carrier material, enhances the wettability of medicine, thus can greatly improve dissolution and the absorption characteristic of medicine, improve its mouth
Take bioavailability.
Major part insoluble drug belongs to faintly acid or weakly basic drugs, and its dissolubility is affected relatively big by pH, therefore gastrointestinal tract
The pH environment of different parts frequently can lead to that drug absorption is insufficient and bioavailability reduces.And one new technique is micro-
Environment pH control technique then can make medicine realize non-pH dependent release.Researcher is had to be applied by microenvironment pH control technique
In the preparation of solid dispersion, the release of insoluble drug in solid dispersion can not only be promoted, may also suppress medicine simultaneously
Crystallization, thus improve the stability of system.
Summary of the invention
Present invention aims to the deficiency of above-mentioned ursolic acid, it is provided that a kind of good water solubility, bioavailability are high
Ursolic acid solid dispersion and preparation method thereof.
Invention embodiment is as follows.
Weigh ursolic acid and sodium lauryl sulphate crosses 80 mesh sieves, the most weighed ursolic acid 10g and dodecyl sulfur respectively
Acid sodium 40g, is made into the mixture of 1:4 (w/w), and fully mixing had both obtained physical mixture.Prepared physical mixture is codissolved in nothing
In water-ethanol, 40 DEG C of heating in water bath stirrings are completely dissolved to feeding intake, and then, add pH adjusting agent 10 ~ 30g, utilize rotary evaporation
Ethanol is volatilized by instrument, dries at 60-90 DEG C in vacuum drying oven, pulverizes with pulverizer, obtains the solid dispersion of ursolic acid.
The raw material standards that the embodiment above is previously mentioned is as follows.
Ursolic acid standard substance: Chinese Pharmacopoeia version one ministerial standard in 2015.
Ursolic acid crude drug: Chinese Pharmacopoeia version one ministerial standard in 2015.
Sodium lauryl sulphate: Chinese Pharmacopoeia version four ministerial standard in 2015.
Citric acid: Chinese Pharmacopoeia version four ministerial standard in 2015.
Succinic acid: Chinese Pharmacopoeia version four ministerial standard in 2015.
Dehydrated alcohol: Chinese Pharmacopoeia version two ministerial standard in 2015.
Raw material used in above ursolic acid solid dispersion all can be commercially available from pharmaceuticals, as long as meeting country
Standard all can be used to implement the present invention program.
Accompanying drawing explanation
Fig. 1 is the In Vitro Dissolution curve of the ursolic acid solid dispersion in embodiment 2 and ursolic acid standard substance.
Fig. 2 is the ursolic acid solid dispersion in embodiment 2 and ursolic acid standard substance blood drug level in SD rat
Time graph.
Detailed description of the invention
The specific embodiment 1 of the present invention.
Weigh ursolic acid and sodium lauryl sulphate crosses 80 mesh sieves, the most weighed ursolic acid 10g and dodecyl sulfur respectively
Acid sodium 40g, is made into the mixture of 1:4 (w/w), and fully mixing had both obtained physical mixture.Prepared physical mixture is codissolved in nothing
In water-ethanol, 40 DEG C of heating in water bath stirrings are completely dissolved to feeding intake, and then, add citric acid 10g, utilize Rotary Evaporators by second
Alcohol volatilizees, and dries at 60-90 DEG C in vacuum drying oven, pulverizes with pulverizer, obtains the solid dispersion of ursolic acid.
The specific embodiment 2 of the present invention.
Weigh ursolic acid and sodium lauryl sulphate crosses 80 mesh sieves, the most weighed ursolic acid 10g and dodecyl sulfur respectively
Acid sodium 40g, is made into the mixture of 1:4 (w/w), and fully mixing had both obtained physical mixture.Prepared physical mixture is codissolved in nothing
In water-ethanol, 40 DEG C of heating in water bath stirrings are completely dissolved to feeding intake, and then, add citric acid 20g, utilize Rotary Evaporators by second
Alcohol volatilizees, and dries at 60-90 DEG C in vacuum drying oven, pulverizes with pulverizer, obtains the solid dispersion of ursolic acid.
The specific embodiment 3 of the present invention.
Weigh ursolic acid and sodium lauryl sulphate crosses 80 mesh sieves, the most weighed ursolic acid 10g and dodecyl sulfur respectively
Acid sodium 40g, is made into the mixture of 1:4 (w/w), and fully mixing had both obtained physical mixture.Prepared physical mixture is codissolved in nothing
In water-ethanol, 40 DEG C of heating in water bath stirrings are completely dissolved to feeding intake, and then, add citric acid 30g, utilize Rotary Evaporators by second
Alcohol volatilizees, and dries at 60-90 DEG C in vacuum drying oven, pulverizes with pulverizer, obtains the solid dispersion of ursolic acid.
The specific embodiment 4 of the present invention.
Weigh ursolic acid and sodium lauryl sulphate crosses 80 mesh sieves, the most weighed ursolic acid 10g and dodecyl sulfur respectively
Acid sodium 40g, is made into the mixture of 1:4 (w/w), and fully mixing had both obtained physical mixture.Prepared physical mixture is codissolved in nothing
In water-ethanol, 40 DEG C of heating in water bath stirrings are completely dissolved to feeding intake, and then, add succinic acid 10g, utilize Rotary Evaporators by second
Alcohol volatilizees, and dries at 60-90 DEG C in vacuum drying oven, pulverizes with pulverizer, obtains the solid dispersion of ursolic acid.
The specific embodiment 5 of the present invention.
Weigh ursolic acid and sodium lauryl sulphate crosses 80 mesh sieves, the most weighed ursolic acid 10g and dodecyl sulfur respectively
Acid sodium 40g, is made into the mixture of 1:4 (w/w), and fully mixing had both obtained physical mixture.Prepared physical mixture is codissolved in nothing
In water-ethanol, 40 DEG C of heating in water bath stirrings are completely dissolved to feeding intake, and then, add succinic acid 20g, utilize Rotary Evaporators by second
Alcohol volatilizees, and dries at 60-90 DEG C in vacuum drying oven, pulverizes with pulverizer, obtains the solid dispersion of ursolic acid.
The specific embodiment 6 of the present invention.
Weigh ursolic acid and sodium lauryl sulphate crosses 80 mesh sieves, the most weighed ursolic acid 10g and dodecyl sulfur respectively
Acid sodium 40g, is made into the mixture of 1:4 (w/w), and fully mixing had both obtained physical mixture.Prepared physical mixture is codissolved in nothing
In water-ethanol, 40 DEG C of heating in water bath stirrings are completely dissolved to feeding intake, and then, add succinic acid 30g, utilize Rotary Evaporators by second
Alcohol volatilizees, and dries at 60-90 DEG C in vacuum drying oven, pulverizes with pulverizer, obtains the solid dispersion of ursolic acid.
Above example illustrates, uses two kinds of pH adjusting agents of embodiment of the present invention and at extreme condition and optimization bar
Ursolic acid solid dispersion all can be made under part.
The actual effect of the ursolic acid solid dispersion investigation present invention prepared with embodiment 2 below:
Dissolution in vitro is tested.
1 experimental technique.
Precision weighs each ursolic acid solid dispersion and ursolic acid standard substance are appropriate (containing ursolic acid 30 mg), fills in capsule
In.With 750 mL 0.1 mol L-1Hydrochloric acid solution is release medium, and temperature is (37 ± 0.5) DEG C, rotating speed 100 r min-1, operate in accordance with the law, start to clock when capsule contact solution, when 120 min, add 250 mL of 37 DEG C in a reservoir
0.2 mol·L-1Sodium radio-phosphate,P-32 solution, rotating speed is constant, continues operation.In 5,10,20,30,60,90,120,130,150,210,
240,270,300 min, sample 5 mL, supplement equivalent mediator simultaneously, and sample solution filters through 0.8 m filter membrane, take subsequent filtrate and use
Methanol dilution 5 times, by high performance liquid chromatography, is measured by above-mentioned chromatographic condition, calculates ursolic acid content in dissolution medium.
2 chromatographic conditions.
Agilent EC-C18Chromatographic column (4.6 mm × 250 mm, 5.0 μm)；Flowing is that methanol-pure water is (containing 0.1% mutually
Phosphoric acid) (88:12)；Volume flow 1.0 mL/min；Column temperature is 35 DEG C.
3 experimental results.
Fig. 1 is ursolic acid solid dispersion and the stripping curve of ursolic acid standard substance of preparation, and result shows before dissolution
Two hours, the ursolic acid solid dispersion of preparation did not had dissolution, ursolic acid standard substance to have trace dissolution, and dissolution two hours
After adding sodium radio-phosphate,P-32 solution, ursolic acid solid dispersion starts Fast Stripping, and its dissolution rate is much larger than ursolic acid standard substance, and
Can reach maximum dissolution during 160 min is 98.86 %, but the maximum dissolution of ursolic acid standard substance only has 16.54%.
The above results shows, ursolic acid solid dispersion prepared by the present invention ursolic acid can be made to hardly pick up under one's belt and
Intestinal is absorbing, is preferably playing the hydrotropy effect of Surfactant SDS, relative to ursolic acid standard substance
There is the advantages such as raising dissolution.
SD Rats pharmacokinetics is tested.
1 experimental technique.
Cleaning grade SD rat 18, male female half and half, weight range 230mg 260mg.On pretreatment two weeks and test during
Must not take other medicines, before experiment, fasting 12 hours, is randomly divided into two groups, uses eye socket to take blood, and dosage is 100 mg/
kg.Respectively gavage ursolic acid and the ursolic acid solid dispersion of embodiment 2 preparation, after administration, respectively 0,0.25,0.5,1,2,
3,4,5,6,8,10,12 h time points take blood 0.5 mL in the test tube of anticoagulant heparin, and 10000 r/min are centrifuged 10 min, point
From upper plasma.Taking 100 μ L blood plasma, accurate addition 10 μ L enoxolone (internal standard, mass concentration is 1 μ g/mL), after mixing
Adding 1 mL ethyl acetate, vibrate 5 min, and 10000 r/min are centrifuged 10 min, takes the supernatant and puts N in 45 DEG C of dry bath pots2
Dry up, with 100 μ L methanol dissolved residues, fully ultrasonic 2 min mixings after vibration, then it is centrifuged 5 min through 16000 r/min
After, taking supernatant, sample introduction 10 μ L carries out HPLC-MS quantitative analysis.
2 chromatographic conditions.
Chromatographic column is Yi Lite C18 chromatographic column (4.6 mm × 250 mm, 5.0 μm), Agilent C18 pre-column (4 mm ×
2.0 mm), column temperature is 25 DEG C, and flowing is methanol-pure water (containing 0.02% triethylamine) (v:v(90:10) mutually), flow velocity is 0.5
ML/min, sample size 10 μ L.
3 Mass Spectrometry Conditions.
Using electric spray ion source, negative ion mode measures.Sweep limits m/z 100 ~ 1000.Detection voltage 1.5 kV,
N2Volume flow is 35.0 L/min, and heating-up temperature is 350 DEG C.Acquisition mode is multiple-reaction monitoring (multiple
Reaction monitoring, MRM), the m/z=455.7, the m/z=470.6 of enoxolone of detection object ursolic acid.
4 experimental results.
Ursolic acid crude drug and the ursolic acid solid dispersion blood concentration-time curve such as Fig. 2 institute in rat body
Show.Experimental result display ursolic acid crude drug be administered after start absorb, and upon administration 1.0 h time reach peak value.And ursolic acid
Solid dispersion only has the absorption of trace upon administration, starts upon administration quickly to absorb during 1.5 h, and the peak time time is 3
h.The peak concentration that reaches of ursolic acid solid dispersion is 81 ng/mL, but the peak concentration that reaches of ursolic acid crude drug only has 30 μ g/mL.
Test result indicate that ursolic acid solid dispersion microabsorption under one's belt prepared by the present invention, quickly inhale in intestinal
Receive, and blood drug level is far above ursolic acid crude drug, it was demonstrated that the ursolic acid solid dispersion in the present invention well improves Bears
The bioavailability of fruit acid.
Embodiment described above only have expressed the several embodiments of the present invention, and it describes more concrete and detailed, but also
Can not therefore be construed as limiting the scope of the patent.It should be pointed out that, come for those of ordinary skill in the art
Saying, without departing from the inventive concept of the premise, it is also possible to make some deformation and improvement, these broadly fall into the protection of the present invention
Scope.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
Claims (6)
1. a preparation method for the solid agent dispersant of ursolic acid, its component includes: ursolic acid, surfactant and pH adjusting agent,
It is characterized in that being codissolved in dehydrated alcohol ursolic acid and surfactant in mass ratio, 40 DEG C of heating in water bath stir to feeding intake
It is completely dissolved, then, adds pH adjusting agent, utilize Rotary Evaporators to be volatilized by ethanol, at 60-90 DEG C, vacuum drying oven dries
Dry, pulverize with pulverizer, obtain the solid dispersion of ursolic acid.
2. the preparation method as described in right 1, it is characterised in that its component includes: ursolic acid, surfactant and pH regulator
Agent.
3. the preparation method as described in right 2, it is characterised in that ursolic acid, surfactant and pH adjusting agent mass ratio are 1:4:
1~1:4:3。
4. the preparation method as described in right 1, it is characterised in that described surfactant is sodium lauryl sulphate.
5. the preparation method as described in right 1, it is characterised in that described pH adjusting agent is citric acid, succinic acid etc..
6. a ursolic acid solid dispersion, it is characterised in that be prepared from by the preparation method described in claim 1.
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| CN201610508093.8A CN106109418A (en) | 2016-07-01 | 2016-07-01 | Ursolic acid solid dispersion and preparation method thereof |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113358808A (en) * | 2021-07-01 | 2021-09-07 | 佳木斯大学 | Method for qualitatively identifying polar compounds by using reversed-phase chromatographic retention index |
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| CN101804084A (en) * | 2009-02-18 | 2010-08-18 | 三九医药股份有限公司 | Solid dispersion and preparation method thereof |
| CN102871950A (en) * | 2011-07-15 | 2013-01-16 | 上海睿智化学研究有限公司 | Ursolic acid solid dispersion and preparation method thereof |
| CN102908316A (en) * | 2012-11-12 | 2013-02-06 | 西南大学 | Ivermectin water-soluble solid dispersion and preparation method thereof |
-
2016
- 2016-07-01 CN CN201610508093.8A patent/CN106109418A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101804084A (en) * | 2009-02-18 | 2010-08-18 | 三九医药股份有限公司 | Solid dispersion and preparation method thereof |
| CN102871950A (en) * | 2011-07-15 | 2013-01-16 | 上海睿智化学研究有限公司 | Ursolic acid solid dispersion and preparation method thereof |
| CN102908316A (en) * | 2012-11-12 | 2013-02-06 | 西南大学 | Ivermectin water-soluble solid dispersion and preparation method thereof |
Non-Patent Citations (4)
| Title |
|---|
| JU SONG，等: "Development and Characterisation of Ursolic Acid Nanocrystals Without Stabiliser Having Improved Dissolution Rate and In Vitro Anticancer Activity", 《AAPS PHARMSCITECH》 * |
| 白雪茜，等: "微环境 pH 调控技术在固体分散体中的应用", 《中国新药杂志》 * |
| 祁雯，等: "４种熊果酸固体分散体的体外特性", 《中国医院药学杂志》 * |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113358808A (en) * | 2021-07-01 | 2021-09-07 | 佳木斯大学 | Method for qualitatively identifying polar compounds by using reversed-phase chromatographic retention index |
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Effective date of registration: 20190305 Address after: 154007 No. 148 Xuefu Road, Jiamusi City, Heilongjiang Province Applicant after: Jiamusi University Address before: 154007 No. 148 Xuefu Road, Jiamusi City, Heilongjiang Province Applicant before: Jiamusi University Applicant before: Sun Changhai |
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