CN103006556A - Scutellarin nanosuspension and preparation method thereof - Google Patents
Scutellarin nanosuspension and preparation method thereof Download PDFInfo
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Abstract
本发明属于药物制剂技术领域，涉及一种灯盏乙素纳米混悬液及制备方法。该纳米混悬液由稳定剂和灯盏乙素按重量比为1:1~10:1组成。其制备方法是将灯盏乙素溶于碱性溶液中，然后加入到含有稳定剂的酸性溶液中，由于灯盏乙素在酸溶液与碱溶液中溶解度差异，从而使灯盏乙素过饱和，析出结晶，再经高压微射流均质机均质得灯盏乙素纳米混悬液，粒径在100nm~500nm范围内，多分散指数为0.1~0.5。本发明显著的优点是该纳米混悬液提高灯盏乙素溶解度，增加其口服生物利用度。灯盏乙素纳米混悬液可通过冷冻干燥或喷雾干燥进行固化，应用于片剂、胶囊、颗粒剂和口服混悬液等剂型。本发明制备工艺简单，便于工业化生产。The invention belongs to the technical field of pharmaceutical preparations, and relates to a scutellarin nanosuspension and a preparation method thereof. The nano suspension is composed of a stabilizer and scutellarin in a weight ratio of 1:1 to 10:1. The preparation method is to dissolve scutellarin in an alkaline solution, and then add it to an acidic solution containing a stabilizer. Due to the difference in solubility of scutellarin in an acid solution and an alkaline solution, the scutellarin is supersaturated and crystallized , and then homogenized by a high-pressure micro-jet homogenizer to obtain a scutellarin nanosuspension, with a particle size in the range of 100nm to 500nm and a polydispersity index of 0.1 to 0.5. The obvious advantage of the present invention is that the nano-suspension improves the solubility of scutellarin and increases its oral bioavailability. The scutellarin nanosuspension can be solidified by freeze-drying or spray-drying, and can be applied to dosage forms such as tablets, capsules, granules and oral suspensions. The preparation process of the invention is simple and convenient for industrialized production.
Description
Technical field
The present invention relates to technical field of medicine, specifically a kind of scutellarin nanosuspension and preparation method thereof.
Background technology
Scutellarin is the main effective ingredient of breviscapine, chemistry Baicalein by name-7-O-β-D-Glucose aldehydic acid glycosides.Be mainly used in clinically treating the diseases such as paralysis after cerebral thrombosis, cerebral infarction, the apoplexy, coronary heart disease.Because scutellarin is insoluble in water almost, oral absorption is poor, and bioavailability is low, so greatly limited its application clinically.The Breviscapine of usefulness mainly contains tablet, injectable powder, injection etc. clinically at present.The conventional tablet oral administration biaavailability is low, and normal injection and injectable powder injection administration half-life are short, eliminate rapidly in the body.
For improving dissolubility and the bioavailability of scutellarin, the preparation work person solves this problem by many methods, has patent that breviscapine is made cyclodextrin clathrate (publication number CN 1739537A), injectable emulsion (publication number CN 1875981A), liposome (publication number CN 1444948A), drop pill (publication number CN1408392A), nano injection formulation (publication number CN 1879645A), albumin nano granular (publication number CN102415999A) etc.The related method of above patent has been improved dissolubility and the bioavailability of scutellarin in certain degree, but effect is still unsatisfactory.
The scutellarin nanosuspension can improve its dissolubility can improve its bioavailability again.The scutellarin nanosuspension is comprised of the scutellarin nanoparticle.Be different from other nanometer formulations, the scutellarin nanosuspension does not contain carrier material, only contain a small amount of stabilizing agent and keep scutellarin particle the stablizing in aqueous solution of nanoscale, drug loading is high, can reduce the administration volume, improve dissolution rate, have the intestinal adhesion, can prolong its holdup time in intestinal, improve its bioavailability.Report preparation scutellarin nanosuspension is not yet arranged at present.
The preparation method of nanosuspension mainly contains high pressure homogenization method, the sedimentation method, medium polishing, emulsion process etc.Medium polishing and emulsion process have organic solvent residual; The nanosuspension particle diameter of sedimentation method preparation is inhomogeneous, and polydispersity index is larger; High pressure homogenization method must be in advance with the drug powder processing.The sedimentation method can be used as the treatment step before the high pressure homogenize, prepare nanosuspension in conjunction with high pressure homogenization method, and its particle size distribution range is narrow, thereby obtains desirable nanosuspension.
Nanosuspension can directly be made oral administration mixed suspension, also can carry out dry solidification by lyophilization or spray drying, is applied to prepare tablet, capsule, granule.
Summary of the invention
The objective of the invention is in order to disclose a kind of scutellarin nanosuspension and its preparation method and application, prepared scutellarin nanosuspension can improve its dissolubility and bioavailability.
For achieving the above object, the present invention by the following technical solutions.
A kind of scutellarin nanosuspension, include scutellarin and stabilizing agent, described stabilizing agent and scutellarin weight ratio are 1:1 ~ 10:1, and described stabilizing agent is hydroxypropyl emthylcellulose K100, PVP K30, carboxymethyl starch sodium, PLURONICS F87, poloxamer F127, Tween 80, PEG400, Cremophor RH40 (polyoxyethylene hydrogenated Oleum Ricini 40), Cremophor EL (polyoxyethylene ether (35) Oleum Ricini), the Labrasol(Labraso), Gelucire 44/14 (Gelucire 44/14), the mixture of one or more Gelucire 50/13(stearic acid polyethyleneglycol glyceride).The particle diameter of scutellarin nanosuspension is 100nm ~ 500nm, and polydispersity index is 0.1 ~ 0.5.
Another object of the present invention provides the preparation method of above-mentioned scutellarin nanosuspension.
The technical scheme that realizes above-mentioned purpose is as follows:
A kind of preparation method of above-mentioned scutellarin nanosuspension may further comprise the steps:
(1) scutellarin is dissolved in the alkaline solution that pH value is pH6 ~ pH8, as good solvent; Described alkali
Property solution is a kind of in sodium hydrate aqueous solution, potassium hydroxide aqueous solution, the phosphate buffer;
(2) stabilizing agent is dissolved in the acid solution that pH value is pH1 ~ pH3, as poor solvent; Described acid solution is a kind of in aqueous hydrochloric acid solution, phosphate aqueous solution, the acetic acid aqueous solution;
(3) will be dissolved with the good solvent of scutellarin with in 0.5mL/min ~ 10mL/min adding poor solvent, dispersed with stirring, the method of dispersed with stirring adopts high shearing mixing emulsor stirring or mechanical agitation or magnetic agitation, the control mixing speed is at 100r/min ~ 1000r/min, add complete after, continue to stir 30min ~ 3h, form pre-nanosuspension;
(4) pre-nanosuspension is placed high pressure microjet homogenizer, controlled pressure is at 500bar ~ 1500bar, and cycle-index 2 times ~ 15 times makes nanosuspension.
The present invention is before employing high pressure microjet homogenizer prepares the scutellarin nanosuspension, the principle of the scutellarin crude drug being carried out pre-treatment is: scutellarin is dissolved in pH6 ~ pH8 alkaline solution as good solvent, contain the pH1 of stabilizing agent ~ pH3 acid solution as poor solvent, the good solvent that then will be dissolved with scutellarin joins in the poor solvent, utilize the dissolubility difference of scutellarin in good solvent and poor solvent, form supersaturated solution, cause the scutellarin crystallization, and under the effect of stabilizing agent the particle diameter of control scutellarin crystallization at nano-scale.
Adopt the high pressure micro jetting technology to prepare nanosuspension is mainly controlled medicine by regulating pressure and number of times particle diameter.Along with the increase of homogenization pressure and number of times, the obvious minimizing of the particle diameter of medicine and particle size distribution are more even.Controlled pressure is at 500bar ~ 1500bar, cycle-index 2 times ~ 15 times, and the scutellarin nanosuspension particle diameter of preparation is in 100nm ~ 500nm scope, and polydispersity index is 0.1 ~ 0.5.
Scutellarin nanosuspension of the present invention can improve the scutellarin dissolubility, improves the oral expenditure of making profits.The scutellarin nanosuspension can directly be made oral administration mixed suspension, also can be cured by lyophilization or spray drying, is used for several formulations form such as tablet, capsule, granule etc.
The specific embodiment
The specific embodiment of form is being described in further detail foregoing of the present invention by the following examples, but should not be interpreted as at this point that the scope of the above-mentioned theme of the present invention only limits to following example.
Embodiment 1:
In the described scutellarin nanosuspension of the present embodiment, stabilizing agent is 1.4g, wherein, comprises 0.8g PLURONICS F87 and 0.6g Cremophor EL; More than the scutellarin (purity is 90%(w/w)) be 0.3g, stabilizing agent: scutellarin is 4.7:1.
The preparation method of the described scutellarin nanosuspension of the present embodiment is as follows:,
(1) takes by weighing the 0.3g scutellarin, be dissolved in the 100mL phosphate buffer (pH7.4) as good solvent;
(2) get the 0.8g PLURONICS F87,0.6g Cremophor EL is dissolved in the 100mL phosphate aqueous solution (pH2.0) as poor solvent.
(3) the drip speed of good solvent with 0.5mL/min is splashed in the poor solvent, high shearing mixing emulsor dispersed with stirring, control mixing speed are dripped and are finished at 100r/min, continue to stir 1h, form pre-nanosuspension;
(4) pre-nanosuspension is placed high pressure microjet homogenizer, controlled pressure circulates 15 times at 800bar, makes nanosuspension.Detect with laser particle analyzer, mean diameter is 271.3nm, and polydispersity index is 0.2.
Embodiment 2:
In the described scutellarin nanosuspension of the present embodiment, stabilizing agent is 1g, comprises 0.4g PEG400 and 0.6g Labrasol; Scutellarin is 0.1g, stabilizing agent: scutellarin is 10:1.
The preparation method of the described scutellarin nanosuspension of the present embodiment is as follows:
(1) taking by weighing the 0.1g scutellarin is dissolved in the 100mL sodium hydroxide solution (pH6.8) as good solvent;
(2) get the 0.4g PEG400,0.6g Labrasol is dissolved in the 100mL aqueous hydrochloric acid solution (pH2.0) as poor solvent;
(3) the drip speed of good solvent with 5mL/min is splashed in the poor solvent, mechanical agitation is disperseed, and the control mixing speed is dripped and finished at 500r/min, continues to stir 30 minutes, forms pre-nanosuspension;
(4) pre-nanosuspension is placed high pressure microjet homogenizer, controlled pressure circulates 5 times at 1500bar, makes nanosuspension.Detect with laser particle analyzer, mean diameter is 161.4nm, and polydispersity index is 0.452.
Embodiment 3:
In the described scutellarin nanosuspension of the present embodiment, stabilizing agent is 1.5g, comprises 0.5g hydroxypropyl emthylcellulose K100 and 1gCremophor RH40; Scutellarin is 0.2g, stabilizing agent: scutellarin is 7.5:1.
The preparation method of the described scutellarin nanosuspension of the present embodiment is as follows:
(1) taking by weighing the 0.2g scutellarin is dissolved in the 100mL potassium hydroxide solution (pH7.5) as good solvent;
(2) get 0.5g hydroxypropyl emthylcellulose K100,1g Cremophor RH40 is dissolved in the 100mL acetic acid aqueous solution (pH3) as poor solvent;
(3) the drip speed of good solvent with 2mL/min is splashed in the poor solvent, magnetic agitation is disperseed, and the control mixing speed is dripped and finished at 800r/min, continues to stir 45min, forms pre-nanosuspension;
(4) pre-nanosuspension is placed high pressure microjet homogenizer, controlled pressure circulates 2 times at 1000bar, makes nanosuspension.Detect with laser particle analyzer, mean diameter is 331.7nm, and polydispersity index is 0.450.
Embodiment 4:
In the described scutellarin nanosuspension of the present embodiment, stabilizing agent is 2g, comprises 1g Tween 80 and 1g PVP K30; Scutellarin is 0.3g, stabilizing agent: scutellarin is 6.7:1.
The preparation method of the described scutellarin nanosuspension of the present embodiment is as follows:
(1) taking by weighing the 0.3g scutellarin is dissolved in the 100mL sodium hydroxide (pH7.0) as good solvent;
(2) getting 1g Tween 80 and 1g PVP K30 is dissolved in the 100mL phosphate aqueous solution (pH3.0) as poor solvent;
(3) the drip speed of good solvent with 4mL/min is splashed in the poor solvent, magnetic agitation is disperseed, and the control mixing speed is dripped and finished at 1000r/min, continues to stir 30min, forms pre-nanosuspension;
(4) pre-nanosuspension is placed high pressure microjet homogenizer, controlled pressure circulates 8 times at 1200bar, makes nanosuspension.Detect with laser particle analyzer, mean diameter is 199.1nm, and polydispersity index is 0.377.
Embodiment 5:
In the described scutellarin nanosuspension of the present embodiment, stabilizing agent is 1.5g, comprises 0.5gCremophor EL, 0.5g Gelucire 44/14 and 0.5g carboxymethyl starch sodium; Scutellarin is 0.3g, stabilizing agent: scutellarin is 5:1.
The preparation method of the described scutellarin nanosuspension of the present embodiment is as follows:
(1) taking by weighing the 0.3g scutellarin is dissolved in the 100mL phosphate buffer (pH7.4) as good solvent;
(2) get 0.5g Cremophor EL, 0.5g Gelucire 44/14, the 0.5g carboxymethyl starch sodium is dissolved in the 100mL aqueous hydrochloric acid solution (pH1.0) as poor solvent;
(3) the drip speed of good solvent with 1mL/min is splashed in the poor solvent, high shearing mixing emulsor dispersed with stirring, control mixing speed are dripped and are finished at 200r/min, continue to stir 1h, form pre-nanosuspension;
(4) pre-nanosuspension is placed high pressure microjet homogenizer, controlled pressure circulates 2 times at 500bar, makes nanosuspension.Detect with under the laser particle analyzer, mean diameter is 491.2nm, and polydispersity index is 0.489.
Embodiment 6:
Get scutellarin crude drug 2g and place 50ml water, in 25 ℃ of lower continuous stirring 48 hours, with 0.45 μ m filtering with microporous membrane, filtrate was diluted with an amount of methanol, with high effective liquid chromatography for measuring scutellarin concentration (Agilent 1200 type high performance liquid chromatographs, the DAD detector, Agilent Eclipse XDB C18 chromatographic column, mobile phase is acetonitrile: water: acetic acid=21:79:0.1, flow velocity is 1ml/min, the detection wavelength is 335nm, and 30 ℃ of column temperatures, sample size are 20 μ L).Other gets the scutellarin nanosuspension that makes among the embodiment 1 ~ 5 and operates with method, with high effective liquid chromatography for measuring scutellarin concentration (chromatographic condition is the same).Result such as table 1:
Table 1 scutellarin solubility experiment result
As seen, make nanosuspension after, the dissolubility of scutellarin has improved 5 ~ 12 times.
Embodiment 7:
Carry out animal drug disposition dynamic experiment take the scutellarin crude drug as matched group, investigate scutellarin nanosuspension absorption and the bioavailability in animal body that embodiment 1 makes.Method is with 12 of male SD rats, be divided at random two groups, every group 6, gavage gives scutellarin crude drug and scutellarin nanosuspension respectively, regularly gets blood from eye socket, after the processing, take rutin as interior mark, adopt the blood drug level of high effective liquid chromatography for measuring scutellarin, calculate pharmacokinetic parameters, the result is as shown in table 2:
Table 2 scutellarin animal pharmacokinetics experimental result
The result shows, compares with crude drug, and the maximum plasma concentration of scutellarin nanosuspension increases, and peak time shortens, and area under the drug-time curve significantly increases, and oral administration biaavailability significantly improves.
Embodiment 8:
Get the arbitrary nanosuspension that makes among the embodiment 1 ~ 5, add each 3% (weight ratio) of lactose and mannitol, the mix homogeneously lyophilizing gets buff powder.Get this powder an amount of, fully mix with other additive of tablet starch, carboxymethyl starch sodium, micropowder silica gel, magnesium stearate, by the specification of every 20mg scutellarin, full pressed powder obtains satisfactory scutellarin tablet.
Embodiment 9:
Get the arbitrary nanosuspension that makes among the embodiment 1 ~ 5, add 10% microcrystalline Cellulose, spray granulation behind the mix homogeneously.Then add 1% magnesium stearate, encapsulated by the specification of every 20mg scutellarin, obtain satisfactory scutellarin capsule.
Embodiment 10:
Get the arbitrary nanosuspension that makes among the embodiment 1 ~ 5, add in proportion 0.5% sodium carboxymethyl cellulose and 0.5% benzoic acid is received, by the specification packing of every 20mg scutellarin, obtain satisfactory scutellarin oral administration mixed suspension after mixing.
The above embodiment has only expressed several embodiment of the present invention, and it describes comparatively concrete and detailed, but can not therefore be interpreted as the restriction to claim of the present invention.Should be pointed out that for the person of ordinary skill of the art, without departing from the inventive concept of the premise, can also make some distortion and improvement, these all belong to protection scope of the present invention.Therefore, the protection domain of patent of the present invention should be as the criterion with claims.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104161724A (en) * | 2013-09-02 | 2014-11-26 | 郑州后羿制药有限公司 | Long-acting compound sulfamonomethoxine nanometer suspension and preparation method thereof |
| CN106265504A (en) * | 2016-09-29 | 2017-01-04 | 广东温氏大华农生物科技有限公司 | A kind of enrofloxacin nanosuspension and preparation method thereof |
| CN107982222A (en) * | 2017-12-01 | 2018-05-04 | 李文刚 | Breviscapinun freezes the preparation method of enteric coatel tablets or capsulae enterosolubilis |
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| CN1559424A (en) * | 2004-03-03 | 2005-01-05 | 复旦大学 | Breviscapine dry suspension |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104161724A (en) * | 2013-09-02 | 2014-11-26 | 郑州后羿制药有限公司 | Long-acting compound sulfamonomethoxine nanometer suspension and preparation method thereof |
| CN106265504A (en) * | 2016-09-29 | 2017-01-04 | 广东温氏大华农生物科技有限公司 | A kind of enrofloxacin nanosuspension and preparation method thereof |
| CN107982222A (en) * | 2017-12-01 | 2018-05-04 | 李文刚 | Breviscapinun freezes the preparation method of enteric coatel tablets or capsulae enterosolubilis |
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