CN101780047A - Nano-micro structure silibinin drug composite powder and preparation method thereof - Google Patents
Nano-micro structure silibinin drug composite powder and preparation method thereof Download PDFInfo
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- CN101780047A CN101780047A CN200910076989A CN200910076989A CN101780047A CN 101780047 A CN101780047 A CN 101780047A CN 200910076989 A CN200910076989 A CN 200910076989A CN 200910076989 A CN200910076989 A CN 200910076989A CN 101780047 A CN101780047 A CN 101780047A
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- 235000014899 silybin Nutrition 0.000 title claims abstract description 89
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Abstract
The invention relates to a nano-micro structure silibinin drug composite powder and a preparation method thereof. The silibinin drug is dissolved into an organic solvent which is mutually soluble with the water, the mixture is added into a water solution containing water-solubility pharmaceutical excipients to obtain nano silibinin drug particle injectable suspension, the injectable suspension is atomized and dried to obtain the nano-micro structure silibinin drug composite powder. The composite powder has good redispersibility and is dispersed in the water to obtain the uniform injectable suspension with the grain diameter of the drug being less than 1000 nm. The method has simple operation, low cost and promising industrialized production prospect. The powder has fast dissolution rate and high biological utilization rate, and can be used for preparing tablet, capsule, granules or suspensions.
Description
Technical field:
The present invention relates to a kind of nano-micro structure silibinin drug composite powder and preparation method thereof, belong to the medication preparation field.
Background technology:
Silibinin (Silybin), chemistry is called 2,3-dihydro-3-(4-hydroxy 3-methoxybenzene base)-2-methylol-6-(3,5,7-trihydroxy-4-oxo .alpha.-5:6-benzopyran-2-yl) benzodioxane, its structural formula is:
It is a kind of flavone compound that extraction separation obtains from feverfew Herba Silybi mariani fruit; has the effect of significant protection and stable hepatocyte; various hepatic disease all there is in various degree therapeutical effect, is widely used in acute, chronic hepatitis, hepatic fibrosis, first cirrhosis, fatty liver etc. clinically.
Silibinin is insoluble in water, dissolution rate is slow, oral absorption is poor, cause bioavailability lower, about the research that improves the silibinin bioavailability concentrates in the exploitation of novel form and novel formulation mostly, as make phosphatide complexes (patent US 4764508), cyclodextrin clathrate (patent US 5198430), microemulsion (patent US 2007141185A1), liposome (patent CN 1732918A) etc.By said method, the bioavailability of silibinin is improved, but these methods all exist preparation process complexity, production cost problem of higher.
Another effective ways that improve the silibinin bioavailability is super-refinement technology, and patent CN101185611A discloses a kind of method of utilizing the crystalization in supercritical fluid technology to prepare silybin fine particles.Though this method can be controlled the silibinin grain diameter well about 10 μ m, the equipment manufacturing cost costliness, operating process is loaded down with trivial details, and the drug particles of preparation is bigger.
Studies show that for poorly water soluble drugs, process in leaching is the key factor of its bioavailability of restriction.According to Ostwald Freundrich equation, in general, medicine dissolution rate and size of pharmaceutical particles are inverse ratio, reduce the drug particles particle diameter and can significantly improve its dissolution rate.If the employing nanotechnology is made nano-particle to silibinin drug, just can greatly increase the specific surface area of drug particles, improve its dissolution rate, thereby significantly improve the bioavailability of silibinin, reduce its toxic and side effects, reduce individual variation.
Summary of the invention:
The purpose of this invention is to provide a kind of nano-micro structure silibinin drug composite powder and preparation method thereof, carry out the silibinin drug composite powder that spray drying makes nano-micro structure by silibinin raw material medicine solution and the suspension that the aqueous solution that contains pharmaceutic adjuvant obtains, disperse to form again the silybin nanostructured suspension of mean diameter after adding water, thereby improve the dissolution rate and the bioavailability of medicine less than 1000nm.
A kind of nano-micro structure silibinin drug composite powder provided by the present invention is to be active component, to be the micron order composite particles of carrier with the water solublity pharmaceutic adjuvant with silybin nanostructured granule, its quality percentage composition is that silibinin is 5～50%, pharmaceutic adjuvant 50～95%.
Described nano-micro structure silibinin drug composite powder has redispersible, can form the particulate nanometer suspension liquid of silibinin after adding water, and mean diameter is less than 1000nm, and scope is 70～900nm preferably.
Described water solublity pharmaceutic adjuvant is one or more a mixture of Polyethylene Glycol, poloxamer, polyvinylpyrrolidone, polyethylene oxide, mannitol, chitosan, lactose, hydroxypropyl emthylcellulose.
Nano-micro structure silibinin drug composite powder of the present invention is by the silibinin raw material medicine solution, joins in the aqueous solution that contains the water solublity pharmaceutic adjuvant, obtains in conjunction with spray drying technology by the microemulsion method.Concrete step and method are as follows:
A: the silibinin crude drug is dissolved in the organic solvent that can dissolve each other with water, obtains raw material medicine solution, its concentration is 1～3g/100mL;
B: pharmaceutic adjuvant is soluble in water, and being made into concentration is the adjuvant aqueous solution of 0.05～11.41g/100mL, and the control aqueous temperature is at 3～30 ℃;
C: the raw material medicine solution of A step and the pharmaceutic adjuvant aqueous solution and the while of B step are stirred, obtain flying Ji guest nanometer suspension liquid, wherein the volume ratio of raw material medicine solution and aqueous solution is 1: 5～1: 20;
D: with the C step fly Ji guest nanometer suspension liquid spray drying, obtain drug composite powder.Control spray dryer inlet temperature is 100～160 ℃ during spray drying, and outlet temperature is 60～90 ℃, and charging rate is 5～40ml/min, and compressed air pressure is 0.4～0.8MPa.
The solvent of organic solvent described in the above-mentioned A step for silibinin is had certain solubility and dissolves each other with water, can be a kind of in the following solvent or their mixture: methanol, ethanol, acetone, propanol, isopropyl alcohol, glycerol, n-butyl alcohol, oxolane, N, dinethylformamide, dimethyl sulfoxide, N-Methyl pyrrolidone, but be not limited to above-mentioned solvent.
It is 0～50% ionic surfactant that pharmaceutic adjuvant described in the above-mentioned B step also contains the quality percentage composition, and described ionic surfactant is a kind of in potassium stearate, sodium stearate, enuatrol, sodium lauryl sulphate, dodecylbenzene sodium sulfonate, the Stepanol MG or their mixture.
Silybin nanostructured suspension goes out by prepared with microemulsion reactor, and the dissolving of silibinin crude drug is formed drug molecule, and then with drug solution and the aqueous solution that contains surfactant, microemulsion can form automatically.Along with the phase counterdiffusion of solvent inside and outside the emulsion droplet, emulsion droplet can solidify granulating gradually, forms silybin nanostructured suspension.
The Nano medication granule has very high surface energy, very easily reunites, and evenly is suspended in the liquid medium for a long time even also be difficult under the effect of surfactant.And the Nano medication powder body have good stability, easy to carry and transport, to advantage such as condition of storage is less demanding, so the Nano medication powder body is the basis of subsequent preparation nanometer formulation.Nanometer suspension liquid is prepared into the Nano medication powder body with redispersibility, is the basis that Nano medication is really realized industrialization.
Spray drying technology is the common method that the Nano medication suspension is prepared into the Nano medication powder body, because its simple and efficient advantage has obtained increasing concern and application.By spray drying technology, the Nano medication uniform particles is dispersed in the water-solubility carrier, has avoided the reunion of nanoparticle, makes medicament powder have good redispersible, helps realizing the suitability for industrialized production of nano-drug preparation.
The invention has the beneficial effects as follows:
1, silybin nanostructured granule is by prepared with microemulsion reactor, and this method technology is simple, and easy operating is less demanding to stirring condition.Under common magnetic agitation condition, with drug solution with contain the adjuvant aqueous solution of surfactant after just can obtain silybin nanostructured suspension.
2, with silybin nanostructured suspension spray drying, just can obtain redispersible nano-micro structure silibinin drug composite powder.Whole process of preparation from nanometer suspension liquid to composite granule can be carried out continuously, is easy to amplify and large-scale production.
3, form colloid after the nano-micro structure silibinin drug composite powder of preparation adds water under the optimum condition, grain diameter is very nearly the same before doing with spray, be 70 ± 20nm, particle size distribution is narrower, (polydispersity index is the characteristic index of nanoparticle monodispersity to polydispersity index, this index is more little, shows that the system monodispersity is good more, and particle diameter is got over homogeneous) about 0.1.After placing for two weeks under the room temperature, mean diameter changes little, demonstrates good stable.
4, the composition of nano-micro structure silibinin drug composite powder of the present invention is fairly simple, and carrier material is pharmaceutic adjuvant commonly used.
5, the result of extraction excellence of nano-micro structure silibinin drug composite powder of the present invention is leachable 91% in 15 minutes, and the sieve stripping quantity of physical mixed powder body in 120 minutes of mixing of silibinin crude drug and adjuvant only is 37% in proportion.
6, the nano-micro structure silibinin drug composite powder of the present invention's preparation can be widely used in Nano medication solid or liquid preparation, for example tablet, capsule, granule or suspensoid.
Description of drawings:
Fig. 1 is the particulate sem photograph of silibinin crude drug, the granule-morphology inequality, and particle diameter is very inhomogeneous, does not wait to 40 μ m from 2 μ m.
Fig. 2 is the sem photograph of the nano-micro structure silibinin composite granule of embodiment 3, granule be cave in spherical, the size about 1～5 μ m.
Fig. 3 is a particulate sem photograph in the silybin nanostructured suspension of embodiment 3, and granule-morphology is the homogeneous near-spherical, and size ratio is than homogeneous, and mean diameter is 72.7nm.
Fig. 4 is a particulate sem photograph behind the silibinin drug composite powder water redispersion of embodiment 3, granule-morphology is the homogeneous near-spherical, size ratio is than homogeneous, mean diameter is 71.4nm, by with last figure contrast as can be seen, before spray is done with redispersion after granule from pattern still on the size all much at one.
Fig. 5 is Fourier infrared spectrum (FT-IR) figure of silibinin drug composite powder, adjuvant and the silibinin crude drug of embodiment 3.
Fig. 6 is X-ray diffraction (XRD) figure of silibinin drug composite powder, physical mixed powder body and the silibinin crude drug of embodiment 3.
Fig. 7 is the stripping curve figure of silibinin drug composite powder, physical mixed powder body and the silibinin crude drug of embodiment 3, and the dissolution rate of composite granule is the fastest, and the dissolution rate of crude drug is the slowest.
Below in conjunction with the drawings and specific embodiments the present invention is further described.
The specific embodiment:
Embodiment 1
A: take by weighing 1g silibinin crude drug and be dissolved in the 33.3ml acetone;
B: take by weighing 18.9g Polyethylene Glycol and 0.10g dodecylbenzene sodium sulfonate and be dissolved in the 166.5ml water, will the beaker ice-water bath of this aqueous solution be housed, the control aqueous temperature is about 3 ℃;
C: under the stirring condition of 2000rpm, the raw material medicine solution of preparing in the steps A is poured in the B step aqueous solution, obtained silybin nanostructured suspension;
D: control spray dryer (SD-Basic, Labplant, Britain) inlet temperature is 100 ℃, outlet temperature is 60 ℃, and charging rate is 5ml/min, and compressed air pressure is 0.6MPa, with silybin nanostructured suspension spray drying, obtain nano-micro structure silibinin drug composite powder.
After this composite granule disperseed in water, the granule mean diameter was 895.1nm.
A: take by weighing 1g silibinin crude drug and be dissolved in the 100ml ethanol;
B: take by weighing 0.5g poloxamer and 0.5g sodium stearate and be dissolved in the 2000ml water, will the placing in the constant temperature water bath of this aqueous solution be housed, the control aqueous temperature is about 10 ℃;
C: under the stirring condition of 1500rpm, the raw material medicine solution of preparing in the steps A is poured in the B step aqueous solution, obtained silybin nanostructured suspension;
D: control spray dryer (SD-Basic, Labplant, Britain) inlet temperature is 160 ℃, outlet temperature is 90 ℃, and charging rate is 40ml/min, and compressed air pressure is 0.8MPa, with silybin nanostructured suspension spray drying, obtain nano-micro structure silibinin drug composite powder.
After this composite granule disperseed in water, the granule mean diameter was 774.6nm.
Embodiment 3
A: take by weighing 1g silibinin crude drug and be dissolved in the 50ml acetone;
B: take by weighing 5g polyvinylpyrrolidone and 0.02g sodium lauryl sulphate and be dissolved in the 500ml water, will the placing in the constant temperature water bath of this aqueous solution be housed, the control aqueous temperature is about 3 ℃;
C: under the stirring condition of 1000rpm, the raw material medicine solution of preparing in the steps A is poured in the B step aqueous solution, obtained silybin nanostructured suspension;
D: control spray dryer (SD-Basic, Labplant, Britain) inlet temperature is 140 ℃, outlet temperature is 71 ℃, and charging rate is 20ml/min, and compressed air pressure is 0.6MPa, with silybin nanostructured suspension spray drying, obtain nano-micro structure silibinin drug composite powder.
This composite granule can form colloid after disperseing in water, the granule mean diameter is 71.4nm, and polydispersity index is 0.103.
Embodiment 4
A: take by weighing 1g silibinin crude drug and be dissolved in the 50ml ethanol;
B: take by weighing 5g lactose and 0.50g enuatrol in 1000ml water, will the placing in the constant temperature water bath of this aqueous solution be housed, the control aqueous temperature is about 10 ℃;
C: under the stirring condition of 1000rpm, the raw material medicine solution of preparing in the steps A is poured in the B step aqueous solution, obtained silybin nanostructured suspension;
D: control spray dryer (SD-Basic, Labplant, Britain) inlet temperature is 120 ℃, outlet temperature is 67 ℃, and charging rate is 10ml/min, and compressed air pressure is 0.4MPa, with silybin nanostructured suspension spray drying, obtain nano-micro structure silibinin drug composite powder.
After this composite granule disperseed in water, the granule mean diameter was 635.7nm.
Embodiment 5
A: take by weighing 1g silibinin crude drug and be dissolved in the 100ml ethanol;
B: take by weighing 6g polyvinylpyrrolidone and 4g lactose and be dissolved in the 1000ml water, will the placing in the constant temperature water bath of this aqueous solution be housed, the control aqueous temperature is about 20 ℃;
C: under the stirring condition of 2000rpm, the raw material medicine solution of preparing in the steps A is poured in the B step aqueous solution, obtained silybin nanostructured suspension;
D: control spray dryer (SD-Basic, Labplant, Britain) inlet temperature is 140 ℃, outlet temperature is 71 ℃, and charging rate is 20ml/min, and compressed air pressure is 0.6MPa, with silybin nanostructured suspension spray drying, obtain nano-micro structure silibinin drug composite powder.
After this composite granule disperseed in water, the granule mean diameter was 498.3nm.
Embodiment 6
A: take by weighing 1g silibinin crude drug and be dissolved in the 50ml acetone;
B: take by weighing 10g polyvinylpyrrolidone and 0.05g dodecylbenzene sodium sulfonate and be dissolved in the 500ml water, will the placing in the constant temperature water bath of this aqueous solution be housed, the control aqueous temperature is about 30 ℃;
C: under the stirring condition of 1000rpm, the raw material medicine solution of preparing in the steps A is poured in the B step aqueous solution, obtained silybin nanostructured suspension;
D: control spray dryer (SD-Basic, Labplant, Britain) inlet temperature is 140 ℃, outlet temperature is 80 ℃, and charging rate is 10ml/min, and compressed air pressure is 0.6MPa, with silybin nanostructured suspension spray drying, obtain nano-micro structure silibinin drug composite powder.
After this composite granule disperseed in water, the granule mean diameter was 151.6nm.
Claims (8)
1. nano-micro structure silibinin drug composite powder, be active component, be the composite granule of carrier with the water solublity pharmaceutic adjuvant with silybin nanostructured granule for a kind of, it is characterized in that: described silibinin quality percentage composition is 5～50%, the quality percentage composition of water solublity pharmaceutic adjuvant is 50～95%, the suspension that composite granule granule redispersion obtains in water, the particulate mean diameter of silibinin is less than 1000nm.
2. nano-micro structure silibinin drug composite powder according to claim 1 is characterized in that: the suspension that composite granule granule redispersion obtains in water, the particulate mean diameter of silibinin is 70～900nm.
3. nano-micro structure silibinin drug composite powder according to claim 1 is characterized in that: the water solublity pharmaceutic adjuvant is a kind of in Polyethylene Glycol, poloxamer, polyvinylpyrrolidone, polyethylene oxide, mannitol, chitosan, lactose, the hydroxypropyl emthylcellulose or their mixture.
4. the preparation method of any nano-micro structure silibinin composite granule of claim 1-3, it is characterized in that: by the drug solution of silibinin crude drug preparation, with the aqueous solution that contains the water solublity pharmaceutic adjuvant, the silibinin suspension spray drying that will obtain after will mixing again, promptly obtain nano-micro structure silibinin drug composite powder, concrete step and method are as follows:
A: the silibinin crude drug is dissolved in the organic solvent that can dissolve each other with water, is made into the raw material medicine solution that concentration is 1～3g/100mL;
B: pharmaceutic adjuvant is soluble in water, and being made into concentration is the adjuvant aqueous solution of 0.05～11.41g/100mL, and the control aqueous temperature is at 3～30 ℃;
C: with the raw material medicine solution of A step and the adjuvant aqueous solution of B step, stir, obtain silybin nanostructured suspension;
D: the silybin nanostructured suspension spray drying with the C step obtains nano-micro structure silibinin drug composite powder.
5. according to the preparation method of claim 4, it is characterized in that: organic solvent described in the A step is methanol, ethanol, acetone, propanol, isopropyl alcohol, glycerol, n-butyl alcohol, oxolane, N, a kind of in dinethylformamide, dimethyl sulfoxide or the N-Methyl pyrrolidone or their mixture.
6. preparation method according to claim 4, it is characterized in that: it is 0～50% ionic surfactant that pharmaceutic adjuvant described in the B step also contains the quality percentage composition, and described ionic surfactant is a kind of in potassium stearate, sodium stearate, enuatrol, sodium lauryl sulphate, dodecylbenzene sodium sulfonate, the Stepanol MG or their mixture.
7. preparation method according to claim 4 is characterized in that: the volume ratio of raw material medicine solution and pharmaceutic adjuvant aqueous solution is 1: 5～1: 20 in the C step.
8. preparation method according to claim 4, it is characterized in that: spray drying time control spray dryer inlet temperature is 100～160 ℃ in the D step, outlet temperature is 60～90 ℃, and charging rate is 5～40ml/min, and compressed air pressure is 0.4～0.8MPa.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102228430A (en) * | 2011-06-14 | 2011-11-02 | 中国中医科学院中药研究所 | Nano-suspension for silybin-phospholipid complex and preparation method thereof |
| CN102451159A (en) * | 2010-11-01 | 2012-05-16 | 北京化工大学 | Superfine vinpocetine composite particle and preparation method thereof |
| CN106580877A (en) * | 2016-08-31 | 2017-04-26 | 中国药科大学 | Silybin nanometer suspension and preparation method thereof |
| CN106606419A (en) * | 2015-10-26 | 2017-05-03 | 北京化工大学 | Method for preparing indissolvable drug nanodispersion by applying micro-channel technology |
| CN108560314A (en) * | 2017-12-15 | 2018-09-21 | 华南理工大学 | A kind of nano-cellulose based super hydrophobic coating and preparation method thereof |
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2009
- 2009-01-16 CN CN2009100769893A patent/CN101780047B/en not_active Expired - Fee Related
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102451159A (en) * | 2010-11-01 | 2012-05-16 | 北京化工大学 | Superfine vinpocetine composite particle and preparation method thereof |
| CN102228430A (en) * | 2011-06-14 | 2011-11-02 | 中国中医科学院中药研究所 | Nano-suspension for silybin-phospholipid complex and preparation method thereof |
| CN102228430B (en) * | 2011-06-14 | 2015-12-09 | 中国中医科学院中药研究所 | Nano suspension of silybin-phospholipid complex and preparation method thereof |
| CN106606419A (en) * | 2015-10-26 | 2017-05-03 | 北京化工大学 | Method for preparing indissolvable drug nanodispersion by applying micro-channel technology |
| CN106606419B (en) * | 2015-10-26 | 2019-10-18 | 北京化工大学 | A method of insoluble drug Nanodispersion is prepared using microchannel |
| CN106580877A (en) * | 2016-08-31 | 2017-04-26 | 中国药科大学 | Silybin nanometer suspension and preparation method thereof |
| CN108560314A (en) * | 2017-12-15 | 2018-09-21 | 华南理工大学 | A kind of nano-cellulose based super hydrophobic coating and preparation method thereof |
| CN108560314B (en) * | 2017-12-15 | 2021-06-08 | 华南理工大学 | Nano-cellulose-based super-hydrophobic coating and preparation method thereof |
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