CN109276545A - A kind of preparation method of tanshinone IIA/chitosan pH sensitive solid dispersion - Google Patents
A kind of preparation method of tanshinone IIA/chitosan pH sensitive solid dispersion Download PDFInfo
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Abstract
The invention discloses a kind of tanshinone IIA/chitosan pH sensitive solid dispersion preparation methods, the preparation method is with the ethanol solution of polymer solution blend dispersion tanshinone IIA, adsorb, disperse tanshinone IIA and inhibit tanshinone IIA crystallization to be precipitated using the chitosan molecule in solution, make chitosan molecule that regenerated process be precipitated from solution by adjusting pH value of solution, chitosan is realized to the cladding of tanshinone IIA, the high tanshinone IIA of the oral administration biaavailability with pH sensibility and tanshinone IIA/chitosan pH sensitive solid dispersion is made.
Description
Technical field
The present invention relates to technical field of medicine more particularly to a kind of tanshinone IIA/chitosan pH sensitive solids point
The preparation method of granular media.
Background technique
Tanshinone IIA is the main fat-soluble active ingredient in salviamiltiorrhizabung, to cardiovascular and cerebrovascular disease, the nervous system disease
Good therapeutic effect is suffered from tumour, is the well-targeted of active Chinese drug component monomer component new drug development, particularly with heart and brain
Long-term clinical verification has been obtained in the treatment use of vascular system disease.However, the poorly water-soluble of tanshinone IIA, partly declining
The defects of phase is short directly affects its exploitation and clinical application as monomer new drug.In recent years, scholar utilizes nanoparticle, glue
Beam, micro emulsion, the newtype drugs transmission system such as solid dispersions delivers tanshinone IIA, to improve its bioavilability.
Solid dispersion technology is a kind of efficient, succinct drug delivery skill that drug solubility and bioavilability can be improved
Art, main by reducing drug particle size, raising is drawn moist, the methods of is increased porosity, and is reduced medicine crystal and mentions
High drug solubility.Artificial synthesized high molecular material at present, as polyethylene glycol (PEG), polyvinylpyrrolidone (PVP),
Hydroxypropyl methyl cellulose (HPMC) etc., has been used as carrier material to be widely used in solid dispersion technology, to improve low aqueous solubility
The dissolubility and bioavailability of drug.Application using large biological molecule as solid dispersible carrier also receives extensive pass
Note, as alginic acid, chitosan, cellulose have been used as solid dispersible carrier.
Chitosan is a kind of native biopolymer as obtained by de-acetyl chitin, is that nature amount of storage is only second to
The second largest natural polysaccharide of cellulose.Due to its excellent chemistry and biological nature, such as nontoxic, biocompatibility, biodegrade
Property, pH sensibility, adsorptivity and mucosa-adherent etc., chitosan is widely used in medication delivery system as carrier material
System.It is extensive by the microballoon of carrier matrix, micella, nanoparticle etc. of chitosan in terms of the delivering of drugs of low aqueous solubility
Report has good delivering effect, can effectively improve the dissolubility and bioavilability of drugs of low aqueous solubility.In recent years, Gu
The more easy methods such as body dispersion, the direct absorption carriage of powder be also used for chitosan loaded drugs of low aqueous solubility research and
Exploitation, can effectively improve drugs of low aqueous solubility solubility and bioavilability (V.C.Crucitti, L.M.Migneco,
A.Piozzi,V.Taresco,M.Garnett,R.H.Argent,I.Francolini,Intermolecular
interaction and solid state characterization of abietic acid/chitosan solid
dispersions possessing antimicrobial and antioxidant properties,Eur J Pharm
Biopharm.125(2018)114-123.)。
Summary of the invention
The purpose of the present invention is to provide a kind of tanshinone IIA/chitosan pH sensitive solid dispersion preparation method,
The preparation method is by reducing the crystallinity of tanshinone IIA, to increase the solubility of tanshinone IIA, and its prepare it is resulting
Tanshinone IIA/chitosan pH sensitive solid dispersion has pH sensibility, can greatly improve the oral bio of tanshinone IIA
Availability.
To achieve the above object, the technical solution used in the present invention is as follows:
A kind of preparation method of tanshinone IIA/chitosan pH sensitive solid dispersion, comprising the following steps:
Step 1: it takes tanshinone IIA to be dissolved in the ethanol solution that concentration is 80~100%, is stirred at room temperature, Tanshinone II is made
A concentration is the ethanol solution of the tanshinone IIA of 0.1~5mg/ml, spare；
Step 2: taking chitosan to be dissolved in 1% dilute acetic acid solution, be stirred at room temperature, and obtaining chitosan concentration is 0.5~2%
Chitosan dilute acetic acid solution, and it is molten to chitosan spirit of vinegar to take the ethanol solution of the resulting tanshinone IIA of step 1 to be slowly added to
In liquid, mixed at room temperature stirring obtains tanshinone IIA/chitosan composite solution, spare；
Step 3: being added dropwise NaOH solution into the resulting tanshinone IIA of step 2/chitosan composite solution, adjust pH to
Precipitating is collected by centrifugation in neutrality, is freeze-dried after distilling water washing, obtains tanshinone IIA/chitosan pH sensitive solid dispersion.
Preferably, in the tanshinone IIA of the step 2/chitosan composite solution tanshinone IIA and chitosan matter
Amount is than being 1:5~1:50.
Preferably, the mixing time that mixed at room temperature stirs in the step 2 is 20~120min.
Preferably, the concentration of NaOH solution is 0.5~5% in the step 3.
It is being prepared preferably, the step 3 prepares resulting tanshinone IIA/chitosan pH sensitive solid dispersion
Application in pharmaceutical preparation.
Preferably, the pharmaceutical preparation is oral preparation.
A kind of tanshinone IIA provided by the invention/chitosan pH sensitive solid dispersion preparation method, the preparation side
Method utilizes the chitosan molecule absorption in solution, dispersion Radix Salviae Miltiorrhizae with the ethanol solution of polymer solution blend dispersion tanshinone IIA
II A of ketone simultaneously inhibits tanshinone IIA crystallization to be precipitated, and makes chitosan molecule that regenerated mistake be precipitated from solution by adjusting pH value of solution
Journey realizes chitosan to the cladding of tanshinone IIA, tanshinone IIA/chitosan pH sensitive solid dispersion is made, and existing
There is technology to compare, the invention has the following advantages:
1, preparation process is simple, and easily realization etc. is suitble to industrialized production than amplification.
2, with chitosan molecule chain dispersion, absorption tanshinone IIA molecule, and its crystallization is inhibited to be precipitated, reduces solid dispersion
The crystallinity of tanshinone IIA in body, greatly improves the dissolubility of tanshinone IIA.
3, using a large amount of-NH3 are contained in chitosan molecule chain, it is made easily to protonate and dissolve in acidic environment, in
Property or weakly alkaline environment in it is insoluble and be precipitated characteristic, will be adsorbed with tanshinone IIA molecule chitosan acid solution carry out pH
Overturning is precipitated its regeneration, dispersion and load of the chitin carrier to tanshinone IIA can be realized, to improve carrying drug ratio.
4, using the pH sensibility of chitosan, so that prepared solid dispersions are in gastric juice (acidity) environment because shell is poly-
The quick dissolution of saccharide matrix and can quickly release the drug, because glycan substrate cannot dissolve, Zhi Nengrong in intestinal juice (alkalescent) environment
Swollen characteristic and there is sustained release performance, realize the pH sensibility of pharmaceutical carrier, greatly improve the oral bioavailability of tanshinone IIA
Degree.
Detailed description of the invention
Fig. 1 is tanshinone IIA/chitosan pH sensitive solid dispersion X-ray powder in the embodiment of the present invention 1~4
Last diffraction analysis figure；
Fig. 2 is tanshinone IIA/chitosan pH sensitive solid dispersion in the embodiment of the present invention 1~4 in 0.1mol/L
Hydrochloric acid solution (Ph1.2) in drug release profiles；
Fig. 3 is tanshinone IIA/chitosan pH sensitive solid dispersion in the embodiment of the present invention 1~4 pH7.4's
Drug release profiles in PBS solution.
Specific embodiment
Technical solution of the present invention is described in further details with reference to the accompanying drawings and examples, following embodiment is not constituted
Limitation of the invention.
Embodiment 1: tanshinone IIA/chitosan pH sensitive solid dispersion preparation
(1) 50mg tanshinone IIA (TA) is weighed, is dissolved in 50ml dehydrated alcohol, is stirred at room temperature, be configured to tanshinone IIA
Concentration is the tanshinone IIA ethanol solution of 1mg/ml, spare；
(2) 0.25g chitosan (CS) is weighed, is dissolved in 1% spirit of vinegar of 100ml, is stirred at room temperature, be configured to chitosan weight
It measures content and is 0.25% chitosan dilute acetic acid solution, and the ethanol solution of step (1) resulting tanshinone IIA is taken to be slowly added to
Into chitosan dilute acetic acid solution, mixed at room temperature stirs 30min, and obtaining tanshinone IIA/chitosan composite solution, (TA/CS is compound molten
Liquid), it is spare；
(3) under continuous stirring, 1%NaOH solution is added dropwise into TA/CS composite solution obtained by step (2), until pH is
Precipitating is collected by centrifugation in neutrality, is freeze-dried after distilling water washing, obtains tanshinone IIA/chitosan pH sensitive solid dispersion
Body.
Embodiment 2: tanshinone IIA/chitosan pH sensitive solid dispersion preparation
(1) 50mg tanshinone IIA is weighed, is dissolved in 50ml dehydrated alcohol, is stirred at room temperature, is configured to tanshinone IIA concentration
It is spare for the tanshinone IIA ethanol solution of 1mg/ml；
(2) 0.5g chitosan is weighed, is dissolved in 1% spirit of vinegar of 100ml, is stirred at room temperature, be configured to chitosan weight content
For 0.5% chitosan dilute acetic acid solution, and it is poly- to shell to take the ethanol solution of step (1) resulting tanshinone IIA to be slowly added to
In malt sugar acetum, mixed at room temperature stirs 30min, obtains TA/CS composite solution, spare；
(3) under continuous stirring, 1%NaOH solution is added dropwise into TA/CS composite solution obtained by step (2), until pH is
Precipitating is collected by centrifugation in neutrality, is freeze-dried after distilling water washing, obtains tanshinone IIA/chitosan pH sensitive solid dispersion
Body.
Embodiment 3: tanshinone IIA/chitosan pH sensitive solid dispersion preparation
(1) 100mg tanshinone IIA is weighed, is dissolved in 50ml dehydrated alcohol, is stirred at room temperature, is configured to tanshinone IIA concentration
It is spare for the tanshinone IIA ethanol solution of 2mg/ml；
(2) 2g chitosan is weighed, is dissolved in 1% spirit of vinegar of 100ml, is stirred at room temperature, being configured to chitosan weight content is
2% chitosan dilute acetic acid solution, and it is dilute to chitosan to take the ethanol solution of step (1) resulting tanshinone IIA to be slowly added to
In acetum, mixed at room temperature stirs 30min, obtains TA/CS composite solution, spare；
(3) under continuous stirring, 1%NaOH solution is added dropwise into TA/CS composite solution obtained by step (2), until pH is
Precipitating is collected by centrifugation in neutrality, is freeze-dried after distilling water washing, obtains tanshinone IIA/chitosan pH sensitive solid dispersion
Body.
Embodiment 4: tanshinone IIA/chitosan pH sensitive solid dispersion preparation
(1) 25mg tanshinone IIA is weighed, is dissolved in 50ml dehydrated alcohol, is stirred at room temperature, is configured to tanshinone IIA concentration
It is spare for the tanshinone IIA ethanol solution of 0.5mg/ml；
(2) 1g chitosan is weighed, is dissolved in 1% spirit of vinegar of 100ml, is stirred at room temperature, being configured to chitosan weight content is
1% chitosan dilute acetic acid solution, and it is dilute to chitosan to take the ethanol solution of step (1) resulting tanshinone IIA to be slowly added to
In acetum, mixed at room temperature stirs 30min, obtains TA/CS composite solution, spare；
(3) under continuous stirring, 1%NaOH solution is added dropwise into TA/CS composite solution obtained by step (2), until pH is
Precipitating is collected by centrifugation in neutrality, is freeze-dried after distilling water washing, obtains tanshinone IIA/chitosan pH sensitive solid dispersion
Body.
Embodiment 5: tanshinone IIA bulk pharmaceutical chemicals and tanshinone IIA/chitosan pH sensitive solid dispersion X-ray powder
Last diffraction analysis
Appropriate tanshinone IIA and Examples 1 to 4 is taken to prepare resulting tanshinone IIA/chitosan pH sensitive solid point
Granular media carries out physical property table levies in kind to five kinds of powder using X-ray diffractometer respectively and tests, X-ray powder diffraction result such as Fig. 1 institute
Show.
As seen from the figure, pure tanshinone IIA drug is to have strong diffraction maximum at 7.20 ° at 2 angles θ, is shown stronger
Crystal property.
Compare the diffraction patterns figure of pure tanshinone IIA and the diffraction patterns figure of Examples 1 to 4, in general, pass through by
After tanshinone IIA is prepared into tanshinone IIA/chitosan pH sensitive solid dispersion, (2 angles θ are 7.20 ° to crystal characteristic peak
Place) intensity is remarkably decreased, illustrate in a certain range, and crystallinity of the tanshinone IIA in solid dispersions is on a declining curve, this
Downward trend facilitates the promotion of tanshinone IIA solubility.
Specifically, in conjunction with for the mass ratio of tanshinone IIA in solid dispersions and chitosan, Radix Salviae Miltiorrhizae in Examples 1 to 4
The mass ratio of II A of ketone and chitosan is respectively 1:5,1:10,1:20,1:40, the crystalline substance of tanshinone IIA in corresponding XRD spectrum
Body characteristics peak (2 angles θ be 7.20 ° at) intensity successively weakens, and illustrates the mass ratio of tanshinone IIA and chitosan to tanshinone IIA
Crystallinity in solid dispersions has an impact, and the influence is the mass ratio of tanshinone IIA and chitosan in a certain range
Ratio it is smaller, crystallinity of the tanshinone IIA in solid dispersions is smaller, i.e., relative to the crystallinity of pure tanshinone IIA
Decline degree is bigger.
Embodiment 6: tanshinone IIA/chitosan pH sensitive solid dispersion dissolution in vitro experiment
Experimentation: using the content of high effective liquid chromatography for measuring tanshinone IIA, chromatographic column is SunFire C18 column
(4.6mm × 250mm, 5 μm)；Mobile phase is methanol-water (90:10), flow velocity 1.0mLmin-1；Column temperature is 30 DEG C；Detection
Wavelength is 270nm；Sample volume is 10 μ L.
Taking concentration respectively is 1.0,2.0,5.0,10.0,15.0,20.0mgL-1Tanshinone IIA standard solution, press
It is tested according to chromatographic condition, tanshinone IIA concentration is fitted with peak area, establishes standard curve.
A certain amount of tanshinone IIA/chitosan pH sensitive solid dispersion (contains tanshinone IIA in Example 1~4
Quality be 5.0mg), be scattered in 5ml dissolution medium that (dissolution medium is respectively the hydrochloric acid solution and pH=7.4 of pH=1.2
PBS solution), it is packed into bag filter (molecular cut off 10000), in the corresponding dissolution medium of investment 895ml, in (37 ± 0.5)
(100rmin is vibrated in DEG C water bath with thermostatic control-1), 5ml is sampled respectively at different time points, and supplement the blank medium of same volume,
High effective liquid chromatography for measuring content after 0.22 μm of filtering with microporous membrane of sample, and accumulative release rate, formula are calculated according to formula
It is as follows.
Cumulative release amount:
Accumulative release rate:
In formula: Q is accumulative release rate；MnFor Cumulative release amount；CnN-th sample when solution in tanshinone IIA concentration；V
For liquor capacity；CiIn the operation of preceding n-1 sub-sampling i-th sample when sample solution in tanshinone IIA concentration；ViI-th takes
The volume of samples taken solution when sample.
Experimental result: salt of the tanshinone IIA of the Examples 1 to 4/chitosan pH sensitive solid dispersion in 0.1mol/L
Drug release profiles in acid solution (Ph1.2) are as shown in Figure 2；Tanshinone IIA/chitosan pH sensitive solid dispersion is in pH7.4
PBS solution in drug release profiles as shown in figure 3, in conjunction with diagram can be concluded that
Embodiment 1: hydrochloric acid solution (Ph1.2) of the tanshinone IIA/chitosan pH sensitive solid dispersion in 0.1mol/L
In have apparent immediate release profile, 90min or so i.e. reach dissolution balance, preparation 87.8%；In the PBS of pH7.4
In solution, then good slow release effect is shown, preparation is 47.9% for 24 hours.
Embodiment 2: hydrochloric acid solution (Ph1.2) of the tanshinone IIA/chitosan pH sensitive solid dispersion in 0.1mol/L
In have apparent immediate release profile, 120min or so i.e. reach dissolution balance, preparation 99.3%；In the PBS of pH7.4
In solution, then good slow release effect is shown, preparation is 44.7% for 24 hours.
Embodiment 3: hydrochloric acid solution (Ph1.2) of the tanshinone IIA/chitosan pH sensitive solid dispersion in 0.1mol/L
In have apparent immediate release profile, 150min or so i.e. reach dissolution balance, preparation 99.5%；In the PBS of pH7.4
In solution, then good slow release effect is shown, preparation is 38.0% for 24 hours.
Embodiment 4: hydrochloric acid solution (Ph1.2) of the tanshinone IIA/chitosan pH sensitive solid dispersion in 0.1mol/L
In have apparent immediate release profile, 180min or so i.e. reach dissolution balance, preparation 99.6%, in the PBS of pH7.4
In solution, then good slow release effect is shown, preparation is 32.1% for 24 hours.
It can be obtained by above-mentioned experimental result, each embodiment prepares resulting tanshinone IIA/chitosan pH sensitive solid dispersion
Body has apparent pH sensibility, and quick-release characteristic is presented in acidic environment, and slow release characteristic is presented in weakly alkaline environment.
The above embodiments are merely illustrative of the technical solutions of the present invention rather than is limited, without departing substantially from essence of the invention
In the case where mind and its essence, those skilled in the art make various corresponding changes and change in accordance with the present invention
Shape, but these corresponding changes and modifications all should fall within the scope of protection of the appended claims of the present invention.
Claims (6)
1. a kind of tanshinone IIA/chitosan pH sensitive solid dispersion preparation method, which is characterized in that including following step
It is rapid:
Step 1: it takes tanshinone IIA to be dissolved in the ethanol solution that concentration is 80~100%, is stirred at room temperature, it is dense that tanshinone IIA is made
Degree is the ethanol solution of the tanshinone IIA of 0.1~5mg/ml, spare；
Step 2: taking chitosan to be dissolved in 1% dilute acetic acid solution, be stirred at room temperature, and it is poly- to obtain the shell that chitosan concentration is 0.5~2%
Malt sugar acetum, and the ethanol solution of the resulting tanshinone IIA of step 1 is taken to be slowly added into chitosan dilute acetic acid solution,
Mixed at room temperature stirring, obtains tanshinone IIA/chitosan composite solution, spare；
Step 3: being added dropwise NaOH solution into the resulting tanshinone IIA of step 2/chitosan composite solution, adjusts pH to neutrality,
Precipitating is collected by centrifugation, is freeze-dried after distilling water washing, obtains tanshinone IIA/chitosan pH sensitive solid dispersion.
2. tanshinone IIA as described in claim 1/chitosan pH sensitive solid dispersion preparation method, feature exist
In the mass ratio of tanshinone IIA and chitosan is 1:5~1 in tanshinone IIA/chitosan composite solution of the step 2:
50。
3. tanshinone IIA as described in claim 1/chitosan pH sensitive solid dispersion preparation method, feature exist
In the mixing time that mixed at room temperature stirs in the step 2 is 20~120min.
4. tanshinone IIA as described in claim 1/chitosan pH sensitive solid dispersion preparation method, feature exist
In the concentration of NaOH solution is 0.5~5% in the step 3.
5. tanshinone IIA as described in claim 1/chitosan pH sensitive solid dispersion preparation method, feature exist
In the step 3 prepares resulting tanshinone IIA/chitosan pH sensitive solid dispersion and preparing answering in pharmaceutical preparation
With.
6. tanshinone IIA as claimed in claim 5/chitosan pH sensitive solid dispersion preparation method, feature exist
In the pharmaceutical preparation is oral preparation.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110960491A (en) * | 2019-12-11 | 2020-04-07 | 西北大学 | Preparation method and application of tanshinone IIA-loaded water-soluble chitosan/gamma-polyglutamic acid nano-composite |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110960491A (en) * | 2019-12-11 | 2020-04-07 | 西北大学 | Preparation method and application of tanshinone IIA-loaded water-soluble chitosan/gamma-polyglutamic acid nano-composite |
| CN110960491B (en) * | 2019-12-11 | 2021-04-16 | 西北大学 | Preparation method and application of tanshinone IIA-loaded water-soluble chitosan/gamma-polyglutamic acid nano-composite |
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