CN106466300B - A kind of recombination chitosan nano particle preparations and its preparation method and application loading insoluble drug - Google Patents
A kind of recombination chitosan nano particle preparations and its preparation method and application loading insoluble drug Download PDFInfo
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Abstract
The invention belongs to field of pharmaceutical preparations more particularly to a kind of chitosan nanoparticle preparation and its preparation method and application for loading insoluble drug.The nano particle preparations include chitosan, sodium polyphosphate, increasing/cosolvent and lyophilized preparation, and nano particle preparations load insoluble drug；The present invention is using the nanoparticle of chitosan sodium polyphosphate preparation as carrier, good biocompatibility, adhesion is good, nanoparticle partial size is 50~500nm, drug is easily adsorbed by intestinal epithelial cell after oral, drug can significantly improve the oral administration biaavailability of insoluble drug, improve curative effect with chitosan biological degradation slow release.Preparation method of the invention is suitable for the drug of BCSII poorly water-soluble and good penetrability, and without the residual of other impurities and organic solvent, technique prepares simple possible, and particle diameter distribution is uniform, is conducive to industrial mass production.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, are related to composite high-molecular nano particle preparations, and in particular to a kind of loading indissoluble
The chitosan nanoparticle preparation and its preparation method and application of property drug.The recombination chitosan nanoparticle of the loading insoluble drug
It reaches afterwards by oral administration and plays drug effect in vivo, the oral administration biaavailability of insoluble drug can be significantly improved.
Background technique
Studies have shown that drug must be first dissolved in pipe intestinal digesting liquid before absorption, then could be with Passive diffusion
Or the mechanism of absorption such as active transport pass through alimentary canal mucous membrane, into blood circulation, dissolution of the insoluble drug in digestive juice
Usually its rate-limiting step absorbed.In the past 10 years, in the research of this field, using medicament high flux screening in addition to being widely used in
The reactive compound of therapy of serious disease, but the most molecular weight of reactive compound filtered out is high, hydrophobicity is strong；Currently, new
At least 40% may not apply to clinic because of the lower problem of solubility in the active medicine of exploitation；In addition, being wherein up to 70%
Synthetic drug also all there is a problem of that solubility is low.Therefore, the solubility and dissolution rate for improving insoluble drug often become
Improve its first step that bioavilability is administered orally, by selecting suitable carrier and preparation technique to improve insoluble drug
Physicochemical property, improve itself and gastrointestinal tract mucous compatibility and permeability, be promote its oral absorption effective way.
Bay41-4109 can inhibit viral DNA and core protein simultaneously, and the effect to viral core protein is the disease-resistant of its
Malicious mechanism, pharmacokinetics trial test show Bay41-4109 different genera animal through different approaches be administered its absorb, distribution,
Metabolic conversion and excretion are good, and oral administration biaavailability is good；Compared with traditional anti-hepatic-B virus medicine, Bay41-4109 exists
Have the characteristics that obvious in antiviral mode and mechanism, there is good development prospect.
Chitosan is a kind of natural polysaecharides cellulose, is widely present in insect, shellfish shell and fungal cell
In wall, also known as soluble chitin has many advantages, such as nontoxic, good biocompatibility, degradable, and preparation is simple, abundance, has
Stronger hydrophily；Can be by a variety of enzyme biodegrades such as internal lysozyme, pepsin, catabolite is nontoxic, and can be biological
Body fully absorbs；And there is antiacid, anticoagulation, the ability of antiulcer etc., thorn caused by can preventing or weakening drug under one's belt
Pain reaction.
But so far, there is not yet loading the report of recombination chitosan nano particle preparations of insoluble drug and preparation method thereof
Road.
Summary of the invention
The purpose of the present invention is to provide a kind of composite high-molecular nano particle preparations, for loading the load of insoluble drug
Body solves the problems, such as various insoluble drug oral absorptions to meet.More particularly to a kind of Composite Shell for loading insoluble drug
Glycan nano particle preparations and its preparation method and application.
The present invention provides a kind of recombination chitosan nano particle preparations for loading insoluble drug comprising chitosan, more
Polyphosphate sodium, increasing/cosolvent and lyophilized preparation, the nano particle preparations load insoluble drug；The partial size of the nanoparticle is
50~500nm.
In the present invention, the insoluble drug is fat-soluble and water-insoluble drug Bay41-4109.
In the present invention, the chitosan is a kind of biodegradability high molecular material, from a wealth of sources, safe and reliable,
There are good biocompatibility, the referred to as preferred material of pharmaceutical carrier, the chitosan that the present invention selects is that low molecule is deacetylated
Chitosan, deacetylation are higher than 75%, good water solubility；
In the present invention, increasing/cosolvent selects methanol or ethyl alcohol；
In the present invention, lyophilized preparation is selected one or more of in mannitol, lactose or glycine.
The recombination chitosan nano particle preparations of loading insoluble drug of the invention are prepared by following methods:
(1) it prepares chitosan solution A: the deacetylated Chitosan powder of low molecule is sufficiently swollen in 0.1~1% acetic acid
Solution adjusts the pH value of solution to 5, obtains 0.02~2% chitosan solution A；
(2) it prepares sodium polyphosphate solution B: sodium polyphosphate is diluted with water into 1~5% sodium polyphosphate solution B；
(3) it prepares drug containing solution C: a certain amount of Bay41-4109 is dissolved in increasing/cosolvent, be added to above-mentioned chitosan
In solution A, drug containing solution C is obtained after sonic oscillation 30min；
(4) it prepares drug containing nanoparticle solution: under lasting stirring, B solution being added dropwise in C solution according to the ratio, control drop
1~4ml/min of speed reacts 0.5~2h, is transferred to 6~8kDa bag filter after reaction, removes free group with distilled water dialysis
Point, obtain Bay41-4109 nanoparticle solution；
(5) it prepares nanoparticle lyophilized preparation: lyophilized preparation being added according to the ratio in above-mentioned drug containing nanoparticle solution, freeze
It is dry, Bay41-4109 nano particle preparations are made.
Composite high-molecular nano particle preparations produced by the present invention, the partial size of nanoparticle are 50~500nm, drug delivery
Rate reaches 10~50%.
The present invention provides a kind of recombination chitosan nano particle preparations, insoluble drug can be evenly distributed on chitosan nano
In the grain of rice, hydrophily chitosan is greatly improved to the charging ratio and encapsulation rate of insoluble drug, avoids insoluble drug
It is present in carrier with big crystal form, drug can stablize quick release, and rate of release is controllable；As oral slightly solubility medicine
Object carrier is able to satisfy the bioavailability concerns for solving various insoluble drugs；The product is a kind of oral preparation, due to good
Cell adhesion, cell endocytic and membrane permeability, have good therapeutic effect and lower toxic side effect afterwards by oral administration.Further
It can be used for preparing the pharmaceutical preparation of anti-hepatitis B virus (Hepatitis B Virus, HBV).
Recombination chitosan nano particle preparations of the invention its advantage is that:
1, using the nanoparticle of chitosan sodium polyphosphate preparation as carrier, good biocompatibility, adhesion is good, nanometer
Grain partial size is 50~500nm, and drug is easily adsorbed by intestinal epithelial cell after taking orally, and drug is slowly released with chitosan biological degradation
It puts, curative effect can be significantly improved；
2, nanoparticle dry powder formulations are made in final preparation, convenient for saving, when use is added a small amount of distilled water and can be dispersed
It is easy to use for suspension；
3, preparation method is suitable for the drug of BCSII poorly water-soluble and good penetrability, without other impurities and organic solvent
Residual, technique prepare simple possible, particle diameter distribution is uniform, is conducive to industrial mass production.
Detailed description of the invention
Fig. 1 is that composite nano-granule preparation of the invention prepares diagram.
Fig. 2 is Bay41-4109, chitosan and the microscope photo for carrying medicine composite nano-granule preparation,
Wherein, the microscope photo of a:Bay41-4109；
B: the microscope photo of chitosan；
C: the microscope photo of medicine composite nano-granule preparation is carried.
Fig. 3 is Bay41-4109, chitosan and the X ray diffracting spectrum for carrying medicine composite nano-granule preparation,
Wherein, the X ray diffracting spectrum of a:Bay41-4109；
B: the X ray diffracting spectrum of medicine composite nano-granule preparation is carried；
C: the X ray diffracting spectrum of chitosan.
Fig. 4 is the particle size distribution measuring result for carrying medicine composite nano-granule preparation.
Fig. 5 is the transmission electron microscope photo for carrying medicine composite nano-granule preparation.
Fig. 6 is Bay41-4109, chitosan and the infared spectrum for carrying medicine composite nano-granule preparation,
Wherein, the infared spectrum of a:Bay41-4109；
B: the infared spectrum of chitosan；
C: the infared spectrum of medicine composite nano-granule preparation is carried.
Fig. 7 is Bay41-4109, and chitosan carries the differential heat scan figure of medicine composite nano-granule preparation and blank nanoparticle
Spectrum,
Wherein, the differential heat scan map of a:Bay41-4109；
B: the differential heat scan map of chitosan；
C: the differential heat scan map of medicine composite nano-granule preparation is carried；
D: the differential heat scan map of blank nanoparticle.
Specific embodiment
Now in conjunction with embodiment, the present invention is described in detail
Embodiment 1
As shown in Figure 1, drug-carrying nanometer particle, specific steps are prepared are as follows:
1, appropriate Chitosan powder is weighed, is dissolved in certain density acetum at room temperature, is gathered shell by magnetic agitation
Sugar is completely dissolved, and the concentration of final chitosan is 0.02~2mg/mL, with the pH of 1N NaOH solution adjustment chitosan acetic acid solution
It is worth to 4~8；
2, suitable sodium polyphosphate is weighed, the polyphosphoric acids sodium solution that concentration is 5~10mg/mL is diluted with water to；
3, a certain amount of Bay41-4109 is weighed, is added in the chitosan acetic acid solution prepared, the shell for obtaining drug containing is poly-
Sugar juice under lasting stirring, by different quality than polyphosphoric acids sodium solution to be added dropwise in the chitosan solution of drug containing, controls
1~4ml/min of speed is dripped, 0.5~2h is reacted, is transferred to 6~8kDa bag filter after reaction, is removed with distilled water dialysis free
Component obtains Bay41-4109 nanoparticle solution；
4, freeze-drying proppant will be added according to the ratio in above-mentioned drug containing nano-solution, be freeze-dried to get Bay41- is arrived
4109 freeze-drying nano particle preparations.
Embodiment 2
Appropriate Chitosan powder is weighed, is dissolved in 0.3% acetum at room temperature, makes the final concentration of 2mg/mL of chitosan,
Chitosan is completely dissolved in acetum by magnetic agitation, and the pH value of chitosan-acetic acid solution is adjusted with 1N NaOH solution
It is 5, weighs 50mg Bay41-4109 and be dissolved in obtaining concentration in the chitosan-acetic acid solution prepared being containing for 0.5mg/mL
Medicine chitosan-acetic acid solution is kept under room temperature magnetic agitation state, and the polyphosphoric acids sodium solution that 0.5mL concentration is 5mg/mL is dripped
It is added in the acetum of above-mentioned drug containing chitosan, reacts 1h, nanoparticle is cross-linked by the ionic bonding of negative ions, react
After be transferred to 6~8kDa bag filter, with distilled water dialyse remove free components, obtain Bay41-4109 nanoparticle solution；Essence
Above-mentioned drug containing nanoparticle solution is added in the close 2.5g mannitol that weighs, and is sufficiently stirred after dissolving to freeze after crossing 0.22 μm of miillpore filter and do
It is dry to get arrive Bay41-4109 freeze-drying nano particle preparations.
Embodiment 3
60mg Bay41-4109 is dissolved in 1mL methanol solution, is added in the chitosan-acetic acid solution prepared by embodiment 1,
Sonic oscillation 30min is kept under room temperature magnetic agitation state, and the polyphosphoric acids sodium solution that 0.5mL concentration is 5mg/mL is added dropwise
Into the acetum of above-mentioned drug containing chitosan, 1h is reacted, nanoparticle is cross-linked by the ionic bonding of negative ions, by gained
Solution distilled water is dialysed for 24 hours, is crossed 0.45 μm of filter membrane and is suspended to get the chitosan nanoparticle compound to load Bay41-4109
Liquid；By 4 DEG C of high speed centrifugation (15000rpm) 30min of suspension, lower sediment is collected, after pure water 3 times, freeze-drying is
Obtain the chitosan nanoparticle preparation of load Bay41-4109.
Embodiment 4
Appropriate Chitosan powder is weighed, is dissolved in 0.2% acetum at room temperature, makes the final concentration of 2mg/mL of chitosan,
Chitosan is completely dissolved in acetum by magnetic agitation, and the pH value of chitosan-acetic acid solution is adjusted with 1N NaOH solution
It is 5, weighs 30mg Bay41-4109 and be dissolved in obtaining concentration in the chitosan-acetic acid solution prepared being containing for 0.3mg/mL
Medicine chitosan-acetic acid solution is kept under room temperature magnetic agitation state, and the polyphosphoric acids sodium solution that 0.5mL concentration is 5mg/mL is dripped
It is added in the acetum of above-mentioned drug containing chitosan, reacts 1h, nanoparticle is cross-linked by the ionic bonding of negative ions, react
After be transferred to 6~8kDa bag filter, with distilled water dialyse remove free components, obtain Bay41-4109 nanoparticle solution；Essence
Above-mentioned drug containing nanoparticle solution is added in the close 1.5g lactose that weighs, and is sufficiently stirred after dissolving to freeze after crossing 0.22 μm of miillpore filter and do
It is dry to get arrive Bay41-4109 freeze-drying nano particle preparations.
Embodiment 5
Appropriate Chitosan powder is weighed, is dissolved in 0.3% acetum at room temperature, makes the final concentration of 2mg/mL of chitosan,
Chitosan is completely dissolved in acetum by magnetic agitation, and the pH value of chitosan-acetic acid solution is adjusted with 1N NaOH solution
It is 5, weighs 50mg Bay41-4109 and be dissolved in obtaining concentration in the chitosan-acetic acid solution prepared being containing for 0.5mg/mL
Medicine chitosan-acetic acid solution is kept under room temperature magnetic agitation state, and the polyphosphoric acids sodium solution that 0.5mL concentration is 5mg/mL is dripped
It is added in the acetum of above-mentioned drug containing chitosan, reacts 1h, nanoparticle is cross-linked by the ionic bonding of negative ions；By glue
Liquid solution is collected lower sediment and is freeze-dried with pure water 3 times in 4 DEG C of high speed centrifugation (18000rpm) 30min
The chitosan drug containing nano particle preparations of Bay41-4109；
Crystal habit observation: compare Bay41-4109, chitosan and load medicine complex nanometer granule preparation with optical microscopy
Refraction light variation；Fig. 2 shows the form obtained for carrying medicine complex nanometer granule by the crystalline substance of Bay41-4109 and chitosan
Volume morphing is changed into amorphous form, this metamorphosis result further proves (as shown in Figure 3) by the result of X-ray diffraction；
Particle diameter distribution and average droplet measurement: taking nanoparticle sample appropriate, after diluting with distilled water, uses laser diffraction particle size
Instrument measures its average grain diameter and distribution, Fig. 4 display particle size determination result: the average grain diameter of obtained load medicine composite nano-granule is
167.9nm, particle diameter distribution FACTOR P dI are 0.276, the results showed that Bay41-4109 drug-carrying nanometer particle particle diameter distribution obtained is equal
Even, the transmission electron microscope photo result of the result of the particle diameter distribution as shown in Figure 5 is further verified；
Crosslinking bonding and building stone chemical shift detection: by the Bay41-4109 of infrared scan trace analysis shown in Fig. 6,
Chitosan and the primary structure group drift condition for carrying medicine composite nano-granule, the results showed that this preparation process is ionic cross-linked bond
It closes, the chemical structure displacement of Bay41-4109 will not be generated, ionic cross-linked bond credit union leads to the heat content energy for carrying medicine composite nano-granule
Amount difference changes with temperature, the differential heat scan result description of this result as shown in Figure 7.
Claims (6)
1. a kind of recombination chitosan nano particle preparations for loading insoluble drug, which is characterized in that it includes chitosan, poly phosphorus
Sour sodium, increasing/cosolvent and freeze drying protectant, the nano particle preparations load insoluble drug；The insoluble drug is liposoluble
Property and water-insoluble drug Bay41-4109；The partial size of the nanoparticle is 50 ~ 500 nm.
2. the recombination chitosan nano particle preparations according to claim 1 for loading insoluble drug, which is characterized in that chitosan
For the deacetylated chitosan of low molecule, deacetylation is higher than 75%, good water solubility.
3. the recombination chitosan nano particle preparations according to claim 1 for loading insoluble drug, which is characterized in that described
Increasing/cosolvent selects methanol or ethyl alcohol.
4. the recombination chitosan nano particle preparations according to claim 1 for loading insoluble drug, which is characterized in that the jelly
Dry protective agent selects the one or more of mannitol, lactose or glycine.
5. the preparation method of the recombination chitosan nano particle preparations described in claim 1 for loading insoluble drug, feature exist
In comprising step:
(1) it prepares chitosan solution A: the deacetylated Chitosan powder of low molecule is sufficiently swollen in 0.1 ~ 1% acetum,
The pH value of solution is adjusted to 5, obtains 0.02 ~ 2% chitosan solution A；
(2) it prepares sodium polyphosphate solution B: sodium polyphosphate is diluted with water into 1 ~ 5% sodium polyphosphate solution B；
(3) it prepares drug containing solution C: a certain amount of Bay41-4109 is dissolved in increasing/cosolvent, be added to above-mentioned chitosan solution
In A, drug containing solution C is obtained after 30 min of sonic oscillation；
(4) it prepares drug containing nanoparticle solution: under lasting stirring, B solution being added dropwise in C solution according to the ratio, control drop speed 1 ~ 4
Ml/min reacts 0.5 ~ 2 h, is transferred to 6 ~ 8 kDa bag filters after reaction, is dialysed with distilled water and removes free components, obtained
Bay41-4109 nanoparticle solution；
(5) it prepares nanoparticle lyophilized preparation: freeze drying protectant is added according to the ratio in above-mentioned drug containing nanoparticle solution, freezing is dry
It is dry, Bay41-4109 nano particle preparations are made.
6. the recombination chitosan nano particle preparations of the loading insoluble drug of claim 1 are being used to prepare anti-hepatitis B virus
Pharmaceutical preparation in purposes.
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