CN107802614A - A kind of oral albumin nano granular in intestines and stomach with high stability - Google Patents
A kind of oral albumin nano granular in intestines and stomach with high stability Download PDFInfo
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- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
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Abstract
The present invention is prepared for a kind of oral albumin nano granular in intestines and stomach with high stability.The present invention loads poorly water soluble drugs, using the compound containing sulfydryl as stabilizer with albumin, is prepared for a kind of oral albumin nano preparation.The nanometer formulation can effectively improve the stability of albumin nano granular in the gastrointestinal tract, while improve the oral administration biaavailability of insoluble drug.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, and in particular to a kind of oral albumin in intestines and stomach with high stability
Nanoparticle and preparation method thereof.
Background technology
It is administered orally because its security is good, compliance is high, convenient drug administration, is clinically preferable drug treatment approach.Mesh
The commercially available chemicals of preceding major part or pharmacological activity molecule are often insoluble in the IV of water, especially Biopharmaceutics Classification system
Class medicine, solubility is low, poor permeability, and oral administration biaavailability is very low.Novel nano delivery system can effectively improve
The solubility and oral administration biaavailability of insoluble drug, it is the focus of Pharmaceutical study.Wherein, using albumen as carrier matrix
Nano medicament carrying system, because its is safe, biocompatibility and biodegradability are good, it has also become treating cancer, glycosuria
The multifunctional carrier of the diseases such as disease, rheumatoid arthritis.
There are many reports as the research that carrier is administered orally on albumen at present, such as oralbumin nanoparticle, newborn iron
Protein nano grain, gliadin nanoparticle, zeins nanoparticle etc..Albumin is that one kind is largely deposited in blood plasma
Albumen, there is the advantages of water-soluble high, stability is good, drug loading is high, be the ideal carrier of dewatering medicament, it is more at present
Applied to intravenous injection be administered, as taxol-albumin nano granular (nab-paclitaxel,) be first should
The medicine listed with albumin nano granular technology.In recent years, studied and attempted using albumin as the carrier being administered orally, but
It is that prepared albumin nano granular still has much room for improvement in the stability of intestines and stomach.At present using albumin as oral carrier material
Ultimate challenge be protect albumin carrier not by gastrointestinal tract environment premature failure, degraded, it is stabilized in intestines and stomach,
So as to improve the oral administration biaavailability of medicine.However, the research on this respect is not almost reported at this stage.
In view of the above-mentioned problems, being based on prior art, the invention provides a kind of mouth in intestines and stomach with high stability
Albumin nano granular and preparation method thereof is taken, to effectively improve the stability of albumin nano granular in the gastrointestinal tract, is improved simultaneously
The oral administration biaavailability of insoluble drug.
The content of the invention
It is an object of the invention to provide a kind of oral albumin nano granular and its system in intestines and stomach with high stability
Preparation Method.Oral albumin nano granular of the present invention, it is characterised in that:Bulk drug is poorly water soluble drugs, and auxiliary material includes:
Albumin, curing agent and stabilizer.Nanoparticle of the present invention can be stabilized in the gastrointestinal tract, can improve insoluble drug
Oral administration biaavailability.
A kind of oral albumin nano granular in intestines and stomach with high stability of the present invention, it is characterised in that:
Described poorly water soluble drugs are curcumin, taxol, Docetaxel, Itraconazole, gambogicacid, resveratrol, fenofibrate
Any material in the medicines such as spy, camptothecine.
A kind of oral albumin nano granular in intestines and stomach with high stability of the present invention, it is characterised in that:
The albumin is human serum albumins or bovine serum albumin(BSA).
A kind of oral albumin nano granular in intestines and stomach with high stability of the present invention, it is characterised in that:
Described curing agent is one kind in glutaraldehyde or formaldehyde.
A kind of oral albumin nano granular in intestines and stomach with high stability of the present invention, it is characterised in that:
Described stabilizer is one kind in N-acetyl-L-cysteine, cysteine, TGA.
A kind of preparation method of oral albumin nano granular in intestines and stomach with high stability of the present invention, its
It is characterised by:The albumin aqueous solution mixes in equal volume with the organic solution of insoluble drug, after being incubated altogether, then adds equivalent to water
The organic solvent of phase several times volume is simultaneously added dropwise in mixed liquor, adds curing agent solidification 20h, it is organic molten that removing is evaporated under reduced pressure
Agent, add deionized water to hang again, 0.45 μm of filtering with microporous membrane, produce the common albumin nano granular for carrying medicine;Stabilizer passes through again
The mode of chemical modification is incorporated in the common albumin nano granular surface for carrying medicine, that is, be made has high stability in intestines and stomach
Oral albumin nano granular.
A kind of preparation method of oral albumin nano granular in intestines and stomach with high stability of the present invention, its
It is characterised by:Described stabilizer and the mol ratio of albumin are 360: 1~640: 1.
A kind of preparation method of oral albumin nano granular in intestines and stomach with high stability of the present invention, its
It is characterised by:Described organic solvent is one kind in acetone, methanol, ethanol.
The present invention is that the prescription for carrying medicine albumin nano granular is designed and optimized first, then makes passing through of stabilizer
The mode for learning modification is incorporated in albumin nano granular surface, obtains the oral albumin nano for having high stability in intestines and stomach
Grain.Found in research process, the particle diameter of species and dosage to albumin nano granular of stabilizer and its stabilization in intestines and stomach
Property has a great impact.The present invention has considered many factors, and compound of the final choice containing sulfydryl is as stabilizer, institute
The oral albumin nano granular prepared has the stability of height in intestines and stomach, is remarkably improved the oral bioavailability of medicine
Degree.
Its advantage compared with prior art of the invention:The present invention is by long-term substantial amounts of experiment and point of novelty
Analysis summary obtains inventive formulation, is successfully prepared a kind of oral albumin nano granular in intestines and stomach with high stability.
The present invention is investigated by experiments such as the stability in Imitative gastroenteric environments, preferably goes out the best stabilizer.Prepared by the present invention
Stabilizer modification albumin nano granular can strengthen in its stability in intestines and stomach;Meanwhile height of the present invention is steady
Fixed oral albumin nano granular, the solubility of insoluble drug is added, significantly improves its oral administration biaavailability.This hair
Bright preparation technology is simple, and nonirritant without using any surfactant, toxic side effect is small, safe, has good life
Thing compatibility, cost is relatively low, is easy to industrialize, and is a kind of quite promising oral drugs carrier.
Brief description of the drawings
Fig. 1 is the atomic force microscopy diagram of albumin nano granular prepared by embodiment 2;
Fig. 2 is particle diameter, polydisperse system of the albumin nano granular of different stabilizers modification in embodiment 8 in simulate the gastric juice
Several changing trend diagrams:WhereinFor the particle size of common albumin nano granular,For chitosan-modified albumin nanometer
The particle size of the grain of rice,The particle size for the albumin nano granular modified for chitosan hydrochloride,Modified for carbomer
Albumin nano granular particle size,The particle size for the albumin nano granular modified for N-acetyl-L-cysteine,For the particle size of the albumin nano granular of cysteine modified,The albumin nano granular modified for TGA
Particle size;For the polydispersity coefficient of common albumin nano granular,For chitosan-modified albumin nano granular
Polydispersity coefficient,The polydispersity coefficient for the albumin nano granular modified for chitosan hydrochloride,For the white of carbomer modification
The polydispersity coefficient of protein nano grain,The polydispersity coefficient for the albumin nano granular modified for N-acetyl-L-cysteine,For the polydispersity coefficient of the albumin nano granular of cysteine modified,For the albumin nano of TGA modification
The polydispersity coefficient of grain;
Fig. 3 is particle diameter, polydisperse system of the albumin nano granular of different stabilizers modification in embodiment 8 in simulated intestinal fluid
Several changing trend diagrams:WhereinFor the particle size of common albumin nano granular,For chitosan-modified albumin nanometer
The particle size of the grain of rice,The particle size for the albumin nano granular modified for chitosan hydrochloride,Modified for carbomer
Albumin nano granular particle size,The particle size for the albumin nano granular modified for N-acetyl-L-cysteine,For the particle size of the albumin nano granular of cysteine modified,The albumin nano granular modified for TGA
Particle size;For the polydispersity coefficient of common albumin nano granular,For chitosan-modified albumin nano granular
Polydispersity coefficient,The polydispersity coefficient for the albumin nano granular modified for chitosan hydrochloride,For the white of carbomer modification
The polydispersity coefficient of protein nano grain,The polydispersity coefficient for the albumin nano granular modified for N-acetyl-L-cysteine,For the polydispersity coefficient of the albumin nano granular of cysteine modified,For the albumin nano of TGA modification
The polydispersity coefficient of grain;
Fig. 4 be pharmacokinetics after each curcumin preparation is administered orally in embodiment 9 in rat body through when curve.
Embodiment
The present invention is further illustrated below by way of specific embodiment, but the purpose and scope of the invention is not limited to these implementations
Content described in example.
A kind of curcumin albumin nano grain of embodiment 1 and its preparation
Embodiment is:
1 part of bovine serum albumin(BSA) (BSA) aqueous solution mixes with the ethanol solution of 1 part of curcumin, after being incubated altogether, then adds 3
Part absolute ethyl alcohol is simultaneously added dropwise in mixed liquor;2.5% glutaraldehyde solidification 20h is added, is evaporated under reduced pressure and removes organic solvent, add
Deionized water is hanged again, through 0.45 μm of filtering with microporous membrane, produces curcumin albumin nano grain.
A kind of curcumin albumin nano grain of 2 stabilizer of embodiment modification and its preparation
Curcumin albumin nano grain, stabilizer N-acetyl-L-cysteine is made in preparation method as described in embodiment 1
(NAC) common curcumin albumin nano grain surface is incorporated in by way of chemical modification again, that is, is made in stomach and intestine stage property
There is the oral albumin nano granular of high stability.Embodiment is:
1 part of stabilizer N-acetyl-L-cysteine (NAC) is dissolved in deionized water, adds 1 part of 1- ethyl-(3- dimethyl
Aminopropyl) phosphinylidyne diimine (EDC) and 1 part of N- hydroxysuccinimide (NHS) make dual catalyst, after priming reaction 1h, with
The amount of mol ratio n (NAC): n (BSA)=360: 1 adds NAC activating solutions into curcumin albumin nano grain suspension, keeps away
After light stirring reaction 6h, high speed refrigerated centrifuge (4 DEG C, 16000rpm/min) 30min, supernatant is abandoned, after precipitation is washed 2 times, adds water
It is multiple outstanding, produce the curcumin albumin nano grain of stabilizer modification.
A kind of curcumin albumin nano grain of 3 stabilizer of embodiment modification and its preparation
Curcumin albumin nano grain is made in preparation method as described in embodiment 1, and stabilizer cysteine (Cys) passes through again
The mode of chemical modification is incorporated in common curcumin albumin nano grain surface, that is, be made has high stability in intestines and stomach
Oral albumin nano granular.Embodiment is:
1 part of stabilizer cysteine (Cys) is dissolved in deionized water, is added 1 part of EDC and 1 part of NHS and is made dual catalyst, living
After changing reaction 1h, Cys activating solutions are added to curcumin albumin nano with mol ratio n (Cys): n (BSA)=485: 1 amount
In grain suspension, after lucifuge stirring reaction 6h, high speed refrigerated centrifuge (4 DEG C, 16000rpm/min) 30min, supernatant is abandoned, precipitate water
After washing 2 times, add water to hang again, produce the curcumin albumin nano grain of stabilizer modification.
A kind of curcumin albumin nano grain of 4 stabilizer of embodiment modification and its preparation
Curcumin albumin nano grain is made in preparation method as described in embodiment 1, and stabilizer TGA (TGA) passes through again
The mode of chemical modification is incorporated in common curcumin albumin nano grain surface, that is, be made has high stability in intestines and stomach
Oral albumin nano granular.Embodiment is:
1 part of stabilizer TGA (TGA) is dissolved in deionized water, is added 1 part of EDC and 1 part of NHS and is made dual catalyst, living
After changing reaction 1h, TGA activating solutions are added to curcumin albumin nano with mol ratio n (TGA): n (BSA)=640: 1 amount
In grain suspension, after lucifuge stirring reaction 6h, high speed refrigerated centrifuge (4 DEG C, 16000rpm/min) 30min, supernatant is abandoned, precipitate water
After washing 2 times, add water to hang again, produce the curcumin albumin nano grain of stabilizer modification.
Influence of the surface modification of the variety classes chitosan of embodiment 5 to albumin nano granular
Under the conditions of prior art, the present embodiment is using curcumin albumin nano grain made from embodiment 1 to be general before modification
Logical albumin nano granular.With chitosan (100KDa), chitosan (200KDa), chitosan (300KDa) and chitosan hydrochloride
For stabilizer, common albumin nano granular surface is coated on by way of Electrostatic Absorption, to increase albumin nano granular in stomach
Stability in enteron aisle.Preparation process is as follows:
Accurately weighed appropriate chitosan (100KDa), chitosan (200KDa), chitosan (300KDa) and chitosan
Hydrochloride, 2.Smg/ml solution is respectively made into, temperature is incubated at room temperature with isometric common albumin nano granular suspension respectively
30 minutes, produce the albumin nano granular of different stabilizers modification.The particle diameter and polydispersity coefficient of each nanoparticle are determined, with modification
Preceding common albumin nano granular is control, the results are shown in Table 1.
The albumin nano granular particle diameter and polydispersity coefficient of the variety classes chitosan surface modification of table 1
When selecting chitosan (300KDa), the particle diameter of albumin nano granular changes to about 500nm from 250nm, and particle diameter becomes
Change excessive, polydispersity coefficient also increases to 0.3 from 0.2, and change is also larger.It is therefore preferable that chitosan (100KDa) or chitosan
(200KDa) or chitosan hydrochloride are for further study.
The influence of the chitosan of the various concentrations of embodiment 6 or the surface modification of hydrochloric acid chitosan to albumin nano granular
Under the conditions of prior art, the present embodiment is using curcumin albumin nano grain made from embodiment 1 to be general before modification
Logical albumin nano granular.Using chitosan (100KDa), chitosan (200KDa) and chitosan hydrochloride as stabilizer, respectively will
This three kinds of stabilizers are configured to 0.5mg/ml, 1mg/ml, 2.5mg/ml and 5mg/ml solution.Each solution respectively with it is isometric
Common albumin nano granular suspension at room temperature incubate 30 minutes by temperature, produces the albumin nano granular of different stabilizers modification.Survey
The particle diameter of fixed each nanoparticle, is control with the common albumin nano granular (i.e. 0mg/ml) before modification, the results are shown in Table 2.
The chitosan of the various concentrations of table 2 or the albumin nano granular particle size of hydrochloric acid chitosan surface modification
/:It can not determine
As a result show, when all chitosan solution concentration are 5mg/ml, because solution intrinsic viscosity is larger, make albumin nanometer
The grain of rice is assembled, and prompts chitosan concentration can not be too high.When stabilizer is chitosan (200KDa), chitosan under all concentration
After the albumin nano granular of (200KDa) modification is stood overnight, there is flocculation phenomenon, prompt chitosan molecule amount can not be excessive.
When stabilizer is chitosan (100KDa), when its concentration is 0.5mg/ml, the nanoparticle particle diameter after modification is almost
It is unchanged, illustrate that albumin nano granular surface is almost modified without chitosan molecule, prompt chitosan concentration can not be too low, otherwise
It is unfavorable for albumin nano granular and keeps stable in intestines and stomach;When chitosan (100KDa) concentration is 2.5mg/ml or 1mg/ml, in vain
The particle diameter of protein nano grain slightly increases, and relatively stable;The chitosan of albumin nano granular surface modification is more at most more beneficial for
Its stability in intestines and stomach is maintained, therefore preferably chitosan (100KDa) concentration is 2.5mg/ml.
When stabilizer is chitosan hydrochloride, when its concentration is 0.5mg/ml, nanoparticle particle diameter after modification almost without
Change, illustrate that albumin nano granular surface is almost modified without chitosan molecule, prompt chitosan hydrochloride concentration can not be too low;
When chitosan hydrochloride concentration is 2.5mg/ml or 1mg/ml, the particle diameter of albumin nano granular slightly increases, and relatively stable;White egg
The chitosan hydrochloride of white nanoparticle surface modification is more at most more beneficial for the stability for maintaining it in intestines and stomach, therefore preferably
Chitosan hydrochloride concentration is 2.5mg/ml.
The albumin nano granular of the carbomer surface modification of embodiment 7 and its preparation
Under the conditions of prior art, the present embodiment is using curcumin albumin nano grain made from embodiment 1 to be general before modification
Logical albumin nano granular.Using Carbopol NF and carbomer 947P as stabilizer, carry out room temperature with common albumin nano granular and incubate
Educate, the albumin nano granular of carbomer surface modification is made, to increase the stability of nanoparticle in the gastrointestinal tract.Preparation process is such as
Under:
Accurately weighed appropriate Carbopol NF and carbomer 947P, are respectively made into 2mg/ml, 1mg/ml and 0.5mg/ml
Solution, temperature is incubated 30 minutes at room temperature with isometric curcumin albumin nano grain suspension respectively, produces different stabilizers
The albumin nano granular of modification.The particle diameter of each nanoparticle is determined, is with the common albumin nano granular (i.e. 0mg/ml) before modification
Control, the results are shown in Table 3.
The particle size of the albumin nano granular of the different carbomer surface modifications of table 3
As a result show, when using Carbopol NF as stabilizer, change of size is larger, and stability is poor.When with carbomer
When 947P is stabilizer, when its concentration is 0.5mg/ml, particle diameter prompts carbomer concentration too low without significant change, and
The nanoparticle of 1mg/ml or 2mg/ml carbomer 947P modifications is relatively stable.The carbomer on albumin nano granular surface is more at most more
Be advantageous to the stability for maintaining it in intestines and stomach, therefore preferably carbomer 947P concentration is 2mg/ml.
Study on the stability of the albumin nano granular of the different stabilizers of embodiment 8 modification in Imitative gastroenteric environments
The albumin nano granular of the different stabilizers modification used in the present embodiment is as follows:
(1) concentration is 2.5mg/ml chitosan (100KDa) in chitosan-modified albumin nano granular, i.e. embodiment 6
The albumin nano granular of modification;(2) albumin nano granular of chitosan hydrochloride modification, i.e., concentration is 2.5mg/ in embodiment 6
The albumin nano granular of ml chitosan hydrochloride modification;(3) albumin nano granular of carbomer modification is that is, dense in embodiment 7
Spend the albumin nano granular of the carbomer 947P modifications for 2mg/ml;(4) albumin nano of N-acetyl-L-cysteine modification
Grain, i.e. nanoparticle prepared by embodiment 2;(5) receiving prepared by the albumin nano granular of cysteine modified, i.e. embodiment 3
The grain of rice;(6) albumin nano granular of TGA modification, i.e. nanoparticle prepared by embodiment 4.
The albumin nano granular that 6 kinds of different stabilizers are modified is scattered in simulate the gastric juice and simulated intestinal fluid again, entered
Row study on the stability, and control is used as using the unmodified common albumin nano granular prepared by embodiment 1.Embodiment
For:
Each albumin nano granular is scattered in simulate the gastric juice and simulated intestinal fluid again.The constant temperature under the conditions of 37 DEG C, 150rpm
Stirring, at the appointed time 0h, 1h, 2h, 4h, 6h, 8h (simulate the gastric juice incubation time point 0h, 1h, 2h, 4h) sampling, surveys nanometer
The particle diameter and polydispersity coefficient of grain, investigate stability of the nanoparticle in Imitative gastroenteric environments.As a result as shown in Figure 2 and Figure 3.
As a result show, common albumin nano granular, in simulate the gastric juice, temperature incubates 2h particle diameters and reaches 500nm, in simulation intestines
In liquid, significantly increased after 2h, polydispersity coefficient also significantly increases, and stability is poor.Chitosan-modified albumin nano granular, in mould
Intend in gastric juice, particle diameter increase is slow;But in simulated intestinal fluid, particle diameter gradually increases after 2h, is significantly increased after 4h, 8h particle diameters approach
800nm.The albumin nano granular of carbomer modification is in the environment of simulate the gastric juice and simulated intestinal fluid, and nanoparticle aggregation is obvious,
Unstable, in 1h or so, its particle diameter significantly increases, and polydispersity coefficient reaches 0.4 even 0.5.And with the Guangs of N- acetyl-L- half
The albumin nano granular of the stabilizer modification containing sulfydryl such as propylhomoserin, cysteine, TGA is in simulate the gastric juice and simulated intestinal fluid
In, particle diameter and polydispersity coefficient change are smaller, prompt the albumin nano granular that these three sulfydryl materials are modified in simulated gastrointestinal tract
There is the stability of height under environment.
Therefore, in existing conventional techniques, chitosan-modified, carbomer modification can not preferably increase albumin nano granular
Stability in the gastrointestinal tract, and present invention selection N-acetyl-L-cysteine, cysteine, TGA etc. are as stable
Agent, the stability of albumin nano granular in the gastrointestinal tract can be maintained well, be favorably improved the oral administration biaavailability of medicine.
The present invention of embodiment 9 has the curcumin albumin nano grain of the high stability medicine in rat body in intestines and stomach
The dynamic investigation for learning property
A. it is administered and takes blood scheme:
SD rats 15, are randomly divided into three groups, respectively gavage curcumin suspension, curcumin albumin nano grain, stably
The curcumin albumin nano grain of agent modification (in terms of curcumin, dosage 50mg/kg).Curcumin suspension is by turmeric
Plain bulk drug powder is suspended in 0.5% CMC-Na, and prepared by curcumin albumin nano grain scheme as described in embodiment 1, surely
The curcumin albumin nano grain for determining agent modification is prepared by the methods described of embodiment 2.
Blood is taken respectively at 0.08,0.25,0.5,0.75,1,1.5,2,4,6,8h after administration, takes 0.5ml to put through eye socket every time
In the centrifuge tube of test tube of hepari, and separated plasma immediately.
B. Drug-time curve, as shown in Figure 4.
C. about pharmacokinetic parameters, 4 are shown in Table.
Pharmacokinetic parameters are administered orally in 4 each curcumin preparation of table
From pharmacokinetic parameters result, the blood concentration of the curcumin albumin nano grain of stabilizer surface modification is remote
Higher than curcumin suspension and curcumin albumin nano grain;After the modification of N-acetyl-L-cysteine modification of surfaces, blood Chinese medicine
Cmax (the C of thingmax) be 4.43 times of suspension, blood medicine through when TG-AUC (AUC) be 3.25 times of suspension.Experiment
As a result prompt, after the modification of albumin nano granular surface stabilizer, the oral absorption of insoluble drug curcumin can be effectively facilitated
Effect, significantly improve its oral administration biaavailability.
Claims (8)
- A kind of 1. oral albumin nano granular in intestines and stomach with high stability, it is characterised in that:Bulk drug is that shipwreck is molten Property medicine, auxiliary material include:Albumin, curing agent and stabilizer.Nanoparticle of the present invention can be stabilized in the gastrointestinal tract, can Improve the oral administration biaavailability of insoluble drug.
- 2. a kind of oral albumin nano granular in intestines and stomach with high stability according to claim 1, its feature It is:Described poorly water soluble drugs are curcumin, taxol, Docetaxel, Itraconazole, gambogicacid, resveratrol, non- Any material in the medicines such as nobert, camptothecine.
- 3. a kind of oral albumin nano granular in intestines and stomach with high stability according to claim 1, its feature It is:The albumin is human serum albumins or bovine serum albumin(BSA).
- 4. a kind of oral albumin nano granular in intestines and stomach with high stability according to claim 1, its feature It is:Described curing agent is one kind in glutaraldehyde or formaldehyde.
- 5. a kind of oral albumin nano granular in intestines and stomach with high stability according to claim 1, its feature It is:Described stabilizer is one kind in N-acetyl-L-cysteine, cysteine, TGA.
- 6. the system of the oral albumin nano granular in intestines and stomach with high stability according to any one of claims 1 to 5 Preparation Method, its feature are made up of following steps:The albumin aqueous solution mixes in equal volume with the organic solution of insoluble drug, incubates altogether After educating, then add the organic solvent equivalent to aqueous phase several times volume and be added dropwise in mixed liquor, add curing agent solidification 20h, it is evaporated under reduced pressure and removes organic solvent, add deionized water to hang again, 0.45 μm of filtering with microporous membrane, produces the common white egg for carrying medicine White nanoparticle;Stabilizer is incorporated in the common albumin nano granular surface for carrying medicine by way of chemical modification again, that is, is made Intestines and stomach have the oral albumin nano granular of high stability.
- A kind of 7. preparation side of oral albumin nano granular in intestines and stomach with high stability according to claim 6 Method, it is characterised in that:Described stabilizer and the mol ratio of albumin are 360: 1~640: 1.
- A kind of 8. preparation side of oral albumin nano granular in intestines and stomach with high stability according to claim 6 Method, it is characterised in that:Described organic solvent is one kind in acetone, methanol, ethanol.
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CN109806241A (en) * | 2019-03-04 | 2019-05-28 | 聊城大学 | A kind of double medicine albumin nano granulars and preparation process |
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