CN1290505C - pH sensing controlable nanometer particle carried with 5-Fu and its prepn. method - Google Patents
pH sensing controlable nanometer particle carried with 5-Fu and its prepn. method Download PDFInfo
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- CN1290505C CN1290505C CN 200510014552 CN200510014552A CN1290505C CN 1290505 C CN1290505 C CN 1290505C CN 200510014552 CN200510014552 CN 200510014552 CN 200510014552 A CN200510014552 A CN 200510014552A CN 1290505 C CN1290505 C CN 1290505C
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- pullulan
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- sulfadimethoxine
- fluorouracil
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Abstract
The present invention discloses a pH sensing controllable nanometer particle carrying 5-fluorouracil medicine and a preparation method thereof. The nanometer particle is in a structure in the shape of a nuclear shell of which the shell material is modified pullulan-sulfadimethoxine and the nuclear material is the acetyl portion of modified pullulan; the nanometer particle carrying medicine is consumingly accumulated and releases the medicine when pH is about 6.6 to 6.9, and realizes slow release and maintains granularity when pH is no less than 7.4; the encapsulation efficiency of the medicine is more than 80%. The method comprises the following steps: pullulan is dissolved in formamide solution in which hydrophobic modification is carried out; sulfadimethoxine is grafted in anhydrous 1, 4 dioxane; the prepared and modified pullulan-sulfadimethoxine and 5-fluorouracil are dissolved and dialyzed in dimethyl sulfoxide to form the nanometer particle carrying medicine. The present invention has the advantages that the water solubility of 5-fluorouracil is increased; the controllable release of medicine under the condition of specific pH value is easily realized by changing the conditions of the grafting extent of sulfadimethoxine, etc.; the preparation process is simple, and the particle is an ideal carrier of 5-fluorouracil.
Description
Technical field
The present invention relates to the responsive controllable release nanoparticle of pH and the preparation method of a kind of year 5-fluorouracil medicine, belong to and be used to wrap the nanoparticle technology of carrying 5-fluorouracil.
Background technology
5-fluorouracil (5-Fluorouracil is abbreviated as 5-FU) is one of chemotherapeutic agent the earliest, and nineteen fifty-seven is synthetic by Heidelberger, is the fluoride of miazines, belongs to the antimetabolic antineoplastic agent, to proliferative cell is every lethal effect is arranged all.The clinical breast carcinoma that is mainly used in, colon cancer, rectal cancer, gastric cancer, hepatocarcinoma, ovarian cancer, cervical cancer, bladder cancer, carcinoma of prostate and tumor of head and neck etc. are the first-line treatment medicines of multiple malignant tumor, also can be used as radiocurable sensitizer.Topical application can also be treated basal cell carcinoma and some pernicious dermatosis.But metabolism is fast in vivo for it, and the half-life is short, only is 5-10min; Clinically in order to reach blood drug level in the effective body, often adopt heavy dose of, continue medication or approach such as repeated multiple times administration, because 5-fluorouracil causes patient is produced as inappetence to normal cell and sick cell identification rate variance, feels sick, vomiting, stomatitis, gastritis, stomachache, diarrhoea, hemafecia can appear in severe patient; Bone marrow depression is main toxicity, shows as leukopenia, thrombocytopenia and anemia; Alopecia, fingernail changes, dermatitis, toxic and side effects such as skin pigment increase.In order to improve drug effect, reduce clinical using dosage, prolong delivery time, reduce the side effect of medicine to human body, improve the quality of life of patient at chemotherapeutic period, development 5-fluorouracil controllable release nano-carrier has high clinical value.
As the nanoparticle of pharmaceutical carrier, be the solid colloid granule of particle diameter between 10-1000nm.As pharmaceutical carrier, the nano-grade size owing to carrier has can make medicine escape from engulfing of macrophage with nanoparticle.Nanoparticle has amphipathic nucleocapsid structure, pharmaceutical pack is wrapped among the hydrophobic kernel, thereby, hydrophilic shell can increase the dissolubility of insoluble drug greatly at aqueous phase and having good water-solubility, and suspendible or be wrapped in insoluble drug in the nanoparticle when stripping owing to have the surface area increase that nano level particle size contacts with dissolution medium, so can greatly improve the bioavailability of medicine in aqueous environment, promptly improve drug effect.Because the pH value of tumor cell liquid is a little less than normal cell, be faintly acid (pH ≈ 6.8), if can carry out finishing to pharmaceutical carrier, make carrier under the situation of normal body fluid pH value, keep nano-scale particle size and reduce releasability, and when tumor cell liquid pH, also discharge strongly a large amount of the gathering, just can reach controllable release effect with good targeting.5-fluorouracil is poorly soluble in water, and bioavailability is low, and the pair cell identity is poor, if 5-fluorouracil is carried in the nano-carrier of the pH of surface modification sensitivity, can significantly improve its dissolubility, increase its bioavailability, realize having the controllable release of targeting.
Summary of the invention
The object of the present invention is to provide the responsive controllable release nanoparticle of pH and the preparation method of a kind of year 5-fluorouracil medicine.The bag that makes according to this technology carries the controllable release characteristic that nanoparticle has the pH sensitivity.Its preparation method is simple.
The present invention is realized by following technical proposals; the nanoparticle of the responsive controllable release of the pH of a kind of year 5-fluorouracil medicine; it is characterized in that this nanoparticle is the hud typed structure of 50-200nm; its shell material is modification Pullulan-sulfadimethoxine; its nuclear material is the acetyl group part of modification Pullulan; drug-carrying nanometer particle is in the strong gathering of pH=6.6-6.9 and discharge medicine, and realizes slow release and keep granularity that its entrapment efficiency is more than 80% more than pH=7.4.
The preparation method of above-mentioned drug-carrying nanometer particle is characterized in that comprising following process:
1. the Pullulan of molecular weight at 100000-200000 is dissolved in the formamide solution, be prepared into the solution that concentration is 10-15%, adding acetic anhydride in this solution carries out hydrophobically modified to Pullulan, the weight ratio of Pullulan and acetic anhydride is 1: 3-1: 5 reaction temperatures are controlled at 50-54 ℃, response time 48-50 hour, precipitate obtained the modification Pullulan behind cyclic washing.
2. above-mentioned modification Pullulan is dissolved in anhydrous 1; the 4-dioxane is prepared into the solution that concentration is 10-20%; and with succinic anhydride, dimethyl aminopyridine, triethylamine add in the above-mentioned solution; its weight ratio is 10-12: 8-11: 8-10; its amount is 1 with the Pullulan weight ratio: 1-1.2, and reaction is 24-28 hour under nitrogen protection, and gained solution is removed 1 through Rotary Evaporators; the 4-dioxane, and with removing unreacted reactant in the raffinate in the carbon tetrachloride.Above-mentioned solution is concentrated into 100-150ml with Rotary Evaporators, puts it into then in 2-4 ℃ the ether and precipitate, gained is deposited in 30-40 ℃ of following vacuum drying.Is that 19-21: 5-7: 4-6: 2-4 joins in the anhydrous dimethyl sulphoxide with above-mentioned precipitate and sulfadimethoxine, carbonization dicyclohexyl imines and N-Hydroxysuccinimide by its weight ratio; reaction is 24 hours under room temperature; the gained reactant mixture removes by filter precipitation; gained solution was through distill water dialysis three days; then gained solution is obtained product after three lyophilizing-thaw-freeze dried purge process, i.e. acetylation Pullulan-sulfadimethoxine.
3. the preparation of drug-carrying nanometer particle is dissolved in dimethyl sulfoxide with modification Pullulan-sulfadimethoxine and 5-fluorouracil, dialyses in aqueous solution with dialysis, removes and obtains the medicament-carried nano hydrogel solution that self assembly forms after the organic facies.The lyophilization of gained solution is obtained the drug-carrying nanometer particle powder.
The invention has the advantages that this modification Pullulan-sulfadimethoxine can be in water self assembly form the nanoparticle of constitutionally stable nucleocapsid structure, 5-fluorouracil and hydrophobic acetyl group partly gather nucleation, Pullulan-sulfadimethoxine forms hydrophilic shell, has increased dissolubility and the bioavailability of 5-FU greatly; And the drug-carrying nanometer particle that grafted sulfadimethoxine can make preparation is pH=6.6-6.9 (be tumor cell liquid pH value near), assembles strongly and discharges medicine, and realize slow release and keep granularity (be normal cell liquid pH value near) more than the pH=7.4; This nano-carrier entrapment efficiency height, drug loading is big, and its entrapment efficiency is more than 80%; Carrier prepared in accordance with the present invention is lyophilized into powder rear stability height, and it is convenient to be easy to preserve, to transport, use; Used toxic reagent is few during the preparation carrier, and preparation technology is simple; Biological degradability and bioavailability are good, are the ideal carriers of 5-fluorouracil.
Description of drawings
Fig. 1 is for pressing year 5-fluorouracil nanoparticle stereoscan photograph of embodiment one method preparation.
Fig. 2 is year release in vitro curve chart of 5-fluorouracil nanoparticle under different pH value of modifying without sulfadimethoxine.
Year release in vitro curve chart of 5-fluorouracil nanoparticle under different pH value that Fig. 3 modifies for sulfadimethoxine.
Fig. 4 sulfadimethoxine grafting for a change amount to carry the 5-fluorouracil nanoparticle under different pH value external release influence graph of relation.
The specific embodiment
Embodiment one:
1. Pullulan modification
Get in the formamide solution that the 2g Pullulan is dissolved in 20ml, and 60ml pyridine and 150ml acetic anhydride are added in this solution, under 54 ℃, reacted 48 hours.With gained solution redeposition in distilled water, after methanol solution washing drying, get white powder, i.e. acetylation Pullulan.
2. grafting sulfadimethoxine
2.1. 5g acetylation Pullulan is dissolved in 1; the 4-dioxane; and with the 2.2g succinic anhydride; 2.0g dimethyl aminopyridine; 1.8g triethylamine adds in the above-mentioned solution, reaction is 24 hours under nitrogen protection, and gained solution is removed 1 through Rotary Evaporators; the 4-dioxane, and remove unreacted succinic anhydride in the raffinate in the carbon tetrachloride with 300mL.Above-mentioned solution is concentrated into 150ml with Rotary Evaporators, puts it into then in 4 ℃ the ether and precipitate, gained was precipitated vacuum drying 24 hours.
2.2. with above-mentioned precipitate of 1g and 300mg sulfadimethoxine, 250mg carbonization dicyclohexyl imines, the 150mg N-Hydroxysuccinimide joins in the 40mL anhydrous dimethyl sulphoxide, and reaction is 24 hours under room temperature.The gained reactant mixture removes by filter precipitation, and gained solution is through distill water dialysis three days, then gained solution is obtained product after three lyophilizing-thaw-freeze dried purge process, i.e. acetylation Pullulan-sulfadimethoxine.
3. carry the preparation of nanoparticle
20mg5-fluorouracil and 50mg acetylation Pullulan-sulfadimethoxine are dissolved in the 20ml dimethyl sulfoxide; then this mixed solution was put into the molecular weight that dams and is in 15000 the bag filter dialysis three days; gained solution is filtered through 0.45 μ m filter membrane, promptly get the nano granule powder that carries 5-fluorouracil after the lyophilization.Nanoparticle mean diameter 110nm, good sphericity.
Embodiment two:
To can make year 5-fluorouracil nanoparticle of modifying without the responsive group of pH sulfadimethoxine by the 3rd one step process among the embodiment one by prepared acetylation Pullulan of first step method among the embodiment one and 5-fluorouracil; is respectively at pH=6.0 with the above-mentioned drug-carrying nanometer particle of 20mg under 37 ℃ in temperature; 6.8; 7.4; 8.2 buffer in carry out extracorporeal releasing test, release profiles is as shown in Figure 1.As seen from Figure 1, the total burst size of 5-fluorouracil under different pH value is roughly the same, and average 65% (18 hours) there is no obvious pH sensitivity, but reached certain slow release effect.
Embodiment three:
With 20mg by the made drug-carrying nanometer particle of embodiment one method temperature be under 37 ℃ respectively at pH=6.0, carry out extracorporeal releasing test in 6.8,7.4,8.2 the buffer, release profiles as shown in Figure 2.As seen from Figure 2,5-fluorouracil is jumped to 83.12% of 80.72% and the pH=6.0 of pH=6.8 by 69.94% of 62.92% and the pH=7.4 of pH=8.2 total burst size of 18 hours, has shown very strong pH sensitivity.
Embodiment four:
With embodiment one second in the step amount of sulfadimethoxine increase to 500mg, and can make the drug-carrying nanometer particle of higher sulfadimethoxine grafting amount by same procedure.With above-mentioned drug-carrying nanometer particle temperature be under 37 ℃ not in pH=6.0, carry out extracorporeal releasing test in 6.8,7.4,8.2 the buffer, release profiles as shown in Figure 3.As seen from Figure 3, with respect to the nanometer described in the example two, the drug-carrying nanometer particle that grain has increased sulfadimethoxine grafting amount is at pH=6.8 and had higher release amount of medicine at 6.0 o'clock, and slightly reduce on the contrary at pH=7.4 and 8.0 o'clock burst sizes, than the drug-carrying nanometer particle in example two shown stronger pH sensitivity.
Claims (2)
1. responsive controllable release nanoparticle of pH that carries the 5-fluorouracil medicine; it is characterized in that this nanoparticle is the hud typed structure of particle diameter at 50-200nm; its shell material is modification Pullulan-sulfadimethoxine; its nuclear material is the acetyl group part of modification Pullulan; drug-carrying nanometer particle is in the strong gathering of pH=6.6-6.9 and discharge medicine; and more than pH=7.4, realize slow release and keep granularity that its entrapment efficiency is more than 80%.
2. method for preparing by the described nanoparticle of claim 1 is characterized in that comprising following process:
1). the Pullulan of molecular weight at 100000-200000 is dissolved in the formamide solution, be prepared into the solution that concentration is 10-15%, adding acetic anhydride in this solution carries out hydrophobically modified to Pullulan, the weight ratio of Pullulan and acetic anhydride is 1: 3-1: 5, reaction temperature is controlled at 50-54 ℃, response time 48-50 hour, the gained precipitation obtained the modification Pullulan behind cyclic washing;
2). above-mentioned modification Pullulan is dissolved in exsiccant 1, the 4-dioxane is prepared into the solution that concentration is 10-20%, and with succinic anhydride, dimethyl aminopyridine, triethylamine adds in the above-mentioned solution, its weight ratio is 10-12: 8-11: 8-10, its amount is 1 with the Pullulan weight ratio: 1-1.2, reaction is 24-28 hour under nitrogen protection, gained solution is removed 1 through Rotary Evaporators, the 4-dioxane, and with removing unreacted reactant in the raffinate in the carbon tetrachloride, above-mentioned solution is concentrated into 100-150ml with Rotary Evaporators, put it into then in 2-4 ℃ the ether and precipitate, gained is deposited in 30-40 ℃ of following vacuum drying, with above-mentioned precipitate and sulfadimethoxine, carbonization dicyclohexyl imines, N-Hydroxysuccinimide is that 19-21: 5-7: 4-6: 2-4 joins in the anhydrous dimethyl sulphoxide by its weight ratio, reaction is 24 hours under room temperature, the gained reactant mixture removes by filter precipitation, gained solution is through distill water dialysis three days, then gained solution obtained product after three lyophilizing-thaw-freeze dried purge process, i.e. acetylation Pullulan-sulfadimethoxine;
3). the preparation of drug-carrying nanometer particle, modification Pullulan-sulfadimethoxine and 5-fluorouracil are dissolved in dimethyl sulfoxide, dialyse in aqueous solution with dialysis, remove and obtain the medicament-carried nano hydrogel solution that self assembly forms after the organic facies, the lyophilization of gained solution is obtained the drug-carrying nanometer particle powder.
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Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US10130587B2 (en) | 2011-01-11 | 2018-11-20 | Capsugel Belgium Nv | Hard capsules |
| CN107540761B (en) * | 2016-06-27 | 2020-08-11 | 中国科学院微生物研究所 | Acid-resistant pullulan polysaccharide derivative and preparation method thereof |
| US11576870B2 (en) | 2017-04-14 | 2023-02-14 | Capsugel Belgium Nv | Pullulan capsules |
| WO2018189587A1 (en) | 2017-04-14 | 2018-10-18 | Capsugel Belgium Nv | Process for making pullulan |
| CN109369625B (en) * | 2018-10-17 | 2020-08-04 | 安徽大学 | Ortho ester 5-fluorouracil prodrug molecule, preparation method thereof, acid-sensitive nanoparticle thereof and application |
| CN110384686B (en) * | 2019-07-02 | 2022-06-28 | 常州大学 | Preparation method of pH-responsive pentafluorouracil/mesoporous silica/pullulan oxide polysaccharide drug sustained-release system |
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