CN113289024A - Medicine carrying nano-particles based on attapulgite - Google Patents

Medicine carrying nano-particles based on attapulgite Download PDF

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CN113289024A
CN113289024A CN202110630183.5A CN202110630183A CN113289024A CN 113289024 A CN113289024 A CN 113289024A CN 202110630183 A CN202110630183 A CN 202110630183A CN 113289024 A CN113289024 A CN 113289024A
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attapulgite
polyethylene glycol
drug
substrate
transporter
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CN113289024B (en
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刘艳
王骁潇
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Mingyao Attapulgite Industrial Technology Co ltd
Peking University
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Mingyao Attapulgite Industrial Technology Co ltd
Peking University
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    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds

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Abstract

The invention relates to the technical field of drug-loaded nano materials, in particular to drug-loaded nano particles based on attapulgite. The nanoparticle may comprise attapulgite, a poorly soluble drug, a crystallization inhibitor, a ligand for a specific receptor expressed by small intestinal epithelial cells and/or a substrate for a transporter, and optionally pharmaceutically acceptable excipients. The preparation method is simple and feasible, and the gastrointestinal tract stability is good. Experiments prove that the nano-particles can obviously improve the oral absorption of insoluble drugs, and provide a novel preparation strategy for the oral administration of the insoluble drugs.

Description

Medicine carrying nano-particles based on attapulgite
Technical Field
The invention relates to the technical field of drug-loaded nano materials, in particular to drug-loaded nano particles based on attapulgite.
Background
Oral administration is also the preferred route of administration for most drugs, particularly for the treatment of chronic diseases, because of its economy, safety, convenience, and good patient compliance. However, oral drugs need to be dissolved in the intestinal tract and absorbed into the blood before they can exert their therapeutic effects. At present, the structure of a candidate active compound is gradually complex, and about 70 percent of water solubility is extremely poor, so that the bioavailability is low, and the clinical efficacy of the candidate active compound is seriously influenced; the clinically applied therapeutic drugs are water-insoluble or indissolvable drugs up to 40-70%, and are often poorly absorbed, so that the therapeutic effect is poor, and only the cost of increasing the dosage and improving the curative effect is needed, which causes the increase of toxic and side effects and the increase of the administration cost. Therefore, improving the dissolution rate of the insoluble drug in the gastrointestinal tract and increasing the transmembrane transport of the drug become important links for improving the oral absorption of the insoluble drug, and are also the challenges and the problems to be solved in the current pharmaceutical field.
Various pharmaceutical techniques are used to improve the water solubility and oral absorption of poorly soluble drugs, including salt formation, the use of cosolvents, solubilizers, the preparation of inclusion compounds and solid dispersions, co-crystals, and the like. However, these conventional methods have various problems, such as that the drugs do not necessarily have salt-forming groups, that there are few usable latent solvents or cosolvents, that the solubilizing agents and the inclusion compounds have large toxic and side effects, that solid dispersions are easily aged, and the like, and thus it is difficult to fundamentally solve the problem of oral absorption of poorly soluble drugs. The emerging nanotechnology brings about eosin for solving the problem of oral absorption of insoluble drugs. The nanometer technology can reduce the size of the drug particles to nanometer level, and obviously increase the specific surface area of the drug particles, thereby accelerating the dissolution rate of the insoluble drug; the reduction of the particle size and the increase of the specific surface area of the medicament can also promote the contact of the medicament particles and a biological membrane, so that the dissolved medicament molecules and medicament microcrystals with special sizes are efficiently absorbed in the gastrointestinal tract. At present, the research for improving the oral absorption of insoluble drugs by using nanotechnology mainly focuses on: preparing new dosage forms such as nano crystal, solid lipid nano particle, polymer micelle and nano emulsion. The major disadvantages of these studies are low drug loading (often not sufficient for clinical dosing), inability to inhibit drug recrystallization or reaggregation, etc.
The attapulgite is a water-containing magnesium-rich aluminosilicate clay mineral material which is widely distributed in China, cheap and easily available, easy to exploit, good in quality, non-toxic and tasteless, has a needle-like rod crystal structure, has the characteristic of larger specific surface area and a special pore structure, and therefore has good adsorption performance; the surface is easy to modify; has good thermal stability and chemical stability; easy compounding with other materials, etc.
Therefore, the technical problem to be solved in the field is how to provide the drug-loaded nano-particles based on the attapulgite, and the attapulgite is used as a nano-carrier system of the insoluble drug to improve the absorption rate of oral administration.
Disclosure of Invention
In view of the above, the invention provides the drug-loaded nano-particles based on the attapulgite, and the drug-loaded nano-particles have the advantages of low preparation cost and simple process, and can improve the absorption rate of oral administration.
In order to achieve the purpose, the invention adopts the following technical scheme:
the drug-loaded nano-particles based on the attapulgite are prepared from the following raw materials: attapulgite, insoluble drugs and crystallization inhibitors.
Preferably, the length of the attapulgite is 0.1-5 μm, the diameter is 10-70 nm, and the aperture is 2-50 nm; wherein the attapulgite is unmodified attapulgite or modified attapulgite, and the modification adopts a ligand of a specific receptor expressed by small intestine epithelial cells and/or a substrate of a transporter for modification.
Preferably, the ligand of the specific receptor expressed by the small intestine epithelial cell is one or more of a ligand of transferrin receptor, a ligand of neonatal Fc receptor (FcRn), a ligand of folate receptor, a ligand of epidermal growth factor receptor EGFR, and a ligand of integrin receptor α v β 3.
Preferably, the substrate of the transporter expressed by the small intestinal epithelial cell is one or more of a substrate of an oligopeptide transporter PepT1, a substrate of an organic cation transporter OCT, a substrate of an organic cation/carnitine transporter OCTNs, a substrate of an organic anion transporter OATs, a substrate of a monocarboxylic acid transporter MCT, a substrate of an amino acid transporter LAT, a substrate of a bile acid transporter and a substrate of a glucose transporter;
wherein, the transporter substrate needs to be coupled with PEG in the process of modifying by adopting the transporter substrate, and the molecular weight of the PEG is 600-20000.
Preferably, the substrate content of the ligand and/or transporter of the specific receptor expressed by the small intestine epithelial cells accounts for 1-20% of the weight of the attapulgite.
Preferably, the slightly soluble drug is one of paclitaxel, docetaxel, 9-nitrocamptothecin, 10-hydroxycamptothecin drug, itraconazole, teniposide, etoposide, doxorubicin, curcumin, honokiol, cyclosporine A, tacrolimus, ibuprofen, budesonide, fluorometholone, phentermine, dexamethasone, cortisone acetate, fluticasone propionate, silybin, silymarin, alcoradine, aprepitant and fenofibrate.
Preferably, the crystallization inhibitor is hydroxypropyl methylcellulose, hydroxypropyl cellulose, Soluplus, PEG-DSPE, poloxamer, polyethylene glycol vitamin E succinate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyvinylpyrrolidone, one or more of polyethylene glycol, polyvinyl alcohol, poly (2-ethyl-2-oxazoline), polyethylene glycol-b-polylactic acid, polyethylene glycol-b-polylactic glycolic acid, polyethylene glycol-b-polycaprolactone, polyethylene glycol-b-polylactic acid-b-polyethylene glycol, polyethylene glycol-b-polycaprolactone-b-polyethylene glycol and polymethacrylic acid resin.
Preferably, the weight ratio of the slightly soluble medicament to the attapulgite is 1: 10-10: 1.
preferably, the weight ratio of the insoluble drug to the crystallization inhibitor is 1: 0-10.
The crystallization inhibitor can inhibit the growth of the drug particles in the attapulgite, so that the drug exists in an amorphous form to improve the solubility of the drug. The modified attapulgite can improve the oral absorption of the medicine to a greater extent.
According to the technical scheme, compared with the prior art, the invention has the following beneficial effects:
1) the attapulgite-based drug-loaded nanoparticles prepared by the invention release slowly for a long time, have better slow release characteristics and have better stability in gastrointestinal tracts;
2) the drug-loaded nano-particles based on the attapulgite have low cytotoxicity, and the biocompatibility is good;
3) the drug-loaded nano-particles based on the attapulgite can obviously improve the oral absorption of insoluble drugs, and the modified nano-particles have better absorption promoting effect.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.
FIG. 1 is a transmission electron micrograph of example 2;
FIG. 2 is a transmission electron micrograph of example 9;
FIG. 3 is a graph showing in vitro release profile in simulated gastric fluid;
FIG. 4 is a graph showing in vitro release profiles in simulated intestinal fluid;
FIG. 5 is a graph showing the cytotoxicity results of attapulgite;
FIG. 6 is a graph showing the time course of administration.
Detailed Description
The invention provides a drug-loaded nano particle based on attapulgite, which is prepared from the following raw materials: attapulgite, insoluble drugs and crystallization inhibitors.
In the invention, the length of the attapulgite is 0.1-5 μm, the diameter is 10-70 nm, and the aperture is 2-50 nm; preferably, the length of the attapulgite is 1-3 mu m, the diameter is 30-60 nm, and the aperture is 10-40 nm; more preferably, the attapulgite has a length of 2 μm, a diameter of 50nm and a pore diameter of 25 nm.
In the invention, the attapulgite is unmodified attapulgite or modified attapulgite, and preferably, the modification adopts the substrate modification of a ligand and/or a transporter of a specific receptor expressed by small intestine epithelial cells.
In the invention, the ligand of the specific receptor expressed by the small intestine epithelial cells is one or more of a ligand of a transferrin receptor, a ligand of a neonatal Fc receptor (FcRn), a ligand of a folate receptor, a ligand of an epidermal growth factor receptor EGFR and a ligand of an integrin receptor alpha v beta 3, and preferably one or more of transferrin, FcBP, folic acid, EGF and RGD.
In the invention, the substrate of the transporter expressed by the small intestinal epithelial cell is one or more of a substrate of an oligopeptide transporter PepT1, a substrate of an organic cation transporter OCT, a substrate of an organic cation/carnitine transporter OCTNs, a substrate of an organic anion transporter OATs, a substrate of a monocarboxylic acid transporter MCT, a substrate of an amino acid transporter LAT, a substrate of a bile acid transporter and a substrate of a glucose transporter, and is preferably choline, carnitine, taurocholate, salicylic acid, amino acid or deoxycholic acid;
in the invention, the transporter substrate needs to be coupled with PEG in the process of modifying by adopting the transporter substrate, and the molecular weight of the PEG is 600-20000, preferably 1000-10000, further preferably 2000-5000 and most preferably 2000.
In the invention, the substrate content of the ligand and/or transporter of the specific receptor expressed by the small intestine epithelial cells accounts for 1-20% of the weight of the attapulgite, and preferably 5-15%. More preferably 10 to 15%.
In the invention, the slightly soluble drug is one of paclitaxel, docetaxel, 9-nitrocamptothecin, 10-hydroxycamptothecin drug, itraconazole, teniposide, etoposide, adriamycin, curcumin, honokiol, cyclosporine A, tacrolimus, ibuprofen, budesonide, fluorometholone, phentermine, dexamethasone, cortisone acetate, fluticasone propionate, silybin, silymarin, alcoradine, aprepitant and fenofibrate, preferably one of alcoradine, paclitaxel, docetaxel, honokiol, cyclosporine A and tacrolimus.
In the invention, the crystallization inhibitor is one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, Soluplus, PEG-DSPE, poloxamer, polyethylene glycol vitamin E succinate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, poly (2-ethyl-2-oxazoline), polyethylene glycol-b-polylactic acid, polyethylene glycol-b-polylactic glycolic acid, polyethylene glycol-b-polycaprolactone, polyethylene glycol-b-polylactic acid-b-polyethylene glycol, polyethylene glycol-b-polylactic glycolic acid-b-polyethylene glycol, polyethylene glycol-b-polycaprolactone-b-polyethylene glycol and polymethacrylic resin, preferably hydroxypropyl methylcellulose, hydroxypropyl cellulose, Soluplus, PEG-DSPE, poloxamer, polyethylene glycol vitamin E succinate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, and more preferably hydroxypropyl methylcellulose, Soluplus, PEG-DSPE, and poloxamer.
In the invention, the weight ratio of the slightly soluble medicament to the attapulgite is 1: 10-10: 1, preferably 1:7 to 7:1, and more preferably 3: 1.
In the present invention, the weight ratio of the poorly soluble drug to the crystallization inhibitor is 1:0 to 10, preferably 1:0.3 to 3, and more preferably 1: 1.
The invention also provides a preparation method of the drug-loaded nano-particles based on the attapulgite, which comprises an adsorption equilibrium method, a solvent volatilizing method, a melting method and the like.
The invention also provides application of the drug-loaded nano-particles based on the attapulgite, and particularly can be prepared into various oral preparations according to a conventional method, preferably oral liquid, tablets, capsules and granules.
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
Preparation of paclitaxel-loaded nano-particles based on attapulgite
A preparation method of paclitaxel-loaded nano-particles based on attapulgite comprises the following steps: adding 10mg of attapulgite into 10mL of methanol solution containing 20mg of paclitaxel, ultrasonically dispersing for 10 minutes, stirring at room temperature for 12 hours, filtering, and drying under reduced pressure for 10 hours to obtain the paclitaxel-loaded nanoparticles based on attapulgite. The drug loading was 12.6%.
Example 2
Preparation of paclitaxel-loaded nano-particles based on attapulgite
A preparation method of paclitaxel-loaded nano-particles based on attapulgite comprises the following steps: adding 10mg of attapulgite into 10mL of ethanol solution containing 30mg of paclitaxel and 30mg of Soluplus, ultrasonically dispersing for 10 minutes, stirring for 12 hours at room temperature, filtering, and drying under reduced pressure for 10 hours to obtain the paclitaxel-loaded nanoparticles based on attapulgite. The drug loading was 19.1%.
The transmission electron microscope image of the paclitaxel-loaded nanoparticles based on attapulgite prepared in this example is shown in FIG. 1.
Example 3
Preparation of curcumin-loaded nanoparticles based on attapulgite
A preparation method of curcumin-loaded nanoparticles based on attapulgite comprises the following steps: adding 20mg of attapulgite into 3mL of dichloromethane solution containing 10mg of curcumin, ultrasonically dispersing for 10 minutes, stirring for 3 hours at room temperature, standing overnight and volatilizing to obtain the attapulgite-based curcumin-loaded nanoparticle. The drug loading was 6.2%.
Example 4
Preparation of curcumin-loaded nanoparticles based on attapulgite
A preparation method of curcumin-loaded nanoparticles based on attapulgite comprises the following steps: adding 10mg of attapulgite into 10mL of tetrahydrofuran solution containing 1mg of curcumin, performing ultrasonic dispersion for 10 minutes, stirring at room temperature for 12 hours, centrifuging at 5000rpm for 10 minutes, and drying under reduced pressure for 10 hours to obtain the curcumin-loaded nanoparticles based on the attapulgite. The drug loading was 3.9%.
Example 5
Preparation of curcumin-loaded nanoparticles based on attapulgite
A preparation method of curcumin-loaded nanoparticles based on attapulgite comprises the following steps: adding 2mg of attapulgite into 20mL of tetrahydrofuran solution containing 20mg of curcumin and 10mg of HPMC, ultrasonically dispersing for 10 minutes, stirring for 12 hours at room temperature, centrifuging for 10 minutes at 5000rpm, and drying for 10 hours under reduced pressure to obtain the curcumin-loaded nano-particles based on the attapulgite. The drug loading was 39.8%.
Example 6
Preparation of cyclosporine A-carrying nano-particles based on attapulgite
A preparation method of cyclosporine A-carrying nano particles based on attapulgite comprises the following steps: adding 10mg of attapulgite into 2mL of ethanol solution containing 4mg of cyclosporine A and 40mg of Soluplus, ultrasonically dispersing for 10 minutes, stirring for 12 hours at room temperature, centrifuging for 10 minutes at 5000rpm, and drying for 10 hours under reduced pressure to obtain the cyclosporine A-carrying nano-particles based on the attapulgite. The drug loading was 12.2%.
Example 7
Preparation of attapulgite-based silybin-loaded nanoparticles
A preparation method of silibinin-loaded nanoparticles based on attapulgite comprises the following steps: mixing 30mg of attapulgite and 10mg of silybin, and keeping the temperature at 153 ℃ until the attapulgite and the silybin are melted. Taking out after 5 minutes, stirring at room temperature, keeping the temperature at 153 ℃, taking out after 5 minutes, transferring to an ice-bath aluminum plate for quenching, and storing the obtained solid in a dryer to obtain the attapulgite-based silybin-loaded nanoparticles. The drug loading was 10.2%.
Example 8
Preparation of silibinin-loaded nanoparticles based on deoxycholic acid modified attapulgite
A preparation method of silibinin-loaded nanoparticles based on deoxycholic acid modified attapulgite comprises the following steps:
(1) amination of Attapulgite
Dispersing 1G of attapulgite in 50mL of refined anhydrous toluene, performing ultrasonic treatment for 10min, dropwise adding 5mL of 3-Aminopropyltrimethoxysilane (APTES) under the protection of nitrogen, slowly heating, refluxing at 110 ℃ for 12h, filtering with a G4 sand core funnel, washing the precipitate with ethanol for 3 times, and fully drying the precipitate in a vacuum drying oven at 80 ℃ for 12h to obtain the aminated attapulgite.
(2) Coupling of deoxycholic acid with PEG
Precisely weighing 13.0mg Deoxycholic Acid (DA), 3.7mg hydroxysuccinimide (NHS) and 6.9mg Dicyclohexylcarbodiimide (DCC), dissolving in 20mLDMSO, stirring at 400rpm for 12h at room temperature, filtering, adding 45mg NH to the filtrate2And (3) stirring and reacting for 12h at room temperature and 800rpm, centrifuging for 5min at 13000rpm, and discarding the supernatant to obtain a precipitate, namely DA-PEG-COOH.
(3) Preparation of deoxycholic acid modified attapulgite
Precisely weighing 26.0mg of DA-PEG-COOH, 3.7mg of hydroxysuccinimide (NHS) and 6.9mg of Dicyclohexylcarbodiimide (DCC), dissolving in 20mLDMSO, stirring at room temperature and 400rpm for 12h, filtering, adding 45mg of aminated attapulgite into the filtrate, stirring at room temperature and 800rpm for reaction for 12h, centrifuging at 13000rpm for 5min, discarding the supernatant, and vacuum drying the obtained precipitate to obtain the deoxycholic acid modified attapulgite.
(4) Preparation of silibinin-loaded nanoparticles based on deoxycholic acid modified attapulgite
A preparation method of silibinin-loaded nanoparticles based on deoxycholic acid modified attapulgite comprises the following steps: adding 10mg of deoxycholic acid modified attapulgite into 10mL of ethanol solution containing 20mg of silybin and 20mg of Soluplus, ultrasonically dispersing for 10 minutes, stirring at room temperature for 12 hours, filtering, and drying under reduced pressure for 10 hours to obtain the deoxycholic acid modified attapulgite-based silybin-loaded nanoparticles. The drug loading was 14.7%.
Example 9
Preparation of paclitaxel-loaded nanoparticles based on glycocholic acid-modified attapulgite
A preparation method of paclitaxel-loaded nanoparticles based on glycocholic acid-modified attapulgite comprises the following steps:
(1) amination of Attapulgite
Dispersing 1G of attapulgite in 50mL of refined anhydrous toluene, performing ultrasonic treatment for 10min, dropwise adding 5mL of 3-Aminopropyltrimethoxysilane (APTES) under the protection of nitrogen, slowly heating, refluxing at 110 ℃ for 12h, filtering with a G4 sand core funnel, washing the precipitate with ethanol for 3 times, and fully drying the precipitate in a vacuum drying oven at 80 ℃ for 12h to obtain the aminated attapulgite.
(2) Coupling of Glycocholic acid with PEG
Precisely weighing 16.0mg of glycocholic acid (CG), 3.7mg of hydroxysuccinimide (NHS) and 6.9mg of Dicyclohexylcarbodiimide (DCC), dissolving in 20mLDMSO, stirring at room temperature and 400rpm for 12h, filtering, adding 45mg of NH2-PEG-COOH into the filtrate, stirring at room temperature and 800rpm for reaction for 12h, centrifuging at 13000rpm for 5min, discarding the supernatant, and obtaining the precipitate, namely CG-PEG-COOH.
(3) Preparation of glycocholic acid modified attapulgite
Accurately weighing 28.0mg of CG-PEG-COOH, 3.7mg of hydroxysuccinimide (NHS) and 6.9mg of Dicyclohexylcarbodiimide (DCC), dissolving in 20mLDMSO, stirring at room temperature and 400rpm for 12h, filtering, adding 45mg of aminated attapulgite into the filtrate, stirring at room temperature and 800rpm for reaction for 12h, centrifuging at 13000rpm for 5min, discarding the supernatant, and vacuum drying the obtained precipitate to obtain the glycocholic acid modified attapulgite.
(4) Preparation of paclitaxel-loaded nanoparticles based on glycocholic acid-modified attapulgite
Adding 10mg of glycocholic acid modified attapulgite (glycocholic acid modifier accounts for 6% of the modified attapulgite) into 10mL of ethanol solution containing 30mg of paclitaxel and 30mg of polyvinylpyrrolidone (PVPK30), ultrasonically dispersing for 10 minutes, stirring at room temperature for 12 hours, filtering, and drying under reduced pressure for 10 hours to obtain the paclitaxel-loaded nanoparticles based on the glycocholic acid modified attapulgite. The drug loading was 13.7%. The transmission electron micrograph of the paclitaxel-loaded nanoparticles based on attapulgite prepared in this example is shown in FIG. 2.
Example 10
Preparation of carnitine modified attapulgite-based alcalidine-loaded nanoparticles
A preparation method of an alcalidine-carrying nano-particle based on carnitine modified attapulgite comprises the following steps:
(1) coupling of carnitine to PEG
1g of HOOC-PEG-COOH was dissolved in 20mL of DMF under ice bath, 1.2 equivalents of EDCCl and 0.2 equivalents of DMAP were dissolved in 10mL of DMF, and the solution was added dropwise to the DMF solution of HOOC-PEG-COOH. After reacting for 30 minutes in ice bath, 1.1 equivalent of carnitine (Car) is dissolved in DMF, ultrasonic treatment is carried out, dropwise addition is carried out on the solution to a reaction system, reaction is carried out at room temperature for 48 hours, reaction liquid is collected, dialysis (MWCO ═ 1000) is carried out in water for 48 hours, and freeze-drying is carried out, so that purified Car-PEG-COOH is obtained.
(2) Preparation of carnitine modified attapulgite
Precisely weighing 13.0mg of Car-PEG-COOH, 3.7mg of hydroxysuccinimide (NHS) and 6.9mg of Dicyclohexylcarbodiimide (DCC), dissolving in 20mLDMSO, stirring at room temperature and 400rpm for 12h, filtering, adding 45mg of aminated attapulgite into the filtrate, stirring at room temperature and 800rpm for reaction for 12h, centrifuging at 13000rpm for 5min, discarding the supernatant, and drying the obtained precipitate in a vacuum drier to obtain the carnitine modified attapulgite.
(3) Preparation of carnitine modified attapulgite-based alcalidine-loaded nanoparticles
A preparation method of an alcalidine-carrying nano-particle based on carnitine modified attapulgite comprises the following steps: adding 10mg of carnitine modified attapulgite into 10mL of ethanol solution containing 25mg of alcaladine and 15mg of Soluplus, ultrasonically dispersing for 10 minutes, stirring for 12 hours at room temperature, filtering, and drying under reduced pressure for 10 hours to obtain the carnitine modified attapulgite loaded attapulgite nanoparticles. The drug loading was 13.8%.
Example 11
Preparation of transferrin modified attapulgite-based cyclosporine A-carrying nanoparticles
A preparation method of transferrin modified attapulgite-based cyclosporine A-carrying nanoparticles comprises the following steps:
(1) preparation method of transferrin modified attapulgite
Precisely weighing 13.0mg of transferrin, 3.7mg of hydroxysuccinimide (NHS) and 6.9mg of Dicyclohexylcarbodiimide (DCC), dissolving in 20mL of DMSO, stirring at room temperature and 400rpm for 12h, filtering, adding 45mg of aminated attapulgite into the filtrate, stirring at room temperature and 800rpm for reaction for 12h, centrifuging at 13000rpm for 5min, discarding the supernatant, and drying the obtained precipitate in a vacuum drier to obtain the transferrin-modified attapulgite.
(2) Preparation of transferrin modified attapulgite-based cyclosporine A-carrying nanoparticles
A preparation method of transferrin modified attapulgite-based cyclosporine A-carrying nanoparticles comprises the following steps: adding 20mg of attapulgite into 20mL of ethanol solution containing 40mg of cyclosporin A and 20mg of polyvinylpyrrolidone, ultrasonically dispersing for 10 minutes, stirring at room temperature for 12 hours, centrifuging at 5000rpm for 10 minutes, and drying under reduced pressure for 10 hours to obtain the transferrin-modified attapulgite-based cyclosporin A-loaded nanoparticles. The drug loading was 16.4%.
Example 12
Preparation of folic acid modified attapulgite-based honokiol-loaded nanoparticles
A preparation method of a honokiol-loaded nano-particle based on folic acid modified attapulgite comprises the following steps:
(1) preparation of folic acid modified attapulgite
Precisely weighing 13.0mg of folic acid, 3.7mg of hydroxysuccinimide (NHS) and 6.9mg of Dicyclohexylcarbodiimide (DCC), dissolving in 20mL of DMSO, stirring at room temperature and 400rpm for 12h, filtering, adding 45mg of aminated attapulgite into the filtrate, stirring at room temperature and 800rpm for reaction for 12h, centrifuging at 13000rpm for 5min, discarding the supernatant, and drying the obtained precipitate in a vacuum drier to obtain the folic acid modified attapulgite.
(2) Preparation of folic acid modified attapulgite-based honokiol-loaded nanoparticles
A preparation method of a honokiol-loaded nano-particle based on folic acid modified attapulgite comprises the following steps: adding 10mg folic acid modified attapulgite into 10mL ethanol solution containing 30mg honokiol and 30mg Soluplus, ultrasonically dispersing for 10 minutes, stirring for 12 hours at room temperature, filtering, and drying under reduced pressure for 10 hours to obtain the folic acid modified attapulgite-loaded honokiol nano-particles. The drug loading was 15.1%.
Test example 1
In vitro release assay
To evaluate the in vitro release properties of the attapulgite-based drug-loaded nanoparticles of the invention, the nanoparticles of examples 2 and 9 of the invention were examined as follows for their in vitro release in simulated gastrointestinal fluids, and the commercially available formulation Taxol was used as a control.
A dialysis bag method is adopted. Inventive example 2, example 9 and the commercial formulation Taxol (containing 0.15mg paclitaxel) were separately placed in activated dialysis bags (MWCO: 8000- + 14000) and sealed with dialysis clamps, and then placed in 30mL simulated gastric and intestinal fluids containing 0.1% Tween80, and shaken in a 37C, 100rpm water bath shaker, with each sample run in triplicate. 0.5mL of release medium was withdrawn at 1, 2, 4, 8, 12 and 24h, respectively, while being replenished with 0.5mL of fresh release medium. The release medium taken out at each time point was filtered through a 0.22m filter membrane, and the content of paclitaxel was measured by RP-HPLC method, and the cumulative release percentage of the drug was calculated to plot the release curve.
The chromatographic conditions were as follows: diambosil ODSC18 column, 250X 4.6mm, 5 μm; mobile phase: acetonitrile water ═ 2: 1; flow rate: 1 mL/min; column temperature: 50 ℃; detection wavelength: 227 nm; sample introduction amount: 20 μ L.
The release curves are shown in fig. 3 and 4. Comparing the release curves of the three groups shows that the two groups of attapulgite-based drug-loaded nanoparticles release slightly faster initially than the Taxol group in simulated gastric fluid or simulated intestinal fluid, which may be caused by the burst release of paclitaxel adsorbed on the outer surface of the attapulgite. The release of example 2 and example 9 was slower over time, especially the release of example 9 was slower. The result shows that the attapulgite-based paclitaxel-loaded nano particles prepared by the invention have better sustained release property and better stability in gastrointestinal tract.
Test example 2
Biocompatibility test of Attapulgite
The method for determining the influence of the attapulgite on the Caco-2 cell survival rate by adopting an MTT method comprises the following specific experimental steps:
(1) the Caco-2 cells were cultured in DMEM complete medium, and the flasks were incubated at 37 ℃ with 5% CO2And the relative humidity is 90 percent. When the confluency of the cells reaches more than 80%, the cells are digested and counted. Cells were diluted to a density of 5X 10 with DMEM complete medium4The cells were suspended at a concentration of 200. mu.L/mL in a 96-well plate, and 200. mu.L of PBS was added to the wells around the 96-well plate, followed by incubation for 36 hours.
(2) Absorbing and discarding the culture solution, respectively adding culture medium suspension of attapulgite with different concentrations, 200 μ L per well to make the final concentration of the attapulgite be 0.25, 0.5, 1.0, 2.0, 4.0, 8.0 and 12mg/mL, setting 6 multiple wells per concentration, adding 200 μ L DMEM complete culture medium per well of a blank control group, incubating for 24h, absorbing the culture medium, adding DMEM complete culture medium containing 10% MTT per well, and continuing incubating for 4 h.
(3) And (3) absorbing the culture solution in the 96-well plate, adding 200L of DMSO solution into each well, oscillating for 15min to ensure that crystals are fully and uniformly dissolved, measuring the OD value of each well at 490nm by using an enzyme-labeling instrument, and calculating the relative survival rate of the cells.
FIG. 5 shows the result of examining cytotoxicity of attapulgite by MTT method. The cytotoxicity of attapulgite shows a certain concentration dependence. As can be seen from the results of the cell survival rate experiments, the cell survival rate is still over 80 percent even if the concentration of the attapulgite is increased to 12 mg/mL. Therefore, the biocompatibility of the attapulgite is better.
Test example 3
Pharmacokinetic testing
In order to evaluate the oral absorption of the inventive attapulgite-based drug-loaded nanoparticles, pharmacokinetic experiments were carried out on the inventive nanoparticles as follows.
15 male SD rats (300 + -20 g) were randomly divided into three groups, i.e., a Taxol group, an example 2 group and an example 9 group. Fasting for 12h before experiment, free drinking water can be provided. The administration dosage by intragastric administration is 15 mg/kg. Serum was obtained by centrifugation at 8000rpm for 15min from 0.5mL of blood taken from the retro-orbital venous plexus of rat to heparinized EP tubes at 0.25, 0.5, 1, 2, 3, 4, 8, 12, 24, 48h timing before and at 0.25, 0.5, 1, 2, 3, 4, 8, 12, 24, 48h timing, respectively. Precisely sucking 100 μ L into a 5mL LEP tube, adding 10 μ L (300 μ g/mL) of diazepam as an internal standard solution and 3mL of tert-butyl methyl ether, vortexing for 5min, and centrifuging at 1000rpm for 15 min. Taking 1mL of supernatant, drying by nitrogen, adding 100 mu L of methanol for redissolving, filtering by a 0.2 mu m filter membrane, and measuring the concentration of the medicine in the blood by adopting an RP-HPLC method.
The chromatographic conditions were as follows: the chromatographic conditions were as follows: diambosil ODSC18 column, 250X 4.6mm, 5 μm; mobile phase: acetonitrile water ═ 1: 1; flow rate: 1 mL/min; column temperature: 50 ℃; detection wavelength: 227 nm; sample introduction amount: 20 μ L.
The time course of the drug is shown in FIG. 6. The results show that compared with the Taxol group, the peak values of the blood concentration of the groups of example 2 and example 9 are respectively improved by 1.9 and 3.9 times, and the AUC values are respectively improved by 3.7 times and 10.5 times; the peak value of the blood concentration of the group in the example 9 is improved by 2.1 times compared with the group in the example 2, and the AUC is improved by 2.9 times. Therefore, the attapulgite-based nanoparticles can obviously improve the oral absorption of paclitaxel, and the substrate-modified nanoparticles have better absorption promoting effect, thereby showing the superiority of the attapulgite-based nanoparticles.
The embodiments in the present description are described in a progressive manner, each embodiment focuses on differences from other embodiments, and the same and similar parts among the embodiments are referred to each other.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.

Claims (9)

1. The drug-loaded nano-particles based on the attapulgite are characterized by comprising the following raw materials: attapulgite, insoluble drugs and crystallization inhibitors.
2. The drug-loaded nanoparticle based on attapulgite according to claim 1, characterized in that the attapulgite has a length of 0.1-5 μm, a diameter of 10-70 nm and a pore diameter of 2-50 nm; the attapulgite is unmodified attapulgite or modified attapulgite, and the modification adopts the substrate modification of a ligand of a specific receptor and/or a transporter expressed by small intestine epithelial cells.
3. The attapulgite-based drug-loaded nanoparticle according to claim 2, wherein the ligand of the specific receptor expressed by the small intestine epithelial cells is one or more of a ligand of transferrin receptor, a ligand of neonatal Fc receptor (FcRn), a ligand of folate receptor, a ligand of epidermal growth factor receptor EGFR, and a ligand of integrin receptor α v β 3.
4. The attapulgite-based drug-loaded nanoparticle according to claim 2, wherein the substrate of the transporter expressed by the small intestinal epithelial cells is one or more of a substrate of oligopeptide transporter PepT1, a substrate of organic cation transporter OCT, a substrate of organic cation/carnitine transporter OCTNs, a substrate of organic anion transporter OATs, a substrate of monocarboxylic acid transporter MCT, a substrate of amino acid transporter LAT, a substrate of bile acid transporter, and a substrate of glucose transporter;
wherein, the transporter substrate needs to be coupled with PEG in the process of modifying by adopting the transporter substrate, and the molecular weight of the PEG is 600-20000.
5. The attapulgite-based drug-loaded nanoparticle according to any one of claims 1 to 4, wherein the substrate content of the ligand and/or transporter of the specific receptor expressed by the small intestine epithelial cells accounts for 1 to 20 percent of the weight of the attapulgite.
6. The attapulgite-based drug-loaded nanoparticle according to any one of claims 1 to 4, wherein the poorly soluble drug is one of paclitaxel, docetaxel, 9-nitrocamptothecin, 10-hydroxycamptothecin drug, itraconazole, teniposide, etoposide, doxorubicin, curcumin, honokiol, cyclosporin A, tacrolimus, ibuprofen, budesonide, fluorometholone, phentermine, dexamethasone, cortisone acetate, fluticasone propionate, silybin, silymarin, alcoradine, aprepitant and fenofibrate.
7. The drug-loaded nanoparticle based on attapulgite according to claims 1-4, characterized in that the crystallization inhibitor is hydroxypropyl methylcellulose, hydroxypropyl cellulose, Soluplus, PEG-DSPE, poloxamer, polyethylene glycol vitamin E succinate, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyvinylpyrrolidone, polyethylene glycol, polyvinyl alcohol, poly (2-ethyl-2-oxazoline), polyethylene glycol-b-polylactic acid, polyethylene glycol-b-polylactic glycolic acid, polyethylene glycol-b-polycaprolactone, polyethylene glycol-b-polylactic acid-b-polyethylene glycol, polyethylene glycol-b-polycaprolactone-b-polyethylene glycol, polyethylene glycol-b-polycaprolactone-b-polyethylene glycol, polyethylene glycol-b-2-polyethylene glycol, polyethylene glycol-b-polyethylene glycol, polyethylene glycol-b-polycaprolactone-b-polyethylene glycol, and the like, One or more of polymethacrylic resin.
8. The attapulgite-based drug-loaded nanoparticle according to claim 6, wherein the weight ratio of the slightly soluble drug to the attapulgite is 1: 10-10: 1.
9. the attapulgite-based drug-loaded nanoparticle according to claim 7, wherein the weight ratio of the poorly soluble drug to the crystallization inhibitor is 1: 0-10.
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