CN113289024B - Medicine carrying nano-particle based on attapulgite - Google Patents

Medicine carrying nano-particle based on attapulgite Download PDF

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CN113289024B
CN113289024B CN202110630183.5A CN202110630183A CN113289024B CN 113289024 B CN113289024 B CN 113289024B CN 202110630183 A CN202110630183 A CN 202110630183A CN 113289024 B CN113289024 B CN 113289024B
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attapulgite
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room temperature
glycocholic acid
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CN113289024A (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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    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
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    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
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    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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    • A61K9/141—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
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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 medicine-carrying nano materials, in particular to an attapulgite-based medicine-carrying nano particle. The nanoparticle may comprise attapulgite, poorly soluble drugs, crystallization inhibitors, ligands for specific receptors expressed by small intestine epithelial cells and/or substrates for transporters, optionally pharmaceutically acceptable excipients. The preparation method is simple and easy to implement, and has good gastrointestinal stability. Experiments prove that the nano particles can obviously improve the oral absorption of the insoluble medicine, and provide a novel preparation strategy for the oral administration of the insoluble medicine.

Description

Medicine carrying nano-particle based on attapulgite
Technical Field
The invention relates to the technical field of medicine-carrying nano materials, in particular to an attapulgite-based medicine-carrying nano particle.
Background
Oral administration is the optimal route of administration due to its economy, safety, convenience, and patient compliance, and is the preferred mode of administration for most drugs, especially for the treatment of chronic diseases. However, oral administration of drugs requires dissolution in the intestine and absorption into the blood for therapeutic efficacy. At present, candidate active compounds have increasingly complex structures, about 70% of the candidate active compounds have extremely poor water solubility, so that the bioavailability of the candidate active compounds is low, and the clinical efficacy of the candidate active compounds is seriously influenced; the clinical application of the medicine is as high as 40-70% of water insoluble or indissolvable medicine, the curative effect is poor due to small absorption, and the medicine can only be used at the cost of increasing the dosage and improving the curative effect, which causes the increase of toxic and side effects and the increase of the medication cost. Therefore, improving the dissolution rate of insoluble drugs in the gastrointestinal tract and increasing the transmembrane transport of drugs become important links for improving the oral absorption of the drugs, and are challenging and urgent difficulties facing the current pharmaceutical field.
Various pharmaceutical techniques are used to enhance the water solubility and oral absorption of poorly soluble drugs, including salifying, using latent solvents, co-solvents, solubilizing agents, preparing inclusion compounds and solid dispersions, co-crystals, and the like. However, these conventional methods have various problems such as the fact that the drugs do not necessarily have salt-forming groups, few usable latent solvents or cosolvents, large toxic and side effects of solubilizers and inclusion compounds, easy aging of solid dispersions, etc., and thus it is difficult to fundamentally solve the problem of oral absorption of poorly soluble drugs. Emerging nanotechnology brings the problem of oral absorption of poorly soluble drugs with the creation of dawn. The nano technology can reduce the size of the drug particles to nano level, and obviously increase the specific surface area of the drug particles, so that the dissolution rate of insoluble drugs can be accelerated; the decrease of the particle size and the increase of the specific surface area of the drug can promote the contact between the drug particles and the biological membrane, so that the dissolved drug molecules and drug microcrystals with special sizes are efficiently absorbed in the gastrointestinal tract. At present, the research of improving the oral absorption of insoluble drugs by nano technology is mainly focused on: and preparing new dosage forms such as nanocrystals, solid lipid nanoparticles, polymer micelles, nanoemulsions and the like. The main disadvantages of these studies are low drug loading (generally not satisfactory for clinical use), inability to inhibit drug recrystallization or reaggregation, etc.
The attapulgite is an aqueous magnesium-rich aluminosilicate clay mineral material which is widely distributed in China, is cheap and easy to obtain, is easy to mine, has good quality, is nontoxic and tasteless, has a needle-like rod crystal structure, has the characteristic of larger specific surface area and a special pore structure, and has good adsorption performance; the surface is easy to modify and modify; has good thermal stability and chemical stability; easy compounding with other materials, etc.
Therefore, how to provide a drug-loaded nanoparticle based on attapulgite, which uses attapulgite as a nano-carrier system of insoluble drugs, and improving the absorption rate of oral administration is a technical problem to be solved in the field.
Disclosure of Invention
In view of the above, the invention provides the medicine carrying nano-particles based on the attapulgite, which have lower preparation cost and simple process and can improve the absorption rate of oral administration.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the medicine carrying nano-particle based on the attapulgite is prepared from the following raw materials: attapulgite, insoluble drugs and crystallization inhibitors.
Preferably, the length of the attapulgite is 0.1-5 mu m, 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 is carried out by adopting a ligand of a specific receptor expressed by intestinal epithelial cells and/or a substrate of a transporter.
Preferably, the ligand of the specific receptor expressed by the small intestine epithelial cells is one or more of ligand of transferrin receptor, ligand of neonatal Fc receptor (FcRn), ligand of folic acid receptor, ligand of EGFR (epidermal growth factor receptor), ligand of integrin receptor alpha v beta 3.
Preferably, the substrate of the transporter expressed by the intestinal epithelial cells is one or more of oligopeptide transporter PepT1, organic cation transporter OCT, organic cation/carnitine transporter OCTNs, organic anion transporter OATs, monocarboxylic acid transporter MCT, amino acid transporter LAT, cholic acid transporter and glucose transporter;
wherein the transporter substrate is required to be coupled with PEG in the modification process by adopting the transporter substrate, and the molecular weight of the PEG is 600-20000.
Preferably, the ligand of the specific receptor expressed by the intestinal epithelial cells and/or the substrate content of the transporter account for 1-20% of the weight of the attapulgite.
Preferably, the poorly soluble drug is one of paclitaxel, docetaxel, 9-nitrocamptothecin, 10-hydroxycamptothecin, itraconazole, teniposide, etoposide, doxorubicin, curcumin, honokiol, cyclosporin a, tacrolimus, ibuprofen, budesonide, fluorometholone, phentermine, dexamethasone, cortisone acetate, fluticasone propionate, silybin, silymarin, aclacin, aprepitant and fenofibrate.
Preferably, 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 acid glycolic acid-b-polyethylene glycol, polyethylene glycol-b-polycaprolactone-b-polyethylene glycol, and polymethacrylic acid resin.
Preferably, the weight ratio of the poorly soluble drug to the attapulgite is 1: 10-10: 1.
preferably, the weight ratio of the poorly soluble drug to the crystallization inhibitor is 1:0-10.
The crystallization inhibitor can inhibit the particle size of the drug carried in the attapulgite, and enable the drug to exist in an amorphous form so as to improve the solubility of the drug. The modified attapulgite can improve the oral absorption of medicines to a greater extent.
Compared with the prior art, the invention has the following beneficial effects:
1) The attapulgite-based drug-loaded nano particles prepared by the invention are slow to release in a long time, have better slow release characteristics and have better stability in gastrointestinal tracts;
2) The cytotoxicity is low, and the drug-loaded nano-particles based on the attapulgite prepared by the invention have good biocompatibility;
3) The medicine carrying nano-particles based on the attapulgite prepared by the invention can obviously improve the oral absorption of insoluble medicines, 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 that are required to be used in the embodiments or the description of the prior art will be briefly described below, and it is obvious that the drawings in the following description are only embodiments of the present invention, and that other drawings can be obtained according to the provided drawings without inventive effort for a person skilled in the art.
FIG. 1 is a diagram showing a transmission electron microscope of example 2;
FIG. 2 is a diagram showing a transmission electron microscope in example 9;
FIG. 3 is a graph of in vitro release profile in simulated gastric fluid;
FIG. 4 is a graph showing in vitro release profile in simulated intestinal fluid;
FIG. 5 is a graph showing the cytotoxicity results of attapulgite;
fig. 6 is a graph of the drug time.
Detailed Description
The invention provides an attapulgite-based drug-loaded nanoparticle, 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 mu m, 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 25nm.
In the present invention, the attapulgite is unmodified attapulgite or modified attapulgite, and preferably, the modification is a modification of a ligand of a specific receptor expressed by intestinal epithelial cells and/or a substrate of a transporter.
In the invention, the ligand of the specific receptor expressed by the small intestine epithelial cells is one or more of transferrin receptor ligand, neonatal Fc receptor (FcRn) ligand, folic acid receptor ligand, EGFR ligand and integrin receptor alpha v beta 3 ligand, preferably one or more of transferrin, fcBP, folic acid, EGF and RGD.
In the present invention, the substrate of the transporter expressed by the intestinal epithelial cells is one or more of oligopeptide transporter PepT1, organic cation transporter OCT, organic cation/carnitine transporter OCTNs, organic anion transporter OATs, monocarboxylic acid transporter MCT, amino acid transporter LAT, cholic acid transporter and glucose transporter, preferably choline, carnitine, bezoar cholate, salicylic acid, amino acid and deoxycholic acid;
in the present invention, it is necessary to couple the transporter substrate to PEG in the modification process using the transporter substrate, and the molecular weight of PEG is 600 to 20000, preferably 1000 to 10000, more preferably 2000 to 5000, and most preferably 2000.
In the present invention, the substrate content of the ligand and/or transporter of the specific receptor expressed by the small intestine epithelial cells is 1 to 20% by weight, preferably 5 to 15% by weight, of the attapulgite. More preferably 10 to 15%.
In the present invention, the poorly soluble drug is one of paclitaxel, docetaxel, 9-nitrocamptothecin, 10-hydroxycamptothecin, itraconazole, teniposide, etoposide, doxorubicin, curcumin, honokiol, cyclosporin a, tacrolimus, ibuprofen, budesonide, fluorometholone, phentermine, dexamethasone, cortisone acetate, flucartone propionate, silibinin, silymarin, aclacin, aprepitant and fenofibrate, preferably, aclacin, paclitaxel, docetaxel, honokiol, cyclosporin a, tacrolimus.
In the present 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 glycolic acid, polyethylene glycol-b-polycaprolactone, polyethylene glycol-b-polylactic acid-b-polyethylene glycol, polyethylene glycol-b-polylactic acid glycolic acid-b-polyethylene glycol, polyethylene glycol-b-polycaprolactone-b-polyethylene glycol, 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, further preferably hydroxypropyl methylcellulose, soluplus, PEG-DSPE, poloxamer.
In the invention, the weight ratio of the poorly soluble drug 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 medicine carrying nano-particles based on the attapulgite, which comprises an adsorption balance method, a solvent volatilizing method, a melting method and the like.
The invention also provides application of the attapulgite-based drug-loaded nano-particles, which can be prepared into various oral preparations, preferably oral liquid, tablets, capsules and granules according to a conventional method.
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
Preparation of paclitaxel-loaded nanoparticles based on attapulgite
The preparation method of the attapulgite-based paclitaxel-loaded nanoparticle comprises the following steps: adding 10mg of attapulgite into 10mL of methanol solution containing 20mg of taxol, performing ultrasonic dispersion for 10 minutes, stirring for 12 hours at room temperature, filtering, and drying under reduced pressure for 10 hours to obtain the nano-particles carrying taxol based on the attapulgite. The drug loading is 12.6%.
Example 2
Preparation of paclitaxel-loaded nanoparticles based on attapulgite
The preparation method of the attapulgite-based paclitaxel-loaded nanoparticle comprises the following steps: adding 10mg of attapulgite into 10mL of ethanol solution containing 30mg of paclitaxel and 30mg of Soluplus, performing ultrasonic dispersion for 10 minutes, stirring for 12 hours at room temperature, filtering, and drying under reduced pressure for 10 hours to obtain the nano-particles carrying paclitaxel based on the attapulgite. The drug loading is 19.1%.
The transmission electron microscope image of the paclitaxel-loaded nanoparticle based on the attapulgite prepared in the embodiment is shown in fig. 1.
Example 3
Preparation of curcumin-loaded nano-particles based on attapulgite
The preparation method of the curcumin-loaded nano-particle based on the attapulgite comprises the following steps: adding 20mg of attapulgite into 3mL of dichloromethane solution containing 10mg of curcumin, performing ultrasonic dispersion for 10 minutes, stirring for 3 hours at room temperature, and standing overnight for volatilizing to obtain the curcumin-carrying nano-particles based on the attapulgite. The drug loading is 6.2%.
Example 4
Preparation of curcumin-loaded nano-particles based on attapulgite
The preparation method of the curcumin-loaded nano-particle based on the 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-carrying nano-particles based on the attapulgite. The drug loading is 3.9%.
Example 5
Preparation of curcumin-loaded nano-particles based on attapulgite
The preparation method of the curcumin-loaded nano-particle based on the attapulgite comprises the following steps: adding 2mg of attapulgite into 20mL of tetrahydrofuran solution containing 20mg of curcumin and 10mg of HPMC, 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-carrying nanoparticle based on the attapulgite. The drug loading is 39.8%.
Example 6
Preparation of cyclosporine A-loaded nano-particles based on attapulgite
The preparation method of the cyclosporine A-loaded nano-particles based on the attapulgite comprises the following steps: adding 10mg of attapulgite into 2mL of ethanol solution containing 4mg of cyclosporin A and 40mg of soluplus, 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 cyclosporin A-based nano-particles. The drug loading is 12.2%.
Example 7
Preparation of silybin-loaded nano-particles based on attapulgite
The preparation method of the attapulgite-based silibinin-loaded nano-particles comprises the following steps: 30mg of attapulgite was mixed with 10mg of silybin and the mixture was kept at 153℃until it melted. Taking out after 5 minutes, stirring at room temperature, keeping the temperature constant at 153 ℃, taking out after 5 minutes, transferring to an aluminum tray of an ice bath, quenching, and placing the obtained solid in a dryer for preservation, thus obtaining the silybin-carrying nano-particles based on the attapulgite. The drug loading is 10.2%.
Example 8
Preparation of silibinin-carrying nano-particles based on deoxycholic acid modified attapulgite
A preparation method of silibinin-loaded nano-particles based on deoxycholic acid modified attapulgite comprises the following steps:
(1) Amination of attapulgite
Dispersing 1G of attapulgite in 50mL of refined anhydrous toluene, carrying out ultrasonic treatment for 10min, dropwise adding 5mL of 3-aminopropyl trimethoxysilane (APTES) under the protection of nitrogen, slowly heating, refluxing at 110 ℃ for 12h, filtering with a G4 sand core funnel, washing precipitate with ethanol for 3 times, and fully drying the precipitate at 80 ℃ in a vacuum drying oven for 12h to obtain the aminated attapulgite.
(2) Coupling of deoxycholic acid with PEG
13.0mg Deoxycholic Acid (DA), 3.7mg hydroxysuccinimide (NHS) and 6.9mg Dicyclohexylcarbodiimide (DCC) were precisely weighed, dissolved in 20 mM DS SO, stirred at room temperature at 400rpm for 12 hours, filtered, and 45mg NH was added to the filtrate 2 PEG-COOH was reacted at room temperature under 800rpm for 12 hours with stirring, centrifuged at 13000rpm for 5 minutes, and the supernatant was discarded to obtain a precipitate 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 20ml of LDMSO, stirring for 12 hours at room temperature and 400rpm, filtering, adding 45mg of aminated attapulgite into the filtrate, stirring for reaction for 12 hours at room temperature and 800rpm, centrifuging for 5 minutes at 13000rpm, discarding the supernatant, and drying the obtained precipitate in vacuum to obtain the deoxycholic acid modified attapulgite.
(4) Preparation of silibinin-carrying nano-particles based on deoxycholic acid modified attapulgite
A preparation method of silibinin-loaded nano-particles 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, performing ultrasonic dispersion for 10 minutes, stirring for 12 hours at room temperature, filtering, and drying under reduced pressure for 10 hours to obtain the nano-particle carrying silybin based on the deoxycholic acid modified attapulgite. The drug loading was 14.7%.
Example 9
Preparation of paclitaxel-loaded nanoparticle based on glycocholic acid modified attapulgite
A preparation method of paclitaxel-loaded nano-particles based on glycocholic acid modified attapulgite comprises the following steps:
(1) Amination of attapulgite
Dispersing 1G of attapulgite in 50mL of refined anhydrous toluene, carrying out ultrasonic treatment for 10min, dropwise adding 5mL of 3-aminopropyl trimethoxysilane (APTES) under the protection of nitrogen, slowly heating, refluxing at 110 ℃ for 12h, filtering with a G4 sand core funnel, washing precipitate with ethanol for 3 times, and fully drying the precipitate at 80 ℃ in a vacuum drying oven for 12h to obtain the aminated attapulgite.
(2) Coupling of glycocholic acid with PEG
16.0mg of glycocholic acid (CG), 3.7mg of hydroxysuccinimide (NHS) and 6.9mg of Dicyclohexylcarbodiimide (DCC) are precisely weighed, dissolved in 20 mM DS (MSO), stirred for 12 hours at room temperature and 400rpm, filtered, 45mg of NH2-PEG-COOH is added to the filtrate, stirred for reaction for 12 hours at room temperature and 800rpm, centrifuged for 5 minutes at 13000rpm, and the supernatant is discarded, thus obtaining the precipitate, namely CG-PEG-COOH.
(3) Preparation of glycocholic acid modified attapulgite
28.0mg of CG-PEG-COOH, 3.7mg of hydroxysuccinimide (NHS) and 6.9mg of Dicyclohexylcarbodiimide (DCC) are precisely weighed, dissolved in 20ml of LDMSO, stirred for 12 hours at room temperature and 400rpm, filtered, 45mg of aminated attapulgite is added into the filtrate, stirred for reaction for 12 hours at room temperature and 800rpm, centrifuged for 5 minutes at 13000rpm, the supernatant is discarded, and the obtained precipitate is dried in vacuum to obtain the glycocholic acid modified attapulgite.
(4) Preparation of paclitaxel-loaded nanoparticle based on glycocholic acid modified attapulgite
Adding 10mg of the attapulgite modified by glycocholic acid (the glycocholic acid modifier accounts for 6% of the modified attapulgite) into 10mL of ethanol solution containing 30mg of paclitaxel and 30mg of polyvinylpyrrolidone (PVPK 30), performing ultrasonic dispersion for 10 minutes, stirring for 12 hours at room temperature, filtering, and drying under reduced pressure for 10 hours to obtain the paclitaxel-loaded nano-particles based on the glycocholic acid modified attapulgite. The drug loading was 13.7%. The transmission electron microscope image of the paclitaxel-loaded nanoparticle based on the attapulgite prepared in the example is shown in fig. 2.
Example 10
Preparation of Alcalidine-loaded nanoparticles based on carnitine-modified attapulgite
The preparation method of the alcaftadine-carrying nano-particles based on the carnitine modified attapulgite comprises the following steps:
(1) Coupling of carnitine with PEG
1g of HOOC-PEG-COOH was dissolved in 20 mM LDMF under ice bath, 1.2 equivalents of EDCHCl and 0.2 equivalents of DMAP were dissolved in 10 mM LDMF, respectively, and added dropwise to a DMF solution of HOOC-PEG-COOH. After 30 minutes of reaction in ice bath, 1.1 equivalent of carnitine (Car) is taken and dissolved in DMF, ultrasonic is carried out, the solution is dripped into a reaction system, the reaction solution is collected after 48 hours of reaction at room temperature, and after 48 hours of dialysis in water (MWCO=1000), the solution is freeze-dried, thus obtaining the purified Car-PEG-COOH.
(2) Preparation of carnitine-modified attapulgite
13.0mg of Car-PEG-COOH, 3.7mg of hydroxysuccinimide (NHS) and 6.9mg of Dicyclohexylcarbodiimide (DCC) are precisely weighed, dissolved in 20ml of LDMSO, stirred for 12 hours at room temperature and 400rpm, filtered, 45mg of aminated attapulgite is added to the filtrate, stirred for reaction for 12 hours at room temperature and 800rpm, centrifuged for 5 minutes at 13000rpm, the supernatant is discarded, and the obtained precipitate is dried in a vacuum dryer to obtain the carnitine modified attapulgite.
(3) Preparation of Alcalidine-loaded nanoparticles based on carnitine-modified attapulgite
The preparation method of the alcaftadine-carrying nano-particles based on the carnitine modified attapulgite comprises the following steps: adding 10mg of the carnitine modified attapulgite into 10mL of ethanol solution containing 25mg of aclacin and 15mg of Soluplus, performing ultrasonic dispersion for 10 minutes, stirring for 12 hours at room temperature, filtering, and drying under reduced pressure for 10 hours to obtain the nano-particles carrying the aclacin based on the carnitine modified attapulgite. The drug loading is 13.8%.
Example 11
Preparation of cyclosporin A-carrying nanoparticles based on transferrin-modified attapulgite
A preparation method of cyclosporin A-loaded nano-particles based on transferrin modified attapulgite comprises the following steps:
(1) Preparation of transferrin modified attapulgite
13.0mg of transferrin, 3.7mg of hydroxysuccinimide (NHS) and 6.9mg of Dicyclohexylcarbodiimide (DCC) are precisely weighed, dissolved in 20mL of DMSO, stirred for 12 hours at room temperature and 400rpm, filtered, 45mg of aminated attapulgite is added into the filtrate, stirred for reaction for 12 hours at room temperature and 800rpm, centrifuged for 5 minutes at 13000rpm, the supernatant is discarded, and the obtained precipitate is dried in a vacuum dryer to obtain the transferrin modified attapulgite.
(2) Preparation of cyclosporin A-carrying nanoparticles based on transferrin-modified attapulgite
A preparation method of cyclosporin A-loaded nano-particles based on transferrin modified attapulgite comprises the following steps: 20mg of attapulgite is added into 20mL of ethanol solution containing 40mg of cyclosporin A and 20mg of polyvinylpyrrolidone, the mixture is dispersed for 10 minutes by ultrasonic, and after stirring for 12 hours at room temperature, the mixture is centrifuged at 5000rpm for 10 minutes and dried under reduced pressure for 10 hours, thus obtaining the cyclosporin A-loaded nano-particles based on transferrin modified attapulgite. The drug loading is 16.4%.
Example 12
Preparation of folic acid modified attapulgite-based honokiol-loaded nano-particles
A preparation method of a supported honokiol nano-particle based on folic acid modified attapulgite comprises the following steps:
(1) Preparation of folic acid modified attapulgite
13.0mg of folic acid, 3.7mg of hydroxysuccinimide (NHS) and 6.9mg of Dicyclohexylcarbodiimide (DCC) are precisely weighed, dissolved in 20mL of DMSO, stirred for 12 hours at room temperature and 400rpm, filtered, 45mg of aminated attapulgite is added into the filtrate, stirred for reaction for 12 hours at room temperature and 800rpm, centrifuged for 5 minutes at 13000rpm, the supernatant is discarded, and the obtained precipitate is dried in a vacuum dryer to obtain the folic acid modified attapulgite.
(2) Preparation of folic acid modified attapulgite-based honokiol-loaded nano-particles
A preparation method of a supported honokiol nano-particle based on folic acid modified attapulgite comprises the following steps: adding 10mg of folic acid modified attapulgite into 10mL of ethanol solution containing 30mg of honokiol and 30mg of Soluplus, performing ultrasonic dispersion for 10 minutes, stirring for 12 hours at room temperature, filtering, and drying under reduced pressure for 10 hours to obtain folic acid modified attapulgite-based nano-particles carrying honokiol. The drug loading is 15.1%.
Test example 1
In vitro Release test
In order to evaluate the in vitro release characteristics of the attapulgite-based drug-loaded nanoparticles of the present invention, the nanoparticles of examples 2 and 9 of the present invention were examined in vitro in simulated gastrointestinal fluids as follows, and the commercial formulation Taxol was used as a control.
The dialysis bag method is adopted. The preparation of the invention, taxol (containing 0.15mg of paclitaxel) from example 2, example 9 and the commercially available preparation of the invention were placed in activated dialysis bags (MWCO: 8000-14000), sealed with dialysis clips, and then placed in 30mL simulated gastric fluid and simulated intestinal fluid containing 0.1% Tween80, and shaken in a 37C, 100rpm water bath shaker, and each sample was run in triplicate. 0.5mL of release medium was removed at 1, 2, 4, 8, 12 and 24h, respectively, while 0.5mL of fresh release medium was replenished. The release medium taken out at each time point was filtered through a 0.22m filter membrane, the content of paclitaxel was determined by RP-HPLC method, the cumulative release percentage of the drug was calculated, and the release curve was drawn.
The chromatographic conditions were as follows: diamobsilODSC18 column, 250X 4.6mm,5 μm; mobile phase: acetonitrile water = 2:1, a step of; flow rate: 1mL/min; column temperature: 50 ℃; detection wavelength: 227nm; sample injection amount: 20. Mu.L.
The release curves are shown in figures 3 and 4. Comparing the release profiles of the three groups, both in simulated gastric fluid and in simulated intestinal fluid, the two groups of attapulgite-based drug-loaded nanoparticles released slightly faster in the initial phase than the Taxol group, which may be due to the burst release of paclitaxel adsorbed on the outer surface of the attapulgite. Over time, the release of examples 2 and 9 was slower, and in particular example 9 was slower. The result shows that the attapulgite-based paclitaxel-loaded nano-particles prepared by the invention have better slow release characteristics and better stability in the gastrointestinal tract.
Test example 2
Biocompatibility test of attapulgite
The MTT method is adopted to measure the influence of the attapulgite on the survival rate of Caco-2 cells, and the specific experimental steps are as follows:
(1) Caco-2 cells were cultured in DMEM complete medium, and the flask was placed at 37℃with 5% CO 2 And a constant temperature incubator with a relative humidity of 90%. When the cell confluency reached 80% or more, digestion was performed and counted. The cells were diluted to a density of 5X 10 with DMEM complete medium 4 The cell suspension was added to a 96-well plate at 200. Mu.L per well, 200. Mu.L of PBS solution was added to wells around the 96-well plate, and incubated for 36h.
(2) Absorbing and discarding culture solution, respectively adding 200 mu L of culture medium suspension of attapulgite in each hole 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 compound holes in each concentration, adding 200 mu L of DMEM complete culture medium in each hole of a blank control group, incubating for 24 hours, absorbing and discarding the culture medium, adding DMEM complete culture medium containing 10% MTT in each hole, and continuously incubating for 4 hours.
(3) The culture solution in the 96-well plate is sucked and removed, 200L of DMSO solution is added into each well, the shaking is carried out for 15min, the crystals are fully and uniformly dissolved, the OD value of each well is measured at 490nm by an enzyme-labeling instrument, and the relative survival rate of the cells is calculated.
FIG. 5 shows the cytotoxicity results of the attapulgite according to MTT assay. The cytotoxicity of attapulgite showed a certain concentration dependence. As can be seen from the results of the cell viability experiments, the cell viability was 80% or more even when the concentration of the attapulgite was increased to 12 mg/mL. Therefore, the biocompatibility of the attapulgite is better.
Test example 3
Pharmacokinetic test
To evaluate the oral absorption of the attapulgite-based drug-loaded nanoparticles of the present invention, the nanoparticles of the present invention were subjected to pharmacokinetic testing as follows.
15 male SD rats were obtained and were randomly divided into three groups, namely, taxol group, inventive example 2 group and inventive example 9 group, with weights (300.+ -.20) g. Fasted for 12 hours before the experiment, and can drink water freely. The dosage of the gastric lavage drug is 15mg/kg. Serum was obtained by centrifugation at 8000rpm for 15min in 0.5mL to heparinized EP tubes from the posterior venous plexus of the rat orbit at 0.25, 0.5, 1, 2, 3, 4, 8, 12, 24, 48h timing before and after dosing, respectively. 100. Mu.L of the internal standard diazepam (300. Mu.g/mL) and 3mL of t-butyl methyl ether were precisely pipetted into a 5mLEP tube, vortexed for 5min and centrifuged at 1000rpm for 15min. Taking 1mL of supernatant, drying with nitrogen, adding 100 mu L of methanol for redissolution, filtering with a 0.2 mu m filter membrane, and measuring the concentration of the medicine in blood by adopting an RP-HPLC method.
The chromatographic conditions were as follows: the chromatographic conditions were as follows: diamobsilODSC18 column, 250X 4.6mm,5 μm; mobile phase: acetonitrile water = 1:1, a step of; flow rate: 1mL/min; column temperature: 50 ℃; detection wavelength: 227nm; sample injection amount: 20. Mu.L.
The time profile is shown in FIG. 6. The results showed that the peak plasma concentrations of the groups of example 2 and example 9 increased by 1.9 and 3.9 times, respectively, and the AUC values increased by 3.7 and 10.5 times, respectively, as compared to the Taxol group; the peak plasma concentration of example 9 was increased by 2.1 times and AUC was increased by 2.9 times as compared to example 2. Therefore, the nano-particles based on the attapulgite can obviously improve the oral absorption of the taxol, and the substrate modified nano-particles have better absorption promoting effect, thus showing the superiority of the nano-particles based on the attapulgite.
In the present specification, each embodiment is described in a progressive manner, and each embodiment is mainly described in a different point from other embodiments, and identical and similar parts between the embodiments are all enough to refer 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 (1)

1. The preparation method of the paclitaxel-loaded nanoparticle based on the glycocholic acid modified attapulgite is characterized by comprising the following steps of:
amination of attapulgite
Dispersing 1G of attapulgite in 50mL of refined anhydrous toluene, carrying out ultrasonic treatment for 10min, dropwise adding 5mL of 3-aminopropyl trimethoxysilane under the protection of nitrogen, slowly heating, refluxing at 110 ℃ for 12h, filtering with a G4 sand core funnel, washing 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;
coupling of glycocholic acid with PEG
Precisely weighing 16.0mg of glycocholic acid, 3.7mg of hydroxysuccinimide and 6.9mg of dicyclohexylcarbodiimide, dissolving in 20 mM DS SO, stirring at room temperature and 400rpm for 12h, filtering, adding 45mg of NH to the filtrate 2- PEG-COOH was reacted under stirring at 800rpm at room temperature for 12h, centrifuged at 13000rpm for 5min, and the supernatant was discarded to obtain a precipitate, namely CG-PEG-COOH;
preparation of glycocholic acid modified attapulgite
Precisely weighing 28.0mg of CG-PEG-COOH, 3.7mg of hydroxysuccinimide and 6.9mg of dicyclohexylcarbodiimide, dissolving in 20ml of LDMSO, stirring at room temperature and 400rpm for 12 hours, filtering, adding 45mg of aminated attapulgite into the filtrate, stirring at room temperature and 800rpm for reaction for 12 hours, centrifuging at 13000rpm for 5 minutes, discarding the supernatant, and vacuum drying the obtained precipitate to obtain the glycylcholic acid modified attapulgite;
preparation of paclitaxel-loaded nanoparticle based on glycocholic acid modified attapulgite
Adding 10mg of attapulgite modified by glycocholic acid, wherein the glycocholic acid modifier accounts for 6% of the modified attapulgite, into 10mL of ethanol solution containing 30mg of paclitaxel and 30mg of polyvinylpyrrolidone, performing ultrasonic dispersion for 10 minutes, stirring for 12 hours at room temperature, filtering, and drying under reduced pressure for 10 hours to obtain paclitaxel-loaded nano-particles based on the glycocholic acid modified attapulgite; the drug loading was 13.7%.
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