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CN114712520B - Nanocrystalline drug stabilization system, preparation method, pharmaceutical composition and application - Google Patents

Nanocrystalline drug stabilization system, preparation method, pharmaceutical composition and application Download PDF

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Publication number
CN114712520B
CN114712520B CN202210393716.7A CN202210393716A CN114712520B CN 114712520 B CN114712520 B CN 114712520B CN 202210393716 A CN202210393716 A CN 202210393716A CN 114712520 B CN114712520 B CN 114712520B
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nanocrystalline
acid
drug
stabilizer
polyphenol
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CN114712520A (en
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殷婷婕
周建平
杨梦楠
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China Pharmaceutical University
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China Pharmaceutical University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
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    • A61K9/5063—Compounds of unknown constitution, e.g. material from plants or animals
    • A61K9/5068—Cell membranes or bacterial membranes enclosing drugs
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings

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Abstract

The invention discloses a nanocrystalline drug stabilization system, a preparation method, a drug composition and application, wherein the nanocrystalline drug stabilization system comprises a phenylboronic acid modified nanocrystalline drug, polyphenol or polyphenol metal ion complex and a stabilizer from inside to outside; the modified nanocrystalline drug is modified by chemical bonding of phenylboronic acid structural molecules and drugs; the modified nanocrystalline drug is coated with polyphenol or polyphenol metal ion complex, and then the surface of the modified nanocrystalline drug is coated with the stabilizer, so that a drug system with good stability, high biological safety and adjustable functions is formed, the requirement limit of acting force between the stabilizer and the nanocrystalline drug surface is reduced, and the selection range of the stabilizer is widened. The drug delivery system can be prepared into a liquid preparation by a mixing and dispersing technology, and can be further added with a protective agent to prepare into a freeze-dried preparation, so that the drug delivery system is suitable for drugs and diagnostic agents through various administration routes such as oral administration, inhalation, injection, ophthalmic, transdermal, mucous membrane and the like.

Description

Nanocrystalline drug stabilization system, preparation method, pharmaceutical composition and application
Technical Field
The invention relates to a stabilization system, a preparation method, a pharmaceutical composition and application of a covalent modification-based nanocrystalline drug, in particular to a nanocrystalline drug stabilization system, a preparation method, a pharmaceutical composition and application with obviously improved stability, biosafety and functional adjustability.
Background
The drug delivery system is a preparation technology for comprehensively regulating and controlling the distribution of drugs in organisms in space, time and dosage, and can realize the effects of synergism and attenuation of the drugs. At present, common drug delivery carriers are of various types such as liposome, micelle, emulsion, microsphere and the like, but the clinical application of a delivery system based on the carriers is very little, and key factors for preventing the clinical transformation of the drug delivery carriers include: the drug loading is low, the carrier biocompatibility is poor, the carrier is not easy to degrade and metabolize or the potential risk exists in undefined metabolism, the carrier construction process is complex, the quality batch difference is large, the preparation process is complex, and the amplification is difficult, etc.
The nanocrystalline drug is mainly composed of pure drug nanoparticles and a stabilizer required for stabilizing nanocrystalline. Compared with the carrier type drug delivery system, the nanocrystalline drug has the advantages of high drug carrying efficiency, no dependence on carrier design and synthesis, low auxiliary material consumption, simple preparation process, easy industrialization and the like. However, despite the wide variety of nanocrystalline pharmaceutical formulations currently on the market, the key manufacturing difficulties of this dosage form remain prominent: the stabilizer generally has amphipathy and is combined with the surface of the nanocrystalline drug by means of good interaction, so that the selection of the stabilizer is based on repeated experiments, the particle size and stability of the target suspension are greatly influenced by the structure and concentration of the stabilizer, the selection range of the stabilizer is limited or cannot be matched with the optimal stabilizer for preparing a stable nanocrystalline preparation, and the structure of the stabilizer cannot be flexibly regulated within the limited selection range of the stabilizer so as to obtain different functional characteristics such as targeting and the like to meet different application requirements of the preparation. In addition, conventional nanocrystalline formulations do not have focal response release characteristics and may affect efficacy by failing to achieve effective therapeutic concentrations quickly.
Disclosure of Invention
The invention aims to: aiming at the defects of complex preparation process, safety risk, certain functions being met and the like of the traditional drug delivery system, the invention aims to provide a nanocrystalline drug stabilization system with obviously improved stability, biosafety and functional adjustability, a preparation method, a drug composition and application.
The technical scheme is as follows: as a first aspect to which the present invention relates, the nanocrystalline drug stabilization system of the present invention includes, from inside to outside, a phenylboronic acid modified nanocrystalline drug, a polyphenol or polyphenol metal ion complex, and a stabilizer; the modified nanocrystalline drug is modified by chemical bonding of phenylboronic acid structural molecules and drugs; the polyphenol or polyphenol metal ion complex firstly coats the modified nanocrystalline drug, and then coats the stabilizer on the surface of the nanocrystalline drug.
Phenylboronic acid (Phenylboronic acid, PBA) molecules contain two basic structures, a benzene ring and boric acid. Boric acid is a lewis acid, boron atoms lack electrons, trisubstituted boron atoms have a triangular plane geometry, and the empty p orbitals are perpendicular to the plane of the molecule, providing the possibility of electron exchange. Phenylboronic acid can occur mainly: forming a cyclic borate bond with cis-o-diol (1, 2-diol, 1, 3-diol); coordination with various heteroatoms including oxygen, sulfur, phosphorus, and nitrogen, and the like. The borate ester bond and coordination have pH responsiveness and active oxygen responsiveness.
Polyphenols are a class of bioadhesive substances that contain a rich catechol structure. The adhesive is realized by virtue of hydrogen bonding, electrostatic interaction, coordination, hydrophobic interaction, chemical bonding of Schiff base and the like and pi-pi interaction generated by a plurality of benzene rings and o-diphenol structures and other hydrophilic and hydrophobic groups on the surfaces of other substances. Meanwhile, catechol can form stable boric acid ester bonds with boric acid groups of phenylboric acid or derivatives thereof and form coordination with boron atoms.
The nanocrystalline drug stabilization system takes polyphenol or polyphenol-metal organic frameworks as bridging, firstly the polyphenol or polyphenol-metal organic frameworks are coated on the surface of the phenylboronic acid modified drug nanocrystalline to form polyphenol-phenylboronic acid drug nanocrystalline, and the adhesion of the polyphenol or polyphenol-metal organic frameworks on the surface of the polyphenol-phenylboronic acid drug nanocrystalline is further utilized to coat an outer stabilizer, so that the efficient stabilized nanocrystalline drug system is formed.
In conclusion, the polyphenol or polyphenol metal organic framework can be stably combined with the phenylboronic acid modified drug nanocrystalline through boric acid ester bonds and other non-covalent actions, meanwhile, the drug nanocrystalline adhesiveness and focus responsiveness are endowed, the matching requirement limit of the external stabilizer and the acting force on the surface of the nanocrystalline drug is reduced, stabilizers with different structures can be adsorbed through simple technological operation based on the various acting forces, the selection range of the nanocrystalline drug stabilizer and the application potential of a target preparation are obviously expanded, and the preparation process difficulty of the highly stabilized nanocrystalline drug is reduced.
Preferably, the mass ratio of the stabilizer to the modified drug nanocrystal is 100:1 to 1:10.
preferably, the grain diameter of the nano-crystal drug stabilizing system is 30 nm-1000 nm, and the drug loading rate is 1% -95%.
Preferably, the medicine comprises one or more of doxorubicin, epirubicin, naproxen, camptothecine, paclitaxel and quercetin.
Preferably, the phenylboronic acid structural molecule comprises one or more of fluorine, methoxy, nitro or trifluoromethyl substituted or unsubstituted carboxyphenylboronic acid, aminophenylboronic acid, hydroxyphenylboronic acid, vinylphenylboronic acid, mercaptophenylboronic acid, formylphenylboronic acid, aminomethylphenylboronic acid, bromomethylphenylboronic acid, hydroxymethylphenylboronic acid, acrylamidophenylboronic acid and acrylate phenylboronic acid.
Preferably, the particle size of the modified nano-crystal drug is 1 nm-1000 nm.
Preferably, the polyphenol comprises one or more of quercetin, kaempferol, myricetin, anthocyanin, luteolin, catechol, gallocatechol gallate, epigallocatechin gallate, digallayl-D-glucose, trigallayl glucose, tetragalloyl glucose, pentagalloyl glucose, gallic acid, digallic acid, tannic acid, ellagitannin, ellagic acid, hydrolyzed tannins, polydopamine; the metal ion complex comprises a complex formed by one or more metal ions of Mn (II), fe (II), co (II), ni (II), cu (II), zn (II), hg (II), ca (II), mg (II), sr (II), sn (II), cd (II), pb (II), ba (II), fe (III), al (III), co (III), cr (III), ce (III), la (III), Y (III), au (III), tb (III), eu (III), pb (IV), pt (IV), ti (IV), sn (IV), V (IV) and Cr (VI) and the polyphenol.
Preferably, the stabilizer comprises one or more of a lipid, a biological membrane, a high molecular polymer and derivatives thereof.
It is further preferred that the composition, the lipid comprises soybean lecithin, egg yolk lecithin, sphingomyelin, hydrogenated lecithin, hydrogenated soybean lecithin, dipalmitoyl phosphatidylserine, dioleoyl phosphatidylserine, distearoyl phosphatidylserine, lysophosphatidylethanolamine, palmitoyl lysolecithin, myristoyl lysolecithin, stearoyl lysolecithin, dimyristoyl phosphatidylethanolamine, distearoyl phosphatidylethanolamine, dipalmitoyl phosphatidylethanolamine, dioleoyl phosphatidylglycerol, egg yolk phosphatidylglycerol, 1-palmitoyl-2-oleoyl phosphatidylglycerol, dipalmitoyl phosphatidylglycerol, palmitoyl phosphatidyl glycerol, and palmitoyl phosphatidyl distearoyl phosphatidylglycerol, dimyristoyl phosphatidylglycerol, distearoyl phosphatidic acid, dipalmitoyl phosphatidic acid, dioleoyl phosphatidic acid, dilauroyl lecithin, dithiin phosphatidylcholine, dioleoyl phosphatidylcholine, dimyristoyl lecithin, 1-palmitoyl-2-oleoyl lecithin, dipalmitoyl phosphatidylcholine, 1-stearoyl-2-oleoyl-lecithin, distearoyl phosphatidylcholine, oleic acid, linoleic acid, linolenic acid, span, tween, cetyl palmitate, a mixture of glyceryl behenates, cholesterol or derivatives thereof.
The biological membrane comprises one or more of a cell membrane, a platelet membrane, a bacterial outer membrane, a cell-derived vesicle, and a fused cell membrane.
The high molecular polymer and the derivative thereof comprise natural high molecular polymer and the derivative thereof, such as one or more of amylose, amylopectin, oxidized starch, hydroxyethyl starch, crosslinked starch, microcrystalline cellulose, cellulose acetate, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose carbonate, hydroxypropyl methyl cellulose acetate succinate, acacia, chitin, dextran, chitosan, hyaluronic acid, alginic acid, heparin, albumin and the derivative thereof; synthetic high molecular polymers and derivatives thereof, such as one or more of polyacrylic acid, polyhydroxyethyl methacrylate, carbomer, polyvinyl alcohol, polyvinyl acetate phthalate, polyvinylpyrrolidone, polyethylene glycol-polylactic acid, polyethylene glycol-polycaprolactone, polyoxyethylated castor oil, polyoxyethylene fatty acid esters, poloxamers, polyglycolic acid, polylactic acid, polycaprolactone, glycolic acid-caprolactone copolymers, polysorbates, polyvinylpyrrolidone, poly (ethyleneimine), d-alpha-tocopheryl polyethylene glycol 1000 succinate, amino acid polymers, poly (ethylene oxide) -poly (propylene oxide) block copolymers, and derivatives thereof.
As a second aspect to which the present invention relates, the method for preparing a nanocrystalline drug stabilization system of the present invention includes the steps of:
(1) Preparing a modified nanocrystalline drug;
the preparation method comprises the steps of preparing the phenylboronic acid modified nanocrystalline medicament by a conventional antisolvent precipitation method, a supercritical fluid technology, a microfluidic technology, an acid-base neutralization reaction, solvent evaporation, spray drying, a freeze thawing method, an ultrasonic method, high-pressure homogenization, a microfluidic technology or a medium grinding method.
(2) Preparation of prefabricated systems
The method comprises the following steps: mixing the modified nanocrystalline drug prepared in the step (1) with polyphenol, and adjusting the pH to 7.0-8.0; the mixing procedure is specifically micro-fluidic technology rapid mixing or simple mixing and ultrasonic, homogenizing, vortex or stirring operation.
The second method is as follows: mixing the modified nanocrystalline drug prepared in the step (1) with polyphenol, then mixing with metal ions, and adjusting the pH to 7.0-8.0; the mixing procedure is the same as the first method.
(3) Stabilization system for preparing nanocrystalline drug
The method comprises the following steps: mixing the prefabricated system prepared in the step (2) with a stabilizer, and removing a solvent to obtain a nanocrystalline drug stabilizing system; the mixing procedure is specifically micro-fluidic technology rapid mixing or further mixing and ultrasonic, homogenizing, vortex or stirring operation; the organic solvent is removed by dialysis, ultrafiltration or evaporation.
The second method is as follows: dispersing a stabilizer into a film, re-dissolving or dispersing the film by the prefabricated system prepared in the step (2), mixing, and removing the solvent to obtain a nanocrystalline drug stabilizing system; the mixing procedure and the solvent removal operation are the same as in the first method.
And a third method: preparing a vesicle system from a stabilizer, mixing the vesicle system with the prefabricated system prepared in the step (2), and removing the solvent to obtain a nanocrystalline drug stabilization system; the preparation method comprises the steps of preparing a stabilizer into an aqueous solution containing large vesicles in advance, carrying out rapid mixing or simple mixing on the aqueous solution and the prepared solution by a microfluidic technology, carrying out ultrasonic treatment, homogenizing, vortex, stirring or extrusion membrane passing operation, and removing an organic solvent by dialysis, ultrafiltration or evaporation to obtain the high-efficiency stabilized nanocrystalline pharmaceutical preparation solution.
More specifically, the ultrasonic frequency is 100-1000W, and the ultrasonic time is 1-30min; the homogenization is implemented by a high-pressure homogenizer or a micro-jet homogenizer, the homogenization pressure is 300-1500Pa, and the homogenization times are 1-30 times; the homogenization is realized by a homogenizer, the rotating speed is 1000-10000rpm, and the homogenization time is 5-120s; the vortex or stirring is realized by a vortex instrument and a stirrer, the rotation speed of the vortex or stirring is generally 500-3000rpm, and the time is 1-30min; the extrusion film passing is realized by an extruder, and the extrusion cycle times are generally 1-10 times; the microfluidic technology is a method of processing small amounts of fluid (10 -9 ～10 -18 l) injecting two-phase fluid into different channels, controlling the relative volume flow rate proportion and realizing rapid mixing. The pharmaceutically acceptable organic solvent is one or more of dimethyl sulfoxide, N-dimethylformamide, formamide, ethanol, acetone, methanol, tetrahydrofuran, dichloromethane, chloroform, ethyl acetate and isopropanol.
As a third aspect to which the present invention relates, the pharmaceutical composition of the present invention comprises the above-described nanocrystalline drug stabilization system and a pharmaceutically acceptable carrier.
The pharmaceutical composition is a liquid injection, an oral solution, eye drops, aerosol, spray, powder fog or freeze-dried preparation composition. Wherein the additive lyoprotectant comprises one or more of glucose, lactose, sorbitol, xylitol, sucrose, trehalose, mannitol, inositol, lactobionic acid, arginine, aspartic acid, dextrin, dextran, soluble starch, albumin, gelatin, povidone, polyethylene glycol, sodium chloride, sodium glutamate, citrate, acetate, and phosphate.
As a fourth aspect of the present invention, the nanocrystalline drug stabilization system or the pharmaceutical composition described above can be prepared as a disease preventive/therapeutic agent or a disease diagnostic agent for oral, inhalation, injection, ophthalmic, transdermal or mucosal administration, and is particularly suitable for the treatment of chronic diseases, inflammatory infections, tumors, autoimmune diseases, and the like.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages:
(1) By utilizing the characteristic that the catechol structure of the polyphenol or polyphenol-metal organic framework and phenylboronic acid form boric acid ester bonds and other interactions, the polyphenol or polyphenol-metal organic framework can be stably coated on the surface of the phenylboronic acid modified drug nanocrystalline, and the specific release characteristic of the drug nanocrystalline focus is endowed, so that the efficacy of synergism and toxicity reduction is exerted;
(2) By utilizing the adhesiveness of polyphenol or polyphenol-metal organic framework, a plurality of stabilizers can be adsorbed by simple process operation, the matching requirement limit of the stabilizer and the acting force on the surface of the nanocrystalline medicament can be reduced, the selection range of the stabilizer is wide, and different functional characteristics such as targeting and the like can be obtained by flexible regulation and control so as to meet different application requirements;
(3) The stabilizer, polyphenol or polyphenol-metal organic framework double-layer structure is adopted to stably cover the surface of the nanocrystalline, so that the problems of medicine leakage, stabilizer falling, poor physiological and dilution stability and the like of the conventional medicine nanocrystalline prepared by the single-layer stabilizer can be solved, and the physicochemical and biological stability of the nanocrystalline medicine preparation is improved.
Drawings
FIG. 1A is a drawing showing the phenylboronated doxorubicin nanocrystal (PNC) and phenylboronated doxorubicin nanocrystal @ tannic acid-Fe in example 1 Ⅲ (PNTF), doxorubicin nanocrystals @ tannic acid-Fe Ⅲ (NTF), erythrocyte membrane @ phenylboronated doxorubicin nanocrystals (RPNC), erythrocyte membrane @ doxorubicin nanocrystals @ tannic acid-Fe Ⅲ (RNTF), erythrocyte membrane @ phenylboronated doxorubicin nanocrystals @ tannic acid-Fe Ⅲ (RPNTF) particle size distribution and dilution stability profile;
FIG. 1B is a drawing of the phenylboronated doxorubicin nanocrystal (PNC) of example 1, phenylboronated doxorubicin nanocrystal @ tannic acid-Fe Ⅲ (PNTF), doxorubicin nanocrystals @ tannic acid-Fe Ⅲ (NTF), erythrocyte membrane @ phenylboronated doxorubicin nanocrystals (RPNC), erythrocyte membrane @ doxorubicin nanocrystals @ tannic acid-Fe Ⅲ (RNTF), erythrocyte membrane @ phenylboronated doxorubicin nanocrystals @ tannic acid-Fe Ⅲ A potential map of (RPNTF);
FIG. 2 is a schematic view ofErythrocyte membrane @ phenylboronated doxorubicin nanocrystals @ tannic acid-Fe in example 1 Ⅲ A transmission electron micrograph of (RPNTF);
FIG. 3A is a chart of red blood cell membrane @ phenylboronated doxorubicin nanocrystal @ tannic acid-Fe of example 1 Ⅲ (RPNTF), erythrocyte membrane @ doxorubicin nanocrystalline @ tannic acid-Fe Ⅲ (RNTF) PBS dilution stability profile with 10% serum;
FIG. 3B is a chart of red blood cell membrane @ phenylboronated doxorubicin nanocrystal @ tannic acid-Fe of example 1 Ⅲ (RPNTF), erythrocyte membrane @ doxorubicin nanocrystalline @ tannic acid-Fe Ⅲ (RNTF) Medium dilution stability profile;
FIG. 4A is a graph showing particle size distribution and dilution stability of the benzoboronated naproxen nanocrystals @ digallic acid (PNG), liposome @ benzoboronated naproxen nanocrystals @ digallic acid (SCP-PNG) of example 5;
FIG. 4B is a potential diagram of the benzoboronated naproxen nanocrystals @ digallic acid (PNG), liposome @ benzoboronated naproxen nanocrystals @ digallic acid (SCP-PNG) of example 5;
FIG. 5A is a sample of phenylborated camptothecin nanocrystals @ digallic acid-Cu from example 10 Ⅱ (PNGC), polyethylene glycol @ phenylborated camptothecin nanocrystals @ digallic acid-Cu Ⅱ (PEG-PNGC) particle size distribution and dilution stability profile;
FIG. 5B is a sample of phenylborated camptothecin nanocrystal @ digallic acid-Cu in example 10 Ⅱ (PNGC), polyethylene glycol @ phenylborated camptothecin nanocrystals @ digallic acid-Cu Ⅱ (PEG-PNGC) potential map;
FIG. 6A is a graph showing particle size distribution and dilution stability of the phenylborated doxorubicin nanocrystal @ EGCG (PNE), polyvinyl alcohol @ phenylborated doxorubicin nanocrystal @ EGCG (PVA-PNE) of example 2;
FIG. 6B is a potential diagram of the phenylborated doxorubicin nanocrystal @ EGCG (PNE), polyvinyl alcohol @ phenylborated doxorubicin nanocrystal @ EGCG (PVA-PNE) of example 2;
FIG. 7 shows the red blood cell membrane @ phenylboronated doxorubicin nanocrystal @ tannic acid-Fe of example 1 Ⅲ (RPNTF), erythrocyte membrane @ doxorubicin nanocrystalline @ tannic acid-Fe Ⅲ (RNTF) At pH 7.4, pH 5.5 and pH 5.5 containing 10mM H 2 O 2 Release behavior under conditions;
FIG. 8 shows the phenylboronated doxorubicin nanocrystals (PNC) and phenylboronated doxorubicin nanocrystals @ tannic acid-Fe of example 1 Ⅲ (PNTF), doxorubicin nanocrystals @ tannic acid-Fe Ⅲ (NTF), erythrocyte membrane @ phenylboronated doxorubicin nanocrystals (RPNC), erythrocyte membrane @ doxorubicin nanocrystals @ tannic acid-Fe Ⅲ (RNTF), erythrocyte membrane @ phenylboronated doxorubicin nanocrystals @ tannic acid-Fe Ⅲ (RPNTF) in vivo tumor tissue profile;
FIG. 9A is a sample of example 1 phenylborated doxorubicin nanocrystals (PNC), phenylborated doxorubicin nanocrystals @ tannic acid-Fe Ⅲ (PNTF), erythrocyte membrane @ phenylboronated doxorubicin nanocrystals (RPNC), erythrocyte membrane @ doxorubicin nanocrystals @ tannic acid-Fe Ⅲ (RNTF), erythrocyte membrane @ phenylboronated doxorubicin nanocrystals @ tannic acid-Fe Ⅲ An in vivo efficacy profile of (RPNTF);
FIG. 9B is a graph showing the phenylboronated doxorubicin nanocrystals (PNC) and phenylboronated doxorubicin nanocrystals @ tannic acid-Fe of example 1 Ⅲ (PNTF), erythrocyte membrane @ phenylboronated doxorubicin nanocrystals (RPNC), erythrocyte membrane @ doxorubicin nanocrystals @ tannic acid-Fe Ⅲ (RNTF), erythrocyte membrane @ phenylboronated doxorubicin nanocrystals @ tannic acid-Fe Ⅲ (RPNTF) tumor weight of in vivo efficacy.
Detailed Description
The technical scheme of the invention is further described below by referring to examples.
Example 1: preparing phenylborated nanocrystalline or non-phenylborated nanocrystalline by anti-solvent precipitation; preparation of phenylborated nanocrystalline @ tannic acid-Fe by mixed ultrasound Ⅲ Doxorubicin nanocrystalline @ tannic acid-Fe Ⅲ The method comprises the steps of carrying out a first treatment on the surface of the Preparation of erythrocyte membrane @ phenylboronated doxorubicin nanocrystalline, erythrocyte membrane @ phenylboronated doxorubicin nanocrystalline @ tannic acid-Fe by mixing ultrasound Ⅲ Erythrocyte membrane @ doxorubicin nanocrystal @ tannic acid-Fe Ⅲ 。
(1) Preparation of phenylborated doxorubicin nanocrystals or doxorubicin nanocrystals
The doxorubicin is modified by 3-carboxyphenylboronic acid to obtain phenylboronated doxorubicin, and the phenylboronated doxorubicin is shown in the above structure. 5mg of phenylboronated doxorubicin or doxorubicin was weighed, 100. Mu.l of DMSO was added to dissolve, 100. Mu.l of phenylboronated doxorubicin solution was slowly dropped into 5ml of water, vigorously stirred at 1500rpm for 10min with a magnetic stirrer, centrifuged at 3000rpm for 10min, and the supernatant was taken to give a clear solution.
(2) Preparation of phenylborated doxorubicin nanocrystalline @ tannic acid-Fe Ⅲ Doxorubicin nanocrystalline @ tannic acid-Fe Ⅲ
Preparing a tannic acid aqueous solution with the concentration of 0.45mg/ml and a ferric trichloride hexahydrate aqueous solution with the concentration of 0.15mg/ml, adding 1ml of tannic acid solution into 5ml of a doxorubicin phenylboronate nanocrystalline solution or a doxorubicin nanocrystalline solution, stirring and mixing for 2min at 1000rpm, performing 200W ultrasonic dispersion for 2min, adding 0.5ml of the ferric trichloride hexahydrate aqueous solution, stirring and mixing for 2min at 1000rpm, performing 200W ultrasonic dispersion for 2min, adjusting the pH to 7.2, and preparing the doxorubicin phenylboronate nanocrystalline @ tannic acid-Fe Ⅲ Or doxorubicin nanocrystalline @ tannic acid-Fe Ⅲ 。
(3) Preparation of erythrocyte membrane @ phenylboronated doxorubicin nanocrystals, erythrocyte membrane @ phenylboronated doxorubicin nanocrystals @ tannic acid-Fe Ⅲ Erythrocyte membrane @ doxorubicin nanocrystal @ tannic acid-Fe Ⅲ
Extracting whole blood to obtain red blood cells, and hypotonically lysing the red blood cells to obtain erythrocyte membranes. According to red cell membrane and phenylborated doxorubicin nanocrystalline @ tannic acid-Fe Ⅲ Or doxorubicin nanocrystalline @ tannic acid-Fe Ⅲ Mixing according to a mass ratio of 1:2, performing vortex mixing at 1000rpm for 2min, performing 500W ultrasonic 1min, centrifuging at 10000g for 20min, adding deionized water, and re-suspending to obtain erythrocyte membrane @ phenylboronated doxorubicin nanocrystalline, erythrocyte membrane @ phenylboronated doxorubicin nanocrystalline @ tannic acid-Fe Ⅲ Erythrocyte membrane @ doxorubicin nanocrystal @ tannic acid-Fe Ⅲ 。
Example 2: microfluidic technology for preparing phenylboronated doxorubicin nanocrystalline @ epigallocatechin gallate (Epigallocatechin gallate, EGCG) and polyvinyl alcohol @ phenylboronated doxorubicin nanocrystalline @ EGCG
(1) Preparation of phenylborated doxorubicin nanocrystals
5mg of doxorubicin phenylboronate is weighed, 1ml of ethanol is added for dissolution, the doxorubicin phenylboronate solution and twice the volume of water are injected into microfluidic equipment, and the flow rate of the doxorubicin phenylboronate solution is regulated to 40 mu l/min and the flow rate of water is regulated to 80 mu l/min, so that a clear solution is obtained.
(2) Preparation of phenylborated doxorubicin nanocrystalline @ EGCG
Preparing 1.2mg/ml of EGCG aqueous solution, injecting 1ml of EGCG solution and 2ml of the prepared phenylboronated doxorubicin nanocrystalline solution into microfluidic equipment, regulating the flow rate of the polyphenol aqueous solution to be 0.5ml/min and the flow rate of the phenylboronated doxorubicin nanocrystalline solution to be 1ml/min to obtain a clear solution, and regulating the pH to be 7.2 to obtain phenylboronated doxorubicin nanocrystalline@EGCG.
(3) Preparation of polyvinyl alcohol @ phenylborated doxorubicin nanocrystalline @ EGCG
Preparing a 3mg/ml polyvinyl alcohol aqueous solution, injecting the prepared phenylboronated doxorubicin nanocrystal@EGCG solution and the prepared polyvinyl alcohol aqueous solution into microfluidic equipment, regulating the flow rate of the phenylboronated doxorubicin nanocrystal@EGCG solution to 80 mu l/ml and the flow rate of the polyvinyl alcohol aqueous solution to 20 mu l/ml, and dialyzing to remove ethanol after the preparation is completed to obtain the polyvinyl alcohol@phenylboronated doxorubicin nanocrystal@EGCG.
Example 3: ultrasonic preparation of phenylboronated doxorubicin nanocrystals, mixing and homogenizing preparation of phenylboronated doxorubicin nanocrystals @ tannic acid, mixing and ultrasonic preparation of liposome @ phenylboronated doxorubicin nanocrystals @ tannic acid
(1) Preparation of phenylborated doxorubicin nanocrystals
5mg of phenylboronated doxorubicin was weighed, 100. Mu.l of DMF was added for dissolution, 100. Mu.l of phenylboronated doxorubicin solution was added dropwise to 5ml of water, stirring was carried out at 1500rpm for 10min, and a 300W probe was sonicated for 10min to give a clear solution.
(2) Preparation of phenylborated doxorubicin nanocrystalline @ tannic acid
Preparing a tannic acid aqueous solution with the concentration of 0.45mg/ml, adding 1ml of tannic acid solution into 5ml of phenylboronated doxorubicin nanocrystalline solution, carrying out vortex mixing at 500rpm for 3min, carrying out high-pressure homogenizing circulation at 1000bar for 5 times, and regulating the pH value to 7.2 to obtain phenylboronated doxorubicin nanocrystalline@tannic acid.
(3) Preparation of Liposome @ phenylborated doxorubicin nanocrystals @ tannic acid
15mg of soybean lecithin, 2mg of cholesterol and 2mg of distearoyl phosphatidylethanolamine-polyethylene glycol 2000 are weighed, 5ml of chloroform is added for dissolution, organic solvent is removed by rotary evaporation at 40 ℃ to prepare a lipid film, vacuum pumping is carried out to remove residual chloroform, 5ml of water is added, and hydration is carried out at 40 ℃ for 30min. Adding the prepared phenylborated doxorubicin nanocrystalline@tannic acid, uniformly mixing, performing ultrasonic treatment for 2min at 300W, and performing ultrafiltration to remove an organic solvent to obtain the liposome@phenylborated doxorubicin nanocrystalline@tannic acid.
Example 4: preparation of benzene borated naproxen nanocrystalline by solvent evaporation and homogenate preparation of benzene borated naproxen nanocrystalline @ EGCG-Fe Ⅲ Preparation of erythrocyte membrane @ benzene borated naproxen nanocrystalline @ EGCG-Fe by extrusion Ⅲ
(1) Preparation of benzene borated naproxen nanocrystalline
The benzene boric acid naproxen is obtained after the naproxen is modified by 3-aminophenylboric acid, and the structure of the benzene boric acid naproxen is shown in the figure. 5mg of benzoboronated naproxen is weighed, 1ml of chloroform is added for dissolution, the benzoboronated naproxen solution is dripped into 5ml of water, vortex is carried out at 500rpm for 10min, a 300W probe is used for ultrasonic treatment for 10min, and a clear solution is obtained after the organic solvent is removed by rotary evaporation.
(2) Preparation of Benzeneboronic naproxen nanocrystalline @ EGCG-Fe Ⅲ
Preparing 1.2mg/ml EGCG aqueous solution and 0.15mg/ml ferric trichloride hexahydrate aqueous solution, adding 1ml EGCG solution into 5ml benzene boronated naproxen nanocrystalline solution, mixing at 500rpm for 3min, adding 05ml of ferric chloride hexahydrate aqueous solution is mixed for 3min by vortex at 500rpm, homogenized for 1min at 1000rpm for dispersion, and pH is regulated to 7.2, thus obtaining the phenylboronated naproxen nanocrystalline @ EGCG-Fe Ⅲ 。
(3) Preparation of erythrocyte membrane @ benzene borated naproxen nanocrystalline @ EGCG-Fe Ⅲ
Extracting whole blood to obtain red blood cells, and hypotonically lysing the red blood cells to obtain erythrocyte membranes. According to erythrocyte membrane and benzene boric acid naproxen nanocrystalline @ EGCG-Fe Ⅲ The mass ratio of the red blood cell membrane to the benzoboronated naproxen nanocrystalline @ EGCG-Fe prepared by the method is 2:5 Ⅲ After vortex mixing at 1000rpm for 2min, extruding and circulating for 2 times by an extruder, centrifuging at 10000g for 20min, collecting precipitate, adding deionized water, and re-suspending to obtain erythrocyte membrane @ phenylboronated naproxen nanocrystalline @ EGCG-Fe Ⅲ 。
Example 5: high-pressure homogenization preparation of benzene borated naproxen nanocrystalline, mixed ultrasonic preparation of benzene borated naproxen nanocrystalline @ digallic acid, and re-dissolution ultrasonic preparation of liposome @ benzene borated naproxen nanocrystalline @ digallic acid
(1) Preparation of benzene borated naproxen nanocrystalline
5mg of benzoboronated naproxen is weighed, 100 μl of DMSO is added for dissolution, 100 μl of benzoboronated naproxen solution is dripped into 5ml of 0.02% polyethylene glycol aqueous solution, high-pressure homogenizing cycle is performed for 5 times at 1000bar, and high-pressure homogenizing cycle is performed for 5 times at 1500bar, so as to obtain a clear solution.
(2) Preparation of Benzeneboronic naproxen nanocrystalline @ digallic acid
Preparing 0.45mg/ml of digallic acid aqueous solution, adding 1ml of digallic acid solution into 5ml of benzene borated naproxen nanocrystalline solution, stirring and mixing at 500rpm for 3min, performing 300W ultrasonic dispersion for 2min, and adjusting pH to 7.2 to obtain benzene borated naproxen nanocrystalline @ digallic acid.
(3) Preparation of Liposome @ Benzeneboronic naproxen nanocrystalline @ digallic acid
15mg of soybean lecithin, 2mg of cholesterol and 2mg of distearoyl phosphatidylethanolamine-polyethylene glycol 2000 are weighed, 5ml of chloroform is added for dissolution, the organic solvent is removed by rotary evaporation at 40 ℃ to prepare a lipid film, and the residual chloroform is removed by vacuum pumping. Adding the prepared benzoboronated naproxen nanocrystalline @ digallic acid, hydrating at 40 ℃ for 30min, performing 300W ultrasonic treatment for 2min, dialyzing, centrifuging and collecting supernatant to obtain the liposome @ benzoboronated naproxen nanocrystalline @ digallic acid.
Example 6: ultrasonic method for preparing benzoboronated naproxen nanocrystalline, ultrasonic mixing for preparing benzoboronated naproxen nanocrystalline @ tannic acid, ultrasonic mixing for preparing erythrocyte membrane @ benzoboronated naproxen nanocrystalline @ tannic acid
(1) Preparation of benzene borated naproxen nanocrystalline
5mg of benzoboronated naproxen is weighed, 100 μl of DMF is added for dissolution, 100 μl of boronated naproxen solution is dripped into 5ml of water, stirring is carried out at 1000rpm for 10min, and a 300W probe is used for ultrasonic treatment for 10min, so as to obtain a clear solution.
(2) Preparation of Benzeneboronized naproxen nanocrystalline @ tannic acid
Preparing a tannic acid aqueous solution with the concentration of 0.45mg/ml, adding 1ml of tannic acid solution into 5ml of benzene borated naproxen nanocrystalline solution, carrying out vortex mixing at 500rpm for 3min, carrying out ultrasonic dispersion at 300W for 2min, and regulating the pH value to 7.2 to obtain the benzene borated naproxen nanocrystalline@tannic acid.
(3) Preparation of erythrocyte membrane @ benzene borated naproxen nanocrystalline @ tannic acid
Extracting whole blood to obtain red blood cells, and hypotonically lysing the red blood cells to obtain erythrocyte membranes. According to the mass ratio of erythrocyte membrane to phenylborated naproxen nanocrystalline @ tannic acid of 1:2, uniformly mixing the erythrocyte membrane with the prepared benzoboronated naproxen nanocrystalline@tannic acid solution, performing ultrasonic treatment at 300W for 2min, centrifuging at 10000g for 20min, collecting precipitate, and adding deionized water to resuspend to obtain the erythrocyte membrane@boronated naproxen nanocrystalline@tannic acid.
Example 7: preparation of phenylboronic acid taxol nanocrystalline by medium grinding and preparation of phenylboronic acid taxol nanocrystalline @ EGCG-Cu by homogenate Ⅱ Liposome @ phenylborated paclitaxel nanocrystalline @ EGCG-Cu prepared by phospholipid dissolution and mixing Ⅱ
(1) Preparation of phenylborated paclitaxel nanocrystalline
The taxol is modified by 4-hydroxymethylphenylboronic acid to obtain phenylboronated taxol, and the phenylboronated taxol has the structure shown in the figure. Weighing 5mg of phenylboronic acid taxol, mixing with 5ml of 0.02% polyvinyl alcohol water solution, uniformly dispersing phenylboronic acid taxol by 200W ultrasonic for 2min, and grinding for 1h by a medium to obtain a clear solution.
(2) Preparation of phenylborated paclitaxel nanocrystalline @ EGCG-Cu Ⅱ
Preparing 1.2mg/ml of EGCG aqueous solution and 0.15mg/ml of copper chloride aqueous solution, adding 1ml of EGCG solution into 5ml of phenylborated taxol nanocrystalline solution, mixing for 2min at 500rpm by vortex, adding 0.5ml of copper chloride aqueous solution, mixing for 2min at 500rpm by vortex, homogenizing for 1min at 2000rpm for dispersion, and regulating pH to 7.2 to obtain phenylborated taxol nanocrystalline @ EGCG-Cu Ⅱ 。
(3) Preparation of Liposome @ phenylborated paclitaxel nanocrystalline @ EGCG-Cu Ⅱ
Weighing 15mg of soybean lecithin, 2mg of cholesterol and 2mg of distearoyl phosphatidylethanolamine-polyethylene glycol 2000, adding 0.3ml of ethanol for dissolution, and adding the mixture into the phenylborated taxol nanocrystalline @ EGCG-Cu prepared by the method Ⅱ The solution is subjected to ultrasonic treatment at 300W for 2min, and the organic solvent is removed by dialysis to obtain liposome @ phenylboronic acid taxol nanocrystalline @ EGCG-Cu Ⅱ 。
Example 8: microfluidic preparation of phenylboronic acid paclitaxel nanocrystalline, mixed ultrasonic preparation of phenylboronic acid paclitaxel nanocrystalline @ tannic acid, and microfluidic preparation of liposome @ phenylboronic acid paclitaxel nanocrystalline @ tannic acid
(1) Preparation of phenylboronic acid paclitaxel nanocrystals 5mg phenylboronic acid paclitaxel was weighed, 1ml of ethanol was added for dissolution, phenylboronic acid paclitaxel solution and twice the water were injected into the microfluidic device, and the flow rate of phenylboronic acid paclitaxel solution was adjusted to 80 μl/min and the flow rate of water was adjusted to 160 μl/min to obtain a clear solution.
(2) Preparation of phenylborated paclitaxel nanocrystalline @ tannic acid
Preparing a tannic acid aqueous solution with the concentration of 0.45mg/ml, adding 1ml of tannic acid solution into the phenylboronic acid taxol nanocrystalline solution prepared by the preparation method, stirring and mixing at 800rpm for 2min, performing ultrasonic dispersion at 300W for 2min, and adjusting the pH value to 7.2 to obtain phenylboronic acid taxol nanocrystalline@tannic acid.
(3) Preparation of Liposome @ phenylborated paclitaxel nanocrystalline @ tannic acid
15mg of soybean lecithin, 2mg of cholesterol and 2mg of distearoyl phosphatidylethanolamine-polyethylene glycol 2000 are weighed, 5ml of chloroform is added for dissolution, organic solvent is removed by rotary evaporation at 40 ℃ to prepare a lipid film, vacuum pumping is carried out to remove residual chloroform, 5ml of water is added, and hydration is carried out at 40 ℃ for 30min. And (3) rapidly mixing the liposome solution with phenylborated taxol nanocrystalline@tannic acid through microfluidic equipment, and dialyzing to remove the organic solvent to obtain the liposome@phenylborated taxol nanocrystalline@tannic acid.
Example 9: homogenizing, high-pressure homogenizing to prepare phenylborated taxol nanocrystalline, mixing ultrasonic to prepare phenylborated taxol nanocrystalline@tannic acid, homogenizing to prepare chitosan@phenylborated taxol nanocrystalline@tannic acid
(1) Preparation of phenylborated paclitaxel nanocrystalline
5mg of phenylborated taxol was weighed and added to 5ml of 0.01% polyvinyl alcohol aqueous solution, homogenized at 7000rpm for 2min, circulated 10 times at 500bar and 10 times at 1000bar to give a clear solution.
(2) Preparation of phenylborated paclitaxel nanocrystalline @ tannic acid
Preparing a tannic acid aqueous solution with the concentration of 0.45mg/ml, adding 1ml of tannic acid solution into 5ml of phenylborated paclitaxel nanocrystalline solution, carrying out ultrasonic dispersion for 2min at 300W after vortex for 3min at 500rpm, and regulating the pH to 7.2 to obtain phenylborated paclitaxel nanocrystalline @ tannic acid.
(3) Preparation of chitosan @ phenylborated paclitaxel nanocrystalline @ tannic acid
Preparing a 3mg/ml chitosan aqueous solution, adding the phenylborated taxol nanocrystalline@tannic acid prepared by the method, and carrying out high-pressure homogenizing circulation for 5 times at 500bar to obtain the chitosan@phenylborated taxol nanocrystalline@tannic acid.
Example 10: reverse-rotationSolvent precipitation method for preparing phenylborated camptothecin nanocrystalline and mixed ultrasonic method for preparing phenylborated camptothecin nanocrystalline @ digallic acid-Cu Ⅱ Preparation of polyethylene glycol@phenylborated camptothecin nanocrystalline@digallic acid-Cu by homogenate Ⅱ
(1) Preparation of phenylborated camptothecin nanocrystals
The camptothecine is modified by 4-carboxyl-3-fluorobenzeneboronic acid to obtain phenylboronated camptothecine, and the phenylboronated camptothecine has the structure shown in the figure. 10mg of phenylborated camptothecin is weighed into 200 μl DMF, added into 10ml of water, stirred at high speed at 1500rpm for 10min, and sonicated for 20min with 300W probe to obtain a clear solution.
(2) Preparation of phenylborated camptothecin nanocrystalline @ digallic acid-Cu Ⅱ
Preparing 0.45mg/ml of digallic acid aqueous solution and 0.2mg/ml of cupric chloride aqueous solution, adding 1ml of digallic acid solution into 10ml of phenylborated camptothecin nanocrystalline solution, stirring and mixing at 500rpm for 3min, dispersing at 800rpm for 5min, adding 0.5ml of cupric chloride aqueous solution, stirring and mixing at 500rpm for 3min, dispersing at 300W for 3min, regulating pH to 7.2, and obtaining phenylborated camptothecin nanocrystalline @ digallic acid-Cu Ⅱ 。
(3) Preparation of polyethylene glycol @ phenylborated camptothecin nanocrystals @ digallic acid-Cu Ⅱ
Preparing 0.2% polyethylene glycol aqueous solution, adding to the prepared phenylborated camptothecin nanocrystalline @ digallic acid-Cu Ⅱ Stirring and mixing the solution at 1000rpm for 5min, homogenizing at 3000rpm for 1min, and dialyzing to remove organic solvent to obtain polyethylene glycol @ phenylborated camptothecin nanocrystalline @ digallic acid-Cu Ⅱ 。
Example 11: preparation of phenylborated camptothecin nanocrystalline by antisolvent precipitation method, preparation of phenylborated camptothecin nanocrystalline @ digallic acid by mixing vortex, and homogenization preparation of liposome @ phenylborated camptothecin nanocrystalline @ digallic acid after liposome redissolution
(1) Preparation of phenylborated camptothecin nanocrystals
10mg of borated camptothecine is weighed into 200. Mu.l of DMF, added into 5ml of water, stirred at a high speed of 1500rpm for 10min and sonicated for 20min by a 300W probe to obtain a clear solution.
(2) Preparation of phenylborated camptothecin nanocrystalline @ digallic acid
Preparing 0.45mg/ml of digallic acid aqueous solution, adding 1ml of digallic acid solution into 5ml of phenylborated camptothecin nanocrystalline solution, stirring and mixing at 800rpm for 3min, dispersing at 800rpm for 5min, and regulating pH to 7.2 to obtain phenylborated camptothecin nanocrystalline@digallic acid.
(3) Preparation of Liposome @ phenylborated camptothecin nanocrystalline @ digallic acid
15mg of soybean lecithin, 2mg of cholesterol and 2mg of distearoyl phosphatidylethanolamine-polyethylene glycol 2000 are weighed, 5ml of chloroform is added for dissolution, the organic solvent is removed by rotary evaporation at 40 ℃ to prepare a lipid film, and the residual chloroform is removed by vacuum pumping. Adding the prepared phenylborated camptothecin nanocrystalline@digallic acid solution, hydrating at 40 ℃ for 30min, homogenizing at 500bar high pressure for 2 times, and dialyzing to remove the organic solvent to obtain the liposome@phenylborated camptothecin nanocrystalline@digallic acid.
Example 12:
the liposome @ phenylborated doxorubicin nanocrystal @ tannic acid prepared in example 3 was freeze-dried and stored with 2% trehalose.
Example 13: formulation characterization of erythrocyte membrane and polyphenol stabilized doxorubicin phenylboronate nanocrystals
Taking the phenylboronated doxorubicin nanocrystalline (PNC) prepared in example 1, phenylboronated doxorubicin nanocrystalline @ tannic acid-Fe Ⅲ (PNTF), doxorubicin nanocrystals @ tannic acid-Fe Ⅲ (NTF), erythrocyte membrane @ phenylboronated doxorubicin nanocrystals (RPNC), erythrocyte membrane @ phenylboronated doxorubicin nanocrystals @ tannic acid-Fe Ⅲ (RPNTF), erythrocyte membrane @ doxorubicin nanocrystalline @ tannic acid-Fe Ⅲ (RNTF) preparation, particle size and potential of the sample were measured by a Markov particle size analyzer. The results are shown in FIGS. 1A and 1BThe variation of particle size and potential of different formulations indicates successful preparation of the target formulation; the shape of RPNTF is observed by a transmission electron microscope, and the result is shown in figure 2, and the target stabilized nanocrystalline preparation has a relatively obvious core-shell structure and relatively good morphological uniformity.
The 6 formulations prepared in example 1 were diluted 30-fold with PBS having a pH of 7.4, and the particle diameters of the diluted samples were measured by a Markov particle diameter meter to examine the dilution stability. As shown in the figure 1A, the dilution stability of the nanocrystalline particles after being coated with the polyphenol metal complex is improved compared with that of the naked nanocrystalline drug, and the phenylboronic acid structure molecule modified drug nanocrystalline further forms phenylboronic acid ester bonds with the polyphenol metal complex on the basis of adhesion, so that the dilution stability of PNTF is higher than that of NTF groups; compared with other control groups, the dilution stability of the RPNTF and RNTF groups obtained by further coating the biomembrane stabilizer outside the bridging layer of the polyphenol metal complex is obviously improved, and the dilution stability of the RPNTF and RNTF groups is especially higher than that of the RPNC groups obtained by directly coating phenylboronated drug nanocrystals with the biomembrane, so that the design of the adhesive polyphenol bridging layer can enhance the acting force of the drug nanocrystals and the external stabilizer and improve the biostability of nanocrystalline drug preparations.
RPNTF and RNTF preparation were diluted 10-fold with PBS containing 10% serum using a medium, placed on a 100rmp shaker at 37 ℃, and the particle size of the samples was measured using a malvern particle sizer, respectively. As shown in fig. 3A and 3B, after the phenylboronic acid drug nanocrystals are stabilized by the polyphenol bridging layer and the outer layer biofilm, the phenylboronic acid drug nanocrystals are more resistant to the simulated physiological environment than the non-phenylboronic acid nanocrystals, thereby further proving the necessity of chemical modification of phenylboronic acid structural molecules in the design of the present invention.
Example 14: characterization of lipid and polyphenol stabilized benzoboronate naproxen nanocrystals
The preparation of the phenylboronated naproxen nanocrystalline @ digallic acid (PNG) and the liposome @ phenylboronated naproxen nanocrystalline @ digallic acid (SCP-PNG) prepared in example 5 was taken, and the particle size and the potential of the sample were directly measured by a Markov particle size meter and the particle size after 30 times dilution with PBS having pH of 7.4 was measured, respectively, so as to compare and examine the dilution stability of the preparation. The results are shown in fig. 4, and the changes of the particle size and the potential of the two preparations indicate successful coating of the outer lipid stabilizer, and the difference of dilution stability proves that the stability of the phenylboronated nanocrystalline is obviously improved after the outer lipid stabilizer is further modified by more phenol monolayer stabilized nanocrystalline.
Example 15: pharmaceutical characterization of polyethylene glycol and polyphenol stabilized phenylborated camptothecin nanocrystals
The phenylborated camptothecin nanocrystalline @ digallic acid-Cu prepared in example 10 was taken Ⅱ (PNGC), polyethylene glycol @ phenylborated camptothecin nanocrystals @ digallic acid-Cu Ⅱ (PEG-PNGC) preparation, the particle size and potential of the sample were directly measured by a Markov particle size analyzer, and the particle size after 30-fold dilution with PBS having pH of 7.4 was measured, respectively, to examine the dilution stability of the preparation by comparison. As shown in figure 5, the changes of the particle size and the potential of the two preparations show that the successful coating of the outer polymer stabilizer and the difference of dilution stability prove that the stability of the phenylboronated nanocrystalline is obviously improved after the outer polymer stabilizer is further modified by more phenol monolayer stabilized nanocrystalline.
Example 16: formulation characterization of polyvinyl alcohol and polyphenol stabilized doxorubicin phenylboronate nanocrystals
The sample particle size and potential were directly measured using a Markov particle size meter and the particle size after 30-fold dilution with PBS having a pH of 7.4 was measured, respectively, to examine the dilution stability of the preparation. As shown in FIG. 6, the changes of the particle size and the potential of the two preparations show that the successful coating of the outer polymer stabilizer and the difference of dilution stability prove that the stability of the phenylboronated nanocrystalline is obviously improved after the outer polymer stabilizer is further modified by more phenol monolayer stabilized nanocrystalline.
The results of examples 14-16 also demonstrate that polyphenols or polyphenol metallo-organic frameworks as bridging layers can effectively expand the range of choice for the external layer stabilizer.
Example 17: in vitro release characterization of erythrocyte membrane and polyphenol stabilized phenylboronated doxorubicin nanocrystals
Taking the RPNTF and RNTF preparation prepared in example 1, and investigating the doxorubicin by dialysisRelease behavior of the element. 2ml of the prepared formulation solution was transferred to a dialysis bag (MWCO: 3000 Da) and 48ml of a release medium (PBS containing 0.1% Tween-80) was placed at 37℃and shaken at 100 rpm. At a predetermined time, 1ml of the release liquid was removed and an equal amount of fresh release medium was added. The concentration of the borated doxorubicin was determined using an enzyme-labeled instrument. The release medium was pH 7.4, pH 5.5 and pH 5.5 plus 10mM H, respectively 2 O 2 . As shown in FIG. 7, on the premise of stabilizing the same biological film and polyphenol, the phenylboronated drug nanocrystalline leaks less and more stably than the unmodified nanocrystalline preparation in the normal physiological environment (pH 7.4), and has pH and active oxygen response drug release characteristics.
Example 18: in vivo distribution characterization of erythrocyte membrane and polyphenol stabilized doxorubicin phenylboronate nanocrystals
Balb/c mice (18-20 g) were randomly divided into 6 groups (n=5), vaccinated in situ with 4T1 cells, tumor size approximately 200mm 3 In this case, PNC, NTF, PNTF, RPNC, RNTF or RPNTF as in example 1 was injected intravenously. After 12h, the tumors were lysed with radioimmunoprecipitation assay buffer (RIPA, 100. Mu.l per 10mg of tumor tissue) and sonicated with an ice-bath probe for 15min. The lysate was centrifuged at 14000g for 10min at 4℃and the supernatant was collected for fluorometry.
The results are shown in fig. 8, and are consistent with the trend of the dilution stability data in fig. 1, which shows that the phenylboronated nanocrystalline pharmaceutical preparation bridged by the polyphenol metal organic framework has excellent physiological stability after the stabilizer is coated on the outer layer, and is beneficial to the accumulation of the phenylboronated nanocrystalline pharmaceutical preparation to solid tumors.
Example 19: in vitro drug effect of erythrocyte membrane and polyphenol stabilized phenylboronated doxorubicin nanocrystalline in 4T1 cell model
Taking 4T1 cells in logarithmic growth phase and good state, digesting with 0.25% trypsin (w/v) to obtain 4T1 cell suspension, centrifuging, re-suspending cells with 1640 medium (v/v) containing 10% fetal bovine serum, counting, and adjusting cell density to 5×10 3 Inoculating into 96-well cell plate, placing cell plate at 37deg.C, 5% CO 2 Incubate overnight in a gas incubator. After the cells had attached, the culture medium in the wells was aspirated and washed 3 times with PBS. Respectively add into The incubation was continued for 48h with PNC, NTF, PNTF, RPNC, RNTF or RPNTF prepared in example 1 diluted to different concentrations with serum free medium. After adding 20. Mu.l MTT solution (5 mg/ml concentration) to each well and further incubating for 4 hours, the medium in the wells was aspirated, then 150. Mu.l DMSO was added to each well, shaking was performed for 10 minutes, and the absorbance value (OD) of each well was measured at 570nm with an ELISA reader sample ). Meanwhile, 4T1 cells are incubated in a serum-free culture medium without preparation as a control group, and a PBS group without cells and samples is a blank group. The absorbance (OD) was measured in the same manner control ，OD blank ). Calculation of survival of 4T1 cells IC for each preparation was calculated as follows 50 Values.
TABLE 1 tumor cell inhibition IC 50 Value of
The results are shown in table 1, with the target formulation group RPNTF exhibiting the highest cytotoxicity based on significantly improved biostability and responsiveness to trigger release.
Example 20: in vivo efficacy of erythrocyte membrane and polyphenol stabilized phenylboronated doxorubicin nanocrystals in 4T1 cell model
Balb/c mice (18-20 g) were randomly divided into 6 groups (n=5), vaccinated in situ with 4T1 cells when tumor size reached 100mm 3 About, physiological saline, PNC, PNTF, RPNC, RNTF or RPNTF in example 1 was intravenously injected, and the dose of doxorubicin phenylboronate was 5mg/kg, once every 3 days, 4 times. The width and length of the tumor were measured during the treatment, and at the end of the experiment, mice were euthanized according to institutional guidelines and the tumor was dissected and weighed.
The tumor volume calculation formula is: tumor volume = length x width/2.
Tumor inhibition = (average weight of control tumor-average weight of experimental tumor)/average weight of control tumor x 100%.
TABLE 2 tumor inhibition rate
The results are shown in Table 2 and FIG. 9, the in vivo effect of each preparation is consistent with the in vitro effect, and the target preparation has better tumor growth inhibition effect, which shows that the phenylboronation and double-layer coated nanocrystals with excellent stability and response release characteristics designed by the invention have obvious in-vivo application effect.

Claims (7)

1. A nanocrystalline drug stabilization system is characterized in that phenylboronic acid modified nanocrystalline drugs, polyphenol or polyphenol metal ion complexes and stabilizers are arranged from inside to outside; the modified nanocrystalline drug is modified by chemical bonding of phenylboronic acid structural molecules and drugs; the polyphenol or polyphenol metal ion complex firstly coats the modified nanocrystalline drug, and then coats the stabilizer on the surface of the nanocrystalline drug;
the medicine is one or more of doxorubicin, naproxen, camptothecine and taxol;
the phenylboronic acid structural molecule is one or more of fluorine substituted or unsubstituted carboxyphenylboronic acid, aminophenylboronic acid and hydroxymethylphenylboronic acid;
The polyphenol is one or more of gallocatechol gallate, digallic acid, tannic acid, quercetin, myricetin, catechol, gallocatechol, epigallocatechin gallate, digalliyl-D-glucose, trigalliyl glucose, tetragalloyl glucose, pentagalloyl glucose, gallic acid, ellagitannin, ellagic acid, hydrolyzed tannin and polydopamine; the metal ion complex is a complex formed by one or more metal ions of Cu (II), fe (III), mn (II), fe (II), co (II), ni (II), zn (II), ca (II), al (III), cr (III), ce (III), tb (III), eu (III) and Ti (IV) and the polyphenol;
the stabilizer is one or more of lipid, biological membrane, high molecular polymer and derivatives thereof; wherein the lipid is selected from one or more of soybean lecithin, egg yolk lecithin, sphingomyelin, hydrogenated lecithin, hydrogenated soybean lecithin, distearoyl phosphatidylethanolamine, cholesterol, the biological membrane is selected from one or more of cell membrane, platelet membrane, bacterial outer membrane, cell derived vesicle, and fusogenic cell membrane, the high molecular polymer and its derivative is selected from one or more of hydroxyethyl starch, cellulose acetate, methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose carbonate, hydroxypropyl methylcellulose succinate acetate, acacia, dextran, chitosan, hyaluronic acid, alginic acid, heparin, albumin, polyacrylic acid, polyhydroxyethyl methacrylate, carbomer, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol-polylactic acid, polyethylene glycol-polycaprolactone, polyoxyethylene castor oil, polyoxyethylene fatty acid esters, poloxamers, polyglycolic acid, polylactic acid, glycolic acid-caprolactone copolymers, polysorbates, polyvinylpyrrolidone, poly (ethyleneimine), d-alpha-tocopheryl 1000 polyethylene glycol succinate, poly (ethylene oxide) -poly (block copolymer);
The preparation method of the nanocrystalline drug stabilization system comprises the following steps:
(1) Preparing a modified nanocrystalline drug;
(2) Preparation of prefabricated systems
The method comprises the following steps: mixing the modified nanocrystalline drug prepared in the step (1) with polyphenol, and adjusting the pH to 7.0-8.0;
the second method is as follows: mixing the modified nanocrystalline drug prepared in the step (1) with polyphenol, then mixing with metal ions, and adjusting the pH to 7.0-8.0;
(3) Stabilization system for preparing nanocrystalline drug
The method comprises the following steps: when the stabilizer is lipid, a biological film or a high molecular polymer and derivatives thereof, mixing the prefabricated system prepared in the step (2) with the stabilizer, and removing the solvent to obtain the nanocrystalline drug stabilizing system;
the second method is as follows: when the stabilizer is lipid or high molecular polymer and derivatives thereof, dispersing the stabilizer into a film, re-dissolving or dispersing and mixing the film by the prefabricated system prepared in the step (2), and removing the solvent to obtain the nanocrystalline drug stabilizing system;
and a third method: when the stabilizer is lipid or a biological membrane, preparing the stabilizer into a vesicle system, mixing the vesicle system with the prefabricated system prepared in the step (2), and removing the solvent to obtain the nanocrystalline drug stabilizing system.
2. The nanocrystalline drug stabilization system according to claim 1, wherein the mass ratio of stabilizer to modified drug nanocrystalline is 100: 1-1: 10.
3. The nanocrystalline drug stabilization system according to claim 1, wherein the particle size is 30 nm to 1000 nm.
4. The nanocrystalline drug stabilization system according to claim 1, wherein the drug loading is 1% -95%.
5. A method for preparing the nanocrystalline drug stabilization system according to any one of claims 1 to 4, comprising the steps of:
(1) Preparing a modified nanocrystalline drug;
(2) Preparation of prefabricated systems
The method comprises the following steps: mixing the modified nanocrystalline drug prepared in the step (1) with polyphenol, and adjusting the pH to 7.0-8.0;
the second method is as follows: mixing the modified nanocrystalline drug prepared in the step (1) with polyphenol, then mixing with metal ions, and adjusting the pH to 7.0-8.0;
(3) Stabilization system for preparing nanocrystalline drug
The method comprises the following steps: when the stabilizer is lipid, a biological film or a high molecular polymer and derivatives thereof, mixing the prefabricated system prepared in the step (2) with the stabilizer, and removing the solvent to obtain the nanocrystalline drug stabilizing system;
the second method is as follows: when the stabilizer is lipid or high molecular polymer and derivatives thereof, dispersing the stabilizer into a film, re-dissolving or dispersing and mixing the film by the prefabricated system prepared in the step (2), and removing the solvent to obtain the nanocrystalline drug stabilizing system;
And a third method: when the stabilizer is lipid or a biological membrane, preparing the stabilizer into a vesicle system, mixing the vesicle system with the prefabricated system prepared in the step (2), and removing the solvent to obtain the nanocrystalline drug stabilizing system.
6. A pharmaceutical composition comprising the nanocrystalline drug stabilization system according to any one of claims 1 to 4 and a pharmaceutically acceptable carrier.
7. Use of a nanocrystalline drug stabilization system according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 6 for the preparation of a disease preventive, therapeutic or disease diagnostic agent for oral, inhalation, injection, ophthalmic, transdermal or mucosal administration.
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014133549A1 (en) * 2013-03-01 2014-09-04 California Institute Of Technology Nanoparticles stabilized with nitrophenylboronic acid compositions
WO2016191816A1 (en) * 2015-06-02 2016-12-08 The University Of Melbourne Glucose sensitive phenylborate acid capsules for insulin delivery
CN108017783A (en) * 2018-01-08 2018-05-11 苏州大学 Polymer with high potency drugs load performance and preparation method and application
CN110801441A (en) * 2019-09-26 2020-02-18 西安交通大学 Capsaicin and adriamycin combined dual-pH-value-response intelligent nano drug delivery system and preparation method and application thereof
CN113181369A (en) * 2021-04-30 2021-07-30 安徽工业大学 Adriamycin prodrug with borate structure and synthesis method thereof
CN113754793A (en) * 2020-06-05 2021-12-07 中国医学科学院药物研究所 Phenylboronic acid grafted chitosan oligosaccharide derivative and preparation method and application thereof
CN114099533A (en) * 2021-11-25 2022-03-01 中国药科大学 Nucleic acid drug delivery system, preparation method, pharmaceutical composition and application

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014133549A1 (en) * 2013-03-01 2014-09-04 California Institute Of Technology Nanoparticles stabilized with nitrophenylboronic acid compositions
WO2016191816A1 (en) * 2015-06-02 2016-12-08 The University Of Melbourne Glucose sensitive phenylborate acid capsules for insulin delivery
CN108017783A (en) * 2018-01-08 2018-05-11 苏州大学 Polymer with high potency drugs load performance and preparation method and application
CN110801441A (en) * 2019-09-26 2020-02-18 西安交通大学 Capsaicin and adriamycin combined dual-pH-value-response intelligent nano drug delivery system and preparation method and application thereof
CN113754793A (en) * 2020-06-05 2021-12-07 中国医学科学院药物研究所 Phenylboronic acid grafted chitosan oligosaccharide derivative and preparation method and application thereof
CN113181369A (en) * 2021-04-30 2021-07-30 安徽工业大学 Adriamycin prodrug with borate structure and synthesis method thereof
CN114099533A (en) * 2021-11-25 2022-03-01 中国药科大学 Nucleic acid drug delivery system, preparation method, pharmaceutical composition and application

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Biocompatible Phenylboronic-Acid-Capped ZnS Nanocrystals Designed As Caps in Mesoporous Silica Hybrid Materials for on-Demand pH-Triggered Release In Cancer Cells;Yolanda Salinas等;ACS Appl. Mater. Interfaces;第10卷(第40期);34029-34038 *
Tannic acid-inspired, self-healing, and dual stimuli responsive dynamic hydrogel with potent antibacterial and anti-oxidative properties;Wen Shi等;J Mater Chem B;第9卷(第35期);7182-7195 *

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