CN111603445B - Nano emulsion drug carrier and preparation method and application thereof - Google Patents
Nano emulsion drug carrier and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a nano-emulsion drug carrier, a preparation method and application thereof. The beta-cyclodextrin is grafted to chitosan quaternary ammonium salt with biological adhesion by utilizing the property of increasing the water solubility of hydrophobic drugs of the beta-cyclodextrin, tacrolimus or other hydrophobic drugs are loaded, and then the principle that polycation and polyanion form polyelectrolyte complex through electrostatic interaction is utilized, the beta-cyclodextrin-chitosan quaternary ammonium salt loaded with the drugs is combined with sodium carboxymethylcellulose solution, so that a target pharmaceutical preparation is obtained; if the loading of tacrolimus or other hydrophobic drugs is omitted, then a nanoemulsion drug carrier is obtained. The nano emulsion drug carrier has good biocompatibility after drug loading, realizes double slow release, can achieve the effect of long-acting treatment, has good stability, uniform particle size, safety and no toxicity, and has wide application.
Description
Technical Field
The invention belongs to the technical field of biomedical polymers, and particularly relates to a nano-emulsion drug carrier, and a preparation method and application thereof.
Background
Dry eye is a multifactorial disorder of the tear and ocular surface, manifested by ocular discomfort, visual disturbances, and instability of the tear film, and potentially damaging to the ocular surface, often associated with ocular surface inflammation. Dry eye appears to be a small problem, affecting people's quality of life, and has been an increasingly serious public health problem, prompting millions of people to seek ophthalmic care. The pathogenesis of the lacrimal gland is very complex, various inducers can influence the normal function of the lacrimal gland through different ways, the reduction of tears enables the ocular surface to be in a relatively dry environment, the ocular surface nerve is excessively stimulated, the autoimmune mechanism is activated, the immune inflammation of the ocular surface and the lacrimal gland is triggered, and the substantive damage of the ocular surface epithelium is caused. Clinically, the dry eye syndrome is mainly treated by locally dripping artificial tears or using medicaments for promoting tear secretion and the like, and the artificial tears can relieve the dry eye syndrome of the eye surface of a patient with mild dry eye syndrome and temporarily stabilize the tear film. As a conventional ophthalmic preparation, eye drops have a simple preparation process, convenient administration and rapid action, but are easily diluted by and excreted from the lacrimal passage with the tear fluid because the drug exists in the form of a solution without bioadhesion, resulting in low bioavailability, and also have a very short action time, which means frequent administration and great inconvenience. In addition, the eye ointment has high viscosity, so that the retention time of the medicine in eyes is prolonged, and the bioavailability is improved. However, in the case of eye ointment, since the water-soluble drug exists in the form of crystal grains and is dissolved only when it comes into contact with lacrimal fluid, it means that the effective concentration of the drug is lowered, and the eye ointment base gives a foreign body sensation to the eyes and, in addition, poor transparency affects the vision, resulting in poor patient compliance. In contrast, the recent advent of ophthalmic drug delivery systems providing novel methods of drug delivery is gradually showing its unique advantages and promise, including micellar systems such as polymeric micelles, microemulsions, liposomes, and the like; particle systems such as nanoparticles, nanocapsules, nanosuspensions, microspheres, nanostructured lipid carriers, solid lipid nanoparticles, and the like; gel systems such as in situ gels, bioadhesive gels, and the like; intercalators and implants, and the like.
Since the recognition of the role of inflammation in dry eye, ocular immunotherapy against dry eye has become a new direction for the treatment of dry eye. Tacrolimus (FK506) is a clinically commonly used immunosuppressant, and can inhibit the expression of inflammatory mediators on the surface of eyes, thereby recovering the secretion of healthy tear film, reducing symptoms and signs and achieving the effect of treating dry eye. Tacrolimus, in turn, is a highly lipophilic macrolide whose hydrophobicity and relatively high molecular weight make it difficult to exist in dissolved form on the corneal surface, which hinders its transport or penetration in the cornea and conjunctiva. Furthermore, nasolacrimal duct drainage, tear irrigation, short residence time of topical solutions further reduce the bioavailability of tacrolimus. Accordingly, there is a need to develop ophthalmic drug carriers and formulations that improve drug solubility, enhance penetration, and prolong pre-corneal residence time.
Disclosure of Invention
In order to overcome the defects and shortcomings in the prior art, the invention aims to provide a preparation method of a nano-emulsion drug carrier. The preparation method comprises the steps of grafting beta-cyclodextrin onto chitosan quaternary ammonium salt with biological adhesiveness by utilizing the property of increasing the water solubility of hydrophobic drugs, and combining the beta-cyclodextrin-chitosan quaternary ammonium salt with sodium carboxymethyl cellulose solution by utilizing the principle that polycation and polyanion form polyelectrolyte complex through electrostatic interaction to obtain the rice emulsion drug carrier.
The invention also aims to provide a nano emulsion drug carrier prepared by the preparation method.
The invention also aims to provide the application of the nano emulsion drug carrier.
The invention further aims to provide a tacrolimus nanoemulsion eye drop and a preparation method thereof, wherein the tacrolimus nanoemulsion eye drop is prepared by grafting beta-cyclodextrin with the performance of increasing the water solubility of hydrophobic drugs onto chitosan quaternary ammonium salt with biological adhesiveness, loading tacrolimus, and combining the beta-cyclodextrin-chitosan quaternary ammonium salt loaded with tacrolimus with sodium carboxymethyl cellulose solution by utilizing the principle that polycation and polyanion form a polyelectrolyte complex through electrostatic interaction. The eye drop has good biocompatibility, is safe to human body, has no toxic effect, and can be used for treating xerophthalmia.
The purpose of the invention is realized by the following technical scheme:
a preparation method of a nano emulsion drug carrier comprises the following steps:
(1) taking a solvent as a reaction medium, reacting beta-cyclodextrin (beta-CD) with maleic anhydride at 60-90 ℃ for 8-12 h, precipitating, washing, carrying out suction filtration, and drying to obtain beta-cyclodextrin maleic acid monoester (CM);
(2) dissolving beta-cyclodextrin maleic acid monoester in water, adding a cross-linking agent for activation for 2-3 h, then adding a chitosan quaternary ammonium salt (HACC) aqueous solution, reacting for 12-36 h at room temperature, dialyzing, and freeze-drying to obtain beta-cyclodextrin maleic acid monoester grafted chitosan quaternary ammonium salt (CMH);
(3) dissolving sodium carboxymethylcellulose (CMC-Na) in water, acidifying for 1-2 h, uniformly mixing chitosan and beta-cyclodextrin maleic acid monoester grafted chitosan quaternary ammonium salt (CMH), adding the mixture into an acidified system, and stirring to obtain the nano emulsion drug carrier.
Preferably, the solvent in step (1) is at least one of N, N-dimethylformamide, pyridine and dimethyl sulfoxide.
Preferably, the molar ratio of the beta-cyclodextrin (beta-CD) to the maleic anhydride in the step (1) is 1: (1-2).
Preferably, the concentration of the beta-cyclodextrin (beta-CD) in the solvent in the step (1) is 0.1-0.2 mol/L.
Preferably, after the reaction beta-cyclodextrin (beta-CD) and maleic anhydride in the step (1) are added into the solvent, the mixture can be stirred at room temperature until the mixture is completely dissolved, and then the temperature is raised for reaction.
Preferably, the precipitating agent used for precipitation in the step (1) is dichloromethane, the washing agent used for washing is acetone, and the drying is vacuum drying.
Preferably, the concentration of the solution obtained by dissolving the beta-cyclodextrin maleic acid monoester in water in the step (2) is 4-8 wt%.
Preferably, the crosslinking agent in the step (2) is a mixture of N-hydroxysuccinimide (NHS) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC), wherein the mass ratio of NHS to EDC is 1: (1-3).
Preferably, the molar ratio of the beta-cyclodextrin maleic acid monoester to the cross-linking agent in the step (2) is (2-4): 1.
preferably, the molar ratio of the beta-cyclodextrin maleic acid monoester in the step (2) to the chitosan quaternary ammonium salt monomer in the chitosan quaternary ammonium salt aqueous solution is (1-2): 1.
preferably, the concentration of the chitosan quaternary ammonium salt (HACC) aqueous solution in the step (2) is 3-6 wt%
Preferably, the dialysis in the step (2) refers to dialysis in water for 2-3 times, and each dialysis lasts for 12-24 hours; the conditions of the freeze-drying are as follows: drying in a freeze dryer at the temperature of minus 90 ℃ for 24-36 h.
Preferably, the concentration of the solution obtained by dissolving the sodium carboxymethylcellulose (CMC-Na) in the step (3) in water is 1-2 wt%.
Preferably, hydrochloric acid with the concentration of 18.2-36.5 wt% is added into the acidification directing system in the step (3) for acidification, wherein the volume ratio of the hydrochloric acid to the sodium carboxymethyl cellulose aqueous solution is (1-2): 30.
preferably, the mass ratio of the sodium carboxymethyl cellulose to the chitosan in the step (3) is 1: (1-2); the mass ratio of the chitosan to the beta-cyclodextrin maleic acid monoester grafted chitosan quaternary ammonium salt is 1: (0.25-0.5).
Preferably, the rotation speed of the stirring in the step (3) is 1000-1200 rpm, and the time is 4-10 h.
The nano emulsion drug carrier prepared by the method.
The application of the nano emulsion drug carrier is provided.
A preparation method of tacrolimus nanoemulsion eye drops comprises the following steps:
(1) taking a solvent as a reaction medium, reacting beta-cyclodextrin (beta-CD) with maleic anhydride at 60-90 ℃ for 8-12 h, precipitating, washing, carrying out suction filtration, and drying to obtain beta-cyclodextrin maleic acid monoester (CM);
(2) dissolving beta-cyclodextrin maleic acid monoester in water, adding a cross-linking agent for activation for 2-3 h, then adding a chitosan quaternary ammonium salt (HACC) aqueous solution, reacting for 12-36 h at room temperature, dialyzing, and freeze-drying to obtain beta-cyclodextrin maleic acid monoester grafted chitosan quaternary ammonium salt (CMH);
(3) adding a tacrolimus (FK506) ethanol solution into a beta-cyclodextrin maleic acid monoester grafted chitosan quaternary ammonium salt water solution under the stirring state, carrying out ultrasonic treatment, stirring, centrifuging, collecting the solution, and freeze-drying to obtain a tacrolimus inclusion;
(4) dissolving sodium carboxymethylcellulose (CMC-Na) in water, acidifying for 1-2 h, uniformly mixing Chitosan (CS) and tacrolimus inclusion, adding the mixture into an acidified system, and stirring to obtain the tacrolimus nano-emulsion eye drops.
Preferably, the solvent in step (1) is at least one of N, N-dimethylformamide, pyridine and dimethyl sulfoxide.
Preferably, the molar ratio of the beta-cyclodextrin (beta-CD) to the maleic anhydride in the step (1) is 1: (1-2).
Preferably, the concentration of the beta-cyclodextrin (beta-CD) in the solvent in the step (1) is 0.1-0.2 mol/L.
Preferably, after the beta-cyclodextrin (beta-CD) and the maleic anhydride are added into the solvent in the step (1), the mixture can be stirred at room temperature until the mixture is completely dissolved, and then the temperature is raised for reaction.
Preferably, the precipitating agent used for precipitation in the step (1) is dichloromethane, and the washing agent used for washing is acetone.
Preferably, the concentration of the solution obtained by dissolving the beta-cyclodextrin maleic acid monoester in water in the step (2) is 4-8 wt%.
Preferably, the crosslinking agent in the step (2) is a mixture of N-hydroxysuccinimide (NHS) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC), wherein the mass ratio of NHS to EDC is 1: (1-3).
Preferably, the molar ratio of the beta-cyclodextrin maleic acid monoester to the cross-linking agent in the step (2) is (2-4): 1.
preferably, the molar ratio of the beta-cyclodextrin maleic acid monoester in the step (2) to the chitosan quaternary ammonium salt monomer in the chitosan quaternary ammonium salt aqueous solution is (1-2): 1.
preferably, the concentration of the chitosan quaternary ammonium salt (HACC) aqueous solution in the step (2) is 3-6 wt%.
Preferably, the dialysis in the step (2) refers to dialysis in water for 2-3 times, and each dialysis lasts for 12-24 hours; the conditions of the freeze-drying are as follows: drying in a freeze dryer at the temperature of minus 90 ℃ for 24-36 h.
Preferably, the concentration of the tacrolimus ethanol solution in the step (3) is 2-4 wt%; the concentration of the beta-cyclodextrin maleic acid monoester grafted chitosan quaternary ammonium salt aqueous solution is 9.8-19.6 wt%.
Preferably, the mass ratio of the tacrolimus in the tacrolimus ethanol solution in the step (3) to the beta-cyclodextrin maleic acid monoester grafted chitosan quaternary ammonium salt in the beta-cyclodextrin maleic acid monoester grafted chitosan quaternary ammonium salt aqueous solution is 1 (49-98).
Preferably, the adding step (3) is to drop tacrolimus ethandiol into the beta-cyclodextrin maleic acid monoester-grafted chitosan quaternary ammonium salt water solution within 2-10 min.
Preferably, the ultrasonic time in the step (3) is 5-10 min; the stirring time is 12-24 h.
Preferably, the conditions of the freeze drying in the step (3) are as follows: drying in a freeze dryer at the temperature of minus 90 ℃ for 24-36 h.
Preferably, the concentration of the solution obtained by dissolving the sodium carboxymethylcellulose (CMC-Na) in the step (4) in water is 1-2 wt%.
Preferably, hydrochloric acid with the concentration of 18.2-36.5 wt% is added into the acidification directing system in the step (4) for acidification, wherein the volume ratio of the hydrochloric acid to the sodium carboxymethyl cellulose aqueous solution is (1-2): 30.
preferably, the mass ratio of the sodium carboxymethyl cellulose to the chitosan in the step (4) is 1: (1-2); the mass ratio of the chitosan to the tacrolimus inclusion is (2-4): 1.
preferably, the rotating speed of the stirring in the step (4) is 1000-1200 rpm, and the time is 4-10 h.
The tacrolimus nanoemulsion eye drops prepared by the method.
The tacrolimus nanoemulsion eye drops are applied to medicine preparation.
The chitosan used in the invention is alkaline polysaccharide formed by monomer beta- (1-4) -2-amino-2-deoxy-D-glucose, has no stimulation effect, good biocompatibility, biological adhesion and biodegradability, and degradation products of the chitosan are nontoxic and can be completely absorbed by organisms, so the chitosan is widely concerned as an ideal drug carrier. The beta-cyclodextrin molecule makes the outer side of the beta-cyclodextrin hydrophilic due to the unique structure, and the inner side of the beta-cyclodextrin molecule is a hydrophobic cavity, so that the beta-cyclodextrin molecule can contain hydrophobic compound molecules, thereby increasing the solubility of the compound. The nanoemulsion eye drops are prepared by grafting beta-cyclodextrin onto chitosan quaternary ammonium salt with biological adhesion, loading tacrolimus and other hydrophobic drugs, have a certain slow release function, and combining the beta-cyclodextrin-chitosan quaternary ammonium salt loaded with tacrolimus and other hydrophobic drugs with sodium carboxymethyl cellulose solution by utilizing the principle that polycation and polyanion form a polyelectrolyte complex through electrostatic interaction, so that the drug-loaded polyelectrolyte complex nanoemulsion eye drops are obtained, double slow release is realized, and long-acting treatment is achieved.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) the drug-loaded polyelectrolyte complex nano-emulsion eye drops or other pharmaceutical preparations are obtained by grafting beta-cyclodextrin onto chitosan quaternary ammonium salt with good biological adhesion, loading hydrophobic drugs such as tacrolimus on a hydrophobic cavity structure of the beta-cyclodextrin, and combining the hydrophobic drugs with sodium carboxymethylcellulose solution, and have good biocompatibility, double slow release is realized, and the effect of long-acting treatment can be achieved.
(2) The tacrolimus nanoemulsion eye drops prepared by the invention have the advantages of good stability, uniform particle size, safety, no toxic effect and good biological adhesion, thereby reducing the administration frequency and improving the bioavailability.
(3) The nano emulsion drug carrier prepared by the invention is not only suitable for tacrolimus, but also suitable for other hydrophobic micromolecular drugs, and has wide application.
Drawings
FIG. 1 is an infrared spectrum of beta-cyclodextrin maleic acid monoester-linked chitosan quaternary ammonium salt obtained in example 1.
FIG. 2 is a DSC chart of Tacrolimus nanoemulsion eye drops obtained in example 1, wherein CMC-Na is sodium carboxymethylcellulose, CS is chitosan, and FK506 is Tacrolimus.
FIG. 3 is the particle size potential diagram of Tacrolimus nanoemulsion ophthalmic solution obtained in example 1 and nanoemulsion drug carrier (no FK506 emulsion) obtained in example 6.
FIG. 4 shows the effect of sustained release of the drug in example 7.
FIG. 5 shows the cytotoxicity results of example 8.
Detailed Description
The present invention will be described in further detail with reference to examples and drawings, but the embodiments of the present invention are not limited thereto.
Those who do not specify specific conditions in the examples of the present invention follow conventional conditions or conditions recommended by the manufacturer. The raw materials, reagents and the like which are not indicated for manufacturers are all conventional products which can be obtained by commercial purchase.
Example 1
(1) Preparation of beta-cyclodextrin maleic acid monoester: at room temperature, 11.34g of beta-cyclodextrin and 9.8g of maleic anhydride are stirred and dissolved in 50ml of N, N-dimethylformamide, heated to 60 ℃ for reaction for 8 hours, precipitated by dichloromethane and washed by acetone, and products are collected by suction filtration and dried to obtain beta-cyclodextrin maleic acid monoester.
(2) Preparing beta-cyclodextrin maleic acid monoester-grafted chitosan quaternary ammonium salt: dissolving 4g of beta-cyclodextrin maleic acid monoester obtained in the step (1) in 50ml of water, and adding 1g of NHS and 1g of EDC into the water to activate the mixture for 2 hours; dissolving 3g of chitosan quaternary ammonium salt in 50ml of water, adding the solution into the solution under magnetic stirring, reacting for 12h at room temperature, dialyzing for 3 times, each time for 12h, freeze-drying, and collecting the product to obtain the beta-cyclodextrin maleic acid monoester-connected chitosan quaternary ammonium salt.
(3) Preparation of tacrolimus inclusion: dissolving 0.98g of beta-cyclodextrin maleic acid monoester-linked chitosan quaternary ammonium salt obtained in the step (2) in 10ml of water; dissolving 0.02g of tacrolimus in 1ml of absolute ethyl alcohol, dropwise adding the solution into the solution within 2mins under magnetic stirring, carrying out ultrasonic treatment for 5min, stirring for 12h, centrifuging, collecting the solution, placing the solution at-20 ℃, storing, solidifying and freezing, and freeze-drying at-90 ℃ for 24h to obtain a tacrolimus inclusion; the mass ratio of the beta-cyclodextrin maleic acid monoester-grafted chitosan quaternary ammonium salt to the tacrolimus is 49: 1.
(4) Preparing the nanoemulsion eye drops: adding 0.6g of sodium carboxymethylcellulose into 30ml of water, stirring and dissolving at the rotating speed of 1000rpm until the solution is clear and transparent, adding 1ml of hydrochloric acid with the concentration of 36.5 wt% and acidifying for 1 h; and (3) uniformly mixing 0.6g of chitosan and 0.3g of tacrolimus inclusion, adding the mixture into the solution, and continuously stirring for 4 hours to finally obtain the polyelectrolyte nano-emulsion eye drops.
Example 2
(1) Preparation of beta-cyclodextrin maleic acid monoester: at room temperature, 11.34g of beta-cyclodextrin and 19.6g of maleic anhydride are stirred and dissolved in 100ml of N, N-dimethylformamide, the temperature is increased to 90 ℃, the reaction lasts for 12 hours, dichloromethane precipitation and acetone washing are carried out, products are collected by suction filtration, and drying is carried out to obtain the beta-cyclodextrin maleic acid monoester.
(2) Preparing beta-cyclodextrin maleic acid monoester-grafted chitosan quaternary ammonium salt: dissolving 2g of beta-cyclodextrin maleic acid monoester obtained in the step (1) in 50ml of water, and adding 0.5g of NHS and 1.5g of EDC to activate for 3 h; dissolving 1.5g of chitosan quaternary ammonium salt in 25ml of water, adding the solution into the solution under magnetic stirring, reacting for 36h at room temperature, dialyzing for 3 times, each time for 24h, freeze-drying, and collecting the product to obtain the beta-cyclodextrin maleic ester-linked chitosan quaternary ammonium salt.
(3) Preparation of tacrolimus inclusion: dissolving 1.96g of beta-cyclodextrin maleic acid monoester-linked chitosan quaternary ammonium salt obtained in the step (2) in 10ml of water; dissolving 0.02g of tacrolimus in 0.5ml of absolute ethyl alcohol, dropwise adding the solution into the solution within 2mins under magnetic stirring, carrying out ultrasonic treatment for 10min, stirring for 24h, centrifuging, collecting the solution, placing the solution at-20 ℃, storing, solidifying and freezing, and freeze-drying at-90 ℃ for 36h to obtain a tacrolimus inclusion; the mass ratio of the beta-cyclodextrin maleic acid monoester-grafted chitosan quaternary ammonium salt to the tacrolimus is 98: 1.
(4) Preparing the nanoemulsion eye drops: adding 0.6g of sodium carboxymethylcellulose into 30ml of water, stirring and dissolving at the rotation speed of 1200rpm until the solution is clear and transparent, adding 2ml of hydrochloric acid with the concentration of 18.2 wt%, and acidifying for 2 hours; and (3) uniformly mixing 1.2g of chitosan and 0.6g of tacrolimus inclusion, adding the mixture into the solution, and continuously stirring for 10 hours to finally obtain the polyelectrolyte nano-emulsion eye drops.
Example 3
(1) Preparation of beta-cyclodextrin maleic acid monoester: at room temperature, 11.34g of beta-cyclodextrin and 14.4g of maleic anhydride are stirred in a solvent in 75ml of pyridine, heated to 75 ℃ for reaction for 10 hours, precipitated by dichloromethane and washed by acetone, and products are collected by suction filtration and dried to obtain beta-cyclodextrin maleic acid monoester.
(2) Preparing beta-cyclodextrin maleic acid monoester-grafted chitosan quaternary ammonium salt: dissolving 4g of beta-cyclodextrin maleic monoester obtained in the step (1) in 50ml of water, and adding 1g of NHS and 1.5g of EDC into the water to activate the mixture for 2.5 h; dissolving 3g of chitosan quaternary ammonium salt in 100ml of water, adding the solution into the solution under magnetic stirring, reacting for 24 hours at room temperature, dialyzing for 3 times, each time for 18 hours, freeze-drying, and collecting the product to obtain the beta-cyclodextrin maleic monoester-linked chitosan quaternary ammonium salt.
(3) Preparation of tacrolimus inclusion: dissolving 1.47g of beta-cyclodextrin maleic acid monoester-linked chitosan quaternary ammonium salt obtained in the step (2) in 10ml of water; dissolving 0.02g of tacrolimus in 0.75ml of absolute ethyl alcohol, dropwise adding the solution into the solution within 2min under magnetic stirring, carrying out ultrasonic treatment for 7min, stirring for 18h, centrifuging, collecting the solution, storing the solution at-20 ℃, freezing and freezing, and freeze-drying at-90 ℃ for 30h to obtain a tacrolimus inclusion; the mass ratio of the beta-cyclodextrin maleic acid monoester-grafted chitosan quaternary ammonium salt to the tacrolimus is 73.5: 1.
(4) Preparing the nanoemulsion eye drops: adding 0.3g of sodium carboxymethylcellulose into 30ml of water, stirring and dissolving at the rotation speed of 1100rpm until the solution is clear and transparent, adding 1ml of hydrochloric acid with the concentration of 18.2 wt% and acidifying for 1.5 h; and (3) uniformly mixing 0.45g of chitosan and 0.15g of tacrolimus inclusion, adding the mixture into the solution, and continuously stirring for 7 hours to finally obtain the polyelectrolyte nano-emulsion eye drops.
Example 4
(1) Preparation of beta-cyclodextrin maleic acid monoester: at room temperature, 11.34g of beta-cyclodextrin and 9.8g of maleic anhydride are stirred and dissolved in 60ml of N, N-dimethylformamide, heated to 60 ℃ for reaction for 12 hours, precipitated by dichloromethane and washed by acetone, and products are collected by suction filtration and dried to obtain beta-cyclodextrin maleic acid monoester.
(2) Preparing beta-cyclodextrin maleic acid monoester-grafted chitosan quaternary ammonium salt: dissolving 4g of beta-cyclodextrin maleic acid monoester obtained in the step (1) in 50ml of water, and adding 1g of NHS and 2g of EDC into the water to activate the mixture for 2 h; dissolving 3g of chitosan quaternary ammonium salt in 75ml of water, adding the solution into the solution under magnetic stirring, reacting for 36h at room temperature, dialyzing for 3 times, each time for 12h, freeze-drying, and collecting the product to obtain the beta-cyclodextrin maleic acid monoester-connected chitosan quaternary ammonium salt.
(3) Preparation of tacrolimus inclusion: dissolving 0.98g of beta-cyclodextrin maleic acid monoester-linked chitosan quaternary ammonium salt obtained in the step (2) in 10ml of water; dissolving 0.02g of tacrolimus in 1ml of absolute ethyl alcohol, dropwise adding the solution into the solution within 2mins under magnetic stirring, carrying out ultrasonic treatment for 10min, stirring for 12h, centrifuging, collecting the solution, placing the solution at-20 ℃, storing, solidifying and freezing, and freeze-drying at-90 ℃ for 24h to obtain a tacrolimus inclusion; the mass ratio of the beta-cyclodextrin maleic acid monoester-grafted chitosan quaternary ammonium salt to the tacrolimus is 49: 1.
(4) Preparing the nanoemulsion eye drops: adding 0.45g of sodium carboxymethylcellulose into 30ml of water, stirring and dissolving at the rotation speed of 1200rpm until the solution is clear and transparent, adding 1ml of hydrochloric acid with the concentration of 22.5 wt% and acidifying for 1 h; and (3) uniformly mixing 0.6g of chitosan and 0.3g of tacrolimus inclusion, adding the mixture into the solution, and continuously stirring for 10 hours to finally obtain the polyelectrolyte nano-emulsion eye drops.
Example 5
(1) Preparation of beta-cyclodextrin maleic acid monoester: at room temperature, 11.34g of beta-cyclodextrin and 19.6g of maleic anhydride are stirred and dissolved in 100ml of dimethyl sulfoxide, the temperature is increased to 90 ℃, the reaction lasts for 8 hours, dichloromethane precipitation and acetone washing are carried out, products are collected by suction filtration, and drying is carried out, so as to obtain the beta-cyclodextrin maleic acid monoester.
(2) Preparing beta-cyclodextrin maleic acid monoester-grafted chitosan quaternary ammonium salt: dissolving 3g of beta-cyclodextrin maleic acid monoester obtained in the step (1) in 50ml of water, and adding 0.5g of NHS and 0.5g of EDC to activate for 3 h; dissolving 2.25g of chitosan quaternary ammonium salt in 50ml of water, adding the solution into the solution under magnetic stirring, reacting for 12h at room temperature, dialyzing for 3 times, each time for 24h, freeze-drying, and collecting the product to obtain the beta-cyclodextrin maleic acid monoester-connected chitosan quaternary ammonium salt.
(3) Preparation of tacrolimus inclusion: dissolving 0.98g of beta-cyclodextrin maleic acid monoester-linked chitosan quaternary ammonium salt obtained in the step (2) in 10ml of water; dissolving 0.02g of tacrolimus in 0.5ml of absolute ethyl alcohol, dropwise adding the solution into the solution within 2mins under magnetic stirring, carrying out ultrasonic treatment for 5min, stirring for 24h, centrifuging, collecting the solution, placing the solution at-20 ℃, storing, solidifying and freezing, and freeze-drying at-90 ℃ for 24h to obtain the tacrolimus inclusion.
(4) Preparing the nanoemulsion eye drops: adding 0.6g of sodium carboxymethylcellulose into 30ml of water, stirring and dissolving at the rotating speed of 1000rpm until the solution is clear and transparent, adding 1ml of hydrochloric acid with the concentration of 36.5 wt% and acidifying for 2 hours; and (3) uniformly mixing 1.2g of chitosan and 0.3g of tacrolimus inclusion, adding the mixture into the solution, and continuously stirring for 4 hours to finally obtain the polyelectrolyte nano-emulsion eye drops.
Example 6 preparation of nanoemulsion drug vehicle (no FK506 emulsion)
(1) Preparation of beta-cyclodextrin maleic acid monoester: at room temperature, 11.34g of beta-cyclodextrin and 9.8g of maleic anhydride are stirred and dissolved in 80ml of N, N-dimethylformamide, the temperature is raised and heated to 60 ℃, the reaction lasts 8 hours, dichloromethane precipitation and acetone washing are carried out, products are collected by suction filtration, and drying is carried out to obtain the beta-cyclodextrin maleic acid monoester.
(2) Preparing beta-cyclodextrin maleic acid monoester-grafted chitosan quaternary ammonium salt: dissolving 4g of beta-cyclodextrin maleic monoester obtained in the step (1) in 50ml of water, and adding 1g of NHS and 1g of EDC into the water to activate the mixture for 2 hours; dissolving 3g of chitosan quaternary ammonium salt in 50ml of water, adding the solution into the solution under magnetic stirring, reacting for 12h at room temperature, dialyzing for 3 times, each time for 12h, freeze-drying, and collecting the product to obtain the beta-cyclodextrin maleic acid monoester-connected chitosan quaternary ammonium salt.
(3) Preparation of nanoemulsion drug carrier (no FK506 emulsion): adding 0.6g of sodium carboxymethylcellulose into 30ml of water, stirring and dissolving at the rotating speed of 1000rpm until the solution is clear and transparent, adding 1ml of hydrochloric acid with the concentration of 36.5 wt% and acidifying for 1 h; 0.6g of chitosan and 0.3g of beta-cyclodextrin maleic acid monoester-linked chitosan quaternary ammonium salt are uniformly mixed, added into the solution and continuously stirred for 4 hours to finally obtain the nano-emulsion drug carrier (without FK506 emulsion).
Example 7 drug Release test
The tacrolimus nanoemulsion eye drops prepared according to the method of example 1 are filled into a dialysis bag, and are shaken in a 0.01mol/L PBS (phosphate buffer solution) with the pH value of 7.4 at 37 ℃ in a shaking table, 2mL of the PBS containing the drug is taken out at regular time, 2mL of fresh PBS is added immediately, the light absorption value of the taken liquid (the PBS containing the drug) is detected, and the slow release rule of the drug is researched.
As shown in fig. 4, the release process of the drug can be divided into three stages, wherein in the first stage, the drug is released quickly within 0-60 hours, and the cumulative release rate reaches 43%; the second stage is a zero-order release stage of the medicine within 60-90 hours, and the accumulative release rate of the medicine reaches 57%; the third stage of drug release is after 90 hours, the drug release rate begins to slow down, and finally reaches equilibrium within 120 hours, and the cumulative release rate is 68%; the slow release of the medicine can be obtained, and the medicine finally tends to be stable and has long-acting slow release effect.
Example 8 tacrolimus nanoemulsion eye drop cytotoxicity assay experiment
Cytotoxicity was measured using mouse fibroblast cells L929 using the CCK8 kit. The scheme is as follows: the recovered L929 cells were cultured in high-glucose DMEM (10% serum) medium (37 ℃, 5% CO)2Under the condition of (1), taking cells in logarithmic growth phase for standby; the cell density is 2X 104cells/mL of the cell suspension were seeded into 96-well plates (200. mu.L/well) and cultured for 24 hours; after 4 hours, the medium in the 96-well plate was removed and the cell culture plate was rinsed with PBS buffer, then tacrolimus nanoemulsion eye drops (10, 20, 50, 100, 200 μ L) prepared in example 1 were added to each well, each group was repeated 3 times, followed by 24 hours of incubation, after a preset time, CCK8 solution (20 μ L/well) was added, incubation was continued for 4 hours, and the absorbance of the solution was measured at 450 nm. Similarly, a nanoemulsion drug carrier (obtained in example 6) without tacrolimus drug was added to each well, and other experimental conditions were consistent with those of the experimental group, and cytotoxicity assay was performed as a negative control group; 0.09% physiological saline was added to each well, and cytotoxicity was measured under the same other experimental conditions as those in the experimental group, as a blank control group.
Calculating the survival rate of the mouse fibroblast according to the absorbance result, wherein the survival rate is more than 75 percent and the mouse fibroblast is considered to have no cytotoxicity; survival rates were less than 50%, considered cytotoxic.
The cell viability calculation formula is as follows:
from fig. 5, it can be seen that the survival rate of the L929 cells is not obviously changed along with the increase of the dosage of the tacrolimus nanoemulsion eye drops, and the survival rate of the L929 cells is always kept above 75%, which indicates that the tacrolimus nanoemulsion eye drops have no cytotoxicity within the dosage range.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. A preparation method of a nano emulsion drug carrier is characterized by comprising the following steps:
(1) taking a solvent as a reaction medium, reacting beta-cyclodextrin and maleic anhydride at 60-90 ℃ for 8-12 h, precipitating, washing, filtering, and drying to obtain beta-cyclodextrin maleic acid monoester;
(2) dissolving beta-cyclodextrin maleic acid monoester in water, adding a cross-linking agent for activation for 2-3 h, then adding a chitosan quaternary ammonium salt aqueous solution, reacting at room temperature for 12-36 h, dialyzing, and freeze-drying to obtain beta-cyclodextrin maleic acid monoester grafted chitosan quaternary ammonium salt;
(3) dissolving sodium carboxymethylcellulose in water, acidifying for 1-2 h, uniformly mixing chitosan and beta-cyclodextrin maleic acid monoester grafted chitosan quaternary ammonium salt, adding the mixture into an acidified system, and stirring to obtain the nano emulsion drug carrier.
2. The method for preparing a nanoemulsion drug carrier according to claim 1, wherein the molar ratio of the beta-cyclodextrin to the maleic anhydride in the step (1) is 1: (1-2);
the molar ratio of the beta-cyclodextrin maleic acid monoester to the cross-linking agent in the step (2) is (2-4): 1;
the molar ratio of the beta-cyclodextrin maleic acid monoester in the step (2) to the chitosan quaternary ammonium salt monomer in the chitosan quaternary ammonium salt aqueous solution is (1-2): 1;
the mass ratio of the sodium carboxymethylcellulose to the chitosan in the step (3) is 1: (1-2); the mass ratio of the chitosan to the beta-cyclodextrin maleic acid monoester grafted chitosan quaternary ammonium salt is 1: (0.25 to 0.5);
the cross-linking agent in the step (2) is a mixture of N-hydroxysuccinimide and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, wherein the mass ratio of NHS to EDC is 1: (1-3).
3. The method for preparing a nanoemulsion drug carrier according to claim 1 or 2, wherein the concentration of the beta-cyclodextrin in the solvent in the step (1) is 0.1-0.2 mol/L; the concentration of a solution obtained by dissolving the beta-cyclodextrin maleic acid monoester in water in the step (2) is 4-8 wt%; the concentration of the chitosan quaternary ammonium salt water solution in the step (2) is 3-6 wt%; the concentration of the solution obtained by dissolving the sodium carboxymethylcellulose in water in the step (3) is 1-2 wt%; and (3) adding hydrochloric acid with the concentration of 18.2-36.5 wt% into the acidification directing system for acidification, wherein the volume ratio of the hydrochloric acid to the sodium carboxymethylcellulose aqueous solution is (1-2): 30, of a nitrogen-containing gas; and (4) stirring in the step (3) at the rotating speed of 1000-1200 rpm for 4-10 h.
4. A nanoemulsion drug carrier prepared by the method of any one of claims 1 to 3.
5. Use of a nanoemulsion drug carrier according to claim 4 in the preparation of a drug.
6. A preparation method of tacrolimus nanoemulsion eye drops is characterized by comprising the following steps:
(1) taking a solvent as a reaction medium, reacting beta-cyclodextrin and maleic anhydride at 60-90 ℃ for 8-12 h, precipitating, washing, filtering, and drying to obtain beta-cyclodextrin maleic acid monoester;
(2) dissolving beta-cyclodextrin maleic acid monoester in water, adding a cross-linking agent for activation for 2-3 h, then adding a chitosan quaternary ammonium salt aqueous solution, reacting at room temperature for 12-36 h, dialyzing, and freeze-drying to obtain beta-cyclodextrin maleic acid monoester grafted chitosan quaternary ammonium salt;
(3) adding a tacrolimus ethanol solution into a beta-cyclodextrin maleic acid monoester grafted chitosan quaternary ammonium salt aqueous solution under the stirring state, carrying out ultrasonic treatment, stirring, centrifuging, collecting the solution, and freeze-drying to obtain a tacrolimus inclusion;
(4) dissolving sodium carboxymethylcellulose in water, acidifying for 1-2 h, uniformly mixing chitosan and tacrolimus inclusion, adding the mixture into an acidified system, and stirring to obtain the tacrolimus nano-emulsion eye drops.
7. The method for preparing Tacrolimus nanoemulsion eye drops according to claim 6, wherein the molar ratio of the beta-cyclodextrin to the maleic anhydride in the step (1) is 1: (1-2); the molar ratio of the beta-cyclodextrin maleic acid monoester to the cross-linking agent in the step (2) is (2-4): 1;
the molar ratio of the beta-cyclodextrin maleic acid monoester in the step (2) to the chitosan quaternary ammonium salt monomer in the chitosan quaternary ammonium salt aqueous solution is (1-2): 1;
the concentration of the tacrolimus ethanol solution in the step (3) is 2-4 wt%; the concentration of the beta-cyclodextrin maleic acid monoester grafted chitosan quaternary ammonium salt aqueous solution is 9.8-19.6 wt%;
the mass ratio of the tacrolimus in the tacrolimus ethanol solution to the beta-cyclodextrin maleic acid monoester grafted chitosan quaternary ammonium salt in the beta-cyclodextrin maleic acid monoester grafted chitosan quaternary ammonium salt aqueous solution in the step (3) is 1 (49-98);
the mass ratio of the sodium carboxymethylcellulose to the chitosan in the step (4) is 1: (1-2); the mass ratio of the chitosan to the tacrolimus inclusion is (2-4): 1.
8. the method for preparing Tacrolimus nanoemulsion eye drops according to claim 6 or 7, wherein the concentration of the beta-cyclodextrin in the solvent in the step (1) is 0.1-0.2 mol/L; the concentration of a solution obtained by dissolving the beta-cyclodextrin maleic acid monoester in water in the step (2) is 4-8 wt%; the cross-linking agent in the step (2) is a mixture of N-hydroxysuccinimide and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, wherein the mass ratio of NHS to EDC is 1: (1-3);
the concentration of the chitosan quaternary ammonium salt water solution in the step (2) is 3-6 wt%; the concentration of the solution obtained by dissolving the sodium carboxymethylcellulose in water in the step (4) is 1-2 wt%; and (4) adding hydrochloric acid with the concentration of 18.2-36.5 wt% into the acidification directing system for acidification, wherein the volume ratio of the hydrochloric acid to the sodium carboxymethylcellulose aqueous solution is (1-2): 30, of a nitrogen-containing gas; and (4) stirring at the rotating speed of 1000-1200 rpm for 4-10 h.
9. A Tacrolimus nanoemulsion eye drop prepared by the method of any one of claims 6 to 8.
10. Use of a tacrolimus nanoemulsion eye drop according to claim 9 in the preparation of a medicament.
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| CN108721251A (en) * | 2018-08-14 | 2018-11-02 | 厦门大学附属第医院 | Target the drug-loading system and its preparation method and application of grafted by beta cyclodextrin chitosan ionomer nanoparticle |
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