CN112999196B - Mortierella lignicola nano preparation for long-acting stable release and preparation method thereof - Google Patents

Mortierella lignicola nano preparation for long-acting stable release and preparation method thereof Download PDF

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CN112999196B
CN112999196B CN202110233932.0A CN202110233932A CN112999196B CN 112999196 B CN112999196 B CN 112999196B CN 202110233932 A CN202110233932 A CN 202110233932A CN 112999196 B CN112999196 B CN 112999196B
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mycophenolate mofetil
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CN112999196A (en
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李科
周韵
左杨
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Xian Medical University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/5123—Organic compounds, e.g. fats, sugars
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Abstract

The invention discloses a mycophenolate mofetil nanometer preparation for long-acting stable release and a preparation method thereof. According to the invention, MMF is prepared into a nanoparticle preparation, ellagic acid is used for enhancing the stability of pi bond accumulation between MMF molecules and PDA nano-package materials, the defect of the existing PDA nano-drug-carrying particle preparation process is overcome, the yield in the production process of the monodisperse MMF nanoparticle preparation can be effectively ensured, and related materials are clinical common auxiliary materials and drugs, so that the safety is ensured. The nano medicine carrying particles prepared by the method have uniform and moderate particle size, good monodispersity and more stable entrapment performance.

Description

Mortierella lignicola nano preparation for long-acting stable release and preparation method thereof
Technical Field
The invention belongs to the technical field of nano preparations, and particularly relates to a mycophenolate mofetil nano preparation for long-acting stable release.
Background
Organ transplantation is the final choice for the end stage of various organ failure diseases, and the patient receiving transplantation needs to take proper immunosuppressant for life, otherwise, the organism can generate rejection reaction mediated by cellular immunity and humoral immunity, and the survival rate of transplanted organs is seriously influenced. The mycophenolic acid (mycophenolic acid, MPA) has high selective effect on lymphocytes, is a highly efficient selective, reversible and non-competitive hypoxanthine mononucleotide dehydrogenase inhibitor, and can inhibit the synthesis of guanine nucleotides in lymphocytes, thereby inhibiting the proliferation of lymphocytes so as to effectively prevent the occurrence of immune rejection. Mycophenolate mofetil (Mycophenolate Mofetil, MMF) is a 2-acetate ester of MPA, has a longer half-life than MPA and is more metabolically stable, and thus MMF can be used as an immunosuppressant for preventing organ transplant rejection. In the current MMF medication scheme, patients receiving organ transplantation need to take the drug continuously for a long time, so that the incidence rate of toxic and side effects of the drug is high, particularly including digestive system diseases such as colonitis, serious infection caused by immunosuppression, respiratory symptoms such as respiratory failure, bone marrow suppression and the like, and the risk of increasing the occurrence of lymphomas and other malignant tumors exists due to the fact that the drug is often combined with glucocorticoid. If the blood concentration can be stably maintained within the therapeutic window for a long period of time while the administration frequency is reduced, the therapeutic effect of MMF can be more stable and the incidence of toxic and side effects can be reduced. Therefore, the development of a MMF long-acting slow-release controlled-release preparation has potential and wide requirements.
Polydopamine (PDA) can be produced by oxidation and self-polymerization of dopamine (dopamine) in an alkaline environment, and due to its excellent adhesion, PDA can be deposited and attached on various material surfaces and form a bionic coating, for example, in patent CN202011080736.6 of Zhang Dawei, yang Jingzhi, ma Lingwei, li Xiaogang, a polydopamine zwitterionic copolymer is cured on a medical metal surface to form a film, and the polydopamine zwitterionic antibacterial coating can be used for development of medical instruments and implant materials. The reaction conditions are further controlled, and the PDA can coat the medicine by means of pi-pi conjugation between the PDA and benzene rings in various medicine structures, so that medicine load is realized, and further, a corresponding nanoparticle preparation is prepared, and after administration, the nanometer packaging material, namely the PDA, is gradually and stably degraded in the body, so that long-acting slow release of the medicine can be realized. The nanoparticle preparation has the advantages of high biocompatibility, good stability, stable degradability, obvious improvement of the metabolic stability of the drug, and the like.
Although the above-described nano-drug carrier technology has been gradually developed and PDA has been applied in many aspects, PDA nanoparticles prepared by simple reaction still have some drawbacks in the existing technology. For example, in patent CN201910046351.9 of Xu Li, shotty and Li Yinping, glucose is used as a targeting molecule, and is connected to a PDA material through a covalent bond, and then an anti-tumor drug is loaded after PDA nanoparticles are formed as a targeting molecule, so that the drug loading rate of the nanoparticles prepared by the process is as low as 10.03%, and the high-efficiency loading of the drug cannot be realized. In patent CN202010934764.3 of Ding Yang, zhang Huaqing, chen Jie et al, although the process of the above patent is improved, the anti-tumor drug and tumor targeting protein are combined with PDA before the drug-loaded nanoparticle is produced, the obtained nanoparticle still has the defects of unstable drug release rate, obviously increased cytotoxicity after the drug concentration is properly increased, and the like.
The deeper level of the disadvantages of the PDA nano drug-loaded particles is that the PDA and the drug to be loaded have differences in molecular structure, physicochemical properties and the like, so that the stability of pi bond accumulation between the PDA and the drug molecules is not high.
Ellagic acid is a widely-existing natural polyphenol substance, and the structure of polyphenol dilactone in molecules of ellagic acid is verified to enhance the stability of pi bond accumulation between PDA and drug molecules, and can obviously improve the entrapment performance and release stability of PDA nano drug-loaded particles. Moreover, ellagic acid has obvious inhibition effect on cancers induced by chemical substances and other cancers, and can reduce the risk of MMF inducing malignant tumors. Thus, ellagic acid can be used as a stabilizer for PDA-entrapped mycophenolate mofetil nanoparticles, and there is no report of the use of ellagic acid in related aspects.
Disclosure of Invention
The invention aims to provide a mycophenolate mofetil nanometer preparation for long-acting stable release, and the prepared nanometer medicine carrying particles have uniform and moderate particle size, good monodispersity and more stable entrapment performance.
Another object of the present invention is to provide a method for preparing the mycophenolate mofetil nano-formulation for long-acting stable release.
The first technical scheme adopted by the invention is as follows: a preparation method of a mycophenolate mofetil nanometer preparation for long-acting stable release, which comprises the following steps:
step 1, preparing mother liquor required by preparation:
mixing mycophenolate mofetil and poloxamer according to the mass ratio of 2:1-4:1, and then mixing with dimethyl sulfoxide according to the mass-volume ratio of 20 mg to 1 ml to prepare a mycophenolate mofetil and poloxamer mixed mother liquor;
preparing ellagic acid dimethyl sulfoxide solution with concentration of 20 mg/ml to obtain ellagic acid mother liquor;
preparing a Tris aqueous solution with the concentration of 30 mg/ml, and regulating the pH value of the solution to 8.8-9.0 by using dilute hydrochloric acid to prepare a Tris-HCl mother solution;
preparing a dopamine hydrochloride aqueous solution with the concentration of 20 mg/ml to prepare a dopamine hydrochloride mother solution;
step 2, dripping the mixed mother solution of mycophenolate mofetil and poloxamer into Tris-HCl mother solution with the volume of 10-15 times, continuously stirring the mixed solution during the period, and performing ultrasonic dispersion on the mixed solution by using an ultrasonic cleaning machine to obtain mycophenolate mofetil nano micelle dispersion liquid at the stirring speed of 1800-2000 rpm;
step 3, adding 1 volume of ellagic acid mother liquor into 10 volumes of mycophenolate mofetil nano micelle dispersion liquid, continuously stirring the solution during the period, wherein the stirring speed is 1000-1500 revolutions per minute, and then carrying out ultrasonic treatment on the mixed solution by using an ultrasonic cleaner;
step 4, adding 2 volumes of dopamine hydrochloride mother solution into 10 volumes of mixed solution, and finally transferring the mixed solution into a sealed tube for light-shielding rotary reaction at 25-28 ℃ for 48-72 hours;
and 5, centrifuging the obtained solution to remove impurities, and removing dimethyl sulfoxide solvent and soluble impurities in the dispersion liquid to obtain the mycophenolate mofetil nanoparticle preparation.
The first technical solution of the invention is also characterized in that,
the poloxamer labels used in step 1 include one of 237, 338 or 407.
The mixed mother solution of mycophenolate mofetil and poloxamer prepared in the step 1 is filtered and filtered by a fat-soluble filter membrane with the aperture of 0.22 microns, and the mother solution of dopamine hydrochloride is filtered and filtered by a water-soluble filter membrane with the aperture of 0.22 microns.
In the step 2, the ultrasonic cleaner performs ultrasonic dispersion on the mixed solution with the power of 225-250W, the working frequency of 40KHz and the time of 30-40 minutes.
In the step 3, the ultrasonic cleaner carries out ultrasonic treatment on the mixed solution with the power of 200-250W, the working frequency of 40KHz and the time of 15-20 minutes.
The rotational speed of centrifugal impurity removal in the step 5 is 12000 rpm, and the time is 15 minutes.
The method for removing dimethyl sulfoxide solvent and soluble impurities in the dispersion liquid in the step 5 is to put the solution into a dialysis bag with the molecular weight cut-off of 10kDa, take physiological saline as external liquid, and dialyze for 24-48 hours, and change the external liquid for 3-5 times.
The second technical scheme adopted by the invention is as follows: the mycophenolate mofetil nanometer preparation for long-acting stable release is prepared by the preparation method.
The beneficial effects of the invention are as follows: the invention provides a mycophenolate mofetil nano preparation for long-acting stable release and a preparation method thereof, MMF is prepared into a nano particle preparation, ellagic acid is used for enhancing the stability of pi bond accumulation between MMF molecules and PDA nano packaging materials, the defect of the existing PDA nano medicine carrying particle preparation process is overcome, the yield in the production process of the monodisperse MMF nano particle preparation can be effectively ensured, related materials are clinical common auxiliary materials and medicines, and the safety is ensured. The nano medicine carrying particles prepared by the method have uniform and moderate particle size, good monodispersity and more stable entrapment performance.
Drawings
FIG. 1 is a transmission electron micrograph of a mycophenolate mofetil nano-formulation prepared in example 1 of the present invention;
FIG. 2 is a graph showing the results of stability testing of the mycophenolate mofetil nano-formulation prepared in example 1 of the present invention in phosphate buffer at 28℃for three months;
FIG. 3 is a graph showing the results of a stability test of the mycophenolate mofetil nano-formulation prepared in example 1 of the present invention in fetal bovine serum at 4℃for three months;
FIG. 4 shows the results of drug release tests of the mycophenolate mofetil nano-formulation prepared in example 1 of the present invention under ordinary conditions within five days;
FIG. 5 shows the results of a drug release test of the mycophenolate mofetil nano-formulation prepared in example 1 of the present invention over 72 hours at different pH conditions;
FIG. 6 shows the results of a drug release test of the mycophenolate mofetil nano-formulation prepared in example 1 of the present invention over 72 hours at different temperatures;
FIG. 7 shows the results of a hemolysis test of a mycophenolate mofetil nano-formulation prepared in example 1 of the present invention;
FIG. 8 shows the results of an in vivo acute toxicity test of the mycophenolate mofetil nano-formulation prepared in example 1 of the present invention.
Detailed Description
The invention will be described in detail with reference to the accompanying drawings and detailed description.
The invention provides a mycophenolate mofetil nanometer preparation for long-acting stable release and a preparation method thereof, comprising the following steps:
step 1, preparing mother liquor required by preparation:
mixing mycophenolate mofetil and poloxamer (with the reference numerals of 237, 338 and 407) according to the mass ratio of 2:1-4:1, mixing with dimethyl sulfoxide according to the mass-volume ratio of 20 mg to 1 ml to prepare a mycophenolate mofetil and poloxamer mixed mother solution, and filtering and removing impurities by using a fat-soluble filter membrane with the pore diameter of 0.22 microns;
preparing ellagic acid dimethyl sulfoxide solution with concentration of 20 mg/ml, preparing ellagic acid mother liquor, and filtering with fat-soluble filter membrane with pore diameter of 0.22 μm to remove impurities;
preparing a Tris aqueous solution with the concentration of 30 mg/ml, and regulating the pH value of the solution to 8.8-9.0 by using dilute hydrochloric acid to prepare a Tris-HCl mother solution;
preparing a dopamine hydrochloride aqueous solution with the concentration of 20 mg/ml, preparing a dopamine hydrochloride mother solution, and filtering and removing impurities by using a water-soluble filter membrane with the pore diameter of 0.22 microns;
step 2, dripping the mixed mother solution of mycophenolate mofetil and poloxamer into Tris-HCl mother solution with the volume of 10-15 times, continuously stirring the mixed solution during the period, performing ultrasonic dispersion on the mixed solution by using an ultrasonic cleaning machine at the power of 225-250W and the working frequency of 40KHz for 30-40 minutes to obtain mycophenolate mofetil nano-micelle dispersion;
step 3, adding 1 volume of ellagic acid mother liquor into 10 volumes of mycophenolate mofetil nano micelle dispersion liquid, continuously stirring the solution at the stirring speed of 1000-1500 rpm, and then carrying out ultrasonic treatment on the mixed solution by using an ultrasonic cleaner, wherein the power is 200-250W, the working frequency is 40KHz, and the time is 15-20 minutes;
step 4, adding 2 volumes of dopamine hydrochloride mother solution into 10 volumes of mixed solution, and finally transferring the mixed solution into a sealed tube for light-shielding rotary reaction at 25-28 ℃ for 48-72 hours;
and 5, centrifuging the obtained solution for impurity removal at the rotating speed of 12000 r/min for 15 min, placing the solution in a dialysis bag with the molecular weight cut-off of 10kDa, taking physiological saline as external liquid, dialyzing for 24-48 hours, replacing the external liquid for 3-5 times, and removing dimethyl sulfoxide solvent and soluble impurities in the dispersion liquid to obtain the mycophenolate mofetil nanoparticle preparation.
Through the mode, the core process of the mycophenolate mofetil nanometer preparation for long-acting stable release and the preparation method thereof provided by the invention is that the stabilizer, ellagic acid, is used for enhancing pi bond accumulation action between a PDA and a benzene ring in a medicine molecular structure, so that the prepared mycophenolate mofetil nanometer preparation is more stable and effective. The specific scheme is as follows: MMF and poloxamer as surfactant are mixed according to a specific proportion and then dissolved in dimethyl sulfoxide, the obtained mixed solution is dispersed into Tris-HCl solution to prepare MMF nano micelle dispersion liquid, a certain volume of ellagic acid solution is added into the MMF nano micelle dispersion liquid and fully mixed, a certain amount of dopamine hydrochloride solution is added, and the mixture is fully reacted to oxidize and self-polymerize and form stable pi bond accumulation with MMF molecules, and the target nano drug-carrying particles are purified after the reaction is finished.
According to the invention, MMF is prepared into a nanoparticle preparation, ellagic acid is used for enhancing the stability of pi bond accumulation between MMF molecules and PDA nano-package materials, the defect of the existing PDA nano-drug-carrying particle preparation process is overcome, the yield in the production process of the monodisperse MMF nanoparticle preparation can be effectively ensured, and related materials are clinical common auxiliary materials and drugs, so that the safety is ensured. The nanometer medicine carrying granule has homogeneous and moderate grain size, high dispersivity and stable entrapment performance, and has no obvious damage to red blood cell or toxicity, stable release rate, capacity of realizing long-term slow release of MMF in body while reducing the administration times, long-term stable blood concentration inside the treating window and less toxic side effect. According to the process provided by the invention, the obtained product has higher practical value.
Example 1
Step 1, preparing mother liquor required by preparation:
MMF and poloxamer 237 are mixed according to the mass ratio of 2:1, then mixed with dimethyl sulfoxide according to the mass ratio of 20 mg to 1 ml to prepare MMF-poloxamer mixed solution, and filtered by a fat-soluble filter membrane with the pore diameter of 0.22 micrometers to remove impurities;
preparing an ellagic acid dimethyl sulfoxide solution with the concentration of 20 mg/ml, and filtering and removing impurities by using a fat-soluble filter membrane with the pore diameter of 0.22 micrometers;
preparing a Tris water solution with the concentration of 30 mg/ml, and adjusting the pH of the solution to 8.8 by using dilute hydrochloric acid;
preparing a dopamine hydrochloride aqueous solution with the concentration of 20 mg/ml, and filtering and removing impurities by using a water-soluble filter membrane with the pore diameter of 0.22 micrometers;
step 2, slowly dripping the mixed solution of mycophenolate mofetil and poloxamer into a Tris solution with the volume of 10 times, continuously stirring the mixed solution at the stirring speed of 1800 revolutions per minute, and then performing ultrasonic dispersion on the reaction solution by using an ultrasonic cleaner, wherein the power is 225W, the working frequency is 40KHz, and the time is 30 minutes to obtain a mycophenolate mofetil nano-micelle dispersion;
step 3, slowly adding 1 volume of ellagic acid solution into 10 volumes of mycophenolate mofetil nano micelle dispersion liquid, continuously stirring the dispersion liquid at the stirring speed of 1000 revolutions per minute, and then carrying out ultrasonic treatment on the mixed reaction liquid by using an ultrasonic cleaner, wherein the power is 200W, the working frequency is 40KHz, and the time is 15 minutes;
step 4, adding 2 volumes of dopamine hydrochloride solution into 10 volumes of mixed solution, and finally transferring the solution into a sealed tube for light-shielding rotary reaction at 25 ℃ for 48 hours;
and 5, after the reaction is finished, centrifuging the obtained solution for removing impurities at the rotating speed of 12000 r/min for 15 min, placing the solution into a dialysis bag with the molecular weight cut-off of 10kDa, taking physiological saline as external liquid, dialyzing for 24 hours, replacing the external liquid for 3 times, and removing dimethyl sulfoxide solvent and other soluble impurities in the dispersion liquid to finally obtain the mycophenolate mofetil nanoparticle preparation.
Example 2
Step 1, preparing mother liquor required by preparation:
MMF and poloxamer 237 are mixed according to the mass ratio of 3:1, then mixed with dimethyl sulfoxide according to the mass ratio of 20 mg to 1 ml to prepare MMF-poloxamer mixed solution, and filtered by a fat-soluble filter membrane with the pore diameter of 0.22 micrometers to remove impurities;
preparing an ellagic acid dimethyl sulfoxide solution with the concentration of 20 mg/ml, and filtering and removing impurities by using a fat-soluble filter membrane with the pore diameter of 0.22 micrometers;
preparing a Tris water solution with the concentration of 30 mg/ml, and adjusting the pH of the solution to 8.8 by using dilute hydrochloric acid;
preparing a dopamine hydrochloride aqueous solution with the concentration of 20 mg/ml, and filtering and removing impurities by using a water-soluble filter membrane with the pore diameter of 0.22 micrometers;
step 2, slowly dripping a mixed solution of mycophenolate mofetil and poloxamer into a Tris solution with 13 times of volume, continuously stirring the mixed solution at 1950 rpm, and then performing ultrasonic dispersion on the reaction solution by using an ultrasonic cleaner with the power of 240W, the working frequency of 40KHz and the time of 35 minutes to obtain a mycophenolate mofetil nano-micelle dispersion;
step 3, slowly adding 1 volume of ellagic acid solution into 10 volumes of mycophenolate mofetil nano micelle dispersion liquid, continuously stirring the dispersion liquid during the period of time, wherein the stirring speed is 1200 revolutions per minute, and then carrying out ultrasonic treatment on the mixed reaction liquid by using an ultrasonic cleaner, wherein the power is 220W, the working frequency is 40KHz, and the time is 18 minutes;
step 4, adding 2 volumes of dopamine hydrochloride solution into 10 volumes of mixed solution, and finally transferring the solution into a sealed tube for light-shielding rotary reaction at 27 ℃ for 60 hours;
and 5, after the reaction is finished, centrifuging the obtained solution for removing impurities at the rotating speed of 12000 r/min for 15 min, placing the solution into a dialysis bag with the molecular weight cut-off of 10kDa, taking physiological saline as external liquid, dialyzing for 36 hours, replacing the external liquid for 4 times, and removing dimethyl sulfoxide solvent and other soluble impurities in the dispersion liquid to finally obtain the mycophenolate mofetil nanoparticle preparation.
Example 3
Step 1, preparing mother liquor required by preparation:
MMF and poloxamer 237 are mixed according to the mass ratio of 4:1, then mixed with dimethyl sulfoxide according to the mass ratio of 20 mg to 1 ml to prepare MMF-poloxamer mixed solution, and filtered by a fat-soluble filter membrane with the pore diameter of 0.22 micrometers to remove impurities;
preparing an ellagic acid dimethyl sulfoxide solution with the concentration of 20 mg/ml, and filtering and removing impurities by using a fat-soluble filter membrane with the pore diameter of 0.22 micrometers;
preparing a Tris water solution with the concentration of 30 mg/ml, and adjusting the pH of the solution to 9.0 by using dilute hydrochloric acid;
preparing a dopamine hydrochloride aqueous solution with the concentration of 20 mg/ml, and filtering and removing impurities by using a water-soluble filter membrane with the pore diameter of 0.22 micrometers;
step 2, slowly dripping a mixed solution of mycophenolate mofetil and poloxamer into a Tris solution with 15 times of volume, continuously stirring the mixed solution at a stirring speed of 2000 revolutions per minute, and then performing ultrasonic dispersion on the reaction solution by using an ultrasonic cleaner, wherein the power is 250W, the working frequency is 40KHz, and the time is 40 minutes to obtain a mycophenolate mofetil nano-micelle dispersion;
step 3, slowly adding 1 volume of ellagic acid solution into 10 volumes of mycophenolate mofetil nano micelle dispersion liquid, continuously stirring the dispersion liquid during the period of time, wherein the stirring speed is 1500 revolutions per minute, and then carrying out ultrasonic treatment on the mixed reaction liquid by using an ultrasonic cleaner, wherein the power is 250W, the working frequency is 40KHz, and the time is 20 minutes;
step 4, adding 2 volumes of dopamine hydrochloride solution into 10 volumes of mixed solution, and finally transferring the solution into a sealed tube for carrying out light-proof rotary reaction at 28 ℃ for 72 hours;
and 5, after the reaction is finished, centrifuging the obtained solution for removing impurities at the rotating speed of 12000 r/min for 15 min, placing the solution into a dialysis bag with the molecular weight cut-off of 10kDa, taking physiological saline as external liquid, dialyzing for 48 hours, and replacing the external liquid for 5 times during the dialysis period, and removing dimethyl sulfoxide solvent and other soluble impurities in the dispersion liquid to finally obtain the mycophenolate mofetil nanoparticle preparation.
Example 4
Step 1, preparing mother liquor required by preparation:
MMF and poloxamer 338 are mixed according to the mass ratio of 2:1, then mixed with dimethyl sulfoxide according to the mass ratio of 20 mg to 1 ml to prepare MMF-poloxamer mixed solution, and filtered by a fat-soluble filter membrane with the pore diameter of 0.22 microns to remove impurities;
preparing an ellagic acid dimethyl sulfoxide solution with the concentration of 20 mg/ml, and filtering and removing impurities by using a fat-soluble filter membrane with the pore diameter of 0.22 micrometers;
preparing a Tris water solution with the concentration of 30 mg/ml, and adjusting the pH of the solution to 8.8 by using dilute hydrochloric acid;
preparing a dopamine hydrochloride aqueous solution with the concentration of 20 mg/ml, and filtering and removing impurities by using a water-soluble filter membrane with the pore diameter of 0.22 micrometers;
step 2, slowly dripping the mixed solution of mycophenolate mofetil and poloxamer into a Tris solution with the volume of 10 times, continuously stirring the mixed solution at the stirring speed of 1800 revolutions per minute, and then performing ultrasonic dispersion on the reaction solution by using an ultrasonic cleaner, wherein the power is 225W, the working frequency is 40KHz, and the time is 30 minutes to obtain a mycophenolate mofetil nano-micelle dispersion;
step 3, slowly adding 1 volume of ellagic acid solution into 10 volumes of mycophenolate mofetil nano micelle dispersion liquid, continuously stirring the dispersion liquid at the stirring speed of 1000 revolutions per minute, and then carrying out ultrasonic treatment on the mixed reaction liquid by using an ultrasonic cleaner, wherein the power is 200W, the working frequency is 40KHz, and the time is 15 minutes;
step 4, adding 2 volumes of dopamine hydrochloride solution into 10 volumes of mixed solution, and finally transferring the solution into a sealed tube for light-shielding rotary reaction at 25 ℃ for 48 hours;
and 5, after the reaction is finished, centrifuging the obtained solution for removing impurities at the rotating speed of 12000 r/min for 15 min, placing the solution into a dialysis bag with the molecular weight cut-off of 10kDa, taking physiological saline as external liquid, dialyzing for 24 hours, replacing the external liquid for 3 times, and removing dimethyl sulfoxide solvent and other soluble impurities in the dispersion liquid to finally obtain the mycophenolate mofetil nanoparticle preparation.
Example 5
Step 1, preparing mother liquor required by preparation:
MMF and poloxamer 338 are mixed according to the mass ratio of 3:1, then mixed with dimethyl sulfoxide according to the mass ratio of 20 mg to 1 ml to prepare MMF-poloxamer mixed solution, and filtered by a fat-soluble filter membrane with the pore diameter of 0.22 microns to remove impurities;
preparing an ellagic acid dimethyl sulfoxide solution with the concentration of 20 mg/ml, and filtering and removing impurities by using a fat-soluble filter membrane with the pore diameter of 0.22 micrometers;
preparing a Tris water solution with the concentration of 30 mg/ml, and adjusting the pH of the solution to 8.9 by using dilute hydrochloric acid;
preparing a dopamine hydrochloride aqueous solution with the concentration of 20 mg/ml, and filtering and removing impurities by using a water-soluble filter membrane with the pore diameter of 0.22 micrometers;
step 2, slowly dripping a mixed solution of mycophenolate mofetil and poloxamer into a Tris solution with a volume of 12 times, continuously stirring the mixed solution at a stirring speed of 1900 revolutions per minute, and then performing ultrasonic dispersion on the reaction solution by using an ultrasonic cleaner, wherein the power is 230W, the working frequency is 40KHz, and the time is 35 minutes to obtain a mycophenolate mofetil nano-micelle dispersion;
step 3, slowly adding 1 volume of ellagic acid solution into 10 volumes of mycophenolate mofetil nano micelle dispersion liquid, continuously stirring the dispersion liquid during the period of 1300 revolutions per minute, and then carrying out ultrasonic treatment on the mixed reaction liquid by using an ultrasonic cleaner, wherein the power is 220W, the working frequency is 40KHz, and the time is 16 minutes;
step 4, adding 2 volumes of dopamine hydrochloride solution into 10 volumes of mixed solution, and finally transferring the solution into a sealed tube for light-shielding rotary reaction at 26 ℃ for 60 hours;
and 5, after the reaction is finished, centrifuging the obtained solution for removing impurities at the rotating speed of 12000 r/min for 15 min, placing the solution into a dialysis bag with the molecular weight cut-off of 10kDa, taking physiological saline as external liquid, dialyzing for 36 hours, replacing the external liquid for 4 times, and removing dimethyl sulfoxide solvent and other soluble impurities in the dispersion liquid to finally obtain the mycophenolate mofetil nanoparticle preparation.
Example 6
Step 1, preparing mother liquor required by preparation:
MMF and poloxamer 338 are mixed according to the mass ratio of 4:1, then mixed with dimethyl sulfoxide according to the mass ratio of 20 mg to 1 ml to prepare MMF-poloxamer mixed solution, and filtered by a fat-soluble filter membrane with the pore diameter of 0.22 microns to remove impurities;
preparing an ellagic acid dimethyl sulfoxide solution with the concentration of 20 mg/ml, and filtering and removing impurities by using a fat-soluble filter membrane with the pore diameter of 0.22 micrometers;
preparing a Tris water solution with the concentration of 30 mg/ml, and adjusting the pH of the solution to 9.0 by using dilute hydrochloric acid;
preparing a dopamine hydrochloride aqueous solution with the concentration of 20 mg/ml, and filtering and removing impurities by using a water-soluble filter membrane with the pore diameter of 0.22 micrometers;
step 2, slowly dripping a mixed solution of mycophenolate mofetil and poloxamer into a Tris solution with 15 times of volume, continuously stirring the mixed solution at a stirring speed of 2000 revolutions per minute, and then performing ultrasonic dispersion on the reaction solution by using an ultrasonic cleaner, wherein the power is 250W, the working frequency is 40KHz, and the time is 40 minutes to obtain a mycophenolate mofetil nano-micelle dispersion;
step 3, slowly adding 1 volume of ellagic acid solution into 10 volumes of mycophenolate mofetil nano micelle dispersion liquid, continuously stirring the dispersion liquid during the period of time, wherein the stirring speed is 1500 revolutions per minute, and then carrying out ultrasonic treatment on the mixed reaction liquid by using an ultrasonic cleaner, wherein the power is 250W, the working frequency is 40KHz, and the time is 20 minutes;
step 4, adding 2 volumes of dopamine hydrochloride solution into 10 volumes of mixed solution, and finally transferring the solution into a sealed tube for carrying out light-proof rotary reaction at 28 ℃ for 72 hours;
and 5, after the reaction is finished, centrifuging the obtained solution for removing impurities at the rotating speed of 12000 r/min for 15 min, placing the solution into a dialysis bag with the molecular weight cut-off of 10kDa, taking physiological saline as external liquid, dialyzing for 48 hours, and replacing the external liquid for 5 times during the dialysis period, and removing dimethyl sulfoxide solvent and other soluble impurities in the dispersion liquid to finally obtain the mycophenolate mofetil nanoparticle preparation.
Example 7
Step 1, preparing mother liquor required by preparation:
MMF and poloxamer 407 are mixed according to the mass ratio of 2:1, then mixed with dimethyl sulfoxide according to the mass ratio of 20 mg to 1 ml to prepare MMF-poloxamer mixed solution, and filtered by a fat-soluble filter membrane with the pore diameter of 0.22 micrometers to remove impurities;
preparing an ellagic acid dimethyl sulfoxide solution with the concentration of 20 mg/ml, and filtering and removing impurities by using a fat-soluble filter membrane with the pore diameter of 0.22 micrometers;
preparing a Tris water solution with the concentration of 30 mg/ml, and adjusting the pH of the solution to 8.8 by using dilute hydrochloric acid;
preparing a dopamine hydrochloride aqueous solution with the concentration of 20 mg/ml, and filtering and removing impurities by using a water-soluble filter membrane with the pore diameter of 0.22 micrometers;
step 2, slowly dripping the mixed solution of mycophenolate mofetil and poloxamer into a Tris solution with the volume of 10 times, continuously stirring the mixed solution at the stirring speed of 1800 revolutions per minute, and then performing ultrasonic dispersion on the reaction solution by using an ultrasonic cleaner, wherein the power is 225W, the working frequency is 40KHz, and the time is 30 minutes to obtain a mycophenolate mofetil nano-micelle dispersion;
step 3, slowly adding 1 volume of ellagic acid solution into 10 volumes of mycophenolate mofetil nano micelle dispersion liquid, continuously stirring the dispersion liquid at the stirring speed of 1000 revolutions per minute, and then carrying out ultrasonic treatment on the mixed reaction liquid by using an ultrasonic cleaner, wherein the power is 200W, the working frequency is 40KHz, and the time is 15 minutes;
step 4, adding 2 volumes of dopamine hydrochloride solution into 10 volumes of mixed solution, and finally transferring the solution into a sealed tube for light-shielding rotary reaction at 25 ℃ for 48 hours;
and 5, after the reaction is finished, centrifuging the obtained solution for removing impurities at the rotating speed of 12000 r/min for 15 min, placing the solution into a dialysis bag with the molecular weight cut-off of 10kDa, taking physiological saline as external liquid, dialyzing for 24 hours, replacing the external liquid for 3 times, and removing dimethyl sulfoxide solvent and other soluble impurities in the dispersion liquid to finally obtain the mycophenolate mofetil nanoparticle preparation.
Example 8
Step 1, preparing mother liquor required by preparation:
MMF and poloxamer 407 are mixed according to the mass ratio of 3:1, then mixed with dimethyl sulfoxide according to the mass ratio of 20 mg to 1 ml to prepare MMF-poloxamer mixed solution, and filtered by a fat-soluble filter membrane with the pore diameter of 0.22 micrometers to remove impurities;
preparing an ellagic acid dimethyl sulfoxide solution with the concentration of 20 mg/ml, and filtering and removing impurities by using a fat-soluble filter membrane with the pore diameter of 0.22 micrometers;
preparing a Tris water solution with the concentration of 30 mg/ml, and adjusting the pH of the solution to 8.9 by using dilute hydrochloric acid;
preparing a dopamine hydrochloride aqueous solution with the concentration of 20 mg/ml, and filtering and removing impurities by using a water-soluble filter membrane with the pore diameter of 0.22 micrometers;
step 2, slowly dripping a mixed solution of mycophenolate mofetil and poloxamer into a Tris solution with the volume of 14 times, continuously stirring the mixed solution at 1850 revolutions per minute, and then performing ultrasonic dispersion on the reaction solution by using an ultrasonic cleaner with the power of 240W, the working frequency of 40KHz and the time of 35 minutes to obtain a mycophenolate mofetil nano-micelle dispersion;
step 3, slowly adding 1 volume of ellagic acid solution into 10 volumes of mycophenolate mofetil nano micelle dispersion liquid, continuously stirring the dispersion liquid during the period of time, wherein the stirring speed is 1350 revolutions per minute, and then carrying out ultrasonic treatment on the mixed reaction liquid by using an ultrasonic cleaner, wherein the power is 220W, the working frequency is 40KHz, and the time is 18 minutes;
step 4, adding 2 volumes of dopamine hydrochloride solution into 10 volumes of mixed solution, and finally transferring the solution into a sealed tube for light-shielding rotary reaction at 26 ℃ for 55 hours;
and 5, after the reaction is finished, centrifuging the obtained solution for removing impurities at the rotating speed of 12000 r/min for 15 min, placing the solution into a dialysis bag with the molecular weight cut-off of 10kDa, taking physiological saline as external liquid, dialyzing for 40 hours, replacing the external liquid for 4 times, and removing dimethyl sulfoxide solvent and other soluble impurities in the dispersion liquid to finally obtain the mycophenolate mofetil nanoparticle preparation.
Example 9
Step 1, preparing mother liquor required by preparation:
MMF and poloxamer 407 are mixed according to the mass ratio of 4:1, and mixed with dimethyl sulfoxide according to the mass ratio of 20 mg to 1 ml to prepare MMF-poloxamer mixed solution, and the mixed solution is filtered and filtered by a fat-soluble filter membrane with the pore diameter of 0.22 microns;
preparing an ellagic acid dimethyl sulfoxide solution with the concentration of 20 mg/ml, and filtering and removing impurities by using a fat-soluble filter membrane with the pore diameter of 0.22 micrometers;
preparing a Tris water solution with the concentration of 30 mg/ml, and adjusting the pH of the solution to 9.0 by using dilute hydrochloric acid;
preparing a dopamine hydrochloride aqueous solution with the concentration of 20 mg/ml, and filtering and removing impurities by using a water-soluble filter membrane with the pore diameter of 0.22 micrometers;
step 2, slowly dripping a mixed solution of mycophenolate mofetil and poloxamer into a Tris solution with 15 times of volume, continuously stirring the mixed solution at a stirring speed of 2000 revolutions per minute, and then performing ultrasonic dispersion on the reaction solution by using an ultrasonic cleaner, wherein the power is 250W, the working frequency is 40KHz, and the time is 40 minutes to obtain a mycophenolate mofetil nano-micelle dispersion;
step 3, slowly adding 1 volume of ellagic acid solution into 10 volumes of mycophenolate mofetil nano micelle dispersion liquid, continuously stirring the dispersion liquid during the period of time, wherein the stirring speed is 1500 revolutions per minute, and then carrying out ultrasonic treatment on the mixed reaction liquid by using an ultrasonic cleaner, wherein the power is 250W, the working frequency is 40KHz, and the time is 20 minutes;
step 4, adding 2 volumes of dopamine hydrochloride solution into 10 volumes of mixed solution, and finally transferring the solution into a sealed tube for carrying out light-proof rotary reaction at 28 ℃ for 72 hours;
and 5, after the reaction is finished, centrifuging the obtained solution for removing impurities at the rotating speed of 12000 r/min for 15 min, placing the solution into a dialysis bag with the molecular weight cut-off of 10kDa, taking physiological saline as external liquid, dialyzing for 48 hours, and replacing the external liquid for 5 times during the dialysis period, and removing dimethyl sulfoxide solvent and other soluble impurities in the dispersion liquid to finally obtain the mycophenolate mofetil nanoparticle preparation.
Analysis of results
The measurement results of various indexes of the MMF nano drug-loaded particles described in the example 1 show that: the particle size is uniform and moderate (shown in figure 1), no obvious aggregation occurs, and the stability of the particle in the body fluid environment can be predictably ensured (shown in figures 2 and 3). The drug has long and stable and gentle release effect under in-vivo conditions (as shown in figures 4, 5 and 6), and obviously reduces damage and toxicity to erythrocytes after MMF is prepared into nano drug-loaded particles (see figures 7 and 8, wherein the triton is a positive control in figure 7, and the components are respectively set as controls, and the used object in figure 8 is BALB/c mice with weight of 18-22g and each group of male and female halves), so that the expectation of improving the drug administration method of the MMF is basically realized.
Although MMF is widely used as an immunosuppressant in clinic, long-term sustained administration faces the risks of high incidence of toxic and side effects and great harm, and the difference between PDA and drug molecules can cause the defects that the nano particles prepared according to the prior art have uneven particle size, poor stability, incapability of ensuring entrapment performance and release stability and the like. Aiming at the situation, the ellagic acid is introduced to strengthen and stabilize pi bond accumulation between PDA and drug molecules, the novel process is used for preparing the MMF long-acting slow-release preparation, and the toxicity of the slow-release nanoparticle preparation is lower than that of the traditional preparation while improving the treatment effect of MMF by combining the cancer inhibition effect of the ellagic acid. The reproducibility of the obtained result is good, and the quality control is accurate and simple when the mass production is carried out.

Claims (6)

1. The preparation method of the mycophenolate mofetil nanometer preparation for long-acting stable release is characterized by comprising the following steps of:
step 1, preparing mother liquor required by preparation:
mixing mycophenolate mofetil and poloxamer according to the mass ratio of 2:1-4:1, and then mixing with dimethyl sulfoxide according to the mass-volume ratio of 20 mg to 1 ml to prepare a mycophenolate mofetil and poloxamer mixed mother liquor;
preparing ellagic acid dimethyl sulfoxide solution with concentration of 20 mg/ml to obtain ellagic acid mother liquor;
preparing a Tris aqueous solution with the concentration of 30 mg/ml, and regulating the pH value of the solution to 8.8-9.0 by using dilute hydrochloric acid to prepare a Tris-HCl mother solution;
preparing a dopamine hydrochloride aqueous solution with the concentration of 20 mg/ml to prepare a dopamine hydrochloride mother solution;
the prepared mixed mother solution of mycophenolate mofetil and poloxamer is filtered and mixed by adopting a fat-soluble filter membrane with the aperture of 0.22 micrometers, and the dopamine hydrochloride mother solution is filtered and mixed by adopting a water-soluble filter membrane with the aperture of 0.22 micrometers;
step 2, dripping the mixed mother solution of mycophenolate mofetil and poloxamer into Tris-HCl mother solution with the volume of 10-15 times, continuously stirring the mixed solution during the period, wherein the stirring speed is 1800-2000 rpm, and then performing ultrasonic dispersion on the mixed solution by using an ultrasonic cleaner to obtain mycophenolate mofetil nano micelle dispersion liquid;
step 3, adding 1 volume of ellagic acid mother liquor into 10 volumes of mycophenolate mofetil nano micelle dispersion liquid, continuously stirring the solution during the period, wherein the stirring speed is 1000-1500 revolutions per minute, and then carrying out ultrasonic treatment on the mixed solution by using an ultrasonic cleaner;
step 4, adding 2 volumes of dopamine hydrochloride mother solution into 10 volumes of mixed solution, and finally transferring the mixed solution into a sealed tube for light-shielding rotary reaction at 25-28 ℃ for 48-72 hours;
and 5, centrifuging the obtained solution to remove impurities, and removing dimethyl sulfoxide solvent and soluble impurities in the dispersion liquid, wherein the method for removing the dimethyl sulfoxide solvent and the soluble impurities in the dispersion liquid comprises the steps of placing the solution in a dialysis bag with the molecular weight cutoff of 10kDa, taking physiological saline as external liquid, and dialyzing for 24-48 hours, wherein the external liquid is replaced for 3-5 times during the dialysis period, so as to obtain the mycophenolate mofetil nanoparticle preparation.
2. A method of preparing a mycophenolate mofetil nano-formulation for long-acting stable release as claimed in claim 1 wherein the poloxamer reference numerals used in step 1 comprise one of 237, 338 or 407.
3. The method for preparing the mycophenolate mofetil nano-preparation for long-acting stable release according to claim 1, wherein the ultrasonic cleaning machine in the step 2 carries out ultrasonic dispersion on the mixed solution with the power of 225-250W, the working frequency of 40KHz and the time of 30-40 minutes.
4. The method for preparing the mycophenolate mofetil nano-preparation for long-acting stable release according to claim 1, wherein the ultrasonic cleaning machine in the step 3 is used for carrying out ultrasonic treatment on the mixed solution with the power of 200-250W, the working frequency of 40KHz and the time of 15-20 minutes.
5. The method for preparing a mycophenolate mofetil nano-formulation for long-acting stable release according to claim 1, wherein the rotational speed of centrifugal impurity removal in the step 5 is 12000 rpm, and the centrifugation is carried out for 15 minutes.
6. A mycophenolate mofetil nano-formulation for long-acting stable release prepared by the preparation method of claim 1.
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