CN112999196A - Mycophenolate mofetil nano preparation for long-acting stable release and preparation method thereof - Google Patents

Mycophenolate mofetil nano preparation for long-acting stable release and preparation method thereof Download PDF

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CN112999196A
CN112999196A CN202110233932.0A CN202110233932A CN112999196A CN 112999196 A CN112999196 A CN 112999196A CN 202110233932 A CN202110233932 A CN 202110233932A CN 112999196 A CN112999196 A CN 112999196A
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mycophenolate mofetil
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CN112999196B (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 nano 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 stacking action between MMF molecules and PDA nano packing materials, the defects of the existing PDA nano drug-carrying particle preparation process are overcome, the yield of a monodisperse MMF nanoparticle preparation in the production process can be effectively ensured, related materials are common clinical auxiliary materials and drugs, and the safety is guaranteed. The prepared drug-loaded nanoparticles have uniform and moderate particle size, good monodispersity and more stable entrapment performance.

Description

Mycophenolate mofetil 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 in the end stage of various organ failure diseases, patients receiving transplantation need to take proper immunosuppressive agents for life, otherwise, cellular immunity and humoral immunity mediated rejection reactions occur in the body, and the survival rate of transplanted organs is seriously influenced. Mycophenolic acid (MPA) has a high selective effect on lymphocyte, is a highly efficient, selective, reversible and noncompetitive hypoxanthine mononucleotide dehydrogenase inhibitor, and can inhibit synthesis of guanine nucleotide of lymphocyte, so that proliferation of lymphocyte is inhibited, and immune rejection is effectively prevented. Mycophenolate Mofetil (MMF) is a 2-acetate esterified product of MPA, has longer half-life and stronger metabolic stability than MPA, so that MMF can be used as an immunosuppressant for preventing organ transplant rejection. In the current MMF medication, patients who receive organ transplantation need to take the medicine for a long time, which results in high incidence of toxic and side effects of the medicine, specifically including digestive system diseases such as colitis, severe infection caused by immunosuppression, respiratory system symptoms such as respiratory failure and bone marrow suppression, and the like. If the administration frequency is reduced and the blood concentration is maintained stably for a long period of time within the therapeutic window, the therapeutic effect of MMF can be stabilized and the incidence of toxic and side effects can be reduced. Therefore, there is a potential and wide need to develop a long-acting sustained-release and controlled-release formulation of MMF.
Polydopamine (PDA) can be produced by oxidative autopolymerization of dopamine (dopamine) in an alkaline environment, and due to its excellent adhesion, PDA can be deposited and attached on the surface of various materials and form a biomimetic coating, for example, in patent CN202011080736.6 of zhangdawei, yangjing, malaysia, lacha, and the like, a polydopamine zwitterionic copolymer is cured to form a film on the surface of medical metal, and a polydopamine zwitterionic antibacterial coating is obtained and can be used for development of medical instruments and implant materials. Further controlling reaction conditions, and by means of pi-pi conjugation between PDA and benzene rings in various drug structures, the PDA can coat the drug to realize drug loading, so that a corresponding nanoparticle preparation is prepared, and after administration, the nano packaging material-PDA is gradually and stably degraded in vivo, namely, the long-acting slow release of the drug can be realized. The nano-particle preparation has the advantages of high biocompatibility, good stability, stable degradability, obvious improvement of drug metabolic stability and the like.
Although the nano-drug carrier technology has been developed and the PDA has been applied in many aspects, the PDA nano-particles prepared by simple reaction in the prior art still have some defects. For example, in patent CN201910046351.9 of xuli, xiamin, lisilmna, they use glucose as a targeting molecule, and connect it to PDA material through a covalent bond as the targeting molecule, and load the anti-tumor drug after the PDA nanoparticles are formed, and the drug loading rate of the nanoparticles prepared by this process is as low as 10.03%, and efficient loading of the drug cannot be achieved. In the patent CN202010934764.3 of buxus sinica, zhanghuaqing, chenjie et al, although the process of the above patent is improved, the anti-tumor drug and the tumor-targeted protein are combined with PDA and then made into drug-loaded nanoparticles, the obtained nanoparticles still have the defects of unstable drug release rate, obviously increased cytotoxicity after the drug concentration is properly increased, and the like.
The deeper reason for the disadvantages of the PDA drug-loaded nanoparticles is that the stability of pi bond stacking between PDA and drug molecules is not high due to the difference in molecular structure and physicochemical properties between PDA and the drug to be loaded.
Ellagic acid is a widely-existing natural polyphenol substance, and the structure of polyphenol dilactone in the molecules of ellagic acid is verified to be capable of enhancing the stability of the pi bond accumulation effect between PDA and drug molecules, so that the entrapment performance and the release stability of the PDA drug-loaded nanoparticles can be remarkably improved. Furthermore, ellagic acid has significant inhibitory effect on chemical-induced canceration and other multiple canceration, and can reduce risk of MMF-induced malignancy. Therefore, ellagic acid can be used as a stabilizer for PDA-entrapped mycophenolate mofetil nanoparticles, and no report on the application of ellagic acid in related aspects exists at present.
Disclosure of Invention
The invention aims to provide a mycophenolate mofetil nano preparation for long-acting stable release, and the prepared nano medicine carrying particles are uniform and moderate in particle size, good in monodispersity and more stable in entrapment performance.
The invention also aims to provide a preparation method of the mycophenolate mofetil nano preparation for long-acting stable release.
The first technical scheme adopted by the invention is as follows: a preparation method of mycophenolate mofetil nano-preparation for long-acting stable release comprises the following steps:
step 1, preparing required mother liquor:
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: 1 ml to prepare a mixed mother liquor of mycophenolate mofetil and poloxamer;
preparing an ellagic acid dimethyl sulfoxide solution with the concentration of 20 mg/ml to prepare an ellagic acid mother solution;
preparing a Tris aqueous solution with the concentration of 30 mg/ml, and adjusting the pH 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, dropwise adding the mycophenolate mofetil and poloxamer mixed mother liquor into Tris-HCl mother liquor with the volume of 10-15 times, continuously stirring the mixture for 2000 revolutions per minute at the stirring speed of 1800-;
step 3, adding 1 volume of the ellagic acid mother liquor into 10 volumes of mycophenolate mofetil nano micelle dispersion liquid, continuously stirring the mixture for a period of time, wherein the stirring speed is 1000-1500 rpm, and then carrying out ultrasonic treatment on the mixed solution by using an ultrasonic cleaning machine;
step 4, adding 2 volumes of dopamine hydrochloride mother liquor into 10 volumes of mixed solution, finally transferring the mixed solution into a sealed tube, and carrying out dark rotary reaction for 48-72 hours at 25-28 ℃;
and 5, centrifuging the obtained solution to remove impurities, and removing the dimethyl sulfoxide solvent and soluble impurities in the dispersion liquid to obtain the mycophenolate mofetil nanoparticle preparation.
The first technical solution of the present invention is also characterized in that,
the poloxamer designations used in step 1 include one of 237, 338 or 407.
Filtering the mixed mother liquor of mycophenolate mofetil and poloxamer and the ellagic acid mother liquor prepared in the step 1 by adopting a fat-soluble filter membrane with the aperture of 0.22 micrometer to remove impurities, and filtering the dopamine hydrochloride mother liquor by adopting a water-soluble filter membrane with the aperture of 0.22 micrometer to remove impurities.
In the step 2, the power of the ultrasonic cleaning machine for carrying out ultrasonic dispersion on the mixed solution is 225-250W, the working frequency is 40KHz, and the time is 30-40 minutes.
In the step 3, the power of the ultrasonic cleaning machine for carrying out ultrasonic treatment on the mixed solution is 200-250W, the working frequency is 40KHz, and the time is 15-20 minutes.
And 5, the rotation speed of centrifugal impurity removal in the step 5 is 12000 r/min, and the time is 15 min.
The method for removing dimethyl sulfoxide solvent and soluble impurities in the dispersion liquid in step 5 comprises placing the solution in a dialysis bag with molecular weight cutoff of 10kDa, dialyzing with physiological saline as external liquid for 24-48 hr, and replacing 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 invention has the beneficial effects that: 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 packing materials, the defects of the existing PDA nano drug-carrying particle preparation process are overcome, the yield of a monodisperse MMF nano particle preparation in the production process can be effectively ensured, related materials are all clinical common auxiliary materials and drugs, and the safety is ensured. The prepared drug-loaded nanoparticles have uniform and moderate particle size, good monodispersity and more stable entrapment performance.
Drawings
FIG. 1 is a TEM micrograph of mycophenolate mofetil as prepared in example 1 of the present invention;
FIG. 2 shows the results of stability testing of mycophenolate mofetil nano-formulations prepared in example 1 of the present invention in phosphate buffer at 28 ℃ for three months;
FIG. 3 shows the results of stability tests of mycophenolate mofetil nano-formulations prepared in example 1 of the present invention in fetal bovine serum at 4 ℃ for three months;
FIG. 4 shows the drug release test results of mycophenolate mofetil nano-formulations prepared in example 1 of the present invention under normal conditions for five days;
FIG. 5 shows the drug release test results of mycophenolate mofetil nano-formulations prepared in example 1 of the present invention under different pH conditions for 72 hours;
FIG. 6 shows the drug release test results of mycophenolate mofetil nano-formulations 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 the in vivo acute toxicity test of mycophenolate mofetil nano-formulation prepared in example 1 of the present invention.
Detailed Description
The present invention will be described in detail below with reference to the accompanying drawings and specific embodiments.
The invention provides a mycophenolate mofetil nano preparation for long-acting stable release and a preparation method thereof, wherein the preparation method comprises the following steps:
step 1, preparing required mother liquor:
mixing mycophenolate mofetil with poloxamer (the labels include: 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: 1 ml to prepare a mixed mother solution of mycophenolate mofetil and poloxamer, and filtering with a fat-soluble filter membrane with the pore size of 0.22 micron to remove impurities;
preparing 20 mg/ml ellagic acid dimethyl sulfoxide solution to obtain 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 adjusting the pH 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, and filtering and removing impurities by using a water-soluble filter membrane with the pore size of 0.22 micron;
step 2, dropwise adding the mycophenolate mofetil and poloxamer mixed mother liquor into Tris-HCl mother liquor with the volume of 10-15 times, continuously stirring the mixture for the period, wherein the stirring speed is 1800 plus materials at 2000 rpm, then carrying out ultrasonic dispersion on the mixed solution by using an ultrasonic cleaning machine, wherein the power is 225 plus materials at 250W, the working frequency is 40KHz, and the time is 30-40 minutes, so as to obtain mycophenolate mofetil nano-micelle dispersion liquid;
step 3, adding 1 volume of the ellagic acid mother liquor into 10 volumes of mycophenolate mofetil nano micelle dispersion liquid, continuously stirring the mixture for a period of 1500 rpm at the stirring speed of 1000-;
step 4, adding 2 volumes of dopamine hydrochloride mother liquor into 10 volumes of mixed solution, finally transferring the mixed solution into a sealed tube, and carrying out dark rotary reaction for 48-72 hours at 25-28 ℃;
and 5, centrifuging the obtained solution for 15 minutes at a rotating speed of 12000 r/min to remove impurities, placing the solution in a dialysis bag with a molecular weight cutoff of 10kDa, dialyzing for 24-48 hours by taking physiological saline as an external solution, replacing the external solution for 3-5 times during dialysis, and removing a 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 nano preparation for long-acting stable release and the preparation method thereof provided by the invention is that ellagic acid serving as a stabilizer is used for enhancing the pi bond stacking effect between PDA and benzene rings in a drug molecular structure, so that the prepared mycophenolate mofetil nano preparation is more stable and effective. The specific scheme is as follows: mixing MMF and poloxamer serving as a surfactant according to a specific ratio, dissolving the mixture in dimethyl sulfoxide, dispersing the obtained mixed solution into a Tris-HCl solution to prepare an MMF nano micelle dispersion solution, adding a certain volume of ellagic acid solution into the MMF nano micelle dispersion solution, fully mixing, adding a certain amount of dopamine hydrochloride solution, fully reacting to oxidize and self-polymerize the mixture and generate stable pi bond accumulation with MMF molecules, and purifying after the reaction is finished to obtain the target drug-loaded nano-particles.
According to the invention, MMF is prepared into a nanoparticle preparation, ellagic acid is used for enhancing the stability of pi bond stacking action between MMF molecules and PDA nano packing materials, the defects of the existing PDA nano drug-carrying particle preparation process are overcome, the yield of a monodisperse MMF nanoparticle preparation in the production process can be effectively ensured, related materials are common clinical auxiliary materials and drugs, and the safety is guaranteed. The nano drug-loaded particles prepared in this way are relatively uniform and moderate in particle size, good in monodispersity and more stable in entrapment performance, experiments prove that the nano drug-loaded particles can not obviously damage erythrocytes or introduce toxicity and can stably exist in a body blood microenvironment, the release rate is stable and mild, the long-acting slow release in vivo can be realized while the MMF administration frequency is reduced, the blood drug concentration is stably maintained in a treatment window for a long time, and the requirement for the occurrence of toxic and side reactions is reduced. According to the process provided by the invention, the obtained product has higher practical value.
Example 1
Step 1, preparing required mother liquor:
mixing MMF and poloxamer 237 according to the mass ratio of 2:1, mixing with dimethyl sulfoxide according to the mass ratio of 20 mg: 1 ml to prepare an MMF-poloxamer mixed solution, and filtering with a fat-soluble filter membrane with the pore diameter of 0.22 micron to remove impurities;
preparing 20 mg/ml ellagic acid dimethyl sulfoxide solution, and filtering with a 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 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 size of 0.22 micron;
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 rpm, and then carrying out ultrasonic dispersion on the reaction solution by using an ultrasonic cleaning machine, wherein the power is 225W, the working frequency is 40KHz, and the time is 30 minutes, so as to obtain a mycophenolate mofetil nano-micelle dispersion solution;
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 cleaning machine, 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, finally transferring the solution into a sealed tube, and carrying out dark rotary reaction for 48 hours at 25 ℃;
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 in a dialysis bag with the molecular weight cutoff of 10kDa, dialyzing for 24 h by using normal saline as external liquid, replacing the external liquid for 3 times, removing the dimethyl sulfoxide solvent and other soluble impurities in the dispersion liquid, and finally obtaining the mycophenolate mofetil nanoparticle preparation.
Example 2
Step 1, preparing required mother liquor:
mixing MMF and poloxamer 237 according to a mass ratio of 3:1, mixing with dimethyl sulfoxide according to a ratio of 20 mg: 1 ml to prepare an MMF-poloxamer mixed solution, and filtering with a fat-soluble filter membrane with a pore size of 0.22 micron to remove impurities;
preparing 20 mg/ml ellagic acid dimethyl sulfoxide solution, and filtering with a 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 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 size of 0.22 micron;
step 2, slowly dripping the mixed solution of mycophenolate mofetil and poloxamer into a Tris solution 13 times the volume of the mixed solution, continuously stirring the mixed solution at 1950 r/min, and then carrying out ultrasonic dispersion on the reaction solution by using an ultrasonic cleaning machine, wherein the power is 240W, the working frequency is 40KHz, and the time is 35 minutes to obtain a mycophenolate mofetil nano-micelle dispersion solution;
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 1200 revolutions per minute, and then carrying out ultrasonic treatment on the mixed reaction liquid by using an ultrasonic cleaning machine, 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, finally transferring the solution into a sealed tube, and carrying out dark rotary reaction for 60 hours at 27 ℃;
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 in a dialysis bag with the molecular weight cutoff of 10kDa, dialyzing for 36 h by using physiological saline as external liquid, replacing the external liquid for 4 times, removing the dimethyl sulfoxide solvent and other soluble impurities in the dispersion liquid, and finally obtaining the mycophenolate mofetil nanoparticle preparation.
Example 3
Step 1, preparing required mother liquor:
mixing MMF and poloxamer 237 according to a mass ratio of 4:1, mixing with dimethyl sulfoxide according to a ratio of 20 mg: 1 ml to prepare an MMF-poloxamer mixed solution, and filtering with a fat-soluble filter membrane with a pore size of 0.22 micron to remove impurities;
preparing 20 mg/ml ellagic acid dimethyl sulfoxide solution, and filtering with a 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 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 size of 0.22 micron;
step 2, slowly dripping the mixed solution of mycophenolate mofetil and poloxamer into 15 times of Tris solution in volume, continuously stirring the mixed solution at the stirring speed of 2000 r/min, and then carrying out ultrasonic dispersion on the reaction solution by using an ultrasonic cleaning machine, wherein the power is 250W, the working frequency is 40KHz, and the time is 40 minutes, so as to obtain a mycophenolate mofetil nano-micelle dispersion solution;
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 1500 rpm, and then carrying out ultrasonic treatment on the mixed reaction liquid by using an ultrasonic cleaning machine, 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, finally transferring the solution into a sealed tube, and carrying out light-shielding rotary reaction for 72 hours at 28 ℃;
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 in a dialysis bag with the molecular weight cutoff of 10kDa, dialyzing for 48 h by using normal saline as external liquid, replacing the external liquid for 5 times, removing the dimethyl sulfoxide solvent and other soluble impurities in the dispersion liquid, and finally obtaining the mycophenolate mofetil nanoparticle preparation.
Example 4
Step 1, preparing required mother liquor:
mixing MMF and poloxamer 338 according to a mass ratio of 2:1, mixing with dimethyl sulfoxide according to a ratio of 20 mg: 1 ml to prepare an MMF-poloxamer mixed solution, and filtering with a fat-soluble filter membrane with a pore size of 0.22 micron to remove impurities;
preparing 20 mg/ml ellagic acid dimethyl sulfoxide solution, and filtering with a 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 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 size of 0.22 micron;
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 rpm, and then carrying out ultrasonic dispersion on the reaction solution by using an ultrasonic cleaning machine, wherein the power is 225W, the working frequency is 40KHz, and the time is 30 minutes, so as to obtain a mycophenolate mofetil nano-micelle dispersion solution;
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 cleaning machine, 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, finally transferring the solution into a sealed tube, and carrying out dark rotary reaction for 48 hours at 25 ℃;
and 5, after the reaction is finished, centrifuging the obtained solution for removing impurities at 12000 r/min for 15 min, putting the solution into a dialysis bag with the molecular weight cutoff of 10kDa, dialyzing for 24 h by taking physiological saline as external liquid, replacing the external liquid for 3 times during dialysis, removing the dimethyl sulfoxide solvent and other soluble impurities in the dispersion liquid, and finally obtaining the mycophenolate mofetil nanoparticle preparation.
Example 5
Step 1, preparing required mother liquor:
mixing MMF and poloxamer 338 according to a mass ratio of 3:1, mixing with dimethyl sulfoxide according to a ratio of 20 mg: 1 ml to prepare an MMF-poloxamer mixed solution, and filtering with a fat-soluble filter membrane with a pore size of 0.22 micron to remove impurities;
preparing 20 mg/ml ellagic acid dimethyl sulfoxide solution, and filtering with a 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 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 size of 0.22 micron;
step 2, slowly dripping the mixed solution of mycophenolate mofetil and poloxamer into a Tris solution with the volume of 12 times, continuously stirring the mixed solution, wherein the stirring speed is 1900 r/min, and then carrying out ultrasonic dispersion on the reaction solution by using an ultrasonic cleaning machine, wherein the power is 230W, the working frequency is 40KHz, and the time is 35 minutes, so as to obtain a mycophenolate mofetil nano-micelle dispersion solution;
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 1300 r/min, and then carrying out ultrasonic treatment on the mixed reaction liquid by using an ultrasonic cleaning machine, 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, finally transferring the solution into a sealed tube, and carrying out light-shielding rotary reaction for 60 hours at 26 ℃;
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 in a dialysis bag with the molecular weight cutoff of 10kDa, dialyzing for 36 h by using physiological saline as external liquid, replacing the external liquid for 4 times, removing the dimethyl sulfoxide solvent and other soluble impurities in the dispersion liquid, and finally obtaining the mycophenolate mofetil nanoparticle preparation.
Example 6
Step 1, preparing required mother liquor:
mixing MMF and poloxamer 338 according to a mass ratio of 4:1, mixing with dimethyl sulfoxide according to a ratio of 20 mg: 1 ml to prepare an MMF-poloxamer mixed solution, and filtering with a fat-soluble filter membrane with a pore size of 0.22 micron to remove impurities;
preparing 20 mg/ml ellagic acid dimethyl sulfoxide solution, and filtering with a 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 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 size of 0.22 micron;
step 2, slowly dripping the mixed solution of mycophenolate mofetil and poloxamer into 15 times of Tris solution in volume, continuously stirring the mixed solution at the stirring speed of 2000 r/min, and then carrying out ultrasonic dispersion on the reaction solution by using an ultrasonic cleaning machine, wherein the power is 250W, the working frequency is 40KHz, and the time is 40 minutes, so as to obtain a mycophenolate mofetil nano-micelle dispersion solution;
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 1500 rpm, and then carrying out ultrasonic treatment on the mixed reaction liquid by using an ultrasonic cleaning machine, 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, finally transferring the solution into a sealed tube, and carrying out light-shielding rotary reaction for 72 hours at 28 ℃;
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 in a dialysis bag with the molecular weight cutoff of 10kDa, dialyzing for 48 h by using normal saline as external liquid, replacing the external liquid for 5 times, removing the dimethyl sulfoxide solvent and other soluble impurities in the dispersion liquid, and finally obtaining the mycophenolate mofetil nanoparticle preparation.
Example 7
Step 1, preparing required mother liquor:
mixing MMF and poloxamer 407 according to a mass ratio of 2:1, mixing with dimethyl sulfoxide according to a ratio of 20 mg: 1 ml to prepare an MMF-poloxamer mixed solution, and filtering with a fat-soluble filter membrane with a pore size of 0.22 micron to remove impurities;
preparing 20 mg/ml ellagic acid dimethyl sulfoxide solution, and filtering with a 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 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 size of 0.22 micron;
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 rpm, and then carrying out ultrasonic dispersion on the reaction solution by using an ultrasonic cleaning machine, wherein the power is 225W, the working frequency is 40KHz, and the time is 30 minutes, so as to obtain a mycophenolate mofetil nano-micelle dispersion solution;
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 cleaning machine, 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, finally transferring the solution into a sealed tube, and carrying out dark rotary reaction for 48 hours at 25 ℃;
and 5, after the reaction is finished, centrifuging the obtained solution for removing impurities at 12000 r/min for 15 min, putting the solution into a dialysis bag with the molecular weight cutoff of 10kDa, dialyzing for 24 h by taking physiological saline as external liquid, replacing the external liquid for 3 times during dialysis, removing the dimethyl sulfoxide solvent and other soluble impurities in the dispersion liquid, and finally obtaining the mycophenolate mofetil nanoparticle preparation.
Example 8
Step 1, preparing required mother liquor:
mixing MMF and poloxamer 407 according to a mass ratio of 3:1, mixing with dimethyl sulfoxide according to a ratio of 20 mg: 1 ml to prepare an MMF-poloxamer mixed solution, and filtering with a fat-soluble filter membrane with a pore size of 0.22 micron to remove impurities;
preparing 20 mg/ml ellagic acid dimethyl sulfoxide solution, and filtering with a 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 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 size of 0.22 micron;
step 2, slowly dripping the mixed solution of mycophenolate mofetil and poloxamer into a Tris solution with 14 times of volume, continuously stirring the mixed solution, wherein the stirring speed is 1850 r/min, then carrying out ultrasonic dispersion on the reaction solution by using an ultrasonic cleaning machine, wherein the power is 240W, the working frequency is 40KHz, and the time is 35 minutes, so as to obtain a mycophenolate mofetil nano-micelle dispersion solution;
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 1350 revolutions per minute, and then carrying out ultrasonic treatment on the mixed reaction liquid by using an ultrasonic cleaning machine, 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, finally transferring the solution into a sealed tube, and carrying out photophobic rotation reaction at 26 ℃ for 55 hours;
and 5, after the reaction is finished, centrifuging the obtained solution for removing impurities at 12000 r/min for 15 min, putting the solution into a dialysis bag with the molecular weight cutoff of 10kDa, dialyzing for 40 h by taking normal saline as external liquid, replacing the external liquid for 4 times during dialysis, removing the dimethyl sulfoxide solvent and other soluble impurities in the dispersion liquid, and finally obtaining the mycophenolate mofetil nanoparticle preparation.
Example 9
Step 1, preparing required mother liquor:
mixing MMF and poloxamer 407 according to a mass ratio of 4:1, mixing with dimethyl sulfoxide according to a ratio of 20 mg: 1 ml to prepare an MMF-poloxamer mixed solution, and filtering with a fat-soluble filter membrane with a pore size of 0.22 micron to remove impurities;
preparing 20 mg/ml ellagic acid dimethyl sulfoxide solution, and filtering with a 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 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 size of 0.22 micron;
step 2, slowly dripping the mixed solution of mycophenolate mofetil and poloxamer into 15 times of Tris solution in volume, continuously stirring the mixed solution at the stirring speed of 2000 r/min, and then carrying out ultrasonic dispersion on the reaction solution by using an ultrasonic cleaning machine, wherein the power is 250W, the working frequency is 40KHz, and the time is 40 minutes, so as to obtain a mycophenolate mofetil nano-micelle dispersion solution;
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 1500 rpm, and then carrying out ultrasonic treatment on the mixed reaction liquid by using an ultrasonic cleaning machine, 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, finally transferring the solution into a sealed tube, and carrying out light-shielding rotary reaction for 72 hours at 28 ℃;
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 in a dialysis bag with the molecular weight cutoff of 10kDa, dialyzing for 48 h by using normal saline as external liquid, replacing the external liquid for 5 times, removing the dimethyl sulfoxide solvent and other soluble impurities in the dispersion liquid, and finally obtaining 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 relatively uniform and moderate (as shown in figure 1), no obvious aggregation occurs, and the stability of the particles in a body fluid environment can be ensured in a foreseeable way (as shown in figures 2 and 3). The release effect of the drug under in-vivo conditions is long and stable and smooth (as shown in figures 4, 5 and 6), after the MMF is prepared into drug-loaded nanoparticles, the damage and toxicity to erythrocytes are obviously reduced (as shown in figures 7 and 8, triton is a positive control in figure 7, and then all components are added to be respectively set as controls; in figure 8, the used object is a BALB/c mouse, the weight is 18-22g, and each group is half of male and female), and the expectation of improving the MMF drug administration method is basically realized.
Although MMF is widely used in clinic as an immunosuppressant, the risk of high toxic and side effects and great harmfulness exists in long-term continuous drug administration, and the differences between the PDA and the drug molecules can cause the defects that the nano particles prepared by the existing process have uneven particle size, poor stability, and the entrapment performance and release stability cannot be guaranteed. Aiming at the situations, 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 sustained-release preparation, and the sustained-release nanoparticle preparation is lower in toxicity than the traditional preparation while the treatment effect of MMF is improved by combining the cancer inhibition effect of the ellagic acid. The reproducibility of the result obtained by the invention is good, and the quality control is accurate and simple when the mass production is carried out.

Claims (8)

1. A preparation method of mycophenolate mofetil nano-preparation for long-acting stable release is characterized by comprising the following steps:
step 1, preparing required mother liquor:
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: 1 ml to prepare a mixed mother liquor of mycophenolate mofetil and poloxamer;
preparing an ellagic acid dimethyl sulfoxide solution with the concentration of 20 mg/ml to prepare an ellagic acid mother solution;
preparing a Tris aqueous solution with the concentration of 30 mg/ml, and adjusting the pH 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, dropwise adding the mycophenolate mofetil and poloxamer mixed mother liquor into Tris-HCl mother liquor with the volume of 10-15 times, continuously stirring the mixture at the stirring speed of 1800 plus materials at 2000 rpm, and then carrying out ultrasonic dispersion on the mixed solution by using an ultrasonic cleaning machine to obtain mycophenolate mofetil nano micelle dispersion liquid;
step 3, adding 1 volume of the ellagic acid mother liquor into 10 volumes of mycophenolate mofetil nano micelle dispersion liquid, continuously stirring the mixture for a period of time, wherein the stirring speed is 1000-1500 rpm, and then carrying out ultrasonic treatment on the mixed solution by using an ultrasonic cleaning machine;
step 4, adding 2 volumes of dopamine hydrochloride mother liquor into 10 volumes of mixed solution, finally transferring the mixed solution into a sealed tube, and carrying out dark rotary reaction for 48-72 hours at 25-28 ℃;
and 5, centrifuging the obtained solution to remove impurities, and removing the dimethyl sulfoxide solvent and soluble impurities in the dispersion liquid to obtain the mycophenolate mofetil nanoparticle preparation.
2. The method of claim 1, wherein the poloxamer designation used in step 1 includes one of 237, 338, or 407.
3. The method for preparing mycophenolate mofetil nano-preparation for long-acting stable release according to claim 1, wherein the mycophenolate mofetil, poloxamer mixed mother liquor and ellagic acid mother liquor prepared in the step 1 are filtered by a fat-soluble filter membrane with the pore size of 0.22 micron to remove impurities, and the dopamine hydrochloride mother liquor is filtered by a water-soluble filter membrane with the pore size of 0.22 micron to remove impurities.
4. The method for preparing mycophenolate mofetil nano-preparation for long-acting stable release according to claim 1, wherein the power of ultrasonic dispersion of the mixed solution by the ultrasonic cleaning machine in the step 2 is 225-250W, the working frequency is 40KHz, and the time is 30-40 minutes.
5. The method for preparing mycophenolate mofetil nano-preparation for long-acting stable release according to claim 1, wherein the power of the ultrasonic cleaning machine for carrying out ultrasonic treatment on the mixed solution in the step 3 is 200-250W, the working frequency is 40KHz, and the time is 15-20 minutes.
6. The method for preparing mycophenolate mofetil nano-preparations for long-acting stable release according to claim 1, wherein the rotation speed of centrifugal impurity removal in the step 5 is 12000 r/min, and the centrifugal time is 15 min.
7. The method of claim 1, wherein the step 5 of removing the dimethylsulfoxide and soluble impurities in the dispersion comprises placing the solution in a dialysis bag with a molecular weight cut-off of 10kDa, and dialyzing the solution with physiological saline as an external solution for 24-48 hours, wherein the external solution is changed 3-5 times.
8. A mycophenolate mofetil nano-formulation for long-acting stable release prepared by the preparation method of claim 1.
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