CN113133989A - Long-acting preparation for anti-tuberculosis drug rifampicin and preparation method thereof - Google Patents

Long-acting preparation for anti-tuberculosis drug rifampicin and preparation method thereof Download PDF

Info

Publication number
CN113133989A
CN113133989A CN202110255644.5A CN202110255644A CN113133989A CN 113133989 A CN113133989 A CN 113133989A CN 202110255644 A CN202110255644 A CN 202110255644A CN 113133989 A CN113133989 A CN 113133989A
Authority
CN
China
Prior art keywords
rifampicin
solution
carrying
ultrasonic treatment
preparation
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN202110255644.5A
Other languages
Chinese (zh)
Other versions
CN113133989B (en
Inventor
李科
周韵
周宝娜
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Xian Medical University
Original Assignee
Xian Medical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Xian Medical University filed Critical Xian Medical University
Priority to CN202110255644.5A priority Critical patent/CN113133989B/en
Publication of CN113133989A publication Critical patent/CN113133989A/en
Application granted granted Critical
Publication of CN113133989B publication Critical patent/CN113133989B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • 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
    • A61K9/5192—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention discloses a long-acting preparation for anti-tuberculosis drug rifampicin, which takes dopamine hydrochloride as a packaging material and introduces ellagic acid as a stabilizing agent for the first time to ensure the stability of preparation particles formed by dopamine and drug molecules. The invention also discloses a preparation method of the long-acting preparation for the anti-tuberculosis drug rifampicin, which comprises the following steps of firstly preparing mother liquor of each component; then adding the rifampicin and poloxamer mixed solution into a Tris-HCl solution with the volume 10 times that of the mixed solution, and then carrying out ultrasonic treatment on the whole liquid system to obtain rifampicin micelle dispersion liquid; sequentially and slowly adding 1 volume of ellagic acid solution and 2 volumes of dopamine hydrochloride solution into 20 volumes of rifampicin micelle dispersion liquid, continuously stirring the dispersion liquid during the process, then carrying out ultrasonic treatment on the mixed reaction liquid, and finally carrying out sealing reaction on the solutions; and after the reaction is finished, centrifuging the solution, removing the supernatant, carrying out heavy suspension precipitation by using a phosphate buffer solution, and carrying out constant volume to obtain the rifampicin long-acting preparation solution with the required concentration.

Description

Long-acting preparation for anti-tuberculosis drug rifampicin and preparation method thereof
Technical Field
The invention belongs to the technical field of nano preparations, and particularly relates to a long-acting preparation for an anti-tubercular drug rifampicin.
Background
At present, the drugs clinically used for treating tuberculosis comprise rifampicin, isoniazid, pyrazinamide, rifapentine, p-aminosalicylic acid, ethambutol and the like, and generally adopt combined drugs which at least comprise three bactericidal drugs. Due to its powerful bactericidal efficacy, rifampicin is an indispensable important component of combined drug regimens for the treatment of tuberculosis. The rifampicin is used as a broad-spectrum antibiotic, can effectively inhibit bacteria such as mycobacterium tuberculosis, mycobacterium leprae, chlamydia trachomatis and the like, is mainly used for treating tuberculosis with drug resistance to other antitubercular drugs, and has better curative effect on eye diseases caused by drug-resistant staphylococcus aureus, chlamydia trachomatis and mycobacterium leprae. The early tuberculosis treatment scheme prompts that the aim of treatment can be achieved only by taking the medicine for at least six months. It is worth noting that the drugs of rifampicin can prolong the half-life of the drugs in patients with hepatic insufficiency, and cause liver injury, hepatomegaly, jaundice and the like after long-term administration, except for the common digestive tract reactions of nausea, vomiting, abdominal pain, diarrhea and the like caused by the drugs. In addition, the treatment of tuberculosis can be ensured to exert the best curative effect only by long-term continuous taking, the treatment period is prolonged by intermittent administration, and influenza-like comprehensive symptoms such as chill, fever, headache, myalgia and the like can be caused by a large amount of intermittent administration. Can achieve better treatment effect by maintaining long-term stable blood concentration, and avoid adverse reaction to a great extent. Therefore, the application of the long-acting slow release technology has a positive effect on resisting tuberculosis.
In recent years, the development of nanotechnology has led more and more people to pay attention to the great advantages that nanomaterials exhibit as drug carriers. The nanometer material is used as a carrier to be combined with the medicine, so that the stability of the original medicine in the body is improved, the dissolution behavior is improved, the operation and the targeted distribution in the body are promoted, and the curative effect of the medicine is promoted even the multifunctional treatment is realized. Currently, the nano-carrier technology has made great progress, and dozens of drug researches using the nano-carrier technology have entered clinical stage. The nano-particle rice is easy to permeate biological membranes due to small size and large specific surface area, and is widely applied to antibacterial research.
Polydopamine (PDA) is a multifunctional polymer material developed in recent years, which has physicochemical properties that make it form a stable coating with almost all material surfaces, and its abundant surface properties also make it play a role in various fields including biomedicine, as in patent nos. CN202010537758.4 and CN 201911396759.5. According to the adjustment of the preparation process, nanoscale preparation particles with corresponding sizes can be obtained, and the preparation method has the advantages of controllable operation, high drug loading, good compatibility with drugs, good biocompatibility, high safety and the like. However, due to a certain difference between dopamine molecules and drug molecules, a corresponding stabilizer needs to be added in the preparation process to achieve the purpose of uniform and stable shape of the obtained nanoparticles. Ellagic acid is a polyphenol dilactone structure, which can stably combine and deposit PDA and drug molecules, so that ellagic acid can be used as a stabilizer for preparing a nanometer preparation, and a good effect can be achieved.
Disclosure of Invention
The invention aims to provide a long-acting preparation for anti-tubercular drugs rifampicin, which is a nano preparation for anti-tubercular drugs with long-acting slow release performance prepared by taking dopamine hydrochloride as a packaging material and ellagic acid as a stabilizing agent.
The invention adopts a first technical scheme that a long-acting preparation for an anti-tuberculosis drug rifampicin takes dopamine hydrochloride as a packaging material and introduces ellagic acid as a particle stabilizer.
The second technical scheme adopted by the invention is that the preparation method of the long-acting preparation for the anti-tuberculosis drug rifampicin is implemented according to the following steps:
step 1, preparing mother liquor of each component; the components comprise Tris-hydroxymethyl aminomethane-hydrochloric acid buffer solution Tris-HCl, dopamine hydrochloride, rifampicin, poloxamer and ellagic acid;
step 2, slowly adding the rifampicin and poloxamer mixed solution to the bottom of a Tris-HCl solution with the volume 10 times that of the mixed solution, keeping the liquid in a layered state, then carrying out ultrasonic treatment on the whole liquid system, and keeping ice bath all the time in the treatment process to obtain rifampicin micelle dispersion liquid;
step 3, slowly adding 1 volume of ellagic acid solution and 2 volumes of dopamine hydrochloride solution into 20 volumes of the rifampicin micelle dispersion liquid obtained in the step 2 in sequence, continuously stirring the dispersion liquid during the process, then carrying out ultrasonic treatment on the mixed reaction liquid, and finally sealing the solution;
and 4, centrifuging the solution after the reaction is finished, removing the supernatant, carrying out heavy suspension precipitation by using a phosphate buffer solution, carrying out ultrasonic treatment, and carrying out constant volume to obtain the rifampicin long-acting preparation solution with the required concentration.
The second technical aspect of the present invention is also characterized in that,
the step 1 is as follows:
Tris-HCl 30mg/ml, pure water as solvent;
dopamine hydrochloride: 20mg/ml, and the solvent is pure water;
rifampin and poloxamer: 20mg/ml, and the solvent is dimethyl sulfoxide;
ellagic acid: 20mg/ml, and the solvent is dimethyl sulfoxide;
all mother liquor is fully dissolved by ultrasonic treatment, and then is filtered to remove impurities.
The pH value of the Tris-HCl mother liquor in the step 1 is 8.8-9.0.
In the step 1, the poloxamer is one of F118, F237, F338 and F407.
In the step 1, rifampicin and poloxamer are mixed according to the mass ratio of 1: 1-3: 1.
In the step 1, a fat-soluble or water-soluble microporous filter membrane with the diameter of 0.22 mu m is used for filtering to remove impurities.
In the step 2, a probe type ultrasonic crusher is used for carrying out ultrasonic treatment on the whole liquid system, the power is 300-600W, the ultrasonic treatment time per cycle is 4-8 seconds, the interval time is 3-4 seconds, and the total cycle number is 20-30 times.
And 3, continuously stirring the dispersion liquid in the step 3 at the stirring speed of 1000-1500 rpm, carrying out ultrasonic treatment on the mixed reaction liquid by using an ultrasonic cleaning machine, wherein the power of the ultrasonic treatment is 200-250W, the working frequency is 40KHz, and the time is 20-30 minutes, and finally transferring the solution into a sealing tube for dark rotary reaction at the temperature of 25-28 ℃ for 48-72 hours.
And 4, carrying out centrifugation in the step 4 at the rotating speed of 14000 r/min for 45-60 min, and carrying out ultrasonic treatment on the dispersion liquid by using an ultrasonic cleaning machine, wherein the ultrasonic treatment power is 230-.
The preparation method has the beneficial effects that polydopamine is used as a medicine carrying system and applied to the field of biological medicine, and the ellagic acid stabilizer is added in the preparation process of the nano preparation, so that the uniformity and stability of the prepared nano preparation particles are ensured, and the reproducibility of the nano preparation particles is ensured. The nano-carrier preparation can be observed to be uniform and stable in particles under the visual field of 2 mu m, the particle size of the nano-carrier preparation in serum is not obviously changed within one month, the toxicity is high, red blood cells are not obviously damaged, and the survival rate of experimental animals is obviously higher than that of original drugs, so that the nano-carrier preparation can reduce the toxic and side effects of the nano-carrier preparation. The core for supporting the series of excellent performances is a PDA drug molecule hybrid process taking ellagic acid as a stabilizer. The technical steps are simple to operate, the obtained product can be subjected to accurate quality control, and the stability and the release performance are obvious. The nanometer preparation of the antituberculosis drug with long-acting slow release performance is prepared by taking dopamine hydrochloride as a packaging material and ellagic acid as a stabilizing agent. The preparation method specifically comprises the steps of firstly mixing the rifampicin of an antituberculosis drug and a nonionic surfactant-poloxamer according to a proportion, dissolving the rifampicin and the nonionic surfactant-poloxamer into dimethyl sulfoxide, and then dispersing the rifampicin and the poloxamer into a Tris-HCl solution to prepare the rifampicin micelle dispersion liquid. And then, slowly adding the ellagic acid solution and the dopamine hydrochloride solution into the rifampicin micelle dispersion liquid in sequence, and finally carrying out heavy suspension and impurity removal by using a phosphate buffer solution to obtain the rifampicin long-acting preparation solution with the required concentration. The method is single and effective, can prepare stable and uniform-particle nano preparations, can achieve the effect of long-acting stable release in vivo, can be fully applied to the research of anti-tuberculosis drugs, and has good development prospect.
Drawings
FIG. 1 is a TEM photograph of the rifampicin nano-formulation prepared in example 1;
FIG. 2 is the results of the stability test of the rifampicin nano-formulation prepared in example 1 in phosphate buffer at room temperature for three months;
FIG. 3 shows the results of the stability test of the rifampicin nano-formulation prepared in example 1 in fetal calf serum at 4 ℃ for 21 days;
FIG. 4 is a result of a drug release test of the rifampicin nano-formulation prepared in example 1 under normal conditions for four days;
FIG. 5 shows the results of the drug release test of the rifampicin nano-formulation prepared in example 1 at different temperatures for 96 hours;
FIG. 6 shows the results of hemolysis test of rifampicin nano-formulation prepared in example 1 (pure water is positive control, and the former and latter components are respectively set as control);
FIG. 7 results of in vivo acute toxicity test of rifampicin nano-formulations prepared in example 1 (all subjects used were BALB/c mice, weight 18-22g, each group of male and female halves).
Detailed Description
The present invention will be described in detail below with reference to the accompanying drawings and specific embodiments.
The invention relates to a long-acting preparation for anti-tuberculosis drug rifampicin, which takes dopamine hydrochloride as a packaging material and ellagic acid as a stabilizing agent.
A preparation method of a long-acting preparation for an anti-tubercular drug rifampicin is specifically implemented according to the following steps:
step 1, preparing mother liquor of each component; the components comprise Tris-hydroxymethyl aminomethane-hydrochloric acid buffer solution Tris-HCl, dopamine hydrochloride, rifampicin, poloxamer and ellagic acid;
the step 1 is as follows:
Tris-HCl 30mg/ml, pure water as solvent;
dopamine hydrochloride: 20mg/ml, and the solvent is pure water;
rifampin and poloxamer: 20mg/ml, and the solvent is dimethyl sulfoxide;
ellagic acid: 20mg/ml, and the solvent is dimethyl sulfoxide;
all mother liquor is fully dissolved by ultrasonic treatment, and then is filtered to remove impurities.
The pH value of the Tris-HCl mother liquor in the step 1 is 8.8-9.0.
In the step 1, the poloxamer is one of F118, F237, F338 and F407.
In the step 1, rifampicin and poloxamer are mixed according to the mass ratio of 1: 1-3: 1.
In the step 1, a fat-soluble or water-soluble microporous filter membrane with the diameter of 0.22 mu m is used for filtering to remove impurities.
Step 2, slowly adding the rifampicin and poloxamer mixed solution to the bottom of a Tris-HCl solution with the volume 10 times that of the mixed solution, keeping the liquid in a layered state, then carrying out ultrasonic treatment on the whole liquid system, and keeping ice bath all the time in the treatment process to obtain rifampicin micelle dispersion liquid;
in the step 2, a probe type ultrasonic crusher is used for carrying out ultrasonic treatment on the whole liquid system, the power is 300-600W, the ultrasonic treatment time per cycle is 4-8 seconds, the interval time is 3-4 seconds, and the total cycle number is 20-30 times.
Step 3, slowly adding 1 volume of ellagic acid solution and 2 volumes of dopamine hydrochloride solution into 20 volumes of the rifampicin micelle dispersion liquid obtained in the step 2 in sequence, continuously stirring the dispersion liquid during the process, then carrying out ultrasonic treatment on the mixed reaction liquid, and finally sealing the solution;
and 3, continuously stirring the dispersion liquid in the step 3 at the stirring speed of 1000-1500 rpm, carrying out ultrasonic treatment on the mixed reaction liquid by using an ultrasonic cleaning machine, wherein the power of the ultrasonic treatment is 200-250W, the working frequency is 40KHz, and the time is 20-30 minutes, and finally transferring the solution into a sealing tube for dark rotary reaction at the temperature of 25-28 ℃ for 48-72 hours.
And 4, centrifuging the solution after the reaction is finished, removing the supernatant, carrying out heavy suspension precipitation by using a phosphate buffer solution, carrying out ultrasonic treatment, and carrying out constant volume to obtain the rifampicin long-acting preparation solution with the required concentration.
And 4, carrying out centrifugation in the step 4 at the rotating speed of 14000 r/min for 45-60 min, and carrying out ultrasonic treatment on the dispersion liquid by using an ultrasonic cleaning machine, wherein the ultrasonic treatment power is 230-.
Example 1
Step 1, firstly preparing mother liquor of each component,
30mg/ml Tris-HCl, (solvent, pure water, pH adjusted to 8.8);
dopamine hydrochloride: 20mg/ml, (solvent: pure water);
rifampin and poloxamer: 20mg/ml, (solvent: dimethyl sulfoxide) (rifampicin mixed with poloxamer in a 1:1 mass ratio) (poloxamer F118);
ellagic acid: 20mg/ml (solvent: dimethyl sulfoxide).
All mother liquor is fully dissolved by ultrasonic treatment, and then is filtered by a fat-soluble or water-soluble microporous filter membrane with the diameter of 0.22 mu m according to different solvents to remove impurities;
step 2, slowly adding the rifampicin and poloxamer mixed solution to the bottom of a 10-time volume Tris solution, keeping the liquid layered during the process, then carrying out ultrasonic treatment on the whole liquid system by using a probe type ultrasonicator, wherein the power is 600W, the ultrasonic treatment time per cycle is 8 seconds, the interval time is 4 seconds, and the total cycle number is 30 times, and keeping ice bath all the time during the treatment process to obtain rifampicin micelle dispersion liquid;
step 3, slowly adding 1 volume of ellagic acid solution and 2 volumes of dopamine hydrochloride solution into 20 volumes of rifampicin micelle dispersion liquid in sequence, continuously stirring the dispersion liquid during the period, wherein the stirring speed is 1500 rpm, 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, the time is 30 minutes, and finally transferring the solution into a sealing tube, and carrying out light-proof rotary reaction for 72 hours at the temperature of 28 ℃;
and 4, centrifuging the solution after the reaction is finished, wherein the rotating speed is 14000 r/min, the centrifuging time is 60 minutes, removing the supernatant, carrying out heavy suspension precipitation by using a phosphate buffer solution, carrying out ultrasonic treatment on the dispersion by using an ultrasonic cleaning machine, carrying out ultrasonic treatment on the dispersion with the power of 250W, the working frequency of 40KHz for 30 minutes, and carrying out constant volume to obtain the rifampicin long-acting preparation solution with the required concentration.
Example 2
Step 1, firstly preparing mother liquor of each component,
Tris-HCl:30mg/ml (solvent: pure water, pH adjusted to 8.9);
dopamine hydrochloride: 20mg/ml, (solvent: pure water);
rifampin and poloxamer: 20mg/ml, (solvent: dimethyl sulfoxide) (rifampicin mixed with poloxamer in a 1:1 mass ratio) (poloxamer F237);
ellagic acid: 20mg/ml (solvent: dimethyl sulfoxide).
All mother liquor is fully dissolved by ultrasonic treatment, and then is filtered by a fat-soluble or water-soluble microporous filter membrane with the diameter of 0.22 mu m according to different solvents to remove impurities;
step 2, slowly adding the rifampicin and poloxamer mixed solution to the bottom of a 10-time volume Tris solution, keeping the liquid layered during the process, then carrying out ultrasonic treatment on the whole liquid system by using a probe type ultrasonicator, wherein the power is 400W, the ultrasonic treatment time per cycle is 6 seconds, the interval time is 4 seconds, and the total cycle number is 25 times, and keeping ice bath all the time during the treatment process to obtain rifampicin micelle dispersion liquid;
step 3, slowly adding 1 volume of ellagic acid solution and 2 volumes of dopamine hydrochloride solution into 20 volumes of rifampicin micelle dispersion liquid in sequence, continuously stirring the dispersion liquid in the period, wherein the stirring speed is 1200 revolutions per minute, 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, the time is 25 minutes, and finally transferring the solution into a sealing tube, and carrying out dark rotary reaction for 60 hours at 25 ℃;
and 4, centrifuging the solution after the reaction is finished, wherein the rotating speed is 14000 r/min, the centrifuging time is 45 min, removing supernatant, carrying out heavy suspension precipitation by using a phosphate buffer solution, carrying out ultrasonic treatment on the dispersion by using an ultrasonic cleaning machine, carrying out power of 230W, working frequency of 40KHz for 25 min, and carrying out constant volume to obtain the rifampicin long-acting preparation solution with the required concentration.
Example 3
Step 1, firstly preparing mother liquor of each component,
Tris-HCl:30mg/ml (solvent: pure water, pH adjusted to 9.0);
dopamine hydrochloride: 20mg/ml, (solvent: pure water);
rifampin and poloxamer: 20mg/ml, (solvent: dimethyl sulfoxide) (rifampicin mixed with poloxamer in a 1:1 mass ratio) (poloxamer F338);
ellagic acid: 20mg/ml (solvent: dimethyl sulfoxide).
All mother liquor is fully dissolved by ultrasonic treatment, and then is filtered by a fat-soluble or water-soluble microporous filter membrane with the diameter of 0.22 mu m according to different solvents to remove impurities;
step 2, slowly adding the rifampicin and poloxamer mixed solution to the bottom of a 10-time volume Tris solution, keeping the liquid layered during the process, then carrying out ultrasonic treatment on the whole liquid system by using a probe type ultrasonicator, wherein the power is 300W, the ultrasonic treatment time per cycle is 4 seconds, the interval time is 3 seconds, and the total cycle number is 20 times, and keeping ice bath all the time during the treatment process to obtain rifampicin micelle dispersion liquid;
step 3, slowly adding 1 volume of ellagic acid solution and 2 volumes of dopamine hydrochloride solution into 20 volumes of rifampicin micelle dispersion liquid in sequence, continuously stirring the dispersion liquid in the period, wherein the stirring speed is 1000 revolutions per minute, 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, the time is 20 minutes, and finally transferring the solution into a sealing tube, and carrying out light-proof rotary reaction for 48 hours at 28 ℃;
and 4, centrifuging the solution after the reaction is finished, wherein the rotating speed is 14000 r/min, the centrifuging time is 60 minutes, removing supernatant, carrying out heavy suspension precipitation by using a phosphate buffer solution, carrying out ultrasonic treatment on the dispersion by using an ultrasonic cleaning machine, the work is 250W, the working frequency is 40KHz, the time is 20 minutes, and obtaining the rifampicin long-acting preparation solution with the required concentration after constant volume.
Example 4
Step 1, firstly preparing mother liquor of each component,
30mg/ml Tris-HCl, (solvent, pure water, pH adjusted to 8.8);
dopamine hydrochloride: 20mg/ml, (solvent: pure water);
rifampin and poloxamer: 20mg/ml, (solvent: dimethyl sulfoxide) (rifampicin mixed with poloxamer at a 2:1 mass ratio) (poloxamer F407);
ellagic acid: 20mg/ml (solvent: dimethyl sulfoxide).
All mother liquor is fully dissolved by ultrasonic treatment, and then is filtered by a fat-soluble or water-soluble microporous filter membrane with the diameter of 0.22 mu m according to different solvents to remove impurities;
step 2, slowly adding the rifampicin and poloxamer mixed solution to the bottom of a 10-time volume Tris solution, keeping the liquid layered during the process, then carrying out ultrasonic treatment on the whole liquid system by using a probe type ultrasonicator, wherein the power is 600W, the ultrasonic treatment time per cycle is 8 seconds, the interval time is 4 seconds, and the total cycle number is 30 times, and keeping ice bath all the time during the treatment process to obtain rifampicin micelle dispersion liquid;
step 3, slowly adding 1 volume of ellagic acid solution and 2 volumes of dopamine hydrochloride solution into 20 volumes of rifampicin micelle dispersion liquid in sequence, continuously stirring the dispersion liquid during the period, wherein the stirring speed is 1500 rpm, 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, the time is 30 minutes, and finally transferring the solution into a sealing tube, and carrying out dark rotary reaction for 72 hours at 25 ℃;
and 4, centrifuging the solution after the reaction is finished, wherein the rotating speed is 14000 r/min, the centrifuging time is 45 min, removing supernatant, carrying out heavy suspension precipitation by using a phosphate buffer solution, carrying out ultrasonic treatment on the dispersion by using an ultrasonic cleaning machine, carrying out power of 230W, working frequency of 40KHz for 30 min, and carrying out constant volume to obtain the rifampicin long-acting preparation solution with the required concentration.
Example 5
Step 1, firstly preparing mother liquor of each component,
30mg/ml Tris-HCl, (solvent, pure water, pH adjusted to 8.9);
dopamine hydrochloride: 20mg/ml, (solvent: pure water);
rifampin and poloxamer: 20mg/ml, (solvent: dimethyl sulfoxide) (rifampicin mixed with poloxamer at a 2:1 mass ratio) (poloxamer F118);
ellagic acid: 20mg/ml (solvent: dimethyl sulfoxide).
All mother liquor is fully dissolved by ultrasonic treatment, and then is filtered by a fat-soluble or water-soluble microporous filter membrane with the diameter of 0.22 mu m according to different solvents to remove impurities;
step 2, slowly adding the rifampicin and poloxamer mixed solution to the bottom of a 10-time volume Tris solution, keeping the liquid layered during the process, then carrying out ultrasonic treatment on the whole liquid system by using a probe type ultrasonicator, wherein the power is 400W, the ultrasonic treatment time per cycle is 6 seconds, the interval time is 3 seconds, and the total cycle number is 25 times, and keeping ice bath all the time during the treatment process to obtain rifampicin micelle dispersion liquid;
step 3, slowly adding 1 volume of ellagic acid solution and 2 volumes of dopamine hydrochloride solution into 20 volumes of rifampicin micelle dispersion liquid in sequence, continuously stirring the dispersion liquid in the period, wherein the stirring speed is 1200 revolutions per minute, 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, the time is 25 minutes, and finally transferring the solution into a sealing tube, and carrying out light-proof rotary reaction for 60 hours at the temperature of 28 ℃;
and 4, centrifuging the solution after the reaction is finished, wherein the rotating speed is 14000 r/min, the centrifuging time is 60 minutes, removing supernatant, carrying out heavy suspension precipitation by using a phosphate buffer solution, carrying out ultrasonic treatment on the dispersion by using an ultrasonic cleaning machine, carrying out power 240W, working frequency 40KHz for 25 minutes, and carrying out constant volume to obtain the rifampicin long-acting preparation solution with the required concentration.
Example 6
Step 1, firstly preparing mother liquor of each component,
30mg/ml of Tris-HCl, (solvent, pure water, pH adjusted to 9.0);
dopamine hydrochloride: 20mg/ml, (solvent: pure water);
rifampin and poloxamer: 20mg/ml, (solvent: dimethyl sulfoxide) (rifampicin mixed with poloxamer in a 2:1 mass ratio) (poloxamer F237);
ellagic acid: 20mg/ml (solvent: dimethyl sulfoxide).
All mother liquor is fully dissolved by ultrasonic treatment, and then is filtered by a fat-soluble or water-soluble microporous filter membrane with the diameter of 0.22 mu m according to different solvents to remove impurities;
step 2, slowly adding the rifampicin and poloxamer mixed solution to the bottom of a 10-time volume Tris solution, keeping the liquid layered during the process, then carrying out ultrasonic treatment on the whole liquid system by using a probe type ultrasonicator, wherein the power is 300W, the ultrasonic treatment time per cycle is 4 seconds, the interval time is 3 seconds, and the total cycle number is 20 times, and keeping ice bath all the time during the treatment process to obtain rifampicin micelle dispersion liquid;
step 3, slowly adding 1 volume of ellagic acid solution and 2 volumes of dopamine hydrochloride solution into 20 volumes of rifampicin micelle dispersion liquid in sequence, continuously stirring the dispersion liquid in the period, wherein the stirring speed is 1000 revolutions per minute, 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, the time is 20 minutes, and finally transferring the solution into a sealing tube, and carrying out dark rotary reaction for 48 hours at 25 ℃;
and 4, centrifuging the solution after the reaction is finished, wherein the rotating speed is 14000 r/min, the centrifuging time is 45 min, removing supernatant, carrying out heavy suspension precipitation by using a phosphate buffer solution, carrying out ultrasonic treatment on the dispersion by using an ultrasonic cleaning machine, carrying out power of 230W, carrying out working frequency of 40KHz for 20 min, and carrying out constant volume to obtain the rifampicin long-acting preparation solution with the required concentration.
Example 7
Step 1, firstly preparing mother liquor of each component,
30mg/ml Tris-HCl, (solvent, pure water, pH adjusted to 8.8);
dopamine hydrochloride: 20mg/ml, (solvent: pure water);
rifampin and poloxamer: 20mg/ml, (solvent: dimethyl sulfoxide) (rifampicin mixed with poloxamer at a 3:1 mass ratio) (poloxamer F338);
ellagic acid: 20mg/ml (solvent: dimethyl sulfoxide).
All mother liquor is fully dissolved by ultrasonic treatment, and then is filtered by a fat-soluble or water-soluble microporous filter membrane with the diameter of 0.22 mu m according to different solvents to remove impurities;
step 2, slowly adding the rifampicin and poloxamer mixed solution to the bottom of a 10-time volume Tris solution, keeping the liquid layered during the process, then carrying out ultrasonic treatment on the whole liquid system by using a probe type ultrasonicator, wherein the power is 600W, the ultrasonic treatment time per cycle is 8 seconds, the interval time is 4 seconds, and the total cycle number is 30 times, and keeping ice bath all the time during the treatment process to obtain rifampicin micelle dispersion liquid;
step 3, slowly adding 1 volume of ellagic acid solution and 2 volumes of dopamine hydrochloride solution into 20 volumes of rifampicin micelle dispersion liquid in sequence, continuously stirring the dispersion liquid during the period, wherein the stirring speed is 1500 rpm, 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, the time is 30 minutes, and finally transferring the solution into a sealing tube, and carrying out light-proof rotary reaction for 72 hours at the temperature of 28 ℃;
and 4, centrifuging the solution after the reaction is finished, wherein the rotating speed is 14000 r/min, the centrifuging time is 60 minutes, removing supernatant, carrying out heavy suspension precipitation by using a phosphate buffer solution, carrying out ultrasonic treatment on the dispersion by using an ultrasonic cleaning machine, carrying out power 240W, working frequency 40KHz and time 30 minutes, and obtaining the rifampicin long-acting preparation solution with the required concentration after constant volume.
Example 8
Step 1, firstly preparing mother liquor of each component,
30mg/ml Tris-HCl, (solvent, pure water, pH adjusted to 8.9);
dopamine hydrochloride: 20mg/ml, (solvent: pure water);
rifampin and poloxamer: 20mg/ml, (solvent: dimethyl sulfoxide) (rifampicin mixed with poloxamer in a 3:1 mass ratio) (poloxamer F407);
ellagic acid: 20mg/ml (solvent: dimethyl sulfoxide).
All mother liquor is fully dissolved by ultrasonic treatment, and then is filtered by a fat-soluble or water-soluble microporous filter membrane with the diameter of 0.22 mu m according to different solvents to remove impurities;
step 2, slowly adding the rifampicin and poloxamer mixed solution to the bottom of a 10-time volume Tris solution, keeping the liquid layered during the process, then carrying out ultrasonic treatment on the whole liquid system by using a probe type ultrasonicator, wherein the power is 400W, the ultrasonic treatment time per cycle is 6 seconds, the interval time is 3 seconds, and the total cycle number is 30 times, and keeping ice bath all the time during the treatment process to obtain rifampicin micelle dispersion liquid;
step 3, slowly adding 1 volume of ellagic acid solution and 2 volumes of dopamine hydrochloride solution into 20 volumes of rifampicin micelle dispersion liquid in sequence, continuously stirring the dispersion liquid in the period, wherein the stirring speed is 1200 revolutions per minute, then carrying out ultrasonic treatment on the mixed reaction liquid by using an ultrasonic cleaning machine, wherein the power is 200, the working frequency is 40KHz, the time is 25 minutes, and finally transferring the solution into a sealing tube, and carrying out light-proof rotation reaction for 60 hours at the temperature of 28 ℃;
and 4, centrifuging the solution after the reaction is finished, wherein the rotating speed is 14000 r/min, the centrifuging time is 45 min, removing supernatant, carrying out heavy suspension precipitation by using a phosphate buffer solution, carrying out ultrasonic treatment on the dispersion by using an ultrasonic cleaning machine, carrying out ultrasonic treatment on the dispersion with the power of 250W, the working frequency of 40KHz for 25 min, and carrying out constant volume to obtain the rifampicin long-acting preparation solution with the required concentration.
Example 9
Step 1, firstly preparing mother liquor of each component,
30mg/ml of Tris-HCl, (solvent, pure water, pH adjusted to 9.0);
dopamine hydrochloride: 20mg/ml, (solvent: pure water);
rifampin and poloxamer: 20mg/ml, (solvent: dimethyl sulfoxide) (rifampicin mixed with poloxamer in a 3:1 mass ratio) (poloxamer F118);
ellagic acid: 20mg/ml (solvent: dimethyl sulfoxide).
All mother liquor is fully dissolved by ultrasonic treatment, and then is filtered by a fat-soluble or water-soluble microporous filter membrane with the diameter of 0.22 mu m according to different solvents to remove impurities;
step 2, slowly adding the rifampicin and poloxamer mixed solution to the bottom of a 10-time volume Tris solution, keeping the liquid layered during the process, then carrying out ultrasonic treatment on the whole liquid system by using a probe type ultrasonicator, wherein the power is 300W, the ultrasonic treatment time per cycle is 4 seconds, the interval time is 3 seconds, and the total cycle number is 30 times, and keeping ice bath all the time during the treatment process to obtain rifampicin micelle dispersion liquid;
step 3, slowly adding 1 volume of ellagic acid solution and 2 volumes of dopamine hydrochloride solution into 20 volumes of rifampicin micelle dispersion liquid in sequence, continuously stirring the dispersion liquid in the period, wherein the stirring speed is 1000 revolutions per minute, 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, the time is 20 minutes, and finally transferring the solution into a sealing tube, and carrying out dark rotary reaction for 48 hours at 25 ℃;
and 4, centrifuging the solution after the reaction is finished, wherein the rotating speed is 14000 r/min, the centrifuging time is 45 min, removing supernatant, carrying out heavy suspension precipitation by using a phosphate buffer solution, carrying out ultrasonic treatment on the dispersion by using an ultrasonic cleaning machine, carrying out power of 230W, carrying out working frequency of 40KHz for 20 min, and carrying out constant volume to obtain the rifampicin long-acting preparation solution with the required concentration.
Example 10
Step 1, firstly preparing mother liquor of each component,
30mg/ml Tris-HCl, (solvent, pure water, pH adjusted to 8.8);
dopamine hydrochloride: 20mg/ml, (solvent: pure water);
rifampin and poloxamer: 20mg/ml, (solvent: dimethyl sulfoxide) (rifampicin mixed with poloxamer in a 3:1 mass ratio) (poloxamer F237);
ellagic acid: 20mg/ml (solvent: dimethyl sulfoxide).
All mother liquor is fully dissolved by ultrasonic treatment, and then is filtered by a fat-soluble or water-soluble microporous filter membrane with the diameter of 0.22 mu m according to different solvents to remove impurities;
step 2, slowly adding the rifampicin and poloxamer mixed solution to the bottom of a 10-time volume Tris solution, keeping the liquid layered during the process, then carrying out ultrasonic treatment on the whole liquid system by using a probe type ultrasonicator, wherein the power is 600W, the ultrasonic treatment time per cycle is 8 seconds, the interval time is 4 seconds, and the total cycle number is 30 times, and keeping ice bath all the time during the treatment process to obtain rifampicin micelle dispersion liquid;
step 3, slowly adding 1 volume of ellagic acid solution and 2 volumes of dopamine hydrochloride solution into 20 volumes of rifampicin micelle dispersion liquid in sequence, continuously stirring the dispersion liquid during the period, wherein the stirring speed is 1500 rpm, 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, the time is 30 minutes, and finally transferring the solution into a sealing tube, and carrying out light-proof rotary reaction for 72 hours at the temperature of 28 ℃;
and 4, centrifuging the solution after the reaction is finished, wherein the rotating speed is 14000 r/min, the centrifuging time is 60 minutes, removing supernatant, carrying out heavy suspension precipitation by using a phosphate buffer solution, carrying out ultrasonic treatment on the dispersion by using an ultrasonic cleaning machine, carrying out the ultrasonic treatment with the power of 250W, the working frequency of 40KHz and the time of 30 minutes, and obtaining the rifampicin long-acting preparation solution with the required concentration after constant volume.
Example 11
Step 1, firstly preparing mother liquor of each component,
30mg/ml Tris-HCl, (solvent, pure water, pH adjusted to 8.9);
dopamine hydrochloride: 20mg/ml, (solvent: pure water);
rifampin and poloxamer: 20mg/ml, (solvent: dimethyl sulfoxide) (rifampicin mixed with poloxamer at a 2:1 mass ratio) (poloxamer F338);
ellagic acid: 20mg/ml (solvent: dimethyl sulfoxide).
All mother liquor is fully dissolved by ultrasonic treatment, and then is filtered by a fat-soluble or water-soluble microporous filter membrane with the diameter of 0.22 mu m according to different solvents to remove impurities;
step 2, slowly adding the rifampicin and poloxamer mixed solution to the bottom of a 10-time volume Tris solution, keeping the liquid layered during the process, then carrying out ultrasonic treatment on the whole liquid system by using a probe type ultrasonicator, wherein the power is 400W, the ultrasonic treatment time per cycle is 6 seconds, the interval time is 3 seconds, and the total cycle number is 25 times, and keeping ice bath all the time during the treatment process to obtain rifampicin micelle dispersion liquid;
step 3, slowly adding 1 volume of ellagic acid solution and 2 volumes of dopamine hydrochloride solution into 20 volumes of rifampicin micelle dispersion liquid in sequence, continuously stirring the dispersion liquid in the period, wherein the stirring speed is 1200 revolutions per minute, then carrying out ultrasonic treatment on the mixed reaction liquid by using an ultrasonic cleaning machine, wherein the power is 230W, the working frequency is 40KHz, the time is 25 minutes, and finally transferring the solution into a sealing tube, and carrying out light-proof rotary reaction for 60 hours at the temperature of 28 ℃;
and 4, centrifuging the solution after the reaction is finished, wherein the rotating speed is 14000 r/min, the centrifuging time is 60 minutes, removing supernatant, carrying out heavy suspension precipitation by using a phosphate buffer solution, carrying out ultrasonic treatment on the dispersion by using an ultrasonic cleaning machine, carrying out power of 230W, working frequency of 40KHz for 25 minutes, and carrying out constant volume to obtain the rifampicin long-acting preparation solution with the required concentration.
Example 12
Step 1, firstly preparing mother liquor of each component,
30mg/ml of Tris-HCl, (solvent, pure water, pH adjusted to 9.0);
dopamine hydrochloride: 20mg/ml, (solvent: pure water);
rifampin and poloxamer: 20mg/ml, (solvent: dimethyl sulfoxide) (rifampicin mixed with poloxamer in a 1:1 mass ratio) (poloxamer F407);
ellagic acid: 20mg/ml (solvent: dimethyl sulfoxide).
All mother liquor is fully dissolved by ultrasonic treatment, and then is filtered by a fat-soluble or water-soluble microporous filter membrane with the diameter of 0.22 mu m according to different solvents to remove impurities;
step 2, slowly adding the rifampicin and poloxamer mixed solution to the bottom of a 10-time volume Tris solution, keeping the liquid layered during the process, then carrying out ultrasonic treatment on the whole liquid system by using a probe type ultrasonicator, wherein the power is 300W, the ultrasonic treatment time per cycle is 4 seconds, the interval time is 3 seconds, and the total cycle number is 20 times, and keeping ice bath all the time during the treatment process to obtain rifampicin micelle dispersion liquid;
step 3, slowly adding 1 volume of ellagic acid solution and 2 volumes of dopamine hydrochloride solution into 20 volumes of rifampicin micelle dispersion liquid in sequence, continuously stirring the dispersion liquid in the period, wherein the stirring speed is 1000 revolutions per minute, 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, the time is 20 minutes, and finally transferring the solution into a sealing tube, and carrying out dark rotary reaction for 48 hours at 25 ℃;
and 4, centrifuging the solution after the reaction is finished, wherein the rotating speed is 14000 r/min, the centrifuging time is 45 min, removing supernatant, carrying out heavy suspension precipitation by using a phosphate buffer solution, carrying out ultrasonic treatment on the dispersion by using an ultrasonic cleaning machine, carrying out power of 230W, carrying out working frequency of 40KHz for 20 min, and carrying out constant volume to obtain the rifampicin long-acting preparation solution with the required concentration.
Morphological characteristics, particle size, stability, release and in vivo toxicity of the rifampicin nano-formulation prepared in example 1 were measured. The results obtained show that: the nanometer preparation has the characteristics of uniform particle size, good monodispersity, strong stability, uniform morphological characteristics, good monodispersity (shown in figure 1), high stability (shown in figures 2 and 3) and the like. From the results of the release experiments of rifampicin and its nano-preparations, the nano-preparation has a good sustained-release effect, and can effectively ensure the sustained and stable release of the drug in the systemic circulation (see fig. 4 and fig. 5). The toxicity of rifampicin nano preparation was measured by using rifampicin as control, and it was found that the hemolysis of erythrocytes by rifampicin nano preparation was not much different from that of erythrocytes (see fig. 6). Acute toxicity tests in vivo (see fig. 7) are carried out, and the nano preparation is found to be capable of obviously improving the survival rate, which shows that the rifampicin nano preparation can effectively reduce the dosage form toxicity of rifampicin drugs. The particle size and other parameters of the rifampicin nano-preparations prepared in different examples are very close, which shows the universality and stability of the process.
The invention combines the package material dopamine hydrochloride, the stabilizer ellagic acid and the anti-tuberculous drug rifampicin through multiple steps to form the nanometer preparation particles. The prepared nano preparation particles are uniform and stable, have good repeatability, controllable quality and simple process.

Claims (10)

1. A long-acting preparation for anti-tubercular rifampicin is characterized by using dopamine hydrochloride as a packaging material and ellagic acid as a stabilizer.
2. A preparation method of a long-acting preparation for an anti-tubercular drug rifampicin is characterized by comprising the following steps:
step 1, preparing mother liquor of each component; the components comprise Tris (hydroxymethyl) aminomethane-hydrochloric acid (Tris-HCl), dopamine hydrochloride, rifampicin, poloxamer and ellagic acid;
step 2, adding the rifampicin and poloxamer mixed solution to the bottom of a Tris-HCl solution with the volume 10 times that of the mixed solution, keeping the liquid in a layered state, then carrying out ultrasonic treatment on the whole liquid system, and keeping ice bath all the time in the treatment process to obtain rifampicin micelle dispersion liquid;
step 3, slowly adding 1 volume of ellagic acid solution and 2 volumes of dopamine hydrochloride solution into 20 volumes of the rifampicin micelle dispersion liquid obtained in the step 2 in sequence, continuously stirring the dispersion liquid during the process, then carrying out ultrasonic treatment on the mixed reaction liquid, and finally sealing the solution;
and 4, centrifuging the solution after the reaction is finished, removing the supernatant, carrying out heavy suspension precipitation by using a phosphate buffer solution, carrying out ultrasonic treatment, and carrying out constant volume to obtain the rifampicin long-acting preparation solution with the required concentration.
3. The method for preparing a long acting formulation for the anti-tubercular drug rifampicin according to claim 2, wherein the step 1 is as follows:
the Tris-HCl mother liquor comprises the components of Tris-HCl with the concentration of 30mg/ml and pure water as a solvent;
dopamine hydrochloride mother liquor: the components are dopamine hydrochloride with the concentration of 20mg/ml, and the solvent is pure water;
rifampin and poloxamer mother liquor: the components are rifampicin and poloxamer, 20mg/ml, and the solvent is dimethyl sulfoxide;
ellagic acid mother liquor: the component is ellagic acid, 20mg/ml, and the solvent is dimethyl sulfoxide;
all mother liquor is fully dissolved by ultrasonic treatment, and then is filtered to remove impurities.
4. The method for preparing a long-acting preparation for the anti-tubercular drug rifampicin according to claim 3, wherein the pH of the Tris-HCl mother liquor in step 1 is 8.8-9.0.
5. The method for preparing a long-acting formulation for the anti-tubercular drug rifampicin according to claim 3, wherein the poloxamer in step 1 is one of F118, F237, F338 and F407.
6. The method for preparing a long-acting preparation of an anti-tubercular drug rifampicin according to claim 3, wherein rifampicin and poloxamer in step 1 are mixed in a mass ratio of 1: 1-3: 1.
7. The process of claim 3, wherein said step 1 is performed by filtering with a micro-porous membrane with lipid solubility or water solubility of 0.22 μm to remove impurities.
8. The method for preparing the long-acting preparation for the anti-tubercular drug rifampicin according to claim 3, wherein the ultrasonic treatment is performed on the whole liquid system by using a probe-type ultrasonicator in step 2, wherein the power is 300-600W, the ultrasonic treatment time per cycle is 4-8 seconds, the interval time is 3-4 seconds, and the total number of cycles is 20-30.
9. The method as claimed in claim 3, wherein the stirring speed of the dispersion liquid in step 3 is 1500 rpm, the ultrasonic cleaning machine is used to perform ultrasonic treatment on the mixed reaction liquid, the ultrasonic treatment power is 200W and 250W, the working frequency is 40KHz, the time is 20-30 minutes, and finally the solution is transferred to a sealed tube and is subjected to dark rotation reaction at 25-28 ℃ for 48-72 hours.
10. The method as claimed in claim 3, wherein the centrifugation in step 4 is carried out at 14000 rpm for 45-60 minutes, the ultrasonic cleaning machine is used to perform ultrasonic treatment on the dispersion, the ultrasonic treatment power is 230-250W, the working frequency is 40KHz, and the time is 20-30 minutes.
CN202110255644.5A 2021-03-09 2021-03-09 Long-acting preparation for antituberculosis drug rifampicin and preparation method thereof Active CN113133989B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202110255644.5A CN113133989B (en) 2021-03-09 2021-03-09 Long-acting preparation for antituberculosis drug rifampicin and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202110255644.5A CN113133989B (en) 2021-03-09 2021-03-09 Long-acting preparation for antituberculosis drug rifampicin and preparation method thereof

Publications (2)

Publication Number Publication Date
CN113133989A true CN113133989A (en) 2021-07-20
CN113133989B CN113133989B (en) 2023-04-25

Family

ID=76810971

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202110255644.5A Active CN113133989B (en) 2021-03-09 2021-03-09 Long-acting preparation for antituberculosis drug rifampicin and preparation method thereof

Country Status (1)

Country Link
CN (1) CN113133989B (en)

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040258718A1 (en) * 2001-08-24 2004-12-23 John Meadows Synergistic mixed poloxamer systmes for the solubilisation of drugs
US20090098200A1 (en) * 2007-09-25 2009-04-16 Solubest Ltd. Compositions comprising lipophilic active compounds and method for their preparation
WO2010001391A1 (en) * 2008-06-30 2010-01-07 Oron Zachar Dermal application of vasoconstrictors
CN102626518A (en) * 2012-05-09 2012-08-08 中国药科大学 Preparation and application of insoluble drug-entrapped poloxamer/amphiphilic polysaccharide mixed micelle
WO2012176212A1 (en) * 2011-06-20 2012-12-27 V.B. Medicare Pvt. Ltd. Carrier based nanogel formulation for skin targeting.
CN105833287A (en) * 2016-04-20 2016-08-10 国家纳米科学中心 Slow-release nano drug carrier as well as preparation method and application thereof
CN107625745A (en) * 2017-09-11 2018-01-26 西安医学院 A kind of nanometer formulation for coronarospasm treatment and preparation method thereof
US20180360974A1 (en) * 2017-03-10 2018-12-20 Quiapeg Pharmaceuticals Ab Releasable conjugates
CN109331184A (en) * 2017-08-01 2019-02-15 复旦大学 A kind of lotus positively charged drug nano crystallization preparation and preparation method thereof

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040258718A1 (en) * 2001-08-24 2004-12-23 John Meadows Synergistic mixed poloxamer systmes for the solubilisation of drugs
US20090098200A1 (en) * 2007-09-25 2009-04-16 Solubest Ltd. Compositions comprising lipophilic active compounds and method for their preparation
WO2010001391A1 (en) * 2008-06-30 2010-01-07 Oron Zachar Dermal application of vasoconstrictors
WO2012176212A1 (en) * 2011-06-20 2012-12-27 V.B. Medicare Pvt. Ltd. Carrier based nanogel formulation for skin targeting.
CN102626518A (en) * 2012-05-09 2012-08-08 中国药科大学 Preparation and application of insoluble drug-entrapped poloxamer/amphiphilic polysaccharide mixed micelle
CN105833287A (en) * 2016-04-20 2016-08-10 国家纳米科学中心 Slow-release nano drug carrier as well as preparation method and application thereof
US20180360974A1 (en) * 2017-03-10 2018-12-20 Quiapeg Pharmaceuticals Ab Releasable conjugates
CN109331184A (en) * 2017-08-01 2019-02-15 复旦大学 A kind of lotus positively charged drug nano crystallization preparation and preparation method thereof
CN107625745A (en) * 2017-09-11 2018-01-26 西安医学院 A kind of nanometer formulation for coronarospasm treatment and preparation method thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEN ET AL.: "Nanoscale Polydopamine (PDA) Meets π–π Interactions: An Interface-Directed Coassembly Approach for Mesoporous Nanoparticles", 《LANGMUIR》 *
CI ET AL.: "Enhanced Delivery of Imatinib into Vaginal Mucosa via a New Positively Charged Nanocrystal-Loaded in Situ Hydrogel Formulation for Treatment of Cervical Cancer", 《PHARMACEUTICS》 *
刘隆臻: "基于聚多巴胺的纳米药物载体的构建", 《中国优秀硕士学位论文全文数据库 医药科技卫生辑》 *
房林等: "聚多巴胺包覆对金纳米棒光热治疗效果的影响", 《2015年全国高分子学术论文报告会》 *

Also Published As

Publication number Publication date
CN113133989B (en) 2023-04-25

Similar Documents

Publication Publication Date Title
WO1999008660A1 (en) Solid pharmaceutical dosage forms in form of a particulate dispersion
CN109260177B (en) Preparation method and application of berberine hydrochloride compound nanoparticles
CN101984958B (en) Nanoscale albendazole micropowder and preparation method thereof
KR101616134B1 (en) Drug delivery system for administration of a water soluble, cationic and amphiphilic pharmaceutically active substance
CN104523606A (en) Method used for preparing gossypol and gossypol derivative pluronic nanoparticle via self-assembling
CN113133989B (en) Long-acting preparation for antituberculosis drug rifampicin and preparation method thereof
CN108542893B (en) Nanoparticle with excellent blood stability and preparation method thereof
CN110051652B (en) PLGA/FK506 drug-loaded nano-microsphere as well as preparation method and application thereof
JP5466174B2 (en) Drug delivery system for administering water-soluble, cationic and amphiphilic pharmaceutically active substances
CN116135230A (en) Berberine hydrochloride/indocyanine green nanoparticle and preparation method and application thereof
CN113603738B (en) PH responsive amphotericin B derivative and preparation method and application thereof
CN113133987B (en) Preparation method of ultra-long circulating nano-carrier for tenib drugs
CN112999149B (en) Nanometer injection of horizon medicine for long-acting slow release and preparation method thereof
CN109248148B (en) Preparation and in vitro release of dihydromyricetin lecithin-based liquid crystal dispersion particles, antioxidant and cytotoxic effects
CN113171356B (en) Preparation method of sitagliptin drug nano-preparation with stable release performance
CN105997882B (en) A kind of method preparing magnetic vesica and its application on pharmaceutical carrier
CN105902504B (en) Tetrazine diformamide nano preparation and preparation method thereof
Soujanya et al. A Review on Novel Vesicular Drug Delivery System: Proniosomes.
CN112999196B (en) Mortierella lignicola nano preparation for long-acting stable release and preparation method thereof
CN114470229B (en) Preparation and application of carrier-free double-drug self-assembled nanoparticle
CN114939165B (en) Bimetal nanoparticle capable of reversing multi-drug resistance as well as preparation method and application thereof
CN114948880B (en) Preparation method of caffeic acid phenethyl ester nano stable slow release formulation
CN110339163B (en) Cisplatin-polyglutamic acid complex micelle and preparation method thereof
CN117085001B (en) Preparation method and application of dual-targeting core-shell structure nano drug-loaded particles
CN102327221B (en) Cefadroxil liposome solid preparation

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant