CN112316159A - Nanoemulsion contrast therapeutic agent containing pingyangmycin and preparation process thereof - Google Patents

Nanoemulsion contrast therapeutic agent containing pingyangmycin and preparation process thereof Download PDF

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CN112316159A
CN112316159A CN202011217886.7A CN202011217886A CN112316159A CN 112316159 A CN112316159 A CN 112316159A CN 202011217886 A CN202011217886 A CN 202011217886A CN 112316159 A CN112316159 A CN 112316159A
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pingyangmycin
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stirring
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周石
黄智�
曾柱
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Affiliated Hospital of Guizhou Medical University
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Abstract

The invention discloses a nano-emulsion contrast therapeutic agent containing pingyangmycin and a preparation process thereof, which comprises 70-90 parts of superparamagnetic nano-particles, 400-500 parts of iodized oil, 135-175 parts of medical composite gelatin, 1-3 parts of pingyangmycin, 15-25 parts of serum albumin and 5-10 parts of emulsifying agent, wherein the superparamagnetic nano-particles are Fe2O3Nano meterParticles obtained by a vapor deposition method, the diameter of the superparamagnetic nanoparticle is 3-10nm, and the Fe2O3The nano particles are wrapped in the emulsified iodized oil emulsion drops, the medical composite gelatin comprises bone gelatin and skin gelatin in a mass ratio of 10:3, the iodine content of the iodized oil is 100-150mg/ml, the serum albumin is combined on the emulsion drops made of the medical composite gelatin, and the pingyangmycin is combined on the serum albumin.

Description

Nanoemulsion contrast therapeutic agent containing pingyangmycin and preparation process thereof
Technical Field
The invention relates to the technical field of medical radiography, in particular to a nanoemulsion contrast therapeutic agent containing pingyangmycin and a preparation process thereof.
Background
In the medical imaging related field, the molecular imaging technology can provide important information for disease diagnosis and monitoring of living tissues, so that the molecular imaging technology is widely concerned and practically applied, the imaging technology plays an important role in early cancer discovery, the death rate of cancer is relatively high and seriously threatens human life, the early discovery of cancer signs leads to relatively high cure rate of patients, however, early tumors are usually tiny and the size is usually below 1cm, so that the traditional medical imaging technology, such as Computed Tomography (CT), Magnetic Resonance Imaging (MRI), X-ray, Ultrasound (US) and the like, is difficult to accurately diagnose the tiny tumors;
the multi-modal contrast agent can simultaneously carry out the combined imaging of two or more than two imaging devices such as CT, MRI, fluorescence and the like by injecting one contrast agent at a time, and has important effect on the discovery of early micro-tumors;
in the aspect of medicines for treating cancers, pingyangmycin is an antitumor chemotherapeutic medicine, which is mainly a bleomycin antitumor antibiotic medicine generated by pingyangmycin, mainly inhibits DNA synthesis of tumor cells, can cut off the DNA chain of tumors, influences metabolism and functions of the cancer cells, and promotes degeneration and necrosis of the tumors. In multiple studies, pingyangmycin has strong killing effect on liver cancer, nasopharyngeal carcinoma, colon cancer and serosal cavity metastatic cancer. The pingyangmycin also has the same effect as other tumor medicaments, and has obvious inhibiting effect. For the specificity of cell cycle, pingyangmycin belongs to a cell nonspecific medicine and has no definite influence on the immune function and hematopoietic system of the body. Because of this, pingyangmycin can be used in tumor patients with partial immune and hematopoietic hypofunction. The pingyangmycin has positive treatment effect on various tumors in clinical application, including skin tumor, breast, cervix, esophagus, reproductive system tumor, lymphoma and the like.
Disclosure of Invention
The invention aims to provide a nanoemulsion contrast therapeutic agent containing pingyangmycin and a preparation process thereof, and invents a contrast agent which can play a certain therapeutic role while carrying out contrast according to the current situation in the field of contrast.
In order to achieve the purpose, the invention provides the following technical scheme:
a nanoemulsion contrast therapeutic agent containing pingyangmycin and a preparation process thereof comprise the following components in parts by weight: 70-90 parts of superparamagnetic nano particles, 400-500 parts of iodized oil, 135-175 parts of medical composite gelatin, 1-3 parts of pingyangmycin, 15-25 parts of serum albumin and 5-10 parts of an emulsifying agent.
Preferably, the superparamagnetic nanoparticle is Fe2O3Nanoparticles obtained by a vapor deposition method, the diameter of the superparamagnetic nanoparticles being 3-10nm, Fe prepared by the method2O3The nano particles are small in size and are more uniform in size.
Preferably, the Fe2O3Nanoparticles are encapsulated within the emulsified iodized oil emulsion droplets.
Preferably, the medical composite gelatin comprises gelatin for bone preparation and gelatin for skin preparation in a mass ratio of 10: 3.
Preferably, the iodized oil has an iodine content of 100-150 mg/ml.
Preferably, the serum albumin is bonded on the emulsion drops made of the medical compound gelatin, the pingyangmycin is bonded on the serum albumin, and the serum albumin plays a role in transportation and carries the pingyangmycin to a tumor part needing to be treated.
Preferably, the emulsifier comprises 50-60 parts of surfactant and 1-2 parts of cosurfactant by weight;
the surfactant is selected from one of the following materials or a combination thereof: oleic acid, soy lecithin, egg yolk lecithin, cephalin, poloxamer 188, Brij 35, Myrj51, Myrj53, Cremophor RH40, Cremophor EL, Tween 80 and Tween 85;
the cosurfactant is selected from one of the following materials or the combination of the following materials: ethanol, 1, 2-propylene glycol, glycerol, polyethylene glycol 400 and ethylene glycol monoethyl ether.
Preferably, the preparation process of the nanoemulsion contrast therapeutic agent containing pingyangmycin comprises the following steps:
s1: firstly preparing an iodized oil emulsion, mixing iodized oil and deionized water in a weight ratio of 3: 5, putting the mixture into ultrasonic vibration stirring equipment for emulsification, adding an emulsifier, and stirring for 60-90min under the conditions that the frequency is 28 KHz-40 KHz ultrasonic vibration, the temperature is 65-70 ℃, and the rotating speed is 700-900rad/min to obtain a stable oil-in-water nanoemulsion, wherein the diameter range of emulsion droplets of the oil-in-water nanoemulsion is 10-50nm, and the size of the emulsion droplets of the emulsion prepared in an ultrasonic vibration mode is more uniform;
s2: mixing superparamagnetic nano-particles Fe2O3Mixing with the oil-in-water nanoemulsion obtained in the step S1, adding the mixture into ultrasonic vibration stirring equipment, performing vibration stirring and mixing for 50-70min under the conditions of vibration frequency of 2KHz-3KHz, temperature of 60-70 ℃ and rotation speed of 300 plus 350rad/min and nitrogen protection, and then sterilizing the stirred mixed emulsion for 30min under ultraviolet rays;
s3: preparing a medical composite gelatin emulsion, putting the medical composite gelatin and iodized oil into ultrasonic vibration stirring equipment, vibrating and stirring for 60-70min under the conditions that the frequency is 28 KHz-40 KHz ultrasonic vibration, the temperature is 70-80 ℃, and the rotating speed is 800 plus materials and 1200rad/min, emulsifying to obtain the medical composite gelatin emulsion, and then carrying out ultraviolet disinfection on the obtained gelatin emulsion mixed solution for 30 min;
s4: adding serum albumin and pingyangmycin into the medical composite gelatin emulsion obtained in S3, and vibrating, stirring and mixing under the conditions that the vibration frequency is 60Hz-90Hz, the temperature is 60-70 ℃, and the rotating speed is 120 plus 180 rad/min;
s5: storing and taking the obtained product containing the superparamagnetic nano-particle Fe in S22O3Iodized oil emulsion of (A) and medical compound gelatin containing pingyangmycin obtained from S4The emulsion is separately stored in sterile bottle containing inert gas, to avoid light irradiation, high frequency and large vibration, and the temperature is maintained at 0-3 deg.C, and the emulsion is mixed according to S5 within 2-10 hr before use;
s6: mixing the emulsion obtained from S2 and S4 to obtain the nanoemulsion contrast therapeutic agent containing pingyangmycin.
Preferably, the mixing method of step S6 specifically includes: stirring for 20min under the conditions that the vibration frequency is 30Hz-60Hz, the temperature is 60-70 ℃ and the rotating speed is 120-180rad/min, and finally obtaining the nanoemulsion contrast therapeutic agent containing pingyangmycin, wherein the stirring mode can ensure that the emulsion obtained from S2 and S4 is mixed more uniformly.
Preferably, the ultrasonic vibration stirring apparatus used in steps S and S includes: the stirring tank comprises a stirring tank shell with an upward opening and a stirring tank end cover with a downward opening, wherein a main shaft through hole which is through from top to bottom is formed in the center of the stirring tank end cover, a hollow rotating main shaft matching column which extends downwards is fixedly arranged at the position, located at the main shaft through hole, of the lower end of the stirring tank end cover, a rotating main shaft which extends from top to bottom is arranged in a rotating matching mode in the rotating main shaft matching column, a rotating supporting block is fixedly arranged at the lower end of the rotating main shaft, an inner stirring rod connecting rod and an outer stirring rod connecting rod are fixedly arranged on the side face of the rotating supporting block, a plurality of inner stirring rod connecting rods and a plurality of outer stirring rod connecting rods are arranged in an annular array mode, a section of inner spiral stirring rod is fixedly arranged at the other end of the inner stirring rod connecting rod, the inner spiral stirring rod extends spirally around the axis of the rotating main shaft, a section, the self-rotating directions of the inner spiral stirring rod and the outer spiral stirring rod are opposite;
an annular ultrasonic vibration generator shell is fixedly arranged at the lower end of the end cover of the stirring tank, an inner side ultrasonic vibration rod extending downwards is arranged at the position, close to the center, of the lower end of the ultrasonic vibration generator shell, an outer side ultrasonic vibration rod extending downwards is arranged at the position, close to the edge, of the lower end of the ultrasonic vibration generator shell, and a plurality of inner side ultrasonic vibration rods and a plurality of outer side ultrasonic vibration rods are arranged in an annular array;
a supporting restraining ring is arranged at the position, close to the top end, of the rotating main shaft, a main shaft driven gear is fixedly arranged at the top end of the rotating main shaft, a motor is fixedly arranged at the upper end of the end cover of the stirring tank, a main shaft driving gear is fixedly arranged on an output shaft of the motor, and the main shaft driving gear is in meshed connection with the main shaft driven gear;
the upper end of the end cover of the stirring tank is fixedly connected with a sealing cover shell with a downward opening;
the bottom end is equipped with supplementary ultrasonic vibration casing admittedly in the agitator tank casing, supplementary ultrasonic vibration casing top is equipped with a plurality of supplementary ultrasonic vibration sticks that upwards extend.
Compared with the prior art, the invention has the beneficial effects that: the contrast agent disclosed by the invention is reasonable in structural design and remarkable in effect, contains iodized oil capable of being used for CT radiography and superparamagnetic nanoparticles capable of being used for MRI radiography, and remarkably improves the contrast effect.
Drawings
FIG. 1 is a schematic microscopic view of a contrast therapeutic agent of the present invention;
FIG. 2 is a front view (half section) of the ultrasonic vibration stirring apparatus of the present invention;
in the figure, 1-superparamagnetic nanoparticle, 2-iodized oil, 3-medical composite gelatin, 4-serum albumin, 5-surfactant, 6-pingyangmycin, 10-stirring tank shell, 20-stirring tank end cover, 201-main shaft through hole, 21-rotating main shaft matching column, 22-sealing cover shell, 30-rotating supporting block, 31-inner stirring rod connecting rod, 32-outer stirring rod connecting rod, 33-inner spiral stirring rod, 34-outer spiral stirring rod, 35-rotating main shaft, 351-supporting restraining ring, 36-main shaft driven gear, 40-ultrasonic vibration generator shell, 41-outer ultrasonic vibration rod, 42-inner ultrasonic vibration rod, 50-auxiliary ultrasonic vibration shell, 51-auxiliary ultrasonic vibration rod, 60-motor, 61-main shaft driving gear.
Detailed Description
The invention will now be described in detail with reference to fig. 1-2, for ease of description, the orientations described below will now be defined as follows: the up, down, left, right, and front-back directions described below correspond to the up, down, left, right, and front-back directions in the projection relationship of fig. 1 itself.
Example 1:
a nanoemulsion contrast therapeutic agent containing pingyangmycin comprises the following components in parts by weight: 70 parts of superparamagnetic nano particles, 400 parts of iodized oil, 135 parts of medical composite gelatin, 1 part of pingyangmycin, 15 parts of serum albumin and 5 parts of emulsifying agent.
Wherein the superparamagnetic nanoparticle is Fe2O3Nanoparticles obtained by a vapor deposition method, said superparamagnetic nanoparticles having a diameter of 3 nm.
Said Fe2O3Nanoparticles are encapsulated within the emulsified iodized oil emulsion droplets.
The medical composite gelatin comprises gelatin for bone preparation and gelatin for skin preparation in a mass ratio of 10: 3.
The iodized oil has an iodine content of 100 mg/ml.
The serum albumin is combined on the emulsion drops made of the medical composite gelatin, and the pingyangmycin is combined on the serum albumin.
The emulsifier comprises 50 parts of surfactant and 1 part of cosurfactant in parts by weight.
The surfactant is oleic acid.
The cosurfactant is polyethylene glycol 400.
Example 2:
a nanoemulsion contrast therapeutic agent containing pingyangmycin comprises the following components in parts by weight: 80 parts of superparamagnetic nano particles, 450 parts of iodized oil, 155 parts of medical composite gelatin, 2 parts of pingyangmycin, 20 parts of serum albumin and 8 parts of emulsifier.
Wherein the superparamagnetic nanoparticle is Fe2O3Nanoparticles obtained by a vapor deposition method, said superparamagnetic nanoparticles having a diameter of 7 nm.
Said Fe2O3Nanoparticles are encapsulated within the emulsified iodized oil emulsion droplets.
The medical composite gelatin comprises gelatin for bone preparation and gelatin for skin preparation in a mass ratio of 10: 3.
The iodized oil has an iodine content of 125 mg/ml.
The serum albumin is combined on the emulsion drops made of the medical composite gelatin, and the pingyangmycin is combined on the serum albumin.
The emulsifier comprises 55 parts of surfactant and 1.5 parts of cosurfactant in parts by weight.
The surfactant is soybean lecithin.
The cosurfactant is ethylene glycol monoethyl ether.
Example 3:
a nanoemulsion contrast therapeutic agent containing pingyangmycin comprises the following components in parts by weight: 90 parts of superparamagnetic nano particles, 500 parts of iodized oil, 175 parts of medical composite gelatin, 3 parts of pingyangmycin, 25 parts of serum albumin and 10 parts of emulsifier.
Wherein the superparamagnetic nanoparticle is Fe2O3Nanoparticles obtained by a vapor deposition method, said superparamagnetic nanoparticles having a diameter of 10 nm.
Said Fe2O3Nanoparticles are encapsulated within the emulsified iodized oil emulsion droplets.
The medical composite gelatin comprises gelatin for bone preparation and gelatin for skin preparation in a mass ratio of 10: 3.
The iodized oil has an iodine content of 150 mg/ml.
The serum albumin is combined on the emulsion drops made of the medical composite gelatin, and the pingyangmycin is combined on the serum albumin.
The emulsifier comprises 60 parts of surfactant and 3 parts of cosurfactant in parts by weight.
The surfactant is a mixture of cephalin and egg yolk lecithin in a mass ratio of 3: 2.
The cosurfactant is a mixture of glycerol and polyethylene glycol 400 according to the mass ratio of 2: 1.
Example 4:
a nanoemulsion contrast therapeutic agent containing pingyangmycin comprises the following components in parts by weight: 80 parts of superparamagnetic nano particles, 450 parts of iodized oil, 155 parts of medical composite gelatin, 2 parts of pingyangmycin, 20 parts of serum albumin and 8 parts of emulsifier.
Wherein the superparamagnetic nanoparticle is Fe2O3Nanoparticles obtained by a vapor deposition method, said superparamagnetic nanoparticles having a diameter of 7 nm.
Said Fe2O3Nanoparticles are encapsulated within the emulsified iodized oil emulsion droplets.
The medical composite gelatin comprises gelatin for bone preparation and gelatin for skin preparation in a mass ratio of 10: 3.
The iodized oil has an iodine content of 125 mg/ml.
The serum albumin is combined on the emulsion drops made of the medical composite gelatin, and the pingyangmycin is combined on the serum albumin.
The emulsifier comprises 55 parts of surfactant and 1.5 parts of cosurfactant in parts by weight.
The surfactant is soybean lecithin.
The cosurfactant is ethylene glycol monoethyl ether.
The preparation process of the contrast therapeutic agent comprises the following steps:
s1: preparing an iodized oil emulsion, mixing iodized oil and deionized water in a weight ratio of 3: 5, putting the mixture into ultrasonic vibration stirring equipment for emulsification, adding an emulsifier, and stirring for 60min under the conditions that the frequency is 28KHz ultrasonic vibration, the temperature is 65 ℃ and the rotating speed is 700rad/min to obtain a stable oil-in-water nanoemulsion, wherein the diameter range of emulsion droplets of the oil-in-water nanoemulsion is 10-50 nm;
s2: mixing superparamagnetic nano-particles Fe2O3Mixing with the oil-in-water nanoemulsion obtained in S1, adding into ultrasonic vibration stirring equipment, performing vibration stirring and mixing for 50min under the conditions of vibration frequency of 2KHz, temperature of 60 ℃, rotation speed of 300rad/min and nitrogen protection, and then sterilizing the stirred mixed emulsion under ultraviolet raysSterilizing for 30 min;
s3: preparing a medical composite gelatin emulsion, putting the medical composite gelatin and iodized oil into an ultrasonic vibration stirring device, performing vibration stirring for 60min under the conditions that the frequency is 28KHz ultrasonic vibration, the temperature is 70 ℃, and the rotating speed is 800rad/min, emulsifying to obtain the medical composite gelatin emulsion, and then performing ultraviolet disinfection on the obtained gelatin emulsion mixed solution for 30 min;
s4: adding serum albumin and pingyangmycin into the medical composite gelatin emulsion obtained in S3, and vibrating, stirring and mixing under the conditions that the vibration frequency is 60Hz, the temperature is 60 ℃ and the rotating speed is 120 rad/min;
s5: storing and taking the obtained product containing the superparamagnetic nano-particle Fe in S22O3The iodized oil emulsion and the medical composite gelatin emulsion containing pingyangmycin obtained in S4 need to be separately stored in a sterile bottle containing inert gas, the light irradiation is avoided, the high frequency and the large vibration are avoided, the temperature is kept at 0 ℃, and the iodized oil emulsion and the medical composite gelatin emulsion containing pingyangmycin are mixed according to S6 within 2 hours before use;
s6: mixing the emulsion obtained from S2 and S4, and stirring with glass rod for 2min to obtain nanoemulsion contrast therapeutic agent containing pingyangmycin.
Example 5:
a nanoemulsion contrast therapeutic agent containing pingyangmycin comprises the following components in parts by weight: 80 parts of superparamagnetic nano particles, 450 parts of iodized oil, 155 parts of medical composite gelatin, 2 parts of pingyangmycin, 20 parts of serum albumin and 8 parts of emulsifier.
Wherein the superparamagnetic nanoparticle is Fe2O3Nanoparticles obtained by a vapor deposition method, said superparamagnetic nanoparticles having a diameter of 7 nm.
Said Fe2O3Nanoparticles are encapsulated within the emulsified iodized oil emulsion droplets.
The medical composite gelatin comprises gelatin for bone preparation and gelatin for skin preparation in a mass ratio of 10: 3.
The iodized oil has an iodine content of 125 mg/ml.
The serum albumin is combined on the emulsion drops made of the medical composite gelatin, and the pingyangmycin is combined on the serum albumin.
The emulsifier comprises 55 parts of surfactant and 1.5 parts of cosurfactant in parts by weight.
The surfactant is soybean lecithin.
The cosurfactant is ethylene glycol monoethyl ether.
The preparation process of the contrast therapeutic agent comprises the following steps:
s1: preparing an iodized oil emulsion, mixing iodized oil and deionized water in a weight ratio of 3: 5, putting the mixture into ultrasonic vibration stirring equipment for emulsification, adding an emulsifier, and stirring for 75min under the conditions that the frequency is 35KHz ultrasonic vibration, the temperature is 68 ℃, and the rotating speed is 800rad/min to obtain a stable oil-in-water nanoemulsion, wherein the diameter range of emulsion droplets of the oil-in-water nanoemulsion is 10-50 nm;
s2: mixing superparamagnetic nano-particles Fe2O3Mixing with the oil-in-water nanoemulsion obtained in the step S1, adding into an ultrasonic vibration stirring device, performing vibration stirring and mixing for 60min under the protection of nitrogen at the vibration frequency of 2.5KHz and the temperature of 65 ℃ and the rotating speed of 330rad/min, and then sterilizing the stirred mixed emulsion for 30min under ultraviolet rays;
s3: preparing a medical composite gelatin emulsion, putting the medical composite gelatin and iodized oil into an ultrasonic vibration stirring device, performing ultrasonic vibration with the frequency of 35KHz, the temperature of 75 ℃, and the rotating speed of 1000rad/min, performing vibration stirring for 65min, emulsifying to obtain the medical composite gelatin emulsion, and then performing ultraviolet disinfection on the obtained gelatin emulsion mixed solution for 30 min;
s4: adding serum albumin and pingyangmycin into the medical composite gelatin emulsion obtained in S3, and vibrating, stirring and mixing under the conditions that the vibration frequency is 75Hz, the temperature is 65 ℃ and the rotating speed is 150 rad/min;
s5: storing and taking the obtained product containing the superparamagnetic nano-particle Fe in S22O3The iodized oil emulsion and the medical compound gelatin emulsion containing pingyangmycin obtained from S4 need to be separately preserved, and preservedIn a sterile bottle containing inert gas, avoiding illumination, avoiding high frequency and large vibration, keeping the temperature at 1 ℃, and mixing the components according to S6 within 6 hours before use;
s6: mixing the emulsion obtained from S2 and S4, and stirring with glass rod for 2min to obtain nanoemulsion contrast therapeutic agent containing pingyangmycin.
Example 6:
a nanoemulsion contrast therapeutic agent containing pingyangmycin comprises the following components in parts by weight: 80 parts of superparamagnetic nano particles, 450 parts of iodized oil, 155 parts of medical composite gelatin, 2 parts of pingyangmycin, 20 parts of serum albumin and 8 parts of emulsifier.
Wherein the superparamagnetic nanoparticle is Fe2O3Nanoparticles obtained by a vapor deposition method, said superparamagnetic nanoparticles having a diameter of 7 nm.
Said Fe2O3Nanoparticles are encapsulated within the emulsified iodized oil emulsion droplets.
The medical composite gelatin comprises gelatin for bone preparation and gelatin for skin preparation in a mass ratio of 10: 3.
The iodized oil has an iodine content of 125 mg/ml.
The serum albumin is combined on the emulsion drops made of the medical composite gelatin, and the pingyangmycin is combined on the serum albumin.
The emulsifier comprises 55 parts of surfactant and 1.5 parts of cosurfactant in parts by weight.
The surfactant is soybean lecithin.
The cosurfactant is ethylene glycol monoethyl ether.
The preparation process of the contrast therapeutic agent comprises the following steps:
s1: preparing an iodized oil emulsion, mixing iodized oil and deionized water in a weight ratio of 3: 5, putting the mixture into ultrasonic vibration stirring equipment for emulsification, adding an emulsifier, and stirring for 90min under the conditions of 40KHz ultrasonic vibration frequency, 70 ℃ temperature and 900rad/min rotation speed to obtain a stable oil-in-water nanoemulsion, wherein the diameter range of emulsion droplets of the oil-in-water nanoemulsion is 10-50 nm;
s2: mixing superparamagnetic nano-particles Fe2O3Mixing with the oil-in-water nanoemulsion obtained in the step S1, adding into an ultrasonic vibration stirring device, vibrating, stirring and mixing for 70min under the protection of nitrogen under the vibration frequency of 3KHz and the temperature of 70 ℃ and the rotating speed of 350rad/min, and then sterilizing the stirred mixed emulsion for 30min under ultraviolet rays;
s3: preparing medical composite gelatin emulsion, placing medical composite gelatin and iodized oil into ultrasonic vibration stirring equipment, vibrating and stirring for 70min under the conditions that the frequency is 40KHz ultrasonic vibration, the temperature is 80 ℃ and the rotating speed is 1200rad/min, emulsifying to obtain the medical composite gelatin emulsion, and then sterilizing the obtained gelatin emulsion mixed solution for 30min by ultraviolet rays;
s4: adding serum albumin and pingyangmycin into the medical composite gelatin emulsion obtained in S3, and vibrating, stirring and mixing under the conditions that the vibration frequency is 90Hz, the temperature is 70 ℃ and the rotating speed is 180 rad/min;
s5: storing and taking the obtained product containing the superparamagnetic nano-particle Fe in S22O3The iodized oil emulsion and the medical composite gelatin emulsion containing the pingyangmycin obtained in the S4 are required to be separately and independently stored, and are stored in a sterile bottle containing inert gas, so that the light is avoided, the high frequency and the large vibration are avoided, the temperature is kept at 2 ℃, and the iodized oil emulsion and the medical composite gelatin emulsion are mixed according to the S6 within 10 hours before use;
s6: mixing the emulsion obtained from S2 and S4, and stirring with glass rod for 2min to obtain nanoemulsion contrast therapeutic agent containing pingyangmycin.
Example 7:
a nanoemulsion contrast therapeutic agent containing pingyangmycin comprises the following components in parts by weight: 80 parts of superparamagnetic nano particles, 450 parts of iodized oil, 155 parts of medical composite gelatin, 2 parts of pingyangmycin, 20 parts of serum albumin and 8 parts of emulsifier.
Wherein the superparamagnetic nanoparticle is Fe2O3Nanoparticles obtained by a vapor deposition method, said superparamagnetic nanoparticles having a diameter of 7 nm.
Said Fe2O3Nanoparticles are encapsulated within the emulsified iodized oil emulsion droplets.
The medical composite gelatin comprises gelatin for bone preparation and gelatin for skin preparation in a mass ratio of 10: 3.
The iodized oil has an iodine content of 125 mg/ml.
The serum albumin is combined on the emulsion drops made of the medical composite gelatin, and the pingyangmycin is combined on the serum albumin.
The emulsifier comprises 55 parts of surfactant and 1.5 parts of cosurfactant in parts by weight.
The surfactant is soybean lecithin.
The cosurfactant is ethylene glycol monoethyl ether.
The preparation process of the contrast therapeutic agent comprises the following steps:
s1: preparing an iodized oil emulsion, mixing iodized oil and deionized water in a weight ratio of 3: 5, putting the mixture into ultrasonic vibration stirring equipment for emulsification, adding an emulsifier, and stirring for 90min under the conditions of 40KHz ultrasonic vibration frequency, 70 ℃ temperature and 900rad/min rotation speed to obtain a stable oil-in-water nanoemulsion, wherein the diameter range of emulsion droplets of the oil-in-water nanoemulsion is 10-50 nm;
s2: mixing superparamagnetic nano-particles Fe2O3Mixing with the oil-in-water nanoemulsion obtained in the step S1, adding into an ultrasonic vibration stirring device, vibrating, stirring and mixing for 70min under the protection of nitrogen under the vibration frequency of 3KHz and the temperature of 70 ℃ and the rotating speed of 350rad/min, and then sterilizing the stirred mixed emulsion for 30min under ultraviolet rays;
s3: preparing medical composite gelatin emulsion, placing medical composite gelatin and iodized oil into ultrasonic vibration stirring equipment, vibrating and stirring for 70min under the conditions that the frequency is 40KHz ultrasonic vibration, the temperature is 80 ℃ and the rotating speed is 1200rad/min, emulsifying to obtain the medical composite gelatin emulsion, and then sterilizing the obtained gelatin emulsion mixed solution for 30min by ultraviolet rays;
s4: adding serum albumin and pingyangmycin into the medical composite gelatin emulsion obtained in S3, and vibrating, stirring and mixing under the conditions that the vibration frequency is 90Hz, the temperature is 70 ℃ and the rotating speed is 180 rad/min;
s5: storing and taking the obtained product containing the superparamagnetic nano-particle Fe in S22O3The iodized oil emulsion and the medical composite gelatin emulsion containing the pingyangmycin obtained in the S4 are required to be separately and independently stored, and are stored in a sterile bottle containing inert gas, so that the light is avoided, the high frequency and the large vibration are avoided, the temperature is kept at 2 ℃, and the iodized oil emulsion and the medical composite gelatin emulsion are mixed according to the S6 within 10 hours before use;
s6: mixing the emulsion obtained from S2 and S4, stirring for 20min at vibration frequency of 60Hz, temperature of 70 deg.C and rotation speed of 180rad/min to obtain nanoemulsion contrast therapeutic agent containing pingyangmycin.
The ultrasonic vibration stirring device in the embodiment is an ultrasonic vibration stirring device which is manufactured by Hangzhou Jinghao mechanical limited and has the model number of JH1500W 20.
Example 8:
a nanoemulsion contrast therapeutic agent containing pingyangmycin comprises the following components in parts by weight: 80 parts of superparamagnetic nano particles, 450 parts of iodized oil, 155 parts of medical composite gelatin, 2 parts of pingyangmycin, 20 parts of serum albumin and 8 parts of emulsifier.
Wherein the superparamagnetic nanoparticle is Fe2O3Nanoparticles obtained by a vapor deposition method, said superparamagnetic nanoparticles having a diameter of 7 nm.
Said Fe2O3Nanoparticles are encapsulated within the emulsified iodized oil emulsion droplets.
The medical composite gelatin comprises gelatin for bone preparation and gelatin for skin preparation in a mass ratio of 10: 3.
The iodized oil has an iodine content of 125 mg/ml.
The serum albumin is combined on the emulsion drops made of the medical composite gelatin, and the pingyangmycin is combined on the serum albumin.
The emulsifier comprises 55 parts of surfactant and 1.5 parts of cosurfactant in parts by weight;
the surfactant is soybean lecithin;
the cosurfactant is ethylene glycol monoethyl ether.
A preparation process of a nanoemulsion contrast therapeutic agent containing pingyangmycin comprises the following steps:
s1: preparing an iodized oil emulsion, mixing iodized oil and deionized water in a weight ratio of 3: 5, putting the mixture into ultrasonic vibration stirring equipment for emulsification, adding an emulsifier, and stirring for 90min under the conditions of 40KHz ultrasonic vibration frequency, 70 ℃ temperature and 900rad/min rotation speed to obtain a stable oil-in-water nanoemulsion, wherein the diameter range of emulsion droplets of the oil-in-water nanoemulsion is 10-50 nm;
s2: mixing superparamagnetic nano-particles Fe2O3Mixing with the oil-in-water nanoemulsion obtained in the step S1, adding into an ultrasonic vibration stirring device, vibrating, stirring and mixing for 70min under the protection of nitrogen under the vibration frequency of 3KHz and the temperature of 70 ℃ and the rotating speed of 350rad/min, and then sterilizing the stirred mixed emulsion for 30min under ultraviolet rays;
s3: preparing medical composite gelatin emulsion, placing medical composite gelatin and iodized oil into ultrasonic vibration stirring equipment, vibrating and stirring for 70min under the conditions that the frequency is 40KHz ultrasonic vibration, the temperature is 80 ℃ and the rotating speed is 1200rad/min, emulsifying to obtain the medical composite gelatin emulsion, and then sterilizing the obtained gelatin emulsion mixed solution for 30min by ultraviolet rays;
s4: adding serum albumin and pingyangmycin into the medical composite gelatin emulsion obtained in S3, and vibrating, stirring and mixing under the conditions that the vibration frequency is 90Hz, the temperature is 70 ℃ and the rotating speed is 180 rad/min;
s5: storing and taking the obtained product containing the superparamagnetic nano-particle Fe in S22O3The iodized oil emulsion and the medical composite gelatin emulsion containing the pingyangmycin obtained in the S4 are required to be separately and independently stored, and are stored in a sterile bottle containing inert gas, so that the light is avoided, the high frequency and the large vibration are avoided, the temperature is kept at 2 ℃, and the iodized oil emulsion and the medical composite gelatin emulsion are mixed according to the S6 within 10 hours before use;
s6: mixing the emulsion obtained from S2 and S4, stirring for 20min at vibration frequency of 60Hz, temperature of 70 deg.C and rotation speed of 180rad/min to obtain nanoemulsion contrast therapeutic agent containing pingyangmycin.
The ultrasonic vibration stirring device used in the steps S1 and S3 in the preparation process comprises: the stirring tank comprises a stirring tank shell 10 with an upward opening and a stirring tank end cover 20 with a downward opening, wherein a spindle through hole 201 which is through from top to bottom is formed in the center of the stirring tank end cover 20, a hollow rotating spindle matching column 21 which extends downwards is fixedly arranged at the position, located at the spindle through hole 201, of the lower end of the stirring tank end cover 20, a rotating spindle 35 which extends from top to bottom is arranged in a rotating and matching mode in the rotating spindle matching column 21, a rotating supporting block 30 is fixedly arranged at the lower end of the rotating spindle 35, an inner stirring rod connecting rod 31 and an outer stirring rod connecting rod 32 are fixedly arranged on the side face of the rotating supporting block 30, a plurality of inner stirring rod connecting rods 31 and a plurality of outer stirring rod connecting rods 32 are arranged in an annular array mode, a section of inner spiral stirring rod 33 is fixedly arranged at the other end of the inner stirring rod connecting rod 31, the inner spiral stirring rod 33 extends spirally around the axis of the, the outer spiral stirring rod 34 extends spirally around the axis of the rotating main shaft 35, and the inner spiral stirring rod 33 and the outer spiral stirring rod 34 have opposite spinning directions;
an annular ultrasonic vibration generator shell 40 is fixedly arranged at the lower end of the stirring tank end cover 20, an inner side ultrasonic vibration rod 42 extending downwards is arranged at the position, close to the center, of the lower end of the ultrasonic vibration generator shell 40, an outer side ultrasonic vibration rod 41 extending downwards is arranged at the position, close to the edge, of the lower end of the ultrasonic vibration generator shell 40, and a plurality of inner side ultrasonic vibration rods 42 and a plurality of outer side ultrasonic vibration rods 41 are arranged in an annular array;
a supporting restraining ring 351 is arranged at the position, close to the top end, of the rotating main shaft 35, a main shaft driven gear 36 is fixedly arranged at the top end of the rotating main shaft 35, a motor 60 is fixedly arranged at the upper end of the end cover 20 of the stirring tank, a main shaft driving gear 61 is fixedly arranged on an output shaft of the motor 60, and the main shaft driving gear 61 is in meshed connection with the main shaft driven gear 36;
the upper end of the stirring tank end cover 20 is fixedly connected with a sealing cover shell 22 with a downward opening;
the bottom end is firmly equipped with supplementary ultrasonic vibration casing 50 in agitator tank casing 10, supplementary ultrasonic vibration casing 50 top is equipped with a plurality of supplementary ultrasonic vibration stick 51 that upwards extend.
Experimental example 1:
first, biotoxicity test
For the first time
Test subjects: 1500 mice, each half of male and female, with the weight of 18-20g, were fasted without water prohibition for 24h, and 500 mice in each group were randomly allocated to three groups, with no significant difference between the groups.
And (3) test period: and 14 days.
The test method comprises the following steps: first, the drug formulated in example 1 was injected intravenously, 45mg each time, once a day;
second group, i.v. the drug formulated in example 2, 45mg per injection, once a day;
the second group, i.v., injected with 45mg of the drug formulated in example 3 once a day.
For the second time
Test subjects: 1500 mice, each half of male and female, with the weight of 18-20g, were fasted without water prohibition for 24h, and 500 mice in each group were randomly allocated to three groups, with no significant difference between the groups.
And (3) test period: and 14 days.
The test method comprises the following steps: the first group, i.v. the drug formulated in example 1, 50mg per injection, once a day;
second group, i.v. the drug formulated in example 2, 50mg per injection, once a day;
the second group, i.v., injected with 50mg of the drug formulated in example 3 once a day.
The third time
Test subjects: 1500 mice, each half of male and female, with the weight of 18-20g, were fasted without water prohibition for 24h, and 500 mice in each group were randomly allocated to three groups, with no significant difference between the groups.
And (3) test period: and 14 days.
The test method comprises the following steps: the first group, i.v. administered with 55mg of the drug formulated in example 1, once a day;
second group, i.v. the drug formulated in example 2, 55mg each time, once a day;
the second group, i.v., injected with 55mg of the drug formulated in example 3, once a day.
External environment: the room temperature is 23-24 ℃, the indoor humidity is 55-65%, and the air purification blower continuously ventilates.
Detecting parameters: heart rate, body temperature, feces, activity status.
And (3) allergic reaction: the heart rate increases by more than 50% and the body temperature increases by more than 3% after the injection of the drug.
The experimental data are shown in table 1.
Table 1: results of biotoxicity test
Figure BDA0002761044450000171
And (4) test conclusion: the biological reaction to the contrast therapeutic agent of the invention is mild, no severe anaphylactic reaction exists, mild anaphylactic reaction is controlled in a reasonable range, and the biological toxicity is almost 0;
in the experimental example 1, compared among the example 1, the example 2 and the example 3, the toxicity of the drug is almost 0 under different drug ratios, but the allergic reaction ratio of the drug in the example 2 is the lowest, and the best scheme in the example 2 is obtained by comprehensive comparison.
Experimental example 2:
second, clinical effect verification
The verification object is: 360 patients of 20-30 years old, 360 patients of 31-55 years old and 360 patients of 55 years old or more are selected, 60 patients are selected from the patients of 20-30 years old, 60 patients are selected from the patients of 31-55 years old, 60 patients are selected from the patients of 55 years old or more, 180 patients are regarded as one group, the group is divided into six groups in total, the medicines prepared in example 4, example 5, example 6, example 7 and example 8 are respectively used for clinical verification, and the sixth group is a blank control group without any treatment means.
And (3) verification period: for 70 days.
The verification method comprises the following steps: a first group of patients, using the protocol of example 4, was subjected to an imaging observation, every 7 days, and were fasted for 12h before the imaging observation;
a second group of patients, using the protocol of example 5, were subjected to radiographic observation, once every 7 days, and were fasted for 12h before radiographic observation;
a third group of patients, which were subjected to the protocol of example 6, were observed with contrast every 7 days, and were fasted for 12h before the contrast observation;
a fourth group of patients, who were subjected to the protocol of example 7, were observed with contrast every 7 days, and were fasted for 12h before the contrast observation;
a fifth group of patients, which were subjected to radiographic observation using the protocol of example 8, were observed once every 7 days, and were fasted for 12h before radiographic observation;
and in the sixth group of patients, the common contrast agent is adopted for contrast observation, the conventional treatment scheme is adopted, the observation is carried out once every 7 days, and water is forbidden for fasting for 12 hours before the contrast observation.
Evaluation criteria: the contrast effect is evaluated by professional medical staff according to the definition and the integrity of the contrast effect;
the treatment effect is firstly observed and contrasted from the image according to the size difference of the tumor before and after treatment, the regression condition is evaluated according to, the change condition of the circulating tumor cells in the peripheral blood is also detected, the contrast is carried out before and after the treatment, finally, the pathological diagnosis is carried out, and the pathologist observes the regression condition of the tumor under a microscope for evaluation, and in conclusion, the professional medical staff carries out the comprehensive effect evaluation.
The verification results are shown in table 2.
Table 2: clinical effect verification
Figure BDA0002761044450000181
Figure BDA0002761044450000191
And (4) conclusion:
in experimental example 2, from comparison among example 4, example 5 and example 6, the best protocol of example 6 was evaluated according to contrast effect and therapeutic effect under different preparation process conditions.
From the comparison among example 4, example 5, example 6 and example 7, example 7 was the most effective as evaluated from the contrast effect and the therapeutic effect in the different mixing and stirring modes.
From the comparison between example 7 and example 8, example 8 was the most effective as evaluated on the contrast effect and the therapeutic effect under different conditions of the ultrasonic vibration agitation equipment.

Claims (10)

1. A nanoemulsion contrast therapeutic agent containing pingyangmycin is characterized by comprising the following components in parts by weight: 70-90 parts of superparamagnetic nano particles, 400-500 parts of iodized oil, 135-175 parts of medical composite gelatin, 1-3 parts of pingyangmycin, 15-25 parts of serum albumin and 5-10 parts of an emulsifying agent.
2. The nanoemulsion contrast agent containing pingyangmycin according to claim 1, wherein: the superparamagnetic nano-particles are Fe2O3Nanoparticles, which are obtained by a vapor deposition method, wherein the diameter of the superparamagnetic nanoparticles is 3-10 nm.
3. The nanoemulsion contrast agent containing pingyangmycin according to claim 1, wherein: said Fe2O3Nanoparticles are encapsulated within the emulsified iodized oil emulsion droplets.
4. The nanoemulsion contrast agent containing pingyangmycin according to claim 1, wherein: the medical composite gelatin comprises gelatin for bone preparation and gelatin for skin preparation in a mass ratio of 10: 3.
5. The nanoemulsion contrast agent containing pingyangmycin according to claim 1, wherein: the iodine content of the iodized oil is 100-150 mg/ml.
6. The nanoemulsion contrast agent containing pingyangmycin according to claim 1, wherein: the serum albumin is combined on the emulsion drops made of the medical composite gelatin, and the pingyangmycin is combined on the serum albumin.
7. The nanoemulsion contrast agent containing pingyangmycin according to claim 1, wherein: the emulsifier comprises 50-60 parts of surfactant and 1-2 parts of cosurfactant in parts by weight;
the surfactant is selected from one of the following materials or a combination thereof: oleic acid, soy lecithin, egg yolk lecithin, cephalin, poloxamer 188, Brij 35, Myrj51, Myrj53, Cremophor RH40, Cremophor EL, Tween 80 and Tween 85;
the cosurfactant is selected from one of the following materials or the combination of the following materials: ethanol, 1, 2-propylene glycol, glycerol, polyethylene glycol 400 and ethylene glycol monoethyl ether.
8. A process for preparing the nano-emulsion contrast therapeutic agent containing pingyangmycin as claimed in any one of claims 1 to 7, which comprises the following steps:
s1: firstly preparing an iodized oil emulsion, mixing iodized oil and deionized water in a weight ratio of 3: 5, putting the mixture into ultrasonic vibration stirring equipment for emulsification, adding an emulsifier, and stirring for 60-90min under the conditions that the frequency is 28 KHz-40 KHz ultrasonic vibration, the temperature is 65-70 ℃, and the rotating speed is 700-900rad/min to obtain a stable oil-in-water nanoemulsion, wherein the diameter range of emulsion droplets of the oil-in-water nanoemulsion is 10-50 nm;
s2: mixing superparamagnetic nano-particles Fe2O3Mixing with the oil-in-water nanoemulsion obtained in S1, and adding into ultrasonic vibration stirring equipment at vibration frequency of 2KHz-3KHz and temperature of 60 KHzAt the temperature of minus 70 ℃, the rotating speed is 300-;
s3: preparing a medical composite gelatin emulsion, putting the medical composite gelatin and iodized oil into ultrasonic vibration stirring equipment, vibrating and stirring for 60-70min under the conditions that the frequency is 28 KHz-40 KHz ultrasonic vibration, the temperature is 70-80 ℃, and the rotating speed is 800 plus materials and 1200rad/min, emulsifying to obtain the medical composite gelatin emulsion, and then carrying out ultraviolet disinfection on the obtained gelatin emulsion mixed solution for 30 min;
s4: adding serum albumin and pingyangmycin into the medical composite gelatin emulsion obtained in S3, and vibrating, stirring and mixing under the conditions that the vibration frequency is 60Hz-90Hz, the temperature is 60-70 ℃, and the rotating speed is 120 plus 180 rad/min;
s5: storing and taking the obtained product containing the superparamagnetic nano-particle Fe in S22O3The iodized oil emulsion and the medical composite gelatin emulsion containing pingyangmycin obtained in S4 need to be separately stored in a sterile bottle containing inert gas, the light irradiation is avoided, the high frequency and the large vibration are avoided, the temperature is kept at 0-3 ℃, and the iodized oil emulsion and the medical composite gelatin emulsion containing pingyangmycin are mixed according to S5 within 2-10 hours before use;
s6: mixing the emulsion obtained from S2 and S4 to obtain the nanoemulsion contrast therapeutic agent containing pingyangmycin.
9. The preparation process of the nanoemulsion contrast therapeutic agent containing pingyangmycin according to claim 8, which is characterized in that: the mixing method of step S6 specifically includes: stirring for 20min under the conditions that the vibration frequency is 30Hz-60Hz, the temperature is 60-70 ℃ and the rotating speed is 120-180rad/min, and finally obtaining the nanoemulsion contrast therapeutic agent containing pingyangmycin.
10. The process for preparing the nanoemulsion contrast therapeutic agent containing pingyangmycin according to claim 8 or 9, which is characterized in that: the ultrasonic vibration stirring apparatus used in the steps S1 and S3 includes: the stirring tank comprises a stirring tank shell (10) with an upward opening and a stirring tank end cover (20) with a downward opening, wherein a main shaft through hole (201) which is through from top to bottom is formed in the center of the stirring tank end cover (20), a hollow rotating main shaft matching column (21) which extends downwards is fixedly arranged at the position, located at the main shaft through hole (201), of the lower end of the stirring tank end cover (20), a rotating main shaft (35) which extends from top to bottom is arranged in the rotating main shaft matching column (21) in a rotating matching mode, a rotating supporting block (30) is fixedly arranged at the lower end of the rotating main shaft (35), an inner stirring rod connecting rod (31) and an outer stirring rod connecting rod (32) are fixedly arranged on the side face of the rotating supporting block (30), a plurality of inner stirring rod connecting rods (31) and a plurality of outer stirring rod connecting rods (32) are arranged in an annular array mode, the inner spiral stirring rod (33) extends spirally around the axis of the rotating main shaft (35), the other end of the outer stirring rod connecting rod (32) is fixedly provided with an outer spiral stirring rod (34), the outer spiral stirring rod (34) extends spirally around the axis of the rotating main shaft (35), and the self-rotating directions of the inner spiral stirring rod (33) and the outer spiral stirring rod (34) are opposite;
an annular ultrasonic vibration generator shell (40) is fixedly arranged at the lower end of the end cover (20) of the stirring tank, an inner side ultrasonic vibration rod (42) extending downwards is arranged at the position, close to the center, of the lower end of the ultrasonic vibration generator shell (40), an outer side ultrasonic vibration rod (41) extending downwards is arranged at the position, close to the edge, of the lower end of the ultrasonic vibration generator shell (40), and a plurality of inner side ultrasonic vibration rods (42) and a plurality of outer side ultrasonic vibration rods (41) are arranged in an annular array;
a supporting restraining ring (351) is arranged at the position, close to the top end, of the rotating main shaft (35), a main shaft driven gear (36) is fixedly arranged at the top end of the rotating main shaft (35), a motor (60) is fixedly arranged at the upper end of the stirring tank end cover (20), a main shaft driving gear (61) is fixedly arranged on an output shaft of the motor (60), and the main shaft driving gear (61) is in meshed connection with the main shaft driven gear (36);
the upper end of the end cover (20) of the stirring tank is fixedly connected with a sealing cover shell (22) with a downward opening;
the bottom end is firmly equipped with supplementary ultrasonic vibration casing (50) in agitator tank casing (10), supplementary ultrasonic vibration casing (50) top is equipped with a plurality of supplementary ultrasonic vibration stick (51) that upwards extend.
CN202011217886.7A 2020-11-04 2020-11-04 Nanoemulsion contrast therapeutic agent containing pingyangmycin and preparation process thereof Pending CN112316159A (en)

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Publication number Priority date Publication date Assignee Title
CN114028605A (en) * 2021-10-29 2022-02-11 厦门大学 Preparation method and application of injectable gelatin-iodized oil homogeneous preparation for vascular embolism

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102166365A (en) * 2011-04-25 2011-08-31 东南大学 Preparation method of multiplex-mode iodized oil nano-emulsion contrast medium

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102166365A (en) * 2011-04-25 2011-08-31 东南大学 Preparation method of multiplex-mode iodized oil nano-emulsion contrast medium

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114028605A (en) * 2021-10-29 2022-02-11 厦门大学 Preparation method and application of injectable gelatin-iodized oil homogeneous preparation for vascular embolism

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