New Drug Preparation Based On Themo-responsive Nano Composites For Umbilical Cord Therapy: Its Synthetic Method And Clinical Application

OBJECTIVE:1.To preparate the temperature-sensitive nanocomposite（temperature-sensitive hydrogel）with photothermal properties as a carrier for umbilical therapy for dysmenorrhea,and to provide a basis for subsequent experiments.2.To optimize the compound extraction process of umbilical therapy for dysmenorrhea,and evaluate the in vitro release,transdermal absorption and safety of the new dosage patch for umbilical therapy.3.To evaluate the difference in clinical efficacy and safety of the new dosage patch for umbilical therapy and drug-separated moxibustion for treating primary dysmenorrhea,and to provide a certain reference for the clinical application of the new dosage patch for umbilical therapy for the treatment of primary dysmenorrhea.METHODS:1.Fe₃O₄nanoparticles with photothermal properties were prepared by chemical co-precipitation method,and Fe₃O₄nanoparticles were combined with temperature-sensitive polymer material poly N-isopropyla crylamide to prepare temperature-responsive nano composites of different concentrations of Fe₃O₄nanoparticles.And characterized by photothermal conversion test,scanning electron microscope,hydrogel swelling kinetics and other tests,preferably temperature-sensitive nano composites doped with Fe₃O₄nanoparticles for subsequent experiments are preferred.2.Extraction of dysmenorrhea and umbilical therapy compound and optimization of the extraction process to realize the load of umbilical therapy compound by temperature-sensitive nanocomposite,evaluate the in vitro release and transdermal absorption effect of the new dosage patch for umbilical therapy through in vitro drug release and transdermal absorption experiments,and evaluate the safety of the new dosage patch for umbilical therapy.3.Sixty patients with primary dysmenorrhea were randomly divided into the drug-separated moxibustion group and the new umbilical therapy group,30 cases in each group.Observation of clinical efficacy is mainly based on CMSS dysmenorrhea scale,visual analog scale,dysmenorrhea assessment criteria,uterine artery hemodynamics,PGF_2αM,and compare the effectiveness of the two groups.Observed and recorded the adverse reactions and abnormal changes of ALT,BUN,and Cre level before and after treatment during the test,and evaluate the clinical efficacy difference and safety of new umbilical therapy dosage patch and drug-separated moxibustion for the treatment of primary dysmenorrhea,and to provide a reference basis for further clinical application.RESULTS:1.The prepared temperature-sensitive nanocomposite has good moldability and mechanical properties.The photothermal conversion test shows that the temperature of Fe₃O₄nanoparticles and Fe₃O₄@p NIPAM composite hydrogels gradually rises under the conditions of near-infrared light irradiation,and the rate of temperature rise is directly proportional to the concentration of Fe₃O₄nanoparticles;SEM tests show that the prepared Fe₃O₄nanoparticles and Fe₃O₄@p NIPAM composite hydrogel have a uniform structure;hydrogel swelling kinetics tests show that the swelling rate of the hydrogel increases within the first hour quickly,then gradually slowed down.The swelling rate of Fe₃O₄@p NIPAM composite hydrogel is lower than that of blank hydrogel.Considering the mechanical,photothermal properties and swelling rate of the hydrogel as a whole,2.0Fe₃O₄@p NIPAM composite hydrogel was finally selected.As a carrier of new dosage forms for umbilical therapy.2.Optimized to obtain the optimal extraction process of dysmenorrhea and umbilical therapy compound,in vitro drug release and transdermal absorption test showed that the permeation per unit area of drug-loaded Fe₃O₄@p NIPAM composite hydrogels under near-infrared irradiation is higher than that of drug-loaded Fe₃O₄@p NIPAM composite hydrogels（without near-infrared light）,and the permeation per unit area of drug-loaded Fe₃O₄@p NIPAM composite hydrogels（without near-infrared light）is higher than that of Fe₃O₄-free hydrogel containing the drug,the results of skin irritation experiments showed that no obvious erythema and edema appeared in the two groups of rats after the experiment,the results of the acute toxicity experiment showed that after the experiment was blank.There were no significant abnormal changes in the body weight,mental behavior,skin hair,mucous membranes,respiratory circulation,and central nervous system of the rats in the black group,the control group,and the new umbilical therapy dosage group.There was no significant difference between the three groups.It shows that the new dosage form of umbilical therapy has no skin irritation and acute toxicity.3.After one course of treatment,both the drug-separated moxibustion and the new dosage patch for umbilical therapy can significantly reduce VAS readings（P<0.01）.Comparing the groups,there is no difference in the relief effect of the two therapies on the degree of abdominal pain（P>0.05）;compared with before treatment,both the treatments can significantly reduce the total onset time and average severity score of dysmenorrhea symptoms（P<0.01）,However,the improvement of dysmenorrhea in subjects with umbilical cord moxibustion in drug-separated moxibustion group was wider than that in the new umbilical therapy group,there is no difference in the overall relief effect of the two therapies on the total time of onset of dysmenorrhea symptoms and the average severity of one course of treatment（P>0.05）,both therapies can reduce the PI,RI,and A/B values of the left and right uterine arteries and uterine arch arteries of subjects with primary dysmenorrhea（P<0.01 or P<0.05）.Compared between the groups,it is superior to the new dosage patch for umbilical therapy in alleviating left and right uterine artery PI and uterine arch artery RI（P<0.05）,both the treatments can significantly reduce the serum level of PGF_2αM in subjects with primary dysmenorrhea（P<0.01）,comparing the groups,drug-separated moxibustion group was superior to the new umbilical therapy group in reducing the content of PGF_2αM（P<0.05）.The effective rate of the drug-separated moxibustion group was 89.29%,and the effective rate of the new umbilical therapy group was 82.76%.There was no significant difference in the effective rate between the two groups（P>0.05）.During the clinical trial,no adverse reactions occurred in the two groups of patients with primary dysmenorrhea,and there was no abnormal change in the levels of ALT,BUN,and Cre before and after treatment.CONCLUSION:1.The temperature-sensitive nanocomposite doped with Fe₃O₄nanoparticles has good mechanical properties and photothermal properties,and can be used as a drug carrier for new dosage patch for umbilical therapy.2.The in vitro drug release and transdermal absorption test of the new dosage form patch for dysmenorrhea proved that under near-infrared light conditions,the photothermal material Fe₃O₄nanoparticles in the hydrogel converts light energy into thermal energy.The increase in temperature causes the volume of the thermosensitive hydrogel to shrink,to promote drug release and penetration.The safety test results show that the new dosage form of umbilical therapy has no irritating and acute toxicity to the skin,indicating that it can be further used in clinical applications with high safety.3.The new dosage patch for umbilical therapy and drug-separated moxibustion method have a good relief effect on the degree of abdominal pain,the total time of onset of dysmenorrhea symptoms and the average severity of subjects with primary dysmenorrhea,and through the benign adjustment of PI,RI and A/B values of uterine artery and arch artery,increase uterine blood supply to change the state of uterine ischemia and hypoxia,improving the microcirculation of the uterus and reducing the content of PGF_2αM play a role in the treatment of primary dysmenorrhea.There is no difference in the effectiveness of the two therapies in the treatment of primary dysmenorrhea.The new dosage patch for umbilical therapy is is effective in treating primary dysmenorrhea,and the operation is simple,shortened clinical treatment time and the safety is high.It is worth further promotion and application.