| Research background and purpose: For mild to moderate ulcerative colitis(UC)rectal localized treatment,budesonide rectal in situ adhesion temperature-sensitive gel was prepared with glucocorticoid budesonide,bioadhesive material,and temperature-sensitive gel matrix poloxamer.Optimizing the formulation and preparation process of temperature-sensitive gel preparations,and clarifying their key properties such as temperature-sensitive characteristics,adhesion retention,and rectal localized administration.Materials and Methods: The degradation of mass spectra was obtained by destroying the API under the conditions of a strong acid,strong alkali,and strong oxidation.The solubility of budesonide in PBS with different p H and poloxamer with a certain concentration was investigated.The compatibility of raw materials and excipients was investigated by mixing them with water in a certain proportion and then exposed to high temperatures and strong light.Investigate the stability of budesonide in different p H thermosensitive gel matrix.Taking gelation stability,gelatinization temperature,preparation time and operability as indicators,the process of thermosensitive gel preparation was determined.Poloxamer P407 was selected as the temperature-sensitive material and gelation temperature as the index to select the appropriate temperature-sensitive regulator.The yield value and adhesive force were measured by rheometer,and the two parameters were used as indexes to compare the bioadhesive materials such as methylcellulose,hydroxypropylmethylcellulose,sodium methylcellulose,sodium alginate,and different types of hydroxypropylmethylcellulose.The bioadhesive properties of bioadhesive materials in vivo were verified by the rectal retention test.A rheometer is used to measure the changing trend of the elastic modulus(G')and the loss modulus(G")of thermo-sensitive gel with temperature,and the intersection point is used as the gelation temperature.The gel temperature was used as the evaluation index,and the prescription was optimized by CCD-RSM.The dosage of poloxamer P407,poloxamer P188,and HPMC K4 M was optimized by three factors and five levels of star point design experiment.The gel temperature,modulus,rectal retention performance and in vitro release were used as the evaluation indexes to further screen the optimal prescription.Objective to establish an HPLC method for the determination of budesonide in the thermosensitive gel.A vertical Franz diffusion cellwas used to establish a method for the in vitro release of thermosensitive gels and to investigate the release properties of thermosensitive gels under different conditions.The effects of strong light(4500lx + 500lx),high temperature(60 C),centrifugation and freeze-thaw on the stability of the preparation were investigated with impurity content,uniformity of budesonide content and gel temperature.The physical and chemical stability of the preparation was preliminarily evaluated.SD rats were randomly divided into 3 groups.After 7 days of budesonide rectal in situ thermosensitive gel,blank thermosensitive gel,and normal saline,the SD rats were dissected and the rectal visually observed and examined for histopathological changes to evaluate the mucosal irritation of the preparation.SD male and female halves were randomly divided into 4 groups,which were injected with budesonide solution via tail vein,gavage,enema,budesonide temperature-sensitive gel enema,and the plasma and rectal tissues of rats were taken at different time points after administration.And determine the concentration of budesonide in rat plasma and rectum,use DAS3.0 software to process the pharmacokinetic data,and calculate the bioavailability(F),rectal targeting efficiency(DTE)and target index(DTI).Result: 1.The degradation information of budesonide was obtained through the forced degradation experiment.It was found that the solubility of budesonide was almost unchanged under different p H conditions,indicating that p H had little effect on its solubility,but the solubility of budesonide increased significantly in 18% P407 solution.The results show that budesonide has no compatibility with the selected excipients.At the same time,the stability of different p H thermosensitive gels showed that budesonide had the highest stability in the p H condition of p H4.5.2.the preparation process of thermosensitive gel is as follows: add bioadhesive to agitation and dissolve under stirring,then add thermosensitive regulator and stir until it is dissolved.Finally,add thermosensitive material,budesonide,and benzalkonium bromide to stir to dissolve.The results of the rheometer showed that HPMC K4 M was better than other adhesion materials in yield value and adhesion,and HPMC K4 M was better in different types of HPMC,so HPMC K4 M was selected as biological adhesion material.3.Poloxamer P407,poloxamer P188,and HPMC K4 M were selected as temperature-sensitive materials,gelling temperature regulation and bioadhesive agents.The dosage ranges were 15%-20%,0.9-6%,0.2%-1.6% respectively.The best formulation was obtained by central composite design response surface methodology: Budesonide 0.004%,HPMC K4 M 0.74%,P188 4.87%,P407 19%,benzalkonium bromide 0.02%,gel p H 4.5,gelatinization temperature 31.7 + 0.3 degrees,rectal retention test showed that it could stay in the body and prevent leakage.4.There was no significant difference in drug release behavior in p H 6.8,p H 7.0 buffer(PBS)and purified water.The drug release curves at 100,200 and 400 R / min showed that the f2 values between the two were greater than 50,indicating that the rotational speed did not affect drug release.The release of f2 was compared between the rectal membrane and cellulose acetate membrane in vitro There was no significant difference when the value was more than 50,indicating that the release of the rectal membrane could be studied in vitro.In vitro release results showed that the gel could achieve sustained release of 12 h.5.The results of the stability test show that the high temperature will increase the related substances,and the total impurities will increase by 1.12% after 15 days.Light,centrifugation,and freeze-thaw did not affect budesonide content,related substances,and gelation temperature.It shows that the gel has stable physical properties,but the effect of high temperature should be avoided in preparation and preservation.6.After 7 days of budesonide rectal in situ thermosensitive gel,no significant congestion and pathological changes were observed in rectal tissues of SD rats,indicating that the preparation had no irritation on the rectal mucosa of rats.7.According to the pharmacokinetic results,the AUC in the temperature-sensitive gel plasma is 2.21 times that of the enema and 2.96 times that of the solution,and its bioavailability is higher.The MRT in the temperature-sensitive gel plasma is 3.87 times that of the enema solution and 1.93 times that of the solution gavage,indicating that it stays in the body longer and can release the drug continuously for a long time.The AUC of rectal tissue is 2.31 times that of solution enema,and the average residence time is 1.36 times that of solution enema,indicating that compared with enema,temperature-sensitive gel can increase the retention of drugs in the rectum,with obvious localized administration advantage.Conclusion: Budesonide is unstable under alkaline,oxidation and high-temperature conditions,and the light does not affect budesonide.The above conditions should be avoided in the production and preservation process.The solubility of budesonide in pure water was low,and p H had no effect on the solubility but increased in the P407 solution.The best formulation and preparation process of budesonide rectal thermosensitive gel was screened.The preparation has suitable gelation temperature,gel strength,and bioadhesive property,and can be released for a long time in vivo,and it has no irritation to the rectal mucosa.Compared with other routes of administration and other dosage forms,it shows obvious advantages of rectal location administration and shows good application potential. |
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