| In situ gel refers to the phase transition of the drug preparation system after reaching the drug delivery site,from the solution state to the non-chemically cross-linked gel state,which can adhere to the lesion site,increase the local drug concentration and enhance the drug.The formulation system usually uses polymer materials as the matrix and is constructed by secondary bonds,which combines the pharmacological advantages of solution and gel.It is a new type of pharmaceutical formulation."Sanqi Baiji San" is a commonly used compound used in clinical treatment of peptic ulcer in Chinese medicine.It has the effects of reducing swelling,removing blood stasis,promoting muscle growth and hemostasis,and has significant clinical effects.Dendrobium officinale is known as the "fairy grass",and it is known as"thicken intestines and stomach" in traditional Chinese medicine theory.In this study,Panax notoginseng,Bletilla striata and Dendrobium officinale were selected to form the "Bletilla striata and Panax notoginseng gastric-protecting recipe(PGR)",which has better curative effect on peptic ulcer.This article uses PGR as the main medicine,selects low-acetyl gellan gum(Kel)and sodium alginate(SA)as the gel matrix,and designs "Bletilla striata and Panax notoginseng gastric-protecting mucilago with pH sensitivity(PBG)" that can be tactile into gel in a gastric acid environment,hoping to increase the local concentration of the lesion,enhance the protective effect of the gastric mucosa,prolong the residence time of the drug in the lesion,and improve compliance of patients with difficulty in swallowing solid preparations.The overall idea of this study is:(1)Use animal experiments to verify the efficacy of the prescription PGR and determine the prescription dosage;(2)Use the characteristics of phase change of Kel and S A to form a gel under the pH of gastric acid to investigate and determine the best extraction and concentration process of PGR,Design the preparation process of PBG preparation;(3)Conduct preliminary investigations on the fluidity,in-vivo and in-situ gel properties,rheological properties,in vitro drug release properties and biological adhesion of PBG preparations;(4)Further verification Protective effect of PBG preparation on gastric mucosa.In this study,the pre-prescription drug efficacy evaluation was first carried out.The acute gastric mucosal injury model was made by ethanol,and the gastric tissue morphology,histopathological section,gastric ulcer index and inhibition rate,gastric mucosal protection related biochemical indicators(SOD,MDA,IL-6,TNF-α,PGE2,EGF,VEGF-A)are evaluation indicators to verify the effectiveness of PGR and whether it improves the protective effect of traditional "Sanqi Baiji San" on gastric mucosa.The results showed that the low,medium,and high dose groups all had a certain protective effect on the acute gastric mucosal injury caused by ethanol,and showed a dose-dependent relationship;the efficacy of Panax notoginseng&Bletilla striata group(PB)was slightly stronger than that of the low-dose group,lower than that of the medium and high-dose group Dose group.Compared with PB group,the dosage of PGR middle-dose group was lower and the gastric mucosal protective effect was stronger.The protective effect of PGR on gastric mucosa may be related to anti-oxidation,anti-inflammatory,and promotion of ulcer healing.The middle and high doses did not show significant differences in most indicators.Therefore,it is determined that the converted dose of the middle dose group is the recommended amount for use,and the prescription composition at this recommended dose is:3g of Panax notoginseng,3g of Bletilla striata,and 3g of Dendrobium officinale.Then,the extraction and concentration process of PGR and the preparation process of PBG preparation were studied.In the investigation of the PGR extraction process,the comprehensive score of the total content of the index components and the extraction rate is used as the evaluation index,and the soaking time,the decoction time,the amount of water and the number of decoctions are investigated by a single factor and after the L9(34)orthogonal experiment,The single-factor investigation on the number of extractions,and the determination of the extraction process parameters are:1 prescription amount of medicinal materials,add 12 times of water,soak for 45 minutes,extract 90 minutes after the water boils,and extract twice.In the PGR concentration process investigation,the concentration degree and the concentration method were investigated successively,and the comprehensive scores of the state of the concentrated liquid,the content of the index components and the yield rate were used as the evaluation indicators.The final concentration process parameters were determined as follows:normal pressure concentration to 10 times,relative The density is 1.04,and the concentration is about 0.5 g/mL.In the preparation process research,the normalized value of PBG apparent viscosity and pH response incremental viscosity was used as the evaluation index.The star point design-response surface method was used to further optimize the dosage of Kel in PBG to 0.1%w/v and the dosage of SA to 0.5%w/v.The normalized values of PBG form,apparent viscosity and pH response incremental viscosity are used as evaluation indicators to investigate the influence of process factors(heating temperature,stirring speed during heating,stirring speed during cooling)on PBG.The results show that process factors have little effect on the apparent viscosity and pH response incremental viscosity of PBG,and have a certain effect on the morphology of the preparation.The final formulation process is as follows:Kel(0.1%w/v)and SA(0.5%w/v)are fully swelled in deionized water to form an in-situ gel matrix solution,slowly poured into the concentrated solution,heated at 90℃,After stirring at 150 rpm,stir and cool to room temperature at 170 rpm.Next,the PBG was evaluated for formulation characteristics.PBG has good in vitro fluidity,is easy to pour,and the sample viscosity is moderate,which is good for oral administration.Whether in the simulated gastric juice or in the rat stomach,the gel can be formed in a short time,indicating that PBG has good in-situ gel properties.The rheological measurement results show that the viscosity of PBG decreases with the increase of shear rate,showing a phenomenon of shear thinning.It is a pseudoplastic fluid.The trend of the rheological characteristic curve is consistent with that of the blank gel matrix.The addition of PGR does not change the gel-forming properties of the gel matrix;at the same time,the addition of PGR enhances the water holding capacity of the gel matrix,improves the stability and mechanical properties of the gel matrix,and improves the syneresis phenomenon after the gel matrix is formed into a gel,and PBG is relatively stable in the range of 25～45℃.In vitro release studies have shown that the release of the active ingredient Militarine is pH sensitive.In water and pH 6.8 media,the cumulative release rate of 12 h is only about 80%,while the cumulative release rate of 12 h in pH 1.2 media can reach 100%.The release of the drug is more consistent with the first-order kinetic equation.PBG has good gastric adhesion performance in vitro.In the investigation experiment of gastric retention time and the residual amount of active ingredients in vivo,it is found that compared with the extract,PBG can stay in the stomach of rats for a longer period of time,and it still remains after 240 min after administration.Related medicinal ingredients can be detected in the stomach contents,indicating that PBG can delay the gastric emptying of the active ingredients and prolong the action time of the drug in the stomach after PBG forms a gel in the stomach.Finally,verify whether PBG improves the efficacy of PGR.The acute gastric mucosal injury model was made by ethanol,and the gastric tissue morphology,histopathological section,gastric ulcer index and inhibition rate,gastric mucosal protection related biochemical indicators(SOD,MDA,IL-6,TNF-α,PGE2,EGF,VEGF-A)is an evaluation index to evaluate the pharmacodynamic effect of PBG.The results show that PBG can significantly improve the gastric mucosal injury caused by ethanol,and it has a stronger pharmacological effect than PGR in terms of gastric tissue morphology,histopathological sections,gastric ulcer index and inhibition rate,and gastric mucosal protection-related biochemical indicators(SOD、VEGF-A、EGF). |
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