Research On The Preparation In Vitro Evaluation And Absorption Behavior Of Paeoniflorin In-situ Nasal Gel

The blood brain barrier(BBB)refers to the barrier between the blood and brain cells formed by the glaucoma wall and glial cells and the barrier between the blood and cerebrospinal fluid formed by choroid plexus.These barriers can prevent certain substances from entering the brain tissue from the blood and prevent harmful substances into the brain to cause damage to brain tissue.But the blood-brain barrier also blocked a lot of drugs from the blood into the brain,is not conducive to the efficacy of drugs play.In situ nasal administration,in situ gel as a new type of drug delivery system has a unique advantage,so the paeoniflorin as a model drug to study its preparation process,to explore whether paeoniflorin nasal in situ gel with slow release and Specific brain targeting and possible mechanisms for the development and utilization of paeoniflorin for reference.The main research content has the following aspects.1.Study on Physicochemical Properties of PaeoniflorinThe physical and chemical properties of traditional Chinese medicine extracts have great influence on the permeability of the transmucosal membrane.The balanced solubility of the drug and the apparent oil-water partition coefficient are two important indexes affecting the absorption of transmucosal mucosa.In this paper,the solubility of paeoniflorin and the apparent oil-water partition coefficient were used to characterize the permeability of paeoniflorin in paeoniflorin nasal in situ gel.The oil-water partition coefficient of paeoniflorin in different solvents and different PBS buffers was determined by experiment,the results showed that paeoniflorin was a water-soluble drug,which was not easy to penetrate through the mucosa.Addition of appropriate absorption enhancer was necessary to improve the mucosal absorption of paeoniflorin.2.Absorption Accelerator for Purification of Paeoniflorin by Nasal Administration Based on Rat Nasal FractionationIn this experiment,the modified rat nasal perfusion model was used to screen the type and amount of absorption enhancers of paeoniflorin nasal administration.Using the volume correction method to calculate the remaining dose,to avoid the nasal secretion and absorption of perfusate volume of the impact,The percentage of the remaining dose at each time point is logarithmically followed by the corresponding time,and the slope of the regression line is the absorption rate constant.The results showed that the best mass concentration of water-soluble azone concentration is 20 g·L-1.3.Screening and preparation of in situ gel prescription of paeoniflorin nasalIn this paper,the effects of poloxamer 407,poloxamer 188 and polyethylene glycol 6000 on the gelation temperature of in situ gel were investigated by single factor experiment,thus determining the factors and levels of orthogonal experiments.The composition of in situ gel matrix was optimized by orthogonal experiment,taking into account the irritation of the pH of the nasal administration formulation to the nasal cavity,a suitable pH adjuster is selected.Finally,the preparation and process of paeoniflor:in nasal in situ gel were determined and the method of measuring the content of paeoniflorin in gel was established.4.Study on in vitro release behavior of paeoniflorin in situ gelThe release time and release rate of paeoniflorin nasal in situ gel prepared according to the optimal process will affect its absorption,distribution,metabolism and excretion in vivo,and use appropriate methods to analyze and evaluate the release of drugs.Using appropriate methods to analyze and evaluate the release of drugs,and then can master the release of drugs and understand the release of in vitro behavior.In this paper,the in vitro release behavior of gel was studied by diffusion pool method and membrane-free method.The results showed that paeoniflorin in in situ gel was mainly released by dissolution.5.Study on pharmacokinetics and brain tissue distribution of paeoniflorin nasal in situ gel in ratsIn this study,the rats were treated with nasal administration and tail vein injection.The pharmacokinetic parameters of paeoniflorin in rats were compared.Although the paeoniflorin nasal in situ gel administration compared with intravenous injection,the drug bioavailability of only 63.4 injection,but the average residence time was extended by 1 times,significantly prolonged drug action time,paeoniflorin nasal in situ gel showed a certain sustained release effect.At the same time,the BTI of paeoniflorin nasal in situ gel was 1.49,indicating that paeoniflorin administered by nasal cavity could bypass the blood-brain barrier and enter the brain more easily than intravenous injection.6.Evaluation of the toxicity of paeoniflorin nasal in situ gel in nasal mucosaIn this study,we use the toad palmar mucosa as a model,respectively,using in vitro method and in vivo method of comprehensive study of paeoniflorin nasal in situ gel cilia toxicity.Experimental results show that paeoniflorin nasal in situ gel with a certain degree of cilia toxicity,but its recovery by physiological saline can be restored,indicating that the toxicity is reversible,can still swing after swinging for a long time,so that the preparation will not cause Nasal mucosal cilia injury.