Study On Preparation And Application Of Nobiletin Solid Dispersion Based On Plant Protein

Nobiletin(NOB)is a methoxy flavone compound,which has many physiological activities and pharmacological functions,such as antioxidant,anti-inflammatory,anti thrombotic,anticancer,etc.However,NOB is almost insoluble in water.It is a poorly soluble drug.Therefore,oral bioavailability is relatively low(about 4%),which greatly limits its application in food and clinic.The efficiency of NOB depends on its dissolution state.In order to improve the bioavailability of insoluble bioactive substances,the preparation process of NOB solid dispersion was studied.The preparation conditions were optimized by combining single factor and orthogonal experiments.The best combination process was screened by dissolution time limit,pill weight difference,sensory evaluation and other indicators.Then,the differential scanning calorimetry(DSC),Fourier Transform infrared spectroscopy(FTIR)and scanning electron microscope(SEM)were used to identify and analyze the selected samples.Preliminary stability study has been done to explore whether NOB prepares as an amorphous state in solid dispersions with the plant proteins on NOB solid dispersions.It is found that NOB solid dispersions can maintain good stability under high temperature,high humidity and accelerated experiments,and are not suitable for preservation under light conditions.The first chapter we summarized the structure of NOB and its application in food and medicine,as well as the research on improving the bioavailability of NOB;the properties of plant proteins,including Zein and soy protein isolate(SPI),as well as the research of carriers as well as the summarization of application and characterization methods of solid dispersions.NOB has a low bioavailability,because hydroxyl groups are methoxylated,leads to poor solubility in water.Plant protein not only has surfactant,but also can be used as a carrier or substrate for embedding nutrients and insoluble substances.Most studies have prepared NOB in the self microemulsion or solid lipid nanoparticles to improve its bioavailability.In the present study,solid dispersion technology was used to combine NOB with natural plant proteins for the first time.The second chapter we studied the preparation process of NOB solid dispersion.First,single-factor experiments are conducted to examine different matrix types,different condensing agent types,different drugs to matrix ratio(mass ratio),different drip temperatures and different drops.Under the conditions of the control distance,the dripping of NOB solid dispersion,the inspection indicators are: dissolution time limit,RSD,sensory evaluation.The four factors that have a significant effect on NOB are: different matrix types,drug to matrix ratio(mass ratio),drip temperature,and drip distance.Based on the four-factor three-level orthogonal table,three indicators were measured and comprehensively scored.The optimal preparation process conditions for NOB solid dispersion were as follows: the different matrix types were PEG4000+SPI,the drug-to-matrix ratio The(mass ratio)was 1: 134,the dropping temperature was 90℃,and the dropping distance was 8 cm.Then,a verification experiment was performed to prepare three batches of NOB solid dispersions under the optimal process conditions.The three indicators were examined,and the roundness and weight difference of each batch of NOB solid dispersions were examined.The limit analysis showed that the roundness of 0.916 is greater than 0.8,which is acceptable.Only one batch of NOB solid dispersion in the batch analysis of weight difference exceeded the weight difference limit standard,which complies with the requirements of the Pharmacopoeia.The third chapter we characterized the NOB solid dispersion prepared under the optimal process conditions by using a differential scanning calorimeter(DSC),a Fourier infrared spectrometer(FTIR),and a scanning electron microscope(SEM).To investigate whether NOB formed amorphous and the effect of plant protein(soy protein isolate)on the formation of NOB solid dispersion.The results showed that in the differential scanning calorimetry(DSC),the melting peak at 137℃ of NOB in the solid dispersion of PEG4000 + NOB and the solid dispersion of PEG4000 + SPI + NOB basically disappeared,and the solid dispersion added with soy protein isolate was better than the solid dispersion added.The solid dispersion prepared by PEG4000 as a matrix has a smoother melting peak.In the Fourier transform infrared spectrum(FTIR),the solid dispersion of PEG4000 + SPI + NOB is a solid dispersion compared with the physical mixture of PEG4000 + SPI + NOB.The intensity of the characteristic absorption peak is significantly weakened or disappeared,but the peak still exists in the physical mixture.In the scanning electron microscope(SEM),the solid dispersion of PEG4000+SPI +NOB is compared with the physical mixture of PEG4000+SPI+NOB.The surface of the solid dispersion is uniform and no crystalline form exists.In physical mixing,the crystalline form of the drug and the matrix still exists.The results show that NOB forms an amorphous form,the process of pelleting NOB solid dispersion is not a simple fusion or chemical adsorption,but an amorphous solid dispersion is formed.It shows that SPI can not only be used as part of the matrix to prepare NOB solid dispersion to reduce the use of chemical matrix,thereby reducing toxicity,but also use SPI as a part of the matrix to promote the formation of nobiletin as an amorphous,uniform dispersion.The fourth chapter we appearance inspection and preliminary stability investigation on the solid dispersion of NOB prepared under the best process conditions.The appearance and roundness are used as the inspection indicators by doing high temperature,high humidity,light and accelerated experiments.The results showed that the solid dispersion of NOB was milky yellow,without tailing,blocking,and uniform in size.Under the conditions of high temperature and high humidity,the appearance of the solid dispersion did not change significantly for 0,3,6,9 days,and the roundness was greater than 0.8;under the light conditions,it was placed for 0,3,6,9 days,The appearance of the solid dispersion becomes rough and uneven in size.On the 9th day,the roundness is less than 0.8;under accelerated experiments,the appearance of the solid dispersion is placed for 0,1,2,3,4,5,6 months There is no obvious change,and the roundness is greater than 0.8.It shows that the prepared solid dispersion of NOB has certain stability under high temperature,high humidity and accelerated experiments,but it needs to be stored in dark place.