Preparation And Evaluation Of Butaselen Cyclodextrin Inclusion Complex

Gliomas are the most common primary tumours in the brain and spinal cord.Gliomas are the most common malignant tumours affecting the central nervous system and are mainly characterised by a high recurrence rate and a short survival period,with a poor prognosis for patients with gliomas despite more aggressive treatment.Despite more aggressive treatment,the prognosis of glioma patients remains poor.The blood-brain barrier has led to a reduction in the efficiency of drug therapy for glioma.In this study,we propose to prepare an intrathecal injection of Butaselen cyclodextrin,which can be injected directly into the subarachnoid space by lumbar puncture,thus reducing the diffusion effect of the blood-brain barrier and increasing the blood concentration in the cerebrospinal fluid within a short period of time.This topic focuses on five main areas of research,which are as follows:First,a pre-prescription study was conducted on porphyrin,which was found to be a water-insoluble drug with a solubility in water of 0.14μg/m L.The solubility of the API in different solvents was investigated and showed that it was soluble in acetone,methylene chloride and isopropanol,and very soluble in dimethyl sulfoxide（DMSO）and N,N-dimethylformamide（DMF）.The solubility of the API in different concentrations of Tween 80 was examined and the results showed that the solubilising effect of Tween 80 on Butaselen did not increase significantly.The solubility was examined for different p H saturations and there was no p H dependence.Due to the greater toxic effects of organic solvents on humans,based on a search of the relevant literature,i.e.the cyclodextrin inclusion was finally chosen for the development of Butaselen injection.The compatibility of the original excipients and the type of cyclodextrin was investigated and the results showed good compatibility,i.e.hydroxypropyl-β-cyclodextrin（HP-β-CD）and 2,6-dimethyl-β-cyclodextrin（DM-β-CD）were selected for the preparation of Butaselen cyclodextrin inclusion.Secondly,the prescription and process study,based on the analysis of the single-factor cyclodextrin dosage,drug to cyclodextrin mass ratio and the Do E prescription design,the stirring time and stirring temperature of the prescription preparation process were optimized,and the critical process parameters（CPPs）were defined to obtain the optimal preparation process and prescription composition.Thirdly,the physicochemical properties of the inclusions were investigated.The inclusions were prepared by the saturated aqueous solution method on the determined prescription composition and preparation process of cyclodextrin inclusions,the lyophilised powder was produced by the freeze-drying method and the lyophilised powder needles produced were characterised by the inclusions,the structure of the inclusions and the effect of the inclusions on The results showed that the inclusions of the powdered needles were not suitable for the preparation of Butaselen.The results showed that the inclusion ratio was（91.24±0.42）%and the results of X-ray diffraction（XRD）,infrared spectrophotometry（IR）and microscopic imaging demonstrated the formation of inclusion complexes and the significant improvement of Butaselen solubility by the cyclodextrin inclusion technique.Fourth,quality study,-High performance liquid chromatography（HPLC）using an established Ascentis（?）Express C₁₈ column（2.7μm 4.6×150 mm）,mobile phase A 0.05%trifluoroacetic acid in water and mobile phase B 0.05%trifluoroacetic acid in acetonitrile,detection at 225 nm,column temperature 30°C,flow rate 1 m L/min,injection volume 5μL.The method was validated for the determination of Butaselen in Butaselen hydroxypropyl-β-cyclodextrin complexes and quantified by external standard method.The linear equation was found to be y=0.2986x-1.4446（r=0.999）with good linearity in the concentration range of 200μg/m L to 600μg/m L for Butaselen;the mean recovery（n=9）was100.75%with an RSD value of 0.38%.The results showed that the established HPLC method is rapid,simple,accurate,adaptable,specific and reproducible for the determination of Butaselen in Butaselen cyclodextrin inclusions.Fifthly,the stability study determined that the product was less stable under high temperature conditions,light conditions,low temperature cycles and freezing cycles through the influencing factors;the accelerated test and long-term test showed that the product was stable under long-term（25±2℃）and accelerated（40±2℃）conditions within 3 months.In this study,we propose to improve the solubility of Butaselen by using the encapsulation technique,optimize the preparation process of Butaselen cyclodextrin inclusion,and validate the inclusion,which can provide a reliable experimental basis and technical support for the later development of a new formulation of Butaselen.