Preparation And Evaluation Of Budesonide Rectal Foam Aerosol

Research background and purpose:Ulcerative colitis（UC）is a chronic,nonspecific inflammation of the colon,rectal mucosa,and submucosa as the main lesions.Its pathogenic mechanism is complex and unclear,and it is difficult to cure and has a high recurrence rate.At present,the drugs used for the treatment of UC are mainly sulfasalazine enteric-coated tablets,mesalazine sustained-release granules,etc.,but they are not effective because they cannot be in direct contact with the lesion site.Budesonide is a second-generation glucocorticoid,which has pharmacological effects such as anti-inflammatory,anti-allergic,antipruritic,anti-exudation,and etc,its local anti-inflammatory effect is efficient,strong catabolic ability,high safety,can significantly reduce the production and release of lipid inflammatory mediators such as leukotrienes,prostaglandins,and reduce UC symptoms.Foam aerosol can adhere to the intestinal mucosa,long-lasting,and has little irritation to the mucosa,high safety,rapid operation,and a wide range of action,which is the advantageous dosage form for the treatment of UC abroad.In this paper,a foam aerosol for rectal use was developed with the reference of budesonide foam aerosol commercially available abroad.Budesonide is used as raw material,screen and optimize the formulation prescription and key preparation processes of foaming agent,foaming agent,p H adjuster and stabilizer,and investigate and clarify its foam characteristics,foam stability,foam expansion ratio and other key properties to prepare budesonide rectal foam aerosol.In contrast to the reference preparations,the quality standards of the self-made preparations were formulated,and the quality stability of the self-made preparations,the irritation of the rectal mucosa and the performance of rectal positioning and drug administration were comprehensively evaluated.Through this research,new preparations with stable and controllable quality,safe and effective,and more convenient to use were developed,and the performance evaluation index of foam aerosol was improved.Materials and Methods:1.Selection and quality analysis of reference preparations By consulting relevant patent literature websites and reference preparation manuals at home and abroad,select suitable reference preparations,obtain prescription composition,and clarify the types of auxiliary materials such as foaming agents,foaming agents,and stabilizers.According to the needs of rectal administration and the characteristics of foam aerosol dosage form,the quality of the reference preparation was analyzed,its key attributes were determined,and the mass,volume,density,surface tension,viscosity,foam foaming,foam stability and foam expansion ratio of foam per spray were determined.2.Formulation prescription process research According to the nature of budesonide,according to the specific requirements of foam aerosol dosage form and process,the aerosol prescription and preparation process are screened at the same time.Cetyl alcohol and cetyl stytracanol were selected as foaming agents,Tween-60 and Brij^?S10 were selected as foaming agents,and the dosage was preliminarily determined by taking foam characteristics,foam stability and foam expansion ratio as evaluation indicators.The dosages of cetyl alcohol,Tween-60 and Brij^?S10 were optimized by star point design-effect surface method（CCD-RSM）.Then the optimal prescription was filled,and HFA-134A was used as the projectile,and the filling process was investigated by the quality of foam per spray and the API content of foam per spray.Taking the number of foam,foam diameter and liquid film thickness as indicators,the water bath temperature,stirring time and speed were investigated to determine the foam aerosol preparation process.3.Comparative study on quality standards of budesonide foam aerosol A high performance liquid chromatography method for determining the content of budesonide in foam aerosol and related substances was established.The quality standards of budesonide foam aerosol were compared with the physical and chemical properties of budesonide foam aerosol such as properties,viscosity,surface tension,p H value,foam mass per spray,API content uniformity,foam characteristics,foam stability and foam expansion ratio.4.Comparative study on the quality stability of budesonide foam aerosol To detect the influencing factor test,acceleration test,long-term test and high-speed centrifugation test under the conditions of preparation properties,foam expansion ratio,related substances and budesonide content.Preliminary evaluation of the physical and chemical stability of foam aerosol after filling.5.Comparative evaluation of rectal mucosal irritation and pharmacokinetics The rectal mucosal irritation and pharmacokinetic behavior of budesonide foam aerosol in rats were studied.Normal saline and blank foam aerosol were used as the control group,homemade preparations were used as the experimental group,and the reference preparation was the positive control group,and the rectal lesions of rats were observed to evaluate the mucosal irritation of foam aerosol.Taking the reference preparation as the control,LC-MS detected the content of budesonide in the blood and rectum at different time points after rectal administration of the reference preparation and the self-made preparation,plotted the drug-time curve,analyzed the DAS3.0 pharmacokinetic statistical software to obtain the pharmacokinetic characteristics of the two preparations,and investigated the consistency of the biopharmaceutical behavior of the self-made preparation and the reference preparation in rats.Results:1.Determine the starting point of Budenofalk^?Rektalschaum produced by Dr.Falk Pharma Gmb H is the reference preparation.The formulation is formulated as cetyl alcohol,cetyl stylenol,Tween-60,Brij^?S10,EDTA-2Na,citric acid monohydrate,propane,butane,and isobutane.Among them,Tween-60 and Brij^?S10 are foaming agents,cetyl alcohol and cetyl glycol are foaming agents,EDTA-2Na is stabilizer,citric acid monohydrate is p H adjuster,and propane,butane and isobutane are propellants.The mass of foam per spray was determined to be 1.05 g,the volume was 18.14 m L,and the foam expansion ratio was 17.47.The foam stability was good at 9 h of the reference preparation.The p H value of the defoaming solution was 3.5,the surface tension was 32.06 m N·m^-1,and the viscosity was 936.98 m Pa·s.Calculate the 90%quantity foam with an average diameter of 94μm and an average liquid film thickness of 4.76μm.2.The dosage of the screened foaming agent cetyl alcohol and cetyl octadecanol was0.18%～1.45%and 0.18%～1.45%,respectively,the dosage of foaming agent tween-60and Brij^?S10 was 0.18%～1.45%and 0.35%～2.80%,and the ratio of propylene glycol to water was 70∶30～30∶70.Among them,the optimal prescription was 0.82%of cetyl alcohol,1.05%of cetyl alcohol,0.73%of Tween-60,1.64%of Brij^?S10,propylene glycol∶water was 60∶40,the dosage of stabilizer EDTA-2Na was 0.10%,and the dosage of propellant was 6.5%.After filling,compared with the reference preparation,the foam characteristics,foam stability,foam expansion ratio and other indicators of the self-madepreparation are similar.The foam aerosol preparation process was determined as follows:stirring time 60 min,speed 700 rpm,water bath temperature 60°C.3.The quality standard of budesonide foam aerosol self-made preparation was formulated,and the detection method of budesonide foam aerosol content was established by HPLC method and verified.Compared with the quality,volume,foam characteristics,foam stability,foam expansion ratio,viscosity and surface tension of budesonide foam aerosol reference preparation and homemade preparation,it was proved that the quality of homemade preparation and reference preparation were consistent.4.Compared with the quality stability of budesonide foam aerosol reference preparation and homemade preparation,each stability test proved that the quality stability of the homemade preparation and the reference preparation was good and consistent.5.After the SD rat was administered for 7 consecutive days and the mucosal irritation experiment was observed for 7 days after discontinuation,no obvious hyperemia and pathological changes were observed in the rectal tissues of the reference preparation and the homemade preparation,indicating that the reference preparation and the homemade preparation were non-irritating to the rectal mucosa of rats,and the homemade preparation was consistent with the reference preparation.According to the pharmacokinetic results,under the drug-time curve,the AUC value of the self-made preparation was 1.06 times that of the reference preparation,and C_max was 1.02 times that of the self-made preparation,indicating that the pharmacokinetic parameters of the self-made preparation and the reference preparation were well similar.Conclusion:The recommended formulation and preparation process of budesonide foam aerosol and its prescription composition and key quality parameters were clarified,and the optimal formulation and preparation process of self-made foam aerosol were determined by screening,which had similar foaming properties,foam stability and pharmacokinetic behavior to the reference preparation,and had no irritation to the rectal mucosa.