Studies On The Preparation And Quality Standards Of Doxofylline Injection

Doxyfylline, as a derivative of theophylline, is an anti-bronchospasmdrugs belong to methylxanthines, while have few toxic and side effects togastrointestinal tract, never system, heart and kidney etc. Doxyfylline iscommonly used for acute, chronic obstructive airway disease in clinical, suchas bronchial asthma, chronic asthmatic bronchitis and other breathingdifficulties caused by bronchial spasm Domestic research has started from1993and the preparation process was improved. With various dosage formsdeveloped, such as tablet, injection, infusion and raw materials, doxyfyllinehas better curative effect and lower toxicity compared with heophylline andaminophylline. In this research, preparation process, quality standard, stabilityand biosafety on injection of doxyfylline has been studied, providing evidencefor quality consistency, and so as to register for doxyfylline injection. Thispaper mainly includes the following aspects:1. Preparation process study of Doxyfylline injectionThrough material selection study, prescription screening research, theinfluence of pH value, the dosage of activated carbon filter, filter materialcompatibility test and sterilization technological research of preparationtechnology, finally determined that prescription is composed of (Doxyfylline，NaCl, NaOH), pH range (4.5～6.5), activated carbon (0.1%),sterilizationconditions (121℃，15min). According to the result of prescription and processstudy, prepare three batch of test sample; upon examination, the qualityindexes, relevant material and content determination meet the requirements. It shows that the prescription design reasonable, preparation process stable andproduct quality controllable.2. Quality standard research of Doxyfylline injectionOn the basis of the comprehensive quality research, formulate scien-tific,reasonable and convenient quality standards, including character, ide-ntification,examination and content determination etc.Content was determi-ned by HPLC, the results show the method a good linear relationship(Y=20944X-17994，r=0.9997),the recovery rate of qualified(RSD=100.3%),sampling precision(RSD=0.13%),stability(RSD=0.23%),intermediate precisi-on(RSD=0.31%), reproducibility of content (RSD=0.50%),which have sho-wed good reproducibility. Using HPLC method has a good specificity.3. Investigation on stability of Doxyfylline injectionBased on the scientific quality standards, according to the requirementsof Pharmacopoeia appendix, study the stability of the packaged samples, after6months accelerated test (40±2℃, RH75%±5%), there was no obviouschanges on character, pH value, clarity, color and visible foreign matter. Theresult meets the required quality standards. Related substances increasedslightly and content declined slightly at the same time. That showed thequality of this product under accelerated conditions of6months is stable.The long-term test (25±2℃, RH60%±10%) for6months, test results showedthat the index in the experiment process were not changed obviously, whichproves that the preparation process and quality standards were stable feasible.4. Safety test of Doxyfylline injectionAccording to the requirement of “chemical irritation, allergy andhemolysis research technical guidance”, the doxofylline at6mg·ml-1concentration of vascular irritation test, compared with sterilized water forinjection, there was no irritation on rabbit ear vein and tissue; guinea pigsmoved freely with no allergic phenomenon after injected. Upon hemolytic test, there was no hemolysis and aggregation effect, which indicates safety clinicaluse of this product. All experiments proved doxofylline injection is safe,reliable for clinical application.The result of this research provided a theoretical basis and reference forformulation and preparation process, quality standard research, period ofvalidity and clinical application.