| Fluticasone propionate,which is a new generation of topical application of steroid medicaitons,is a potent agonist of the glucocorticoid receptor,and has local anti-inflammatory and anti-allergic effects.Clinically,it could be useful for the prevention and treatment of allergic rhinitis.According to the Drug Registration Regulation and the related technical requirements,the prescription,the preparation process,quality standards,the stability,the local stimulation and skin hypersusceptibility of fluticasone propionate nasal spray systematically were studied in this paper.1.Study on the preparation processAccording to the instructions of commercial fluticasone propionate nasal spray and Rxlist(online prescription drug index)about the introduction of prescription,we identified the formulation,the specification,and the components of the prescription.Referring to the conventional dosages of the accessories and the physical-chemical properties of the commercial drugs,we investigated viscosity and sedimentation volume ratio for different amounts of microcrystalline cellulose-sodium carboxymethyl cellulose solution,and we determined that the best amount of microcrystalline cellulose-sodium carboxymethyl cellulose was 1.7% and optimized the best prescription by prescription screening.The results showed that.We optimized production processes of the small test with the study of the amount of purified water,dissolving time,suspending effect and stirring time.On this basis,we expand the production to text mixing time of the high shear with the character and sedimentation volume ratio and to exam cycle-mixing time with the character,pH,and the content,and we finally determined the production process.The results showed that: being stirred for 30~60min with the high shear emulsifying machine after the purified water dissolving other components(excluding the main drug),and being added the main drug to loop mixing 20~30min,the finished product met the requirements of selection standard.2.Research on quality standardsThe description,the loading capacity,total spray times per bottle and the weight per spray were tested by the methods of the import drug registration standards JX20050199 and the Chinese Pharmacopoeia 2010 edition,the results showed that: it was a white suspension,the weight of loading capacity per bottle should not be less than 7g,total spray times per bottle should be no less than 60 times,the weight per spray should be labeled amount(100mg)of 80.0%~120.0%.Referring to the standard of fluticasone propionate nasal spray in USP 35,we detected the identification,pH,particle size,foreign particulates,microbial limits,delivered dose uniformity(within container and within batch).The results showed that: pH value should be between 5.0 and 7.0,foreign particulates should be less than 250mm,the main drug content of per dose(within container and within batch)should be NLT 85.0% and NMT 115.0% of the labeled claimed.We did a methodological study for related substances and impurities D by HPLC,using methanol-acetonitrile-0.01mol/L ammonium dihydrogen phosphate solution(Adjusting with 20% of phosphoric acid to a pH of 3.4±0.1)(462: 138: 400)as the mobile phase.The results: the peak of each impurity,the peaks of the degradation products,the main peak and the peak of accessories could be effectively separated.The detection wavelength of the impurity D was 239 nm.The limit of quantification was approximately 1ng,and the limit of minimum detection was approximately 0.3ng.The standard curve equation y=3.0046x-0.0079,the correlation coefficient r= 0.9999,the linear range was 0.09 mg/ml ~ 1.80mg/ml.The average recovery was 99.5%,and RSD was 1.70%.The precision RSD was 1.84%.Stability in the 12 h RSD was 1.20%.Both of the methods had good repeatability,sensitivity and specificity.The content of phenylethyl alcohol and the assaying of fluticasone propionate were tested by High Performance Liquid Chromatography.Chromatographic conditions: the column: DiKMA Diamonsil-C18(2)(250 mm×4.6 mm,5mm),the mobile phase: 0.01mol/L of ammonium dihydrogen phosphate solution(Adjusting with 20% of phosphoric acid to a pH of 3.5±0.05)-methanol-acetonitrile(35:50:15),the column temperature: 40?,the flow rate: 1.5ml/min.Results: The detection wavelength of phenylethyl alcohol was 210 nm.The limit of quantification was approximately 0.08 ng and the limit of minimum detection was approximately 0.02 ng.The standard curve equation: y= 0.7420x+0.5777,the correlation coefficient r = 0.9998,the linear range was from 9.944mg/ml to 99.440mg/ml.The average recovery was 99.6%,and RSD was 0.5%.The precision RSD was 0.25%.Stability in the 12 h RSD was 0.27%.Fluticasone propionate detection wavelength was 239 nm.The limit of quantification was about 0.6ng,and the limit of the minimum detection was about 0.2ng.Standard curve equation: y= 0.5749x-0.2137,the correlation coefficient r = 0.9999,the linear range of 17.65mg/ml~ 176.50mg/ml.The average recovery was 99.3%,and RSD was 0.93%.The precision degree RSD was 0.43%.Stability in the 12 h RSD was 1.45%.The content of benzalkonium chloride was measured by the titration method.The results showed that: Standard curve equation: y= 170.4916x-29.2498,the correlation coefficient r = 0.9998,the linear range of 666mg/ml~4440mg/ml.The average recovery was 98.8%,and RSD was 0.55%.The precision RSD was 0.16%,Stability in the 12 h RSD was 0.30%.3.Study on the stabilityWe inspected the rule of fluticasone propionate nasal spray with time change under the influence of the temperature,the humidity,the light and the microorganism.Using stress test,a batche of samples removing the external packing were placed respectively for 10 days at high temperature(40?),high humidity(25?,90%±5%RH),or strong light,and were tested at 0,5,10 days according to the key inspection projects of the stability.Using accelerated test,three batches of samples in commercial packaging were stored for six months at 40?±2?temperature,25%±5% relative humidity,and were tested at 0,1,2,3,6 months according to the key inspection projects of the stability.Adopting the long-term test,three batches of samples in commercial packaging were stored for eighteen months at 25 ?± 2 ?temperature,60%±10% relative humidity,and were tested at 0,3,6,9,12,18 months according to the key inspection projects of the stability.The results: every inspection item conformed with the regulations and did not change significantly in the experiment period.The results indicated that the preparation had good stability.4.Study on the local stimulation and skin hypersusceptibilityThe purposes of this section were mainly to investigate the safety of topical medication of fluticasone propionate nasal spray.Eighting rabbits were randomly divided into three groups and were continuously administered for 7d.Mucosal irritations that the noses of rabbits produced after coming in contact with fluticasone propionate nasal spray for several times were observed.Fifty guinea pigs were randomly divided into four groups.The epilatory skins on the left of the guinea pigs' backs were sensitized at 0,7,14 days and the epilatory skins of the guinea pigs' flanks were stimulated on the twenty-eighth day.It was used to observe whether fluticasone propionate nasal spray might cause allergic reactions on the skins or whole body of guinea pigs.Results: fluticasone propionate nasal spray did not cause irritative reactions on noses of rabbits,and allergic reactions on the skins of guinea pigs.The results showed that fluticasone propionate nasal spray topical medication is safe and reliable. |
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