Preparation Of Alprazolam Orally Disintegrating Tablet

Alprazolam is a new type of benzodiazepine sedative,hypnotic,anti-anxiety drug. The sedative and hypnosis effect of alprazolam is 25～30 and 3.5～11 times of Diazepam, respectively.It has a dominant application in psychiatric drugs.Orally disintegrating tablet is a novel dosage form developed in the 1990s,which designs for patients suffering from difficulty in swallowing,as well as traveling patients who may not have ready access to water,or just for reasons of faster medical intervention and easy administration.Administered without the aid of extra water,orally disintegrating tablet disintegrates or dissolves quickly in the oral cavity upon contact with saliva,resulting in solutions or suspensions of the administered medicine.Advantages of orally disintegrating tablet over conventional tablets include rapid drug absorption earlier in oral cavity,quick drug therapy intervention,convenience of administration,and patient acceptance,especially for pediatric,geriatric,and psychiatric patients.The purpose of this study was to develop a new formulation of alprazolam, alprazolam orally disintegrating tablet,which are easy to swallow as well as onset rapidly after administration so as to improve the therapeutic effect of alprazolam.First,the tablets were prepared using the direct compression method.Correctants, disintegrants and lubricants were screened and its amounts used in the formulation were optimized by single factor test and orthogonal design.Tablets containing aspartame, peppermint essence and citric acid at the ratio of 3.5:1:0.5 have desirable taste and feel in the mouth.Crospovidone(PVPP) was chosen as a disintegrant as it exhibits pronounced hydration capacity with little tendency to form gel.Compared with croscarmellose sodium(CCNa) and carboxymethylstarch sodium(CMS-Na),the preparations containing PVPP disintegrated fastest and scattered thoroughly.Second,the qualities of alprazolam orally disintegrating tablets were evaluated.The results showed that the appearance,weight difference,hardness,disintegration time in vitro and in oral cavity,taste,content as well as content uniformity of tablets were up to quality standard.The cumulative dissolution percentage of alprazolam from the orally disintegrating tablets was 97.38%in 2 min and dissolute completely within 4 min.Third,the stability of the preparations was investigated by the influencing factors test, accelerated test and long-term test.The results of influencing factors test showed that the tablets increased its weight significantly when storing in high humidity conditions, suggesting it should be packaged with moisture-insulation materials.The results of long-term test indicated that the orally disintegrating tablets are stable at least 9 months after preparation.Fourth,a LC-MS assay for simultaneous determination of alprazolam and its active metaboliteα-hydroxy-alprazolam in dog plasma was developed.The calibration curves were linear over the range of 0.5～50 ng/mL and 0.5～32 ng/mL for alprazolam andα-hydroxy-alprazolam,respectively.The lower limits of quantification were 0.5 ng/mL, and the extraction recoveries of alprazolam and its metabolite from plasma were more than 80%.Method recovery was 97.30～102.48%,within-and between-batch variations were less than 10.40%and 12.20%,respectively.The selectivity of the assay is good without any interfering peak.Accordingly,the method was suitable for the pharmacokinetic study of alprazolam tablets in dogs.Using alprazolam common tablets as reference,the relative bioavailability of orally disintegrating tablets in beagle dogs was investigated.After oral administration,the orally disintegrating tablets resulted in a rapid absorption.Its plasma concentration was 11.65±5.60 ng/mL at 20 min after oral dose,while 2.61±1.55 ng/mL obtained by oral common tablets(p＜0.01).The t_max was significantly shorter after oral the rapidly disintegrating tablets than that of common tablets(1.08±0.47 h vs 1.67±0.41 h,p＜0.05).Its relative bioavailability was 109.59±23.17%(n=6).The statistic analysis showed the two preparations are bioequivalent.