The Study Of Agomelation Orally Disintegrating Tablets With Multi-particulate Form

Agomelatine is an antagonist of 5-HT2 C receptors and an agonist of melatonin MT1/MT2 receptor, so it has a positive phase adjustment function of sleep, and it also can regulate the biological rhythms. Moreover, agomelatine has less adverse reactions, and a good antidepressant effect. At present, only ordinary tablet is available in the market, with few other dosage forms, which is not suitable for the use on special groups. To achieve the goal of masking taste, the research adopted fluidized bed coating technology to prepare agomelatine into coating pellets, then the orally disintegrating tablets with multi-particulate forms was prepared using a direct power compressing method with appropriate excipients. Orally disintegrating tablets which is convenient to be administered has improved medication compliance, is especially suitable for medical use in special environment and is for the merits of special groups.Suitable methods were selected for the preparation research, disintegration time,dissolution assay, content and the related substance of agomelation orally disintegrating tablets with multi-particulate forms was also established. Disintegration time was determined by modified disintegration instrumenrt. And dissolution rate was detected by ultraviolet spectrophotometry, 75 rpm was chosen as the dissolution speed, and 1000 ml 0.01 M HCl solution as the dissolution medium. Content and the related substance was tested by high-performance liquid chromatography, whose methods are simple, fast and accurate, and can be used in orally disintegrating tablets prescription screening and quality study. Material compatibility experiment was carried out for the preliminary screening of excipients, there was no interference between drug and excipients.Eudragit E100 was selected as coating material, and the coating pellets was prepared by fluidized bed coating technology, the pellets has the effect of smell covering, and they also guarantee the rapid release of drug in the stomach. The agomelation orally disintegrating tablets with multi-particulate forms was prepared using a direct power compressing method, disintegration time and dissolution were adopted as indexes, a single factor experiment was opted to optimize the prescription process while screening for the proper accessories and a optimum tablet hardness. Determine chooses 10 mg dose of PVPP, mannitol and microcrystalline cellulose 1:1 as filling agent, talcum powder as a lubricant, hardness optimization for 55±5 N, then get the optimal prescription. Ensure the orally disintegrating tablets are of quick collapse, instant dissolution and good taste. tablet has a certain extent of strength, make sure to meet the requirement of orally disintegrating tablets storage and transportation.The three batches test and pilot enlarge production of process validation, obtained the quality qualification of products, taste of cool and refreshing, process stability, good reproducibility and suitable for industrial production.Quality standard has been researched systematically, and the characters of properties,identification, disintegration time, hardness the content and related substance and dissolution were studied, Provide a more comprehensive quality standards for the agomelation orally disintegrating tablets with multi-particulate form, which can be used in quality evaluation of orally disintegrating tablets.The three pilot samples was examined, the disintegrating time was less than 1 minute and the taste is good, hardness is within the scope of 55±5 N, the dissolution of 45 minute is greater than 85%, and the content is between 95% ~ 105%, the impurity was not detected, all the indexes meet the requirements, the quality of orally disintegrating tablets qualified accordingly.Stability of agomelation orally disintegrating tablets with multi-particulate form was studied, including stress testing, accelerated testing and long-term testing. The results showed that the orally disintegrating tablets were to agglomerated with ease under the condition of high temperature, and were prone to agglomerate under the condition of high humidity, but the content and related substance, dissolution and other indicators have been no significant changes, it suggests that tablets should be kept in dry storage at low temperature. the marketed medicine, was Simulate by packaging the orally disintegrating tablets with double layer, the stability results showed the accelerated and long-term stability of either 6 months or more were promising and the products quality was good.Study agomelation orally disintegrating tablets with multi-particulate form and commercial preparation of the relative bioavailability and pharmacokinetic properties, a random, two crossing experiment in two weeks was performed, the experiment was using six beagle, and single dose oral test preparation and reference preparation respectively. The experimental results shows that the mean Tmax of reference preparation was 2.07± 2.19 hours, and the test preparation was 3.75 ± 2.79 hours, the time to peak of test preparation was slightly extended, but there was no significant difference; the mean Cmax of reference preparation was 85.28 ± 45.43 ng/mL, and the test preparation was 57.08 ± 46.68 ng/mL, the maximum concentration was no significant difference; the mean retention time(MRTA) of reference preparation was 8.17 ± 2.36 hours, and the test preparation was 10.37 ± 3.33 hours, the MRT of test preparation was slightly extended, but there was no significant difference. Pharmacokinetic parameters of agomelation orally disintegrating tablets with multi-particulate form and commercial preparation were not significantly different, which indicates that test preparation has similar pharmacokinetic characteristics of reference preparation. The relative bioavailability of test preparation relative to reference preparation with same dose was 102.6 ± 42.2%, shows that two preparation have similar bioavailability.