Preparation And Studies Of Indapamide Lyophilized Orally Disintegrating Tablets

Objectives: Recently, a new pharmaceutical dosage form, orally disintegrating tablets (ODT), which can disintegrate rapidly (10~60s) in the oral cavity without drinking water, has attracted the interests of many researchers. This type of tablets offers the advantage of easy taking, quick absorption and good compliance of patients.The preparation of orally disintegrating tablets mainly includes the following methods: spray drying, solid-state dissolution method, wet granulation method, direct compression and lyopyilization. The spray drying and solidstate dissolution methods are difficult to industrialization because of complex operation process, high cost and inconventional manufacturing equipments. Wet granulation method and direct compression utilize common equipments, but need bulk water-soluble filler and high performance disintegrant. Lyopyilization, using freeze drying processes, is one of the first of generations of fast disintegrating dosage forms. This formulation is a freeze-dried product of combination of water-soluble matrix material with drug, which is freeze dried to remove the water by sublimation. The resultant structure is very porous and the tablet can rapidly disintegrate or dissolve upon contact with saliva. Methods:On the basis of single factor tests, maltodextrin, gelatin, and Indapamide-PEG6000 solid dispersion were adopted as matrix to make up lyophilized orally disintegrating tablets. Parameters of the preparation process were optimized by using orthogonal experimental design, in which the concentration of gelatin solution, the amount of maltodextrin and the ratio of Indapamide to PEG6000 were taken as three influential factors and each factor had three different levels (refer to the L9(34) orthogonal design table). The disintegrating time and mechanical strength were selected as evaluation index. The optimum preparation conditions were determined by range analysis and analysis of variance.A series of quality control experiments were carried out not only including related substance, disintegration time, mechanical strength, content uniformity, dissolution test and so on, but also critical relative humidity and moisture analysis.A Kromasil C18 analytical column (250mm×4.6mm, 5μm) was employed for the separation. The mobile phase was delivered at 1.0 ml·min-1 and consisted of 55 volumes of phosphate buffer solution (a solution of 2g of potassium dihydrogen phosphate, 3ml of phosphoric acid, and 3.5ml of triethylamine in 1000ml of water), 40 volumes of acetonitrile and 5 volumes of methanol. The UV detection was carried out at 240 nm. A liquor of 20μl was injected into the HPLC column.The Beagle dogs participated in a single dose crossover bio-equivalence study with a one-week interval between each administration. Liquid chromatograph with ultraviolet detector was adopted in examining concentration of whole blood. A non-compartmental pharmacokinetic analysis was performed for each of the treatments and for each formulation.Results: The optimal formulation were determined by range analysis and analysis of variance, which is 0.5% gelatin solution, 20% maltodextrin and Indapamide-PEG6000 (1:10) solid dispersion.The results of related subatance, dissolution test of Indapamide ODT and uniformity of dosage units accorded with the regulations (A+1.80S = 4.24). The disintegration time was (12.4±3.2) s , mechanical strength was (17.2±2.9) N and the critical relative humidity was 49.5%.The results of the system serve experiment of the HPLC method to determine the content of Indapamide were showed as follow: the reserve time was about 9.28min, the recoveries were 100.3%~101.0%, the within-day precision was 0.07%~1.52%, the between-day precision was 1.33%~1.52%. The method could determine the content of Indapamide accurately and precisely.The productions of freeze dried were sensitive to humidity. There were not changes in the physical appearance and in drug content of the Indapamide ODT exposed to high temperature and strong illumination. Stability experiment showed no significant difference in cumulative release and content of Indapamide ODT when stored at 60℃for 3 month compared to the same formulation before heating.Parameters were obtained from direct observation of the data include Cmax and Tmax. The area under the whole blood concentration–time curve (AUC) from the time of drug administration to the last blood sampling time (AUC0–t) was calculated according to the linear trapezoidal rule. The mean values of major pharmacokinetic parameters of Tmax, Cmax, AUC0–∞, and MRT of Indapamide in Beagle dogs after oral administration a single 5.0mg dose for the ODT and common tablets were (1.59±0.04) h and (2.71±0.08) h, (6.10±0.32)μg·ml-1 and (5.89±0.44)μg·ml-1, (89.66±8.34)μg·h-1·ml-1 and (67.58±2.56)μg·h-1·ml-1, (18.91±1.32) h and (16.80±0.90) h, respectively. There were significant differences between the two formulations. The relative bioavailability of the ODT is 132.7% by contrast the common tablets.Conclusions: Indapamide lyophilized orally disintegrating tablet had good effect of release property and repetition in vitro. The methods of identification test,assay and dissolution for ODT were established, which provided a guideline with quality control. The experiment in vivo showed the shorter Tmax and elevated relative bioavailability.