Preparation Of Mesylate Doxazosin Microporous Osmotic Pump Tablets

Objectives: Mesylate doxazosin (DOX) for quinoline derivatives, are selective postsynapticα1-adrenergic receptors blockers. By blocking theα1-recepters to expand blood vessels, reduce vascular resistance,in order to decrease the blood pressure. It has little effect on cardiac output which is applicable to primary mild to moderate hypertension and accompanied by high blood pressure in patients with benign prostatic hyperplasia. As otherα1-recepter blockers, DOX has great impacts on orthostatic blood pressure and heart rate. In the application of ordinary tablets, if take the therapeutic doses directly,it may cause a sharp fall in blood pressure which led to syncope, orthostatic hypotension and other adverse reactions due to a sudden increase in blood concentration. Therefore we must adjust the dosage from the beginning small dose, taking a lot of inconvenience in applications. As a typical representative of controlled-release formulations, osmotic pump controlled-release formulations with zero-order release characteristic, independ on the media environment, pH, gastric motility, food and other factors in drug release process, which have a good correlation as well as in vivo and in vitro drug release. The study prepared DOX porous osmotic pump tablets. By controlling the release rate to make the plasma concentration placidity, not only improved the patient's tolerance but also simplifies the process of dose adjustment, showing the more good clinical superiority.Methods: With tartaric acid, lactose, mannitol as the main excipients prepared the core tablets by the sigle-punch machine. Cellulose acetate, PEG400, diethyl phthalate and acetone were respectively used as coating material, channeling agent, plasticizer and solvent. DOX porous osmotic pump tablets were coat by pan coating method. On the basis of pretesting and scientific literatures, the type and amount of consolvent, the type of adhesive, the type and amount of osmotic agent, the concentration of coating solution, the amount of porogen and plasticizer, the thickness of coating membrane were investigated and evaluated by similarity (f2). The orthogonal experiment was designed to optimize formula in which the amount of osmotic agent, PEG400 and the thickness of coating membrane were taken as three influential factors and three different levels were selected. Each of them was selected refer to the L₉(3⁴) orthogonal design table. According to accumulative release percentage at 2h, 12h, 24h and the correlation coefficient (r) of the 0²4h drug release profile to select optimal formula with the colligation evaluation.The concertration of DOX was determined using a HPLC system on the basis of pretesting and scientific literatures. Separation was achieved by using a Hypersil OSD2 column (4.6mm×150mm, 5μm). The mobile phase was methanol- acetic acid buffer(glacial acetic acid 15ml, triethylamine 1ml, add water to 500ml)(52:48)(v/v).The flow rate was 1.0ml/min. All chromatographic separations were performed at 30℃. The wavelength of detectionwas set at 246nm.The chemical and physical stability of optimal formula was investigated under following circumstances: high humidity, high temperature, and strong illumination. At the end of the study period, the formula was observed for change in physical appearance, drug content and drug release characteristics.Pharmacokinetics study in vivo: With the commercial DOX tablet as the reference, the pharmacokinetic study of self-prepared DOX porous osmotic pump controlled-release tablets was performed in six Beagle dogs. With crossover design, HPLC method was employed to detect the concentration in dogs'plasma administerd with single dose. The pharmacokinetics parameters were caculated by non-compartmental model analysis method.Results: The optimal technology and formula were defined through simple factor test and orthogonal experiments. The tableting technology were as follows:the diameter of tablet, 11mm; the hardness of tablet, 8kg; the weight of tablet, 0.3g.The coating technology were as follows: the coating temperature, 35⁴0℃; the rotation rate of pot, 60rpm/min; the spray pressure, 2kg/cm2. The optimal formula was as follows: tartaric acid as cosolvent;lactose-mannitol (1:1) 150mg as osmotic agent; the acetone solution of cellulose acetate as the coating solution; PEG400 in cellulose acetate, 100%(g/g); diethyl phthalate in cellulose acetate,20% (g/g); the weight of coating membrane, 3%;the concentraton of coating solution, 3%(w/v).The content of DOX was determined by HPLC. The blank excipient has no effect on the determinations. The regression equation was A=69126C-777.49(r=0.9999), and the linearity range was 0.25⁵.0μg/ml. The average within-day precision was 0.35%, and the average between-day precision was 0.79%. The average recovery was 99.64%.In the stability experiment,the weight of DOX osmotic pump tablets which was exposed in the 92.5% relative humidity was increased a lot after 5 days and 10 days. But the weight of DOX osmotic pump tablets which was exposed in the 75% relative humidity was increased a bit after 5 days and 10 days, and there was little change in physical appearance, drug content and drug release characteristics. When the DOX osmotic pump tablets were exposed in high temperature (60℃) and strong illumination (4500±500lx), there was no change in physical appearance, drug content and drug release characteristics after 5 days and 10 days.The pharmacokinetics studies were took in Beagle dogs with the reference tablets Pfizer commercial controlled-release tablets. According to the defined HPLC condition, the main pharmacokinetics parameters were respectively as following: Testing tablets Reference tablets tmax(h) 7.67±1.51 9.67±0.82 Cmax(ng/ml) 55.84±2.69 54.37±1.72 AUC(ng·h/ml) 1208.36±44.54 1175.33±64.66 AUMC 20977.5±2499.5 23647.0±2179.4 MRT 17.33±1.55 20.09±0.77 F (%) 103.03 100Compared with the commercial release tablets, Cmax and AUC had no significant differences, but the t_max is sightly short.Conclusions: DOX microporous osmotic pump tablets had good effect of controlled release property and repetition in vitro. The quality is independent on temperature, humidity and illumination. The methods of assay and dissolution for DOX microporous osmotic pump tablets were established, which provided a guideline with quality control. The experiment in vivo showed that C_max and AUC had no significant differences, but the tmax is sightly short.