| Tramadol Hydrochloride (TR) is a centrally acting analgesic which possesses opioid agonist properties and activates monoaminergic spinal inhibition of pain. In this paper, micro-porous osmotic pumps (MPOP) are prepared, taking TR as the model drug. Based on the comprehensive pre-formulation research, compressible starches are used to make the tablet core. Cellulose acetate (CA), dibutylphthalate (DBF) and polyethylene glycol 400 (PEG-400) are selected as the coating materials and acetone-isopropanol (20:5) co-solvent is employed as the coating medium. Tablets are coated by pan-spray methods, and the coating process is described as spray rate 2.0ml/min, air temperature 40 C and pan speed 20rpm. At the same time, the effects of the coating solvent, DBP, PEG-400, coating level, spray rate, air temperature and pan speed on the drug release character are investigated. The coating formulation and process are optimized by orthogonal design, having the linear correlation coefficient of the accumulative release amount and time (r) in 8h and the release rate (K, mg/h) in 8h as the evaluation standard.After water penetrates into the core and forms a saturated drug solution, the osmotic pressure induces a water influx resulting in a rapid expansion of the membrane leading to the formation of pores, through which the drug are released. The effects of fillers, coating levels and the osmotic properties of therelease medium on tablets swelling behavior are described. The release rate is dependent on the osmotic pressure difference across the membrane, r=0.9936. Meanwhile, according to the determination of the drug solubility, it is proved that TR MPOP delivers drug by both osmotic pressure and diffusion mechanisms. The delivery rate is not influenced by the pH of dissolution medium, dissolution method and paddle stirring rate. The drug release conformed to the model of zero order in 8h.TR elementary osmotic pump system (OROS) based on TR MPOP is presented. The coating level and PEG-400 amount are selected as the causal factors, and the optimum formulation is screened. In TR OROS, the accumulative release amount at 8h exceeds 80%, and the linear correlation coefficient exceeds 0.99. Changing the size of orifice and coating process, no effects are observed on the drug release. The release mechanism is discussed and it is indicated that the release rate of TR from OROS device is driven by the osmotic pressure difference across the membrane. Compared with OROS, MPOP has lag time, which is resolved through improving the tablet core and coating formulation. In the industrialization manufacture of MPOP, the well-defined formulation and well-controlled process are necessary. OROS has not lag time, but fabricating OROS is a costly process because the hole must be produced consistently with a laser drill.The stability test results show that TR MPOP is unstable under high humidity conditions, and is stable when exposed to strong light, high temperature. The accelerating experiment indicates that the drug release character, appearance and content of the packaged preparation do not change.Using HPLC with UV detection for determining TR concentrations in plasma and using commercial conventional tablets as the reference, the relative bioavailability and pharmacokinetics study of TR MPOP is performed in four healthy dogs. The AUC of reference tablets (200mg) and TR MPOP (200mg) are 10230.6+2312.1 and 10808.8+1794.3(ng/ml).h respectively. The Cmax and Tmax of reference tablets are 1670.6+252.3ng/ml and 2.0+0.4h. The Cmax andTmax of TR MPOP are 812.7+94.3ng/ml and 7.5+1.9h. The two formulations are bioequivalent according to the results of analysis of variance. TR MPOP has good correlation between absorption in vivo and drug release in vitro.
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