The Study And Evaluation Of Innovative Preparation Technology In The Industrialization Of Osmotic Pump Controlled Release Dosage Forms

The purpose of this thesis was to improve the industrialization situation of osmotic pump dosage forms in China so that more osmotic pump products can be launched onto the market. Main works of this thesis were focused on the resolution or simplification of the limiting step in the manufacture process of osmotic pump, laser drilling. Three new technologies (in situ formed orifice technology, two sides drilling technology and differentially release technology) were applied in this study, and different types of osmotic pump (monolithic osmotic pump (MOP), push-pull osmotic pump (PPOP) and sandwiched osmotic pump (SOTs)) which were suitable for water-soluble and water-insoluble drugs were studied in this thesis.By using of in situ formed orifice technology (ISFOT), delivery orifice of MOP can be formed automatically during tableting and coating process, thus laser drilling machine can be cast aside. Although the ability to prepare delivery orifice by ISFOT for MOP has been recognized for years, there are still few reports about the study and application of such technology. For this reason, a MOP was prepared using ISFOT in this study, and water-soluble drug propranolo hydrochloride was chosen as model drug. Influencing factors including core formulation, coating formulation and granulation method were evaluated using similarity factor (f₂), and an optimal formulation was achieved based on such study. With optimal formula, the dissolution profiles of two kinds of MOP whose orifice was prepared mechanically and by ISFOT, respectively, were compared, it was found that there was no significant difference between them (6=73.6), which meant that similar drug delivery behavior could be achieved by preparing the orifice mechanically or by use of ISFOT.As of PPOP, it is necessary to enclose pigment in the core formula, and a color identification device is needed in the manufacture process to figure out the drug layer so that an orifice can be drilled on the drug layer side. Although the ISFOT can resolve the laser drilling process of MOP successfully, it can not be applied to PPOP. For this reason, a novel PPOP was designed and prepared using two side drilling technology (TSDT) and water-insoluble drug gliclazide was employed as model drug. Influencing factors from six aspects were studied which was drug layer formulation, push layer formulation, coating formulation, orifice properties, tableting art and dissolution conditions, respectively, and the difference between the dissolution profiles of novel PPOP and conventional PPOP was also evaluated by similarity factor (f₂). Through determination of the viscosity of drug layer and push layer of the novel PPOP, the mechanism of drug release from novel PPOP was discussed by the help of Poiseuille's law of laminar flow. As of novel PPOP, since is orifices can be drilled simply on both side surfaces, the pigment in core formula and the color identification device can be cast aside, thus simplify the core formulation and drilling process.For sandwiched osmotic tablet system (SOTs), since its two drug layers are attached to middle push layer from two sides, it dose not need side identification in the drilling process either. In the third chapter of this thesis, a SOTs which could differentially release model drug gliclazide from two drug layers was designed and prepared, such SOTs could release model drug gliclazide at relative faster rate during the first few hours while release gliclazide at relative lower rate in the following hours. By calculating the pharmacokinetic parameters of model drug, the gliclazide amount in plasma was predicted, and according to this result, the drug distribution and controlled release period of the two drug layers were designed. Methods to achieve differentially drug release from the two drug layers were studied by adjusting the coating level and the weight, viscosity differences between the two drug layers. By using of differentially drug release technology, various drug release profiles can be obtained by SOTs, and also, the weight of three layers of SOTs can be accommodated separately with unchanged dissolution profiles, thus, optimal formula which is suitable for tri-layer tableting machine can be achieved.Using self-made conventional PPOP as reference, relative bioavailability and pharmacokinetic study of novel PPOP and novel SOTs were performed in six beagle dogs by three-circle crossover design, drug concentration in plasma of beagle dogs after single dose oral administered of three kinds of osmotic pumps was detected by HPLC method. The results showed that the AUC of conventional PPOP, novel PPOP and SOTs was 178.2±25.9, 180.8±24.0 and 164.7±21.2 (μg·h/ml), respectively. As of conventional PPOP and novel PPOP, the C_max were 8.48±1.63 and 9.12±1.87 (μg/ml), and T_max were 10.33±0.82 andl0±0.00 (h). While for the SOTs, the "peak" in the concentration-time curve was substituted by a platform, the concentration of the platform within 4-12h was about 7μg/ml. In this chapter, the in vitro-in vivo correlation (IVTVC) of the three osmotic pumps were also studied.