Preparation And In Vitro And In Vivo Correlation Of Pramipexole Waxy Matrix Tablets

Parkinson’s disease (PD) is a chronic progressive, neurodegenerative movement disorder, commonly found in middle-aged and elderly population.The incidence of the disease in the people older than 65 is about 2%. Pramipexole is a full nonergoline dopamine agonist with selective affinity for dopamine receptors of the D2 subfamily recommended widely by neurologists and approved as a domestic and foreign first-line treatment for PD. A once-daily oral extended-release (ER) formulation of pramipexole by Boehringer Ingelheim has been developed with the aim of reducing pill burden (relative to the three times daily dosing with pramipexole IR), improving treatment adherence and decreasing peak/trough fluctuation. The drug release of Mirepax ER(?) is controlled by hydrophilic matrix and affected easily by in vivo physiological conditions. The erosion of the gel layer in the matrix tablet is affected by the surrounding medium and the different hydrodynamic, shear-stress and fictional forces in the GI tract and HPMC matrices have been reported to exhibit unusually rapid or unpredictable drug release when administered with a large meal due to the delaying of gastric emptying time and GI tract transit time and changed surrounding medium. However the lipid matrix is favorable for developing the extended-release formulation for soluble drugs, possessing several advantages such as pH-independent drug release and minimized burst-out effect. So it counts a lot to develop a lipid matrix with more stable release of pramipexole in vivo. This study was focused on designing an extended-release matrix tablet based on Compritol 888 ATO by direct compression and hot-melt extrusion. The in vitro release and in vivo performance were compared with the marketed hydrophilic matrix tablet and in vivo-in vitro correlation was evaluated.1. Formulation optimization of pramipexole wax matrices(1) Estabishment of UPLC analysis method for pramipexole. Pramipexole is a freely soluble drug and usually analyzed by iron-pair HPLC with a long run time and complicated mobile phase preparation. Therefore, an UPLC method was established and validated to be simple, specific and short-time consuming with good precision and accuracy.(2) Optimization of wax matrix tablet by direct compression (DC). The matrix tablets were prepared by direct compression and evaluated in terms of hardness and dissolution rate. The type of fillers and pre-mixed excipients, the amount of the lipid matrix and another inert hydrophobic matrix were screened and optimized. ATO888/EC dual matrix was chosen which had the similar release profile with the marketed formulation. Three batches of the optimized formulation were produced with good repeatability and the value of f2 was calculated to be higher than 70 compared with Mirapex ER.(3) Optimization of wax matrix formulation by hot-melt extrusion (HME). The matrix tablets were prepared by hot-melt extrusion method and optimized by taking hardness and dissolution rate as indexes. The type of pore formers was screened and the effect of lipid matrix/pore former on the release rate of matrix tablet was investigated. The content of ATO888 (X1) and PVP(X2) were chosen as two independent variables to conduct a two-level five-factors central composite design while the dependent response was similarity factor of release profiles of the developed formulation compared to that of Mirapex ER. The casual factor and response observed were related using quadratic model with the contour plot and three dimensional response surface plot obtained in order to select the optimal areas. Finally, predicted responses were verified. The results showed that the optimal wax tablets could be achieved by hot-melt extrusion with a stable repeatability and the value of fi was higher than 75 compared with Mirapex ER.2. Pharmacokinetics in Beagle dogs and and in vivo-in vitro correlationThe pharmacokinetics of the two lipid matrics and commercial formulation in beagle dogs were investigated in a randomized cross-over way. The results showed that the concentration-time curves of pramipexole could be fitted to two-compartment model. The pharmacokinetics of PPX in wax matrices prepared by DC or HME indicated a slow absorption, slow elimination process compared with that of IR tablet. The results of two one side t-test, confidence interval and non-parametric test showed AUC and Tmax of wax matrix by DC was bioequivalent to Mirapex ER and Cmax of wax matrix by DC was decreased with more stable release in vivo, while wax matrix by HME had an improved AUC compared to Mirapex ER with the bioequivalent Cmaxand Tmax, probably due to slower release and longer transit time in vivo of wax matrix by HME. A Level A IVIVC was developed for wax matrices eithor by DCor by HME. But the correlation coefficient of Mirapex ER was lower than DC or HME probably due to the slow release rate in vitro and the unexpected increasing of in vivo released amount at 4h.3. Biorelevance dissolution study using BiodisThe reciprocating cylinder apparatus (USP apparatus 3, BioDis) is widely used for the study of modified-release formulations since it can simulate the in vivo dissolution behavior using pH gradient, residence times, different media, and hydrodynamic conditions. In this section, an in vitro dissolution model was established by Biodis based on previous studies. The effect of dip rates and addition of enzymes on the release rate was investigated. The results indicated the release rate of wax matrices by DC or HME was not affected by the dip rate and the addition of enzyme, while showed the release of the wax matrices based on Compritol 888 ATO was little affected by physiological conditions. Although addition of enzymes had little influence on the release rate of Mirapex ER, the release rate increased at higher dip rate attributed to the faster erosion of the polymer, which showed erosion of gel could become faster due to mechanical forces in vivo leading to a faster release rate. The percentage released of Mirapex ER containing carbomer in the medium (pH 1.8) was more than the lipid matrices, which indicated the release rate could increase in the stomach leading to a higher Cmax. PPX was released from wax matrices using DC or HME by diffusion, while the drug released from Mirapex ER by diffusion and erosion. Wax matrix prepared by DC had the similar release profile compared with Mirapex ER, while wax matrix prepared by HME had the different release profiles compared with Mirapex ER. The results were consistent with that of the AUC bioequivalent study, which exhibited Biodis could not reflect the in vivo release of extended-release formulation completely. Maybe improved endeavor in Biodis will be needed to attain the good imitation of in vivo behavior.4. Quality standard and preliminary stability of the lipid matricesQuality control of the drug plays an important role in the research and manufacture of pharmaceutical preparations. In this section, feasible methods for quality control of the two lipid matrices prepared by DC or HME were established, including identification of pramipexole, quantitative determination of pramipexole, release determination and content uniformity test. Stability study indicated that humidity and temperature are the most important factors influencing the stability of the formulations. Thus, the formulations should be kept in dry and cool places and protected against moisture.