Studies On Lovastatin Sustained-Release Tablets

Lovastatin, a lactone prodrug that hydrolyzes to the corresponding lovastatin acid, is a specific and competitive inhibitor of HMG-CoA reductase. Clinical data have shown that this compound can suppress cholesterol synthesis and regulate the number of hepatic low-density lipoprotein receptors. Lovastatin had high selectivity for the liver, its primary site of action. As a consequence of extensive hepatic extration of lovastatin, the availablility of drug to the general circulation is low and variable. Lovastatin extended release （ER） delivers the drug in a more sustained fashion, as shown by a smoother plasma concentration-time profile, with adverse effects generally being mild compared with that of lovastatin immediate release （IR）, In addition to its extended-release characteristics, lovastatin ER tablets also had greater systemic bioavailability than lovastatin ER tablets after a equal oral dose.Two accurate methods for determination of lovastatin in tablets were developed and validated in vitro , drug release studies were conducted by direct UV spectrophotometer, and RP-HPLC was established for determination of lovastatin and related substances. The result of preliminary test on stability indicated that lovastatin should be stored in a well-closed, light-resistant and cool place.According to the results of preformulation and preliminary experiments, release profile of drug in vitro was taken as the index for screening. Matrix tablets of lovastatin using Hydroxypropyl methylcellulose （HPMC）, Kollidon^?SR, sodium alginate and propylene glycol aginate were prepared separately in combination with lactose and other excipients by direct compression process. The release kinetics was found to be governed by the type and content of polymer in the matrix system. Higher polymeric content in the matrix decreased the release rate of drug because of increased tortuosity and decreased porosity. HPMC and Kollidon?SR in the matrix was found to cause strong retardation of drug. After further comparison, the lovastatin sustained-released tablets were prepared by employing HPMC as basic matrices. The quality studies on self-prepared lovastatin ER showed the good release homogeneity and repeatability, less influence on drug release behavior by the in vitro release condition. The results of accelerated and long-term testing demonstrated the stability of formulations. The in vitro release profile showed a tendency to follow zero-order kinetics from HPMC matrix systems whereas drug release mechanism was confirmed as the result of matrix erosion.A sensitive and rapid HPLC/MS method was developed to determination lovastatin in human plasma. The Pharmacokinetics of a single dose and multiple doses of lovastatin was evaluated in 18 healthy male subjects, received either lovastatin ER or lovastatin IR 20 mg. The study was designed in a crossover, random, two-treatment, two-period test. Unlike lovastatin IR, lovastatin ER tablets exhibited delayed- and extended-release characteristics. The relative bioavailability of lovastatin （137.82 + 22.77）% was greater from lovastatin ER tablets as compared with lovastatin IR tablets when given single dose. An even greater increase in the bioavailability of lovastatin （173.62 + 30.09）% was observed when the lovastatin ER tablets were administered under multiple doses.In vitro-in vivo correlation analysis was then applied to elucidate the overall absorption characteristics of the formulation, indicating good support for a level A in vitro-in vivo correlation.