Controlled Release of Paclitaxel from PLGA Microspheres

Abstract

Paclitaxel is a potent anticancer drug with proven activity gainst a number of human tumors, especially ovarian and breast cancer. However, its poor solubility limits clinical use, and alternative drug delivery systems are under development in recent years. As an alternative drug delivery system, microspheres of biodegradable polymers can be used to improve the bioavailability of paclitaxel and reduce the adverse effect of the commercial formulation of paclitaxel. Purpose of this study was to prepare paclitaxel-loaded LGA microspheres by the solvent evaporation method using three emulsifiers- polyvinyl alcohol (PVA), methyl cellulose (MC), ydroxypropyl methyl cellulose (HPMC)- and to ompare the effects of three emulsifiers on the physical roperties. Physical characteristics of each microsphere, i.e., morphology, particle size distribution, paclitaxel content in the microsphere and in vitro release test, were studied. Surface morphology of PLGA microspheres was observed by scanning electron microscopy (SEM). Particle size and istribution were measured by multisizer. Encapsulation efficiency (E.E.) was quantified by HPLC assay. The in vitro release test of microspheres was carried out for 30 days. The microspheres containing paclitaxel-using HPMC, PVA, MC were shown to have spherical shape and prepared with high encapsulation efficiency and a proper particle size in diameter. PLGA microparticles with MC were larger and more broad size distribution, and had impurities. In case of microspheres using HPMC, microparticles were relatively well-sphaped and HPMC are more easily washed out of the microspheres than MC, or PVA. Especially, PLGA microspheres fabricated with HPMC (100 cps.) as emulsifier, were very small and homogeneous, contained good spherical particles, and had higher encapsulation efficiency. Significantly faster paclitaxel release from PLGA microspheres with HPMC was achieved in comparison with microspheres with PVA, as desired. These results show that hydroxylpropyl methyl cellulose HPMC), which has similar or better effect compared with the traditional emulsifier PVA, could be used as a good emulsifier .; Paclitaxel은 Taxus brevifolia에서 추출한 물질로서 난소암과 유방암 을 비롯한 여러 항암 치료에 사용되고 있다. 그러나 이 약은 매우 난용성이어서 임상적인 사용이 어렵기 때문에 이를 개선하기 위한 제형을 연구하려는 시도가 많이 이루어지고 있다. 생분해성 고분자인 Poly(D,L lactide-co-glycolide),(PLGA)를 이용한 microsphere의 제조 또한 이러한 시도 중 하나인데, 이 때 유화제(emulsifier)로서 일반적으로 Polyvinyl alcohol을 사용하고 있다. 본 논문에서는 PLGA microsphere의 emulsion stabilizer로 hydroxypropyl methyl cellulose(HPMC), Methyl cellulose (MC)를 사용하여 solvent evaporation 방법으로 만든 후, 같은 방법으로 PVA를 사용하여 만든 microsphere와 비교해보았다. 세 가지 유화제를 이용하여 만든 microsphere의 물리학적 특성을 비교하기 위해 입자의 크기 분포와 봉입효율을 측정하였고, pH 7.4 phosphate buffer에서 용출시험을 하였다. 각각의 유화제로 만든 microsphere는 Scanning electron microscopy (SEM)를 이용하여 표면의 형태를 살펴보았고, Multisizer를 이용하여 이들의 크기 분포를 확인, 비교하였다. 또한 High performance liquid chromatography (HPLC)를 이용하여 봉입효율(EE)과 한달 간 용출되는 양상을 비교하였다. 세 가지 유화제를 사용한 약물 모두 적당한 크기의 구형의 매끈한 입자가 제조되었고, 높은 EE를 나타냈다. 특히, HPMC 100 cps.를 유화제로 사용하여 제조한 경우, 매우 작고 균일한 양질의 입자가 제조되었는데, 이 입자는 봉입 효율도 더 높았다. 용출 시험에서도, 기존의 입자가 너무 느린 용출 양상을 보인데 반해 HPMC를 이용한 약물의 경우, 확실히 용출속도가 빨라졌다. 이러한 결과를 정리해 볼 때, HPMC는 microsphere 제조 시에 기존에 사용되어 온 PVA를 대체할 수 있는 좋은 유화제로 이용될 것으로 기대된다.