서방성 마약길항제제의 Biocompatibility 및 Pharmacokinetics

Abstract

마약길항제의 효과적인 투여를 위하여 생체분해성 Polyphosphazene을 이용한 서방성 이식제제의 사용 가능성을 검토하고자 하였다. Poly[(diethyl glutamate)-co-(ethyl glycinate)phosphazene] 을 합성하여 10% naloxone hydrochloride를 함유한 이식정제제를 제조하고, rat와 rabbit에 피하이식한 후, biocompatibility와 pharmacokinetics를 관찰하였다. Rat을 이용한 biocornpatibility실험에서는 placebo implant와 naloxone implant를 크기 6×7 mm되도록 제조하여 피하이식 후 7, 14, 21, 28, 35 일의 조직병리학적 반응을 광학현미경을 통해 관찰하였으며, 토끼에 대한 pharmacokinetic 실험은 10% naloxone hydrochloride implant를 200 mg/kg(naloxone hydrochloride 20 mg/kg)투여후 192시간 동안의 혈중농도를 HPLC(ECD)를 이용하여 측정하였다. Rat에서의 조직학적 소견은 시간에 따른 염증반응이 implant주위에 국소적으로 나타났다. 염증부위에서의 염증세포수는 시간이 지남에 따라 placebo implant보다 naloxone implant주위에서 더 많이 관찰되었으나, 모두 mild한 염증반응으로 생체에 적합한 polymer임을 확인하였다. Naloxone implant의 혈중 농도는 적어도 192시간까지 지속적으로 유지되었으나, 초기에 burst effect가 나타나는 문제점을 가지고 있다. 이를 개선한다면, 마약길항제의 서방성 이식정으로의 사용가능성을 기대할 수 있다.;For the effective administration of narcotic antagonist, the application of sustained release implantable systems using biodegradable polyphosphazene was examined. poly[(diethyl glutamate)-co-(ethyl glycine)phosphazene] was produced by substitution of glutamic acid diethyl ester for chloride side groups of poly[dichlorophosphazene]. Using these polymers, the implantable devices containing 10% naloxone hydrochloride were prepared and in vivo implantayion studies were carried out subcutaneously in rat and rabbit with this preparation for the biocompatibility and pharmacokinetics. In the biocompatibility study in rats, naloxone sustained release preparations which included placebo implant, naloxone implant were implanted per rat subcutaneously with 6×7mm size. The histopathological tissue reactions utilizing standard procedures and light microscopic evaluation to the respective naloxone preparations were determined at days 7,14,21,28 and 35. In the pharmacokinetic study in rabbits, 10% naloxone sustained release preparations were implanted subcutaneously per rabbit and then naloxone plasma concentrations were determined in 192 hours after implantation by HPLC(ECD). The histological finding in rats at any time period was the inflammation that occurred focally around the implants. The inflammatory response between naloxone implants and placebo implants increased with increasing time of implantation. But the both implant sires showed a subsequent mild and limited chronic inflammation. Therefore the placebo implants and naloxone implants are considered to be biocompatible formulations histologically. In pharmacokinetic studies, naloxone implants showed the release of naloxone from the naloxone into blood plasma sustained in 192 hours, but the problem of initial burst effect was observed. If this problem was solved, the application of narcotic antagonist sustained release systems can be expected.