Formulation and evaluation of resveratrol oromucosal delivery systems

Abstract

Resveratrol has been demonstrated to show benefits antioxidant, anti-inflammatory, anti-aging, anti-cancer, anti-viral immunity, and against skin disorders. Despite its promising beneficial effects, the clinical use of resveratrol is very limited because of the great hydrophobicity and poor oral bioavailability. The objective of this study was to examine the feasibility of developing resveratrol oromucosal drug delivery systems by investigating the effects of various vehicles on the absorption of resveratrol delivery systems and evaluating pharmacokinetic characteristics of formulated oromucosal delivery systems. The solubility of resveratrol was decreased in the order of EA > OAL > IPA > DMSO >> NMP > PEG 400 = PGMC > IPM > Captex 200 > PGML. Its solubility in water was very low (around 0.11 mg/mL). To find an appropriate vehicle, the effect of pure solvents that showed high and medium enhancing effects, including EA, IPA, and OAL, on the resveratrol permeation from oromucosal delivery systems was examined. Unlike solution formulations, OAL showed the highest permeation fluxes regardless of drug concentrations used among studied vehicles. When the amount of resveratrol was increased, both the release and permeation rates were increased. We investigated the effects of various terpenes, fatty acid, and bile salts when used with OAL on the resveratrol permeation. The addition of enhancers failed to increase resveratrol permeability except for GASS. The enhancement factor of GASS was estimated to be around 1.46. The effects of Janus from oromucosal delivery systems containing OAL through excised hairless mouse skin were evaluated. The permeation flux was relatively high in Janus delivery system (1.41 times) and the lag time was shorter compared to control fabric. The permeation fluxes of resveratrol from formulated oromucosal delivery system was increased up to 2.04 times with the addition of GASS, regardless of the use of Janus. The lag time was shorter with the addition of GASS. The Janus delivery systems showed higher permeation fluxes (1.75 times) compared to control delivery systems when used reconstructed human oral mucosa. Similar to permeation parameters from animal skin studies, the addition of GASS effectively increased the permeation flux. Pharmacokinetic studies using formulated oromucosal delivery systems containing OAL, C_(max) of resveratrol was higher from Janus delivery system compared to that from control delivery system (p < 0.05). Cl was significantly (p < 0.05) lower from Janus delivery system compared to that from control delivery system, resulting in significantly higher AUC_(0-24) (p < 0.05) and AUC_(0-24) (p < 0.01). The addition of GASS to OAL increased C_(max) (p < 0.05). However, it delayed T_(max) significantly (p < 0.01). The significantly decreased Cl (p < 0.01) resulted in increased AUC_(0-24) (p < 0.05) and AUC_(inf) (p < 0.05). The decreased Cl with the GASS addition was attributable to the significantly decreased Vd (p < 0.05). In conclusion, resveratrol oromucosal delivery system containing OAL, GASS and Janus could be effectively used for treatment of inflammatory and infection diseases such as bisphosphonate-related osteonecrosis of the jaw.;포도의 껍질이나 땅콩, 와인 등에 있는 레스베라트롤은 항산화, 항염증, 암 예방 및 노화방지와 피부질환예방 등 다양한 효과가 있다고 알려져 있다. 이처럼 다양한 효과를 갖고 있음에도 불구하고 물에 잘 녹지 않는 특성을 갖고 있어 생체이용률이 낮아 실제 임상에서 사용이 제한되고 있다. 본 연구는 레스베라트롤이 함유된 구강점막제제의 개발 가능성을 검토하기 위하여 다양한 용제 및 투과촉진제들을 사용하고 제조된 구강점막제제에서 레스베라트롤의 약동학적 특성을 평가하고자 하였다. 다양한 용제들로부터 레스베라트롤의 용해도를 측정한 결과 EA > OAL > IPA > DMSO >> NMP > PEG 400 = PGMC > IPM > Captex 200 > PGML 순으로 나타났고 물의 용해도가 (0.11 mg/mL) 가장 낮았다. 용액 중의 투과량이 높았던 EA, IPA, OAL을 최적의 용제로 선택하여 레스베라트롤 구강점막제제를 제조 후 이들로부터 약물방출과 피부투과 특성을 검토했다. OAL을 사용한 레스베라트롤 구강점막제제가 가장 높은 투과량을 나타냈고 약물농도가 증가함에 따라 방출량과 투과량도 증가하였다. 또한 OAL을 포함한 레스베라트롤 구강점막제제를 바탕으로 테르펜류, 지방산류, 담즙산염등의 투과 촉진제의 영향을 살펴봤을 때 GASS만 약 1.46배의 투과량 상승효과가 나타났다. OAL을 포함하는 레스베라트롤 구강점막제제의 Janus delivery systems 효과는 control fabric에 비해 1.41배 피부 투과량이 증가했고, lag time은 감소하는 것으로 나타났다. 또한 GASS를 추가한 경우 2.04배의 투과량 증가와 lag time 감소를 나타냈다. 또한 인공구강점막을 사용한 레스베라트롤 구강점막제제의 Janus delivery systems 효과는 control에 비해 1.75배 투과량이 증가했고, lag time은 감소했다. GASS를 추가함으로써 동물실험의 결과와 유사하게 투과량 상승 효과를 확인 할 수 있었다. 위 결과를 바탕으로 제조된 레스베라트롤 구강점막제제의 약동학적 연구 결과는 control fabric에 비해 C_(max)는 증가 (p < 0.05) 되었고 Cl 감소 (p < 0.05) 되면서 AUC_(0-24) (p < 0.05) 및 AUC_(0-24)는 증가 (p < 0.01) 하는 것으로 나타났다. GASS의 추가 효과는 C_(max) (p < 0.05) 증가와 T_(max) 감소 (p < 0.01), Cl (p < 0.01) 감소로 인해 AUC_(0-24) (p < 0.05) 및 AUC_(inf) (p < 0.05)가 증가와 Vd (p < 0.05)는 감소하는 것을 알수 있었다. 결론적으로 OAL, GASS와 Janus를 사용한 레스베라트롤 구강점막제제는 구내염이나 Bisphosphonate-related osteonecrosis of the jaw (BRONJ) 치료에 효과적으로 사용 될 수 있을 것으로 생각된다.